instruction stringlengths 34 186 | input stringlengths 2.02k 93.8k | output stringlengths 2 418 | meta_questiontype stringclasses 6 values | meta_inputlicense stringclasses 6 values | meta_pmid stringlengths 8 8 | meta_safetyreportid int64 9.51M 21M | meta_articlepubdate stringlengths 4 10 |
|---|---|---|---|---|---|---|---|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Embolism'. | COVID-19 re-infection or persistent infection in patient with acute myeloid leukaemia M3: a mini review.
Coronavirus disease 2019 (COVID-19) pandemic has affected more than 40 million people worldwide. Some patients had episodes of symptom recurrence after the first episode of infection with variable intervals. There are multiple issues and hypotheses about re-infection or re-activation of the virus, especially in immunocompromised patients. In this paper, we present details of an individual with a recent history of COVID-19 who proceeded to acute myeloid leukaemia M3 and immunosuppression by chemotherapy, then we review some recently published articles about possible re-infection or re-activation.
Case history
A 15-year-old boy was referred to our haematology clinic because of pancytopenia (white blood cell count (WBC) 3200/μL, haemoglobin 10.5 mg/dL, platelets 88 000/μL). His mother complained of her son's sudden icteric sclera. He had no past medical, surgical or medication history. One month previously, he had had an episode of coronavirus disease 2019 (COVID-19) with signs and symptoms of cough, dyspnoea and patchy infiltration in the left lung. He had two negative PCR tests. The symptoms then gradually resolved, and only some residual patchy infiltration was visible on lung CT scan. In the physical examination, there were no signs of lymphadenopathies nor of splenomegaly. The PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) was negative, but the antibody test was positive for IgG (33 IU/mL; typically <5 IU/mL) but negative for IgM (3.5 IU/mL; typically <5 IU/mL).
He became a candidate for bone marrow biopsy and aspiration. Results for bone marrow biopsy, aspiration (Fig. 1) and flow cytometry were compatible with acute myeloid leukaemia M3 with positive PML-RARα. After admission, he had no signs or symptoms of active infection, so the chemotherapy regimen started with all-trans retinoic acid (tretinoin; ATRA) (45 mg/m2) and arsenic trioxide (0.15 mg/kg) daily. After about 10 days of treatment, his weight increased by about 10 kg and the WBC count reached 29 000/μL. As with differentiation syndrome, we started dexamethasone 8 mg twice daily and a single dose of idarubicin 12 mg/m2, although he had no sign of respiratory distress. After 3 days, the WBC count decreased to 13 000/μL but then rose again to about 23 000/μL 3 days later, so another single dose of idarubicin 12 mg/m2 was administered. With this second dose, the WBC count dropped to 800/μL, haemoglobin to 7.5 mg/dL and platelets to 15 000/μL. By continuing arsenic trioxide and withholding the ATRA, the WBC count started to decrease. We restarted ATRA 45 mg/m2 and with this decrement, his weight returned to normal.FIG. 1 Bone marrow aspiration shown diffuse infiltration of promyelocytes.
FIG. 1
In the admission course, as he was neutropenic, he became febrile with a temperature of about 39.0°C. He had a cough, shivering and myalgia. We continued ATRA and arsenic trioxide but evaluated him for febrile neutropenia aetiologies. On lung CT scan, a new patchy infiltration was seen in his right lung. Empirical antibiotics (meropenem, vancomycin and levofloxacin) were administered. As the patient's general condition worsened we added the antifungal agent liposomal amphotericin 3 mg/kg to the empirical antibiotics.
After 24 hours, he became severely dyspnoeic, and O2 saturation dropped to 75%. The CT scan showed severe bilateral ground-glass patchy infiltrations compatible with COVID-19 lung involvement (Fig. 2). The patient was intubated and concomitantly a pulmonologist performed a bronchoscopy and took a mini-bronchoalveolar lavage; this was sent for galactomannan and Gram smear, culture and COVID-19 PCR test. After 48 hours, the bronchoalveolar lavage galactomannan was negative, but viral load measured by COVID RT-PCR cycle threshold (CT levels) was 521 868 217 copies/mL.FIG. 2 Upper left: CT scan at first day of admission to hospital; upper right: CT scan showing a new infiltration in the right lower lobe after patient became febrile with neutropenia; lower left: CT scan showing bilateral infiltration suggesting new episode of coronavirus disease 2019; lower right: CT scan on the day of discharge consistent with partial healing.
FIG. 2
We started interferon-β (1.2 million units subcutaneously every other day) and remdesivir (200 mg on day 1 and then 100 mg for 4 days after that) with 3 days of methylprednisolone 500 mg followed by dexamethasone 8 mg twice daily continued. Although ATRA and arsenic trioxide continued during the antiviral treatment. He was also evaluated for pulmonary thromboembolism with pulmonary CT-angiography, which was consistent with thromboembolism. We transfused platelets and maintained the platelet count above 50 000/μL, and started enoxaparin (60 units subcutaneously twice daily). After 5 days on mechanical ventilation, O2 saturation began to rise and some evidence of respiratory recovery was seen. On day 8, the patient was extubated. Antibiotics and antifungal treatments were continued for 14 days, then stopped. Dexamethasone was tapered gradually and continuously. By continuing ATRA and arsenic trioxide administration the platelet count increased gradually and the patient became transfusion independent. Six weeks after admission, the patient was discharged with good general condition and without any dependency on oxygen. WBC was 5600/μL, haemoglobin was 10.5 mg/dL and platelets were 145 000/μL at the time of discharge. Anti-coagulant continued after discharge.
Discussion
Up to October 2020, COVID-19 had affected more than 40 million people with more than one million deaths worldwide. Two significant concerns about SARS-CoV-2, the virus that causes COVID-19, are re-infection and prolonged viral shedding [1,2]. Some patients have positive SARS-CoV-2 PCR tests early after the recovery from infection despite antibody production [3]. Some studies have shown that antibody titres begin to drop about 2 months later [4]. The virus may persist in the body in respiratory secretions while the patient has no symptoms; it can spread throughout the body into the different organs such as the spleen or lymph nodes, which cannot be detected by nasopharyngeal swab [5]. It has been suggested that antibodies are produced against virus spike proteins, which can mutate and lead to reduced neutralization [6,7]. During the second infection described here, IgG antibodies were undetectable after the diagnosis, which would be justifiable considering the low burden of disease in the first episode of infection in some patients [8,9]. T-cell immunity may have a pivotal role in long-term protection against the virus by providing targets against the spike protein with helper and cytotoxic T cells [10,11]. During the convalescence period, viral shedding is still ongoing. There is some evidence that patients with immunodeficiency, such as glucocorticoid use, have prolonged viral shedding [12]. In a report from the COCOREC study group in France, they reported on 11 patients with confirmed viral re-infection at least 3 weeks after the first episode. Four of them had a mild relapse and seven of them had severe relapses and were admitted to intensive care. It was suggested that in patients with mild relapse, prolonged exposure and reduced immunity made them susceptible to re-infection. However, in severe relapses, suboptimal control of infection leads to second infection [13,14]. There are several reports of SARS-CoV-2 re-infection with mild clinical pictures or without any symptoms. The latter may be diagnosed with a positive PCR test in which it could be sample contamination or misdiagnosis due to detecting non-infectious RNA. The PCR test cannot differentiate between infectious and non-infectious RNA, so not all test positives will be a clinical relapse [[15], [16], [17], [18]]. Lancman et al. described a 55-year-old woman with acute lymphoblastic leukaemia who was positive for SARS-CoV-2 infection after induction chemotherapy with severe respiratory signs and symptoms. After receiving remdesivir and showing clinical improvement, she became infected again with positive PCR 1 month later after consolidation therapy. Results of the antibody test were negative despite previous positive results. These supported the SARS-CoV-2 re-activation issue because of a short interval between consolidation therapy and PCR positivity [19]. In this paper, we report on a patient with acute myeloid leukaemia who had previously been infected with SARS-CoV-2 with positive IgG serology and negative PCR at the time of admission. However, as he became leukopenic and lymphopenic in the course of treatment, he became infected again with SARS-CoV-2 and became severely symptomatic, which was confirmed by lung imaging and a positive PCR test result. There are some issues concerning re-infection. First, it may be possible that after a first infection, the virus is not fully removed from bodily secretions, the lymphatic system or pulmonary infiltration as in our patient, So it may be quiescent until an immunosuppression event occurs, which it becomes active again. Chemotherapeutic agents that interact with B-cell function, such as anti-CD20 agents, may impact antibody production against SARS-CoV-2. Phillips et al. reported on an individual with acute lymphoblastic leukaemia who had severe COVID-19 before starting induction chemotherapy. He received only steroids and non-myeloablative chemotherapeutic agents until the critical period of infection had passed, then he received a full course of chemotherapy. In their paper Phillips et al. recommended that after passing the critical phase of infection, chemotherapeutic agents could be introduced [20]. However, this needs more attention, as our report and that of Lancman et al. [19] describe new episodes COVID-19 after myeloablative chemotherapy, so starting chemotherapy would not be completely safe. A recently published report from the Memorial Sloan Kettering Cancer Center in New York, demonstrated severe COVID-19 in 20% of patients with cancer and a 12% Case fatality rate. Treatment with immune checkpoint inhibitors predicted both hospitalization and severe disease [21]. A recent report by Choi et al. [22] described a 40-year-old man with antiphospholipid syndrome, who had received immunosuppressive agents because of alveolar haemorrhage. In the course of his first infection with SARS-CoV-2 until his death, he had four episodes of COVID-19, one new infection and three recurrences.
Second, it may be possible that the virus can transform into a new mutational status, which is more virulent [23], or there may be secondary infection with a new viral strain. However, it is necessary to define the exact genome in each course of infection. Nevertheless, because the previous PCR result was negative, it would not possible to compare the genomic study results in the two episodes of COVID-19. In the Case of new mutational status, it could be possible that a new mutation interacts with a different lymphocyte colony and makes them replicative, which would lead to another phase of cytokine release. So, it may be possible that significantly immunocompromised patients can acquire this infection several times. This issue needs further investigations to confirm these observations.
In summary, we reported on a boy with acute myeloid leukaemia M3, who had a previous history of COVID-19. After administration of chemotherapeutic agents he became infected again with positive findings on CT scan and also PCR test. This may be due to re-activation or re-infection, and needs further investigation.
Ethical approval
All procedures performed in this study were in accordance with the ethical standards of the Helsinki declaration. Informed consent was obtained from all individuals.
Conflict of interest
The authors declare that they have no conflict of interest.
Fundings
The authors received no financial support for the research, author-ship and/or publication of the article. | ARSENIC TRIOXIDE, DEXAMETHASONE, IDARUBICIN, TRETINOIN | DrugsGivenReaction | CC BY-NC-ND | 33425365 | 19,764,362 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Immunosuppression'. | COVID-19 re-infection or persistent infection in patient with acute myeloid leukaemia M3: a mini review.
Coronavirus disease 2019 (COVID-19) pandemic has affected more than 40 million people worldwide. Some patients had episodes of symptom recurrence after the first episode of infection with variable intervals. There are multiple issues and hypotheses about re-infection or re-activation of the virus, especially in immunocompromised patients. In this paper, we present details of an individual with a recent history of COVID-19 who proceeded to acute myeloid leukaemia M3 and immunosuppression by chemotherapy, then we review some recently published articles about possible re-infection or re-activation.
Case history
A 15-year-old boy was referred to our haematology clinic because of pancytopenia (white blood cell count (WBC) 3200/μL, haemoglobin 10.5 mg/dL, platelets 88 000/μL). His mother complained of her son's sudden icteric sclera. He had no past medical, surgical or medication history. One month previously, he had had an episode of coronavirus disease 2019 (COVID-19) with signs and symptoms of cough, dyspnoea and patchy infiltration in the left lung. He had two negative PCR tests. The symptoms then gradually resolved, and only some residual patchy infiltration was visible on lung CT scan. In the physical examination, there were no signs of lymphadenopathies nor of splenomegaly. The PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) was negative, but the antibody test was positive for IgG (33 IU/mL; typically <5 IU/mL) but negative for IgM (3.5 IU/mL; typically <5 IU/mL).
He became a candidate for bone marrow biopsy and aspiration. Results for bone marrow biopsy, aspiration (Fig. 1) and flow cytometry were compatible with acute myeloid leukaemia M3 with positive PML-RARα. After admission, he had no signs or symptoms of active infection, so the chemotherapy regimen started with all-trans retinoic acid (tretinoin; ATRA) (45 mg/m2) and arsenic trioxide (0.15 mg/kg) daily. After about 10 days of treatment, his weight increased by about 10 kg and the WBC count reached 29 000/μL. As with differentiation syndrome, we started dexamethasone 8 mg twice daily and a single dose of idarubicin 12 mg/m2, although he had no sign of respiratory distress. After 3 days, the WBC count decreased to 13 000/μL but then rose again to about 23 000/μL 3 days later, so another single dose of idarubicin 12 mg/m2 was administered. With this second dose, the WBC count dropped to 800/μL, haemoglobin to 7.5 mg/dL and platelets to 15 000/μL. By continuing arsenic trioxide and withholding the ATRA, the WBC count started to decrease. We restarted ATRA 45 mg/m2 and with this decrement, his weight returned to normal.FIG. 1 Bone marrow aspiration shown diffuse infiltration of promyelocytes.
FIG. 1
In the admission course, as he was neutropenic, he became febrile with a temperature of about 39.0°C. He had a cough, shivering and myalgia. We continued ATRA and arsenic trioxide but evaluated him for febrile neutropenia aetiologies. On lung CT scan, a new patchy infiltration was seen in his right lung. Empirical antibiotics (meropenem, vancomycin and levofloxacin) were administered. As the patient's general condition worsened we added the antifungal agent liposomal amphotericin 3 mg/kg to the empirical antibiotics.
After 24 hours, he became severely dyspnoeic, and O2 saturation dropped to 75%. The CT scan showed severe bilateral ground-glass patchy infiltrations compatible with COVID-19 lung involvement (Fig. 2). The patient was intubated and concomitantly a pulmonologist performed a bronchoscopy and took a mini-bronchoalveolar lavage; this was sent for galactomannan and Gram smear, culture and COVID-19 PCR test. After 48 hours, the bronchoalveolar lavage galactomannan was negative, but viral load measured by COVID RT-PCR cycle threshold (CT levels) was 521 868 217 copies/mL.FIG. 2 Upper left: CT scan at first day of admission to hospital; upper right: CT scan showing a new infiltration in the right lower lobe after patient became febrile with neutropenia; lower left: CT scan showing bilateral infiltration suggesting new episode of coronavirus disease 2019; lower right: CT scan on the day of discharge consistent with partial healing.
FIG. 2
We started interferon-β (1.2 million units subcutaneously every other day) and remdesivir (200 mg on day 1 and then 100 mg for 4 days after that) with 3 days of methylprednisolone 500 mg followed by dexamethasone 8 mg twice daily continued. Although ATRA and arsenic trioxide continued during the antiviral treatment. He was also evaluated for pulmonary thromboembolism with pulmonary CT-angiography, which was consistent with thromboembolism. We transfused platelets and maintained the platelet count above 50 000/μL, and started enoxaparin (60 units subcutaneously twice daily). After 5 days on mechanical ventilation, O2 saturation began to rise and some evidence of respiratory recovery was seen. On day 8, the patient was extubated. Antibiotics and antifungal treatments were continued for 14 days, then stopped. Dexamethasone was tapered gradually and continuously. By continuing ATRA and arsenic trioxide administration the platelet count increased gradually and the patient became transfusion independent. Six weeks after admission, the patient was discharged with good general condition and without any dependency on oxygen. WBC was 5600/μL, haemoglobin was 10.5 mg/dL and platelets were 145 000/μL at the time of discharge. Anti-coagulant continued after discharge.
Discussion
Up to October 2020, COVID-19 had affected more than 40 million people with more than one million deaths worldwide. Two significant concerns about SARS-CoV-2, the virus that causes COVID-19, are re-infection and prolonged viral shedding [1,2]. Some patients have positive SARS-CoV-2 PCR tests early after the recovery from infection despite antibody production [3]. Some studies have shown that antibody titres begin to drop about 2 months later [4]. The virus may persist in the body in respiratory secretions while the patient has no symptoms; it can spread throughout the body into the different organs such as the spleen or lymph nodes, which cannot be detected by nasopharyngeal swab [5]. It has been suggested that antibodies are produced against virus spike proteins, which can mutate and lead to reduced neutralization [6,7]. During the second infection described here, IgG antibodies were undetectable after the diagnosis, which would be justifiable considering the low burden of disease in the first episode of infection in some patients [8,9]. T-cell immunity may have a pivotal role in long-term protection against the virus by providing targets against the spike protein with helper and cytotoxic T cells [10,11]. During the convalescence period, viral shedding is still ongoing. There is some evidence that patients with immunodeficiency, such as glucocorticoid use, have prolonged viral shedding [12]. In a report from the COCOREC study group in France, they reported on 11 patients with confirmed viral re-infection at least 3 weeks after the first episode. Four of them had a mild relapse and seven of them had severe relapses and were admitted to intensive care. It was suggested that in patients with mild relapse, prolonged exposure and reduced immunity made them susceptible to re-infection. However, in severe relapses, suboptimal control of infection leads to second infection [13,14]. There are several reports of SARS-CoV-2 re-infection with mild clinical pictures or without any symptoms. The latter may be diagnosed with a positive PCR test in which it could be sample contamination or misdiagnosis due to detecting non-infectious RNA. The PCR test cannot differentiate between infectious and non-infectious RNA, so not all test positives will be a clinical relapse [[15], [16], [17], [18]]. Lancman et al. described a 55-year-old woman with acute lymphoblastic leukaemia who was positive for SARS-CoV-2 infection after induction chemotherapy with severe respiratory signs and symptoms. After receiving remdesivir and showing clinical improvement, she became infected again with positive PCR 1 month later after consolidation therapy. Results of the antibody test were negative despite previous positive results. These supported the SARS-CoV-2 re-activation issue because of a short interval between consolidation therapy and PCR positivity [19]. In this paper, we report on a patient with acute myeloid leukaemia who had previously been infected with SARS-CoV-2 with positive IgG serology and negative PCR at the time of admission. However, as he became leukopenic and lymphopenic in the course of treatment, he became infected again with SARS-CoV-2 and became severely symptomatic, which was confirmed by lung imaging and a positive PCR test result. There are some issues concerning re-infection. First, it may be possible that after a first infection, the virus is not fully removed from bodily secretions, the lymphatic system or pulmonary infiltration as in our patient, So it may be quiescent until an immunosuppression event occurs, which it becomes active again. Chemotherapeutic agents that interact with B-cell function, such as anti-CD20 agents, may impact antibody production against SARS-CoV-2. Phillips et al. reported on an individual with acute lymphoblastic leukaemia who had severe COVID-19 before starting induction chemotherapy. He received only steroids and non-myeloablative chemotherapeutic agents until the critical period of infection had passed, then he received a full course of chemotherapy. In their paper Phillips et al. recommended that after passing the critical phase of infection, chemotherapeutic agents could be introduced [20]. However, this needs more attention, as our report and that of Lancman et al. [19] describe new episodes COVID-19 after myeloablative chemotherapy, so starting chemotherapy would not be completely safe. A recently published report from the Memorial Sloan Kettering Cancer Center in New York, demonstrated severe COVID-19 in 20% of patients with cancer and a 12% Case fatality rate. Treatment with immune checkpoint inhibitors predicted both hospitalization and severe disease [21]. A recent report by Choi et al. [22] described a 40-year-old man with antiphospholipid syndrome, who had received immunosuppressive agents because of alveolar haemorrhage. In the course of his first infection with SARS-CoV-2 until his death, he had four episodes of COVID-19, one new infection and three recurrences.
Second, it may be possible that the virus can transform into a new mutational status, which is more virulent [23], or there may be secondary infection with a new viral strain. However, it is necessary to define the exact genome in each course of infection. Nevertheless, because the previous PCR result was negative, it would not possible to compare the genomic study results in the two episodes of COVID-19. In the Case of new mutational status, it could be possible that a new mutation interacts with a different lymphocyte colony and makes them replicative, which would lead to another phase of cytokine release. So, it may be possible that significantly immunocompromised patients can acquire this infection several times. This issue needs further investigations to confirm these observations.
In summary, we reported on a boy with acute myeloid leukaemia M3, who had a previous history of COVID-19. After administration of chemotherapeutic agents he became infected again with positive findings on CT scan and also PCR test. This may be due to re-activation or re-infection, and needs further investigation.
Ethical approval
All procedures performed in this study were in accordance with the ethical standards of the Helsinki declaration. Informed consent was obtained from all individuals.
Conflict of interest
The authors declare that they have no conflict of interest.
Fundings
The authors received no financial support for the research, author-ship and/or publication of the article. | ARSENIC TRIOXIDE, DEXAMETHASONE, IDARUBICIN HYDROCHLORIDE, TRETINOIN | DrugsGivenReaction | CC BY-NC-ND | 33425365 | 19,660,384 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | COVID-19 re-infection or persistent infection in patient with acute myeloid leukaemia M3: a mini review.
Coronavirus disease 2019 (COVID-19) pandemic has affected more than 40 million people worldwide. Some patients had episodes of symptom recurrence after the first episode of infection with variable intervals. There are multiple issues and hypotheses about re-infection or re-activation of the virus, especially in immunocompromised patients. In this paper, we present details of an individual with a recent history of COVID-19 who proceeded to acute myeloid leukaemia M3 and immunosuppression by chemotherapy, then we review some recently published articles about possible re-infection or re-activation.
Case history
A 15-year-old boy was referred to our haematology clinic because of pancytopenia (white blood cell count (WBC) 3200/μL, haemoglobin 10.5 mg/dL, platelets 88 000/μL). His mother complained of her son's sudden icteric sclera. He had no past medical, surgical or medication history. One month previously, he had had an episode of coronavirus disease 2019 (COVID-19) with signs and symptoms of cough, dyspnoea and patchy infiltration in the left lung. He had two negative PCR tests. The symptoms then gradually resolved, and only some residual patchy infiltration was visible on lung CT scan. In the physical examination, there were no signs of lymphadenopathies nor of splenomegaly. The PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) was negative, but the antibody test was positive for IgG (33 IU/mL; typically <5 IU/mL) but negative for IgM (3.5 IU/mL; typically <5 IU/mL).
He became a candidate for bone marrow biopsy and aspiration. Results for bone marrow biopsy, aspiration (Fig. 1) and flow cytometry were compatible with acute myeloid leukaemia M3 with positive PML-RARα. After admission, he had no signs or symptoms of active infection, so the chemotherapy regimen started with all-trans retinoic acid (tretinoin; ATRA) (45 mg/m2) and arsenic trioxide (0.15 mg/kg) daily. After about 10 days of treatment, his weight increased by about 10 kg and the WBC count reached 29 000/μL. As with differentiation syndrome, we started dexamethasone 8 mg twice daily and a single dose of idarubicin 12 mg/m2, although he had no sign of respiratory distress. After 3 days, the WBC count decreased to 13 000/μL but then rose again to about 23 000/μL 3 days later, so another single dose of idarubicin 12 mg/m2 was administered. With this second dose, the WBC count dropped to 800/μL, haemoglobin to 7.5 mg/dL and platelets to 15 000/μL. By continuing arsenic trioxide and withholding the ATRA, the WBC count started to decrease. We restarted ATRA 45 mg/m2 and with this decrement, his weight returned to normal.FIG. 1 Bone marrow aspiration shown diffuse infiltration of promyelocytes.
FIG. 1
In the admission course, as he was neutropenic, he became febrile with a temperature of about 39.0°C. He had a cough, shivering and myalgia. We continued ATRA and arsenic trioxide but evaluated him for febrile neutropenia aetiologies. On lung CT scan, a new patchy infiltration was seen in his right lung. Empirical antibiotics (meropenem, vancomycin and levofloxacin) were administered. As the patient's general condition worsened we added the antifungal agent liposomal amphotericin 3 mg/kg to the empirical antibiotics.
After 24 hours, he became severely dyspnoeic, and O2 saturation dropped to 75%. The CT scan showed severe bilateral ground-glass patchy infiltrations compatible with COVID-19 lung involvement (Fig. 2). The patient was intubated and concomitantly a pulmonologist performed a bronchoscopy and took a mini-bronchoalveolar lavage; this was sent for galactomannan and Gram smear, culture and COVID-19 PCR test. After 48 hours, the bronchoalveolar lavage galactomannan was negative, but viral load measured by COVID RT-PCR cycle threshold (CT levels) was 521 868 217 copies/mL.FIG. 2 Upper left: CT scan at first day of admission to hospital; upper right: CT scan showing a new infiltration in the right lower lobe after patient became febrile with neutropenia; lower left: CT scan showing bilateral infiltration suggesting new episode of coronavirus disease 2019; lower right: CT scan on the day of discharge consistent with partial healing.
FIG. 2
We started interferon-β (1.2 million units subcutaneously every other day) and remdesivir (200 mg on day 1 and then 100 mg for 4 days after that) with 3 days of methylprednisolone 500 mg followed by dexamethasone 8 mg twice daily continued. Although ATRA and arsenic trioxide continued during the antiviral treatment. He was also evaluated for pulmonary thromboembolism with pulmonary CT-angiography, which was consistent with thromboembolism. We transfused platelets and maintained the platelet count above 50 000/μL, and started enoxaparin (60 units subcutaneously twice daily). After 5 days on mechanical ventilation, O2 saturation began to rise and some evidence of respiratory recovery was seen. On day 8, the patient was extubated. Antibiotics and antifungal treatments were continued for 14 days, then stopped. Dexamethasone was tapered gradually and continuously. By continuing ATRA and arsenic trioxide administration the platelet count increased gradually and the patient became transfusion independent. Six weeks after admission, the patient was discharged with good general condition and without any dependency on oxygen. WBC was 5600/μL, haemoglobin was 10.5 mg/dL and platelets were 145 000/μL at the time of discharge. Anti-coagulant continued after discharge.
Discussion
Up to October 2020, COVID-19 had affected more than 40 million people with more than one million deaths worldwide. Two significant concerns about SARS-CoV-2, the virus that causes COVID-19, are re-infection and prolonged viral shedding [1,2]. Some patients have positive SARS-CoV-2 PCR tests early after the recovery from infection despite antibody production [3]. Some studies have shown that antibody titres begin to drop about 2 months later [4]. The virus may persist in the body in respiratory secretions while the patient has no symptoms; it can spread throughout the body into the different organs such as the spleen or lymph nodes, which cannot be detected by nasopharyngeal swab [5]. It has been suggested that antibodies are produced against virus spike proteins, which can mutate and lead to reduced neutralization [6,7]. During the second infection described here, IgG antibodies were undetectable after the diagnosis, which would be justifiable considering the low burden of disease in the first episode of infection in some patients [8,9]. T-cell immunity may have a pivotal role in long-term protection against the virus by providing targets against the spike protein with helper and cytotoxic T cells [10,11]. During the convalescence period, viral shedding is still ongoing. There is some evidence that patients with immunodeficiency, such as glucocorticoid use, have prolonged viral shedding [12]. In a report from the COCOREC study group in France, they reported on 11 patients with confirmed viral re-infection at least 3 weeks after the first episode. Four of them had a mild relapse and seven of them had severe relapses and were admitted to intensive care. It was suggested that in patients with mild relapse, prolonged exposure and reduced immunity made them susceptible to re-infection. However, in severe relapses, suboptimal control of infection leads to second infection [13,14]. There are several reports of SARS-CoV-2 re-infection with mild clinical pictures or without any symptoms. The latter may be diagnosed with a positive PCR test in which it could be sample contamination or misdiagnosis due to detecting non-infectious RNA. The PCR test cannot differentiate between infectious and non-infectious RNA, so not all test positives will be a clinical relapse [[15], [16], [17], [18]]. Lancman et al. described a 55-year-old woman with acute lymphoblastic leukaemia who was positive for SARS-CoV-2 infection after induction chemotherapy with severe respiratory signs and symptoms. After receiving remdesivir and showing clinical improvement, she became infected again with positive PCR 1 month later after consolidation therapy. Results of the antibody test were negative despite previous positive results. These supported the SARS-CoV-2 re-activation issue because of a short interval between consolidation therapy and PCR positivity [19]. In this paper, we report on a patient with acute myeloid leukaemia who had previously been infected with SARS-CoV-2 with positive IgG serology and negative PCR at the time of admission. However, as he became leukopenic and lymphopenic in the course of treatment, he became infected again with SARS-CoV-2 and became severely symptomatic, which was confirmed by lung imaging and a positive PCR test result. There are some issues concerning re-infection. First, it may be possible that after a first infection, the virus is not fully removed from bodily secretions, the lymphatic system or pulmonary infiltration as in our patient, So it may be quiescent until an immunosuppression event occurs, which it becomes active again. Chemotherapeutic agents that interact with B-cell function, such as anti-CD20 agents, may impact antibody production against SARS-CoV-2. Phillips et al. reported on an individual with acute lymphoblastic leukaemia who had severe COVID-19 before starting induction chemotherapy. He received only steroids and non-myeloablative chemotherapeutic agents until the critical period of infection had passed, then he received a full course of chemotherapy. In their paper Phillips et al. recommended that after passing the critical phase of infection, chemotherapeutic agents could be introduced [20]. However, this needs more attention, as our report and that of Lancman et al. [19] describe new episodes COVID-19 after myeloablative chemotherapy, so starting chemotherapy would not be completely safe. A recently published report from the Memorial Sloan Kettering Cancer Center in New York, demonstrated severe COVID-19 in 20% of patients with cancer and a 12% Case fatality rate. Treatment with immune checkpoint inhibitors predicted both hospitalization and severe disease [21]. A recent report by Choi et al. [22] described a 40-year-old man with antiphospholipid syndrome, who had received immunosuppressive agents because of alveolar haemorrhage. In the course of his first infection with SARS-CoV-2 until his death, he had four episodes of COVID-19, one new infection and three recurrences.
Second, it may be possible that the virus can transform into a new mutational status, which is more virulent [23], or there may be secondary infection with a new viral strain. However, it is necessary to define the exact genome in each course of infection. Nevertheless, because the previous PCR result was negative, it would not possible to compare the genomic study results in the two episodes of COVID-19. In the Case of new mutational status, it could be possible that a new mutation interacts with a different lymphocyte colony and makes them replicative, which would lead to another phase of cytokine release. So, it may be possible that significantly immunocompromised patients can acquire this infection several times. This issue needs further investigations to confirm these observations.
In summary, we reported on a boy with acute myeloid leukaemia M3, who had a previous history of COVID-19. After administration of chemotherapeutic agents he became infected again with positive findings on CT scan and also PCR test. This may be due to re-activation or re-infection, and needs further investigation.
Ethical approval
All procedures performed in this study were in accordance with the ethical standards of the Helsinki declaration. Informed consent was obtained from all individuals.
Conflict of interest
The authors declare that they have no conflict of interest.
Fundings
The authors received no financial support for the research, author-ship and/or publication of the article. | ARSENIC TRIOXIDE, DEXAMETHASONE, IDARUBICIN HYDROCHLORIDE, TRETINOIN | DrugsGivenReaction | CC BY-NC-ND | 33425365 | 19,660,384 | 2021-01 |
What was the dosage of drug 'ARSENIC TRIOXIDE'? | COVID-19 re-infection or persistent infection in patient with acute myeloid leukaemia M3: a mini review.
Coronavirus disease 2019 (COVID-19) pandemic has affected more than 40 million people worldwide. Some patients had episodes of symptom recurrence after the first episode of infection with variable intervals. There are multiple issues and hypotheses about re-infection or re-activation of the virus, especially in immunocompromised patients. In this paper, we present details of an individual with a recent history of COVID-19 who proceeded to acute myeloid leukaemia M3 and immunosuppression by chemotherapy, then we review some recently published articles about possible re-infection or re-activation.
Case history
A 15-year-old boy was referred to our haematology clinic because of pancytopenia (white blood cell count (WBC) 3200/μL, haemoglobin 10.5 mg/dL, platelets 88 000/μL). His mother complained of her son's sudden icteric sclera. He had no past medical, surgical or medication history. One month previously, he had had an episode of coronavirus disease 2019 (COVID-19) with signs and symptoms of cough, dyspnoea and patchy infiltration in the left lung. He had two negative PCR tests. The symptoms then gradually resolved, and only some residual patchy infiltration was visible on lung CT scan. In the physical examination, there were no signs of lymphadenopathies nor of splenomegaly. The PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) was negative, but the antibody test was positive for IgG (33 IU/mL; typically <5 IU/mL) but negative for IgM (3.5 IU/mL; typically <5 IU/mL).
He became a candidate for bone marrow biopsy and aspiration. Results for bone marrow biopsy, aspiration (Fig. 1) and flow cytometry were compatible with acute myeloid leukaemia M3 with positive PML-RARα. After admission, he had no signs or symptoms of active infection, so the chemotherapy regimen started with all-trans retinoic acid (tretinoin; ATRA) (45 mg/m2) and arsenic trioxide (0.15 mg/kg) daily. After about 10 days of treatment, his weight increased by about 10 kg and the WBC count reached 29 000/μL. As with differentiation syndrome, we started dexamethasone 8 mg twice daily and a single dose of idarubicin 12 mg/m2, although he had no sign of respiratory distress. After 3 days, the WBC count decreased to 13 000/μL but then rose again to about 23 000/μL 3 days later, so another single dose of idarubicin 12 mg/m2 was administered. With this second dose, the WBC count dropped to 800/μL, haemoglobin to 7.5 mg/dL and platelets to 15 000/μL. By continuing arsenic trioxide and withholding the ATRA, the WBC count started to decrease. We restarted ATRA 45 mg/m2 and with this decrement, his weight returned to normal.FIG. 1 Bone marrow aspiration shown diffuse infiltration of promyelocytes.
FIG. 1
In the admission course, as he was neutropenic, he became febrile with a temperature of about 39.0°C. He had a cough, shivering and myalgia. We continued ATRA and arsenic trioxide but evaluated him for febrile neutropenia aetiologies. On lung CT scan, a new patchy infiltration was seen in his right lung. Empirical antibiotics (meropenem, vancomycin and levofloxacin) were administered. As the patient's general condition worsened we added the antifungal agent liposomal amphotericin 3 mg/kg to the empirical antibiotics.
After 24 hours, he became severely dyspnoeic, and O2 saturation dropped to 75%. The CT scan showed severe bilateral ground-glass patchy infiltrations compatible with COVID-19 lung involvement (Fig. 2). The patient was intubated and concomitantly a pulmonologist performed a bronchoscopy and took a mini-bronchoalveolar lavage; this was sent for galactomannan and Gram smear, culture and COVID-19 PCR test. After 48 hours, the bronchoalveolar lavage galactomannan was negative, but viral load measured by COVID RT-PCR cycle threshold (CT levels) was 521 868 217 copies/mL.FIG. 2 Upper left: CT scan at first day of admission to hospital; upper right: CT scan showing a new infiltration in the right lower lobe after patient became febrile with neutropenia; lower left: CT scan showing bilateral infiltration suggesting new episode of coronavirus disease 2019; lower right: CT scan on the day of discharge consistent with partial healing.
FIG. 2
We started interferon-β (1.2 million units subcutaneously every other day) and remdesivir (200 mg on day 1 and then 100 mg for 4 days after that) with 3 days of methylprednisolone 500 mg followed by dexamethasone 8 mg twice daily continued. Although ATRA and arsenic trioxide continued during the antiviral treatment. He was also evaluated for pulmonary thromboembolism with pulmonary CT-angiography, which was consistent with thromboembolism. We transfused platelets and maintained the platelet count above 50 000/μL, and started enoxaparin (60 units subcutaneously twice daily). After 5 days on mechanical ventilation, O2 saturation began to rise and some evidence of respiratory recovery was seen. On day 8, the patient was extubated. Antibiotics and antifungal treatments were continued for 14 days, then stopped. Dexamethasone was tapered gradually and continuously. By continuing ATRA and arsenic trioxide administration the platelet count increased gradually and the patient became transfusion independent. Six weeks after admission, the patient was discharged with good general condition and without any dependency on oxygen. WBC was 5600/μL, haemoglobin was 10.5 mg/dL and platelets were 145 000/μL at the time of discharge. Anti-coagulant continued after discharge.
Discussion
Up to October 2020, COVID-19 had affected more than 40 million people with more than one million deaths worldwide. Two significant concerns about SARS-CoV-2, the virus that causes COVID-19, are re-infection and prolonged viral shedding [1,2]. Some patients have positive SARS-CoV-2 PCR tests early after the recovery from infection despite antibody production [3]. Some studies have shown that antibody titres begin to drop about 2 months later [4]. The virus may persist in the body in respiratory secretions while the patient has no symptoms; it can spread throughout the body into the different organs such as the spleen or lymph nodes, which cannot be detected by nasopharyngeal swab [5]. It has been suggested that antibodies are produced against virus spike proteins, which can mutate and lead to reduced neutralization [6,7]. During the second infection described here, IgG antibodies were undetectable after the diagnosis, which would be justifiable considering the low burden of disease in the first episode of infection in some patients [8,9]. T-cell immunity may have a pivotal role in long-term protection against the virus by providing targets against the spike protein with helper and cytotoxic T cells [10,11]. During the convalescence period, viral shedding is still ongoing. There is some evidence that patients with immunodeficiency, such as glucocorticoid use, have prolonged viral shedding [12]. In a report from the COCOREC study group in France, they reported on 11 patients with confirmed viral re-infection at least 3 weeks after the first episode. Four of them had a mild relapse and seven of them had severe relapses and were admitted to intensive care. It was suggested that in patients with mild relapse, prolonged exposure and reduced immunity made them susceptible to re-infection. However, in severe relapses, suboptimal control of infection leads to second infection [13,14]. There are several reports of SARS-CoV-2 re-infection with mild clinical pictures or without any symptoms. The latter may be diagnosed with a positive PCR test in which it could be sample contamination or misdiagnosis due to detecting non-infectious RNA. The PCR test cannot differentiate between infectious and non-infectious RNA, so not all test positives will be a clinical relapse [[15], [16], [17], [18]]. Lancman et al. described a 55-year-old woman with acute lymphoblastic leukaemia who was positive for SARS-CoV-2 infection after induction chemotherapy with severe respiratory signs and symptoms. After receiving remdesivir and showing clinical improvement, she became infected again with positive PCR 1 month later after consolidation therapy. Results of the antibody test were negative despite previous positive results. These supported the SARS-CoV-2 re-activation issue because of a short interval between consolidation therapy and PCR positivity [19]. In this paper, we report on a patient with acute myeloid leukaemia who had previously been infected with SARS-CoV-2 with positive IgG serology and negative PCR at the time of admission. However, as he became leukopenic and lymphopenic in the course of treatment, he became infected again with SARS-CoV-2 and became severely symptomatic, which was confirmed by lung imaging and a positive PCR test result. There are some issues concerning re-infection. First, it may be possible that after a first infection, the virus is not fully removed from bodily secretions, the lymphatic system or pulmonary infiltration as in our patient, So it may be quiescent until an immunosuppression event occurs, which it becomes active again. Chemotherapeutic agents that interact with B-cell function, such as anti-CD20 agents, may impact antibody production against SARS-CoV-2. Phillips et al. reported on an individual with acute lymphoblastic leukaemia who had severe COVID-19 before starting induction chemotherapy. He received only steroids and non-myeloablative chemotherapeutic agents until the critical period of infection had passed, then he received a full course of chemotherapy. In their paper Phillips et al. recommended that after passing the critical phase of infection, chemotherapeutic agents could be introduced [20]. However, this needs more attention, as our report and that of Lancman et al. [19] describe new episodes COVID-19 after myeloablative chemotherapy, so starting chemotherapy would not be completely safe. A recently published report from the Memorial Sloan Kettering Cancer Center in New York, demonstrated severe COVID-19 in 20% of patients with cancer and a 12% Case fatality rate. Treatment with immune checkpoint inhibitors predicted both hospitalization and severe disease [21]. A recent report by Choi et al. [22] described a 40-year-old man with antiphospholipid syndrome, who had received immunosuppressive agents because of alveolar haemorrhage. In the course of his first infection with SARS-CoV-2 until his death, he had four episodes of COVID-19, one new infection and three recurrences.
Second, it may be possible that the virus can transform into a new mutational status, which is more virulent [23], or there may be secondary infection with a new viral strain. However, it is necessary to define the exact genome in each course of infection. Nevertheless, because the previous PCR result was negative, it would not possible to compare the genomic study results in the two episodes of COVID-19. In the Case of new mutational status, it could be possible that a new mutation interacts with a different lymphocyte colony and makes them replicative, which would lead to another phase of cytokine release. So, it may be possible that significantly immunocompromised patients can acquire this infection several times. This issue needs further investigations to confirm these observations.
In summary, we reported on a boy with acute myeloid leukaemia M3, who had a previous history of COVID-19. After administration of chemotherapeutic agents he became infected again with positive findings on CT scan and also PCR test. This may be due to re-activation or re-infection, and needs further investigation.
Ethical approval
All procedures performed in this study were in accordance with the ethical standards of the Helsinki declaration. Informed consent was obtained from all individuals.
Conflict of interest
The authors declare that they have no conflict of interest.
Fundings
The authors received no financial support for the research, author-ship and/or publication of the article. | 0.15 MG/KG, DAILY | DrugDosageText | CC BY-NC-ND | 33425365 | 19,660,384 | 2021-01 |
What was the dosage of drug 'DEXAMETHASONE'? | COVID-19 re-infection or persistent infection in patient with acute myeloid leukaemia M3: a mini review.
Coronavirus disease 2019 (COVID-19) pandemic has affected more than 40 million people worldwide. Some patients had episodes of symptom recurrence after the first episode of infection with variable intervals. There are multiple issues and hypotheses about re-infection or re-activation of the virus, especially in immunocompromised patients. In this paper, we present details of an individual with a recent history of COVID-19 who proceeded to acute myeloid leukaemia M3 and immunosuppression by chemotherapy, then we review some recently published articles about possible re-infection or re-activation.
Case history
A 15-year-old boy was referred to our haematology clinic because of pancytopenia (white blood cell count (WBC) 3200/μL, haemoglobin 10.5 mg/dL, platelets 88 000/μL). His mother complained of her son's sudden icteric sclera. He had no past medical, surgical or medication history. One month previously, he had had an episode of coronavirus disease 2019 (COVID-19) with signs and symptoms of cough, dyspnoea and patchy infiltration in the left lung. He had two negative PCR tests. The symptoms then gradually resolved, and only some residual patchy infiltration was visible on lung CT scan. In the physical examination, there were no signs of lymphadenopathies nor of splenomegaly. The PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) was negative, but the antibody test was positive for IgG (33 IU/mL; typically <5 IU/mL) but negative for IgM (3.5 IU/mL; typically <5 IU/mL).
He became a candidate for bone marrow biopsy and aspiration. Results for bone marrow biopsy, aspiration (Fig. 1) and flow cytometry were compatible with acute myeloid leukaemia M3 with positive PML-RARα. After admission, he had no signs or symptoms of active infection, so the chemotherapy regimen started with all-trans retinoic acid (tretinoin; ATRA) (45 mg/m2) and arsenic trioxide (0.15 mg/kg) daily. After about 10 days of treatment, his weight increased by about 10 kg and the WBC count reached 29 000/μL. As with differentiation syndrome, we started dexamethasone 8 mg twice daily and a single dose of idarubicin 12 mg/m2, although he had no sign of respiratory distress. After 3 days, the WBC count decreased to 13 000/μL but then rose again to about 23 000/μL 3 days later, so another single dose of idarubicin 12 mg/m2 was administered. With this second dose, the WBC count dropped to 800/μL, haemoglobin to 7.5 mg/dL and platelets to 15 000/μL. By continuing arsenic trioxide and withholding the ATRA, the WBC count started to decrease. We restarted ATRA 45 mg/m2 and with this decrement, his weight returned to normal.FIG. 1 Bone marrow aspiration shown diffuse infiltration of promyelocytes.
FIG. 1
In the admission course, as he was neutropenic, he became febrile with a temperature of about 39.0°C. He had a cough, shivering and myalgia. We continued ATRA and arsenic trioxide but evaluated him for febrile neutropenia aetiologies. On lung CT scan, a new patchy infiltration was seen in his right lung. Empirical antibiotics (meropenem, vancomycin and levofloxacin) were administered. As the patient's general condition worsened we added the antifungal agent liposomal amphotericin 3 mg/kg to the empirical antibiotics.
After 24 hours, he became severely dyspnoeic, and O2 saturation dropped to 75%. The CT scan showed severe bilateral ground-glass patchy infiltrations compatible with COVID-19 lung involvement (Fig. 2). The patient was intubated and concomitantly a pulmonologist performed a bronchoscopy and took a mini-bronchoalveolar lavage; this was sent for galactomannan and Gram smear, culture and COVID-19 PCR test. After 48 hours, the bronchoalveolar lavage galactomannan was negative, but viral load measured by COVID RT-PCR cycle threshold (CT levels) was 521 868 217 copies/mL.FIG. 2 Upper left: CT scan at first day of admission to hospital; upper right: CT scan showing a new infiltration in the right lower lobe after patient became febrile with neutropenia; lower left: CT scan showing bilateral infiltration suggesting new episode of coronavirus disease 2019; lower right: CT scan on the day of discharge consistent with partial healing.
FIG. 2
We started interferon-β (1.2 million units subcutaneously every other day) and remdesivir (200 mg on day 1 and then 100 mg for 4 days after that) with 3 days of methylprednisolone 500 mg followed by dexamethasone 8 mg twice daily continued. Although ATRA and arsenic trioxide continued during the antiviral treatment. He was also evaluated for pulmonary thromboembolism with pulmonary CT-angiography, which was consistent with thromboembolism. We transfused platelets and maintained the platelet count above 50 000/μL, and started enoxaparin (60 units subcutaneously twice daily). After 5 days on mechanical ventilation, O2 saturation began to rise and some evidence of respiratory recovery was seen. On day 8, the patient was extubated. Antibiotics and antifungal treatments were continued for 14 days, then stopped. Dexamethasone was tapered gradually and continuously. By continuing ATRA and arsenic trioxide administration the platelet count increased gradually and the patient became transfusion independent. Six weeks after admission, the patient was discharged with good general condition and without any dependency on oxygen. WBC was 5600/μL, haemoglobin was 10.5 mg/dL and platelets were 145 000/μL at the time of discharge. Anti-coagulant continued after discharge.
Discussion
Up to October 2020, COVID-19 had affected more than 40 million people with more than one million deaths worldwide. Two significant concerns about SARS-CoV-2, the virus that causes COVID-19, are re-infection and prolonged viral shedding [1,2]. Some patients have positive SARS-CoV-2 PCR tests early after the recovery from infection despite antibody production [3]. Some studies have shown that antibody titres begin to drop about 2 months later [4]. The virus may persist in the body in respiratory secretions while the patient has no symptoms; it can spread throughout the body into the different organs such as the spleen or lymph nodes, which cannot be detected by nasopharyngeal swab [5]. It has been suggested that antibodies are produced against virus spike proteins, which can mutate and lead to reduced neutralization [6,7]. During the second infection described here, IgG antibodies were undetectable after the diagnosis, which would be justifiable considering the low burden of disease in the first episode of infection in some patients [8,9]. T-cell immunity may have a pivotal role in long-term protection against the virus by providing targets against the spike protein with helper and cytotoxic T cells [10,11]. During the convalescence period, viral shedding is still ongoing. There is some evidence that patients with immunodeficiency, such as glucocorticoid use, have prolonged viral shedding [12]. In a report from the COCOREC study group in France, they reported on 11 patients with confirmed viral re-infection at least 3 weeks after the first episode. Four of them had a mild relapse and seven of them had severe relapses and were admitted to intensive care. It was suggested that in patients with mild relapse, prolonged exposure and reduced immunity made them susceptible to re-infection. However, in severe relapses, suboptimal control of infection leads to second infection [13,14]. There are several reports of SARS-CoV-2 re-infection with mild clinical pictures or without any symptoms. The latter may be diagnosed with a positive PCR test in which it could be sample contamination or misdiagnosis due to detecting non-infectious RNA. The PCR test cannot differentiate between infectious and non-infectious RNA, so not all test positives will be a clinical relapse [[15], [16], [17], [18]]. Lancman et al. described a 55-year-old woman with acute lymphoblastic leukaemia who was positive for SARS-CoV-2 infection after induction chemotherapy with severe respiratory signs and symptoms. After receiving remdesivir and showing clinical improvement, she became infected again with positive PCR 1 month later after consolidation therapy. Results of the antibody test were negative despite previous positive results. These supported the SARS-CoV-2 re-activation issue because of a short interval between consolidation therapy and PCR positivity [19]. In this paper, we report on a patient with acute myeloid leukaemia who had previously been infected with SARS-CoV-2 with positive IgG serology and negative PCR at the time of admission. However, as he became leukopenic and lymphopenic in the course of treatment, he became infected again with SARS-CoV-2 and became severely symptomatic, which was confirmed by lung imaging and a positive PCR test result. There are some issues concerning re-infection. First, it may be possible that after a first infection, the virus is not fully removed from bodily secretions, the lymphatic system or pulmonary infiltration as in our patient, So it may be quiescent until an immunosuppression event occurs, which it becomes active again. Chemotherapeutic agents that interact with B-cell function, such as anti-CD20 agents, may impact antibody production against SARS-CoV-2. Phillips et al. reported on an individual with acute lymphoblastic leukaemia who had severe COVID-19 before starting induction chemotherapy. He received only steroids and non-myeloablative chemotherapeutic agents until the critical period of infection had passed, then he received a full course of chemotherapy. In their paper Phillips et al. recommended that after passing the critical phase of infection, chemotherapeutic agents could be introduced [20]. However, this needs more attention, as our report and that of Lancman et al. [19] describe new episodes COVID-19 after myeloablative chemotherapy, so starting chemotherapy would not be completely safe. A recently published report from the Memorial Sloan Kettering Cancer Center in New York, demonstrated severe COVID-19 in 20% of patients with cancer and a 12% Case fatality rate. Treatment with immune checkpoint inhibitors predicted both hospitalization and severe disease [21]. A recent report by Choi et al. [22] described a 40-year-old man with antiphospholipid syndrome, who had received immunosuppressive agents because of alveolar haemorrhage. In the course of his first infection with SARS-CoV-2 until his death, he had four episodes of COVID-19, one new infection and three recurrences.
Second, it may be possible that the virus can transform into a new mutational status, which is more virulent [23], or there may be secondary infection with a new viral strain. However, it is necessary to define the exact genome in each course of infection. Nevertheless, because the previous PCR result was negative, it would not possible to compare the genomic study results in the two episodes of COVID-19. In the Case of new mutational status, it could be possible that a new mutation interacts with a different lymphocyte colony and makes them replicative, which would lead to another phase of cytokine release. So, it may be possible that significantly immunocompromised patients can acquire this infection several times. This issue needs further investigations to confirm these observations.
In summary, we reported on a boy with acute myeloid leukaemia M3, who had a previous history of COVID-19. After administration of chemotherapeutic agents he became infected again with positive findings on CT scan and also PCR test. This may be due to re-activation or re-infection, and needs further investigation.
Ethical approval
All procedures performed in this study were in accordance with the ethical standards of the Helsinki declaration. Informed consent was obtained from all individuals.
Conflict of interest
The authors declare that they have no conflict of interest.
Fundings
The authors received no financial support for the research, author-ship and/or publication of the article. | 8 MG, 2X/DAY | DrugDosageText | CC BY-NC-ND | 33425365 | 19,660,384 | 2021-01 |
What was the outcome of reaction 'Embolism'? | COVID-19 re-infection or persistent infection in patient with acute myeloid leukaemia M3: a mini review.
Coronavirus disease 2019 (COVID-19) pandemic has affected more than 40 million people worldwide. Some patients had episodes of symptom recurrence after the first episode of infection with variable intervals. There are multiple issues and hypotheses about re-infection or re-activation of the virus, especially in immunocompromised patients. In this paper, we present details of an individual with a recent history of COVID-19 who proceeded to acute myeloid leukaemia M3 and immunosuppression by chemotherapy, then we review some recently published articles about possible re-infection or re-activation.
Case history
A 15-year-old boy was referred to our haematology clinic because of pancytopenia (white blood cell count (WBC) 3200/μL, haemoglobin 10.5 mg/dL, platelets 88 000/μL). His mother complained of her son's sudden icteric sclera. He had no past medical, surgical or medication history. One month previously, he had had an episode of coronavirus disease 2019 (COVID-19) with signs and symptoms of cough, dyspnoea and patchy infiltration in the left lung. He had two negative PCR tests. The symptoms then gradually resolved, and only some residual patchy infiltration was visible on lung CT scan. In the physical examination, there were no signs of lymphadenopathies nor of splenomegaly. The PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) was negative, but the antibody test was positive for IgG (33 IU/mL; typically <5 IU/mL) but negative for IgM (3.5 IU/mL; typically <5 IU/mL).
He became a candidate for bone marrow biopsy and aspiration. Results for bone marrow biopsy, aspiration (Fig. 1) and flow cytometry were compatible with acute myeloid leukaemia M3 with positive PML-RARα. After admission, he had no signs or symptoms of active infection, so the chemotherapy regimen started with all-trans retinoic acid (tretinoin; ATRA) (45 mg/m2) and arsenic trioxide (0.15 mg/kg) daily. After about 10 days of treatment, his weight increased by about 10 kg and the WBC count reached 29 000/μL. As with differentiation syndrome, we started dexamethasone 8 mg twice daily and a single dose of idarubicin 12 mg/m2, although he had no sign of respiratory distress. After 3 days, the WBC count decreased to 13 000/μL but then rose again to about 23 000/μL 3 days later, so another single dose of idarubicin 12 mg/m2 was administered. With this second dose, the WBC count dropped to 800/μL, haemoglobin to 7.5 mg/dL and platelets to 15 000/μL. By continuing arsenic trioxide and withholding the ATRA, the WBC count started to decrease. We restarted ATRA 45 mg/m2 and with this decrement, his weight returned to normal.FIG. 1 Bone marrow aspiration shown diffuse infiltration of promyelocytes.
FIG. 1
In the admission course, as he was neutropenic, he became febrile with a temperature of about 39.0°C. He had a cough, shivering and myalgia. We continued ATRA and arsenic trioxide but evaluated him for febrile neutropenia aetiologies. On lung CT scan, a new patchy infiltration was seen in his right lung. Empirical antibiotics (meropenem, vancomycin and levofloxacin) were administered. As the patient's general condition worsened we added the antifungal agent liposomal amphotericin 3 mg/kg to the empirical antibiotics.
After 24 hours, he became severely dyspnoeic, and O2 saturation dropped to 75%. The CT scan showed severe bilateral ground-glass patchy infiltrations compatible with COVID-19 lung involvement (Fig. 2). The patient was intubated and concomitantly a pulmonologist performed a bronchoscopy and took a mini-bronchoalveolar lavage; this was sent for galactomannan and Gram smear, culture and COVID-19 PCR test. After 48 hours, the bronchoalveolar lavage galactomannan was negative, but viral load measured by COVID RT-PCR cycle threshold (CT levels) was 521 868 217 copies/mL.FIG. 2 Upper left: CT scan at first day of admission to hospital; upper right: CT scan showing a new infiltration in the right lower lobe after patient became febrile with neutropenia; lower left: CT scan showing bilateral infiltration suggesting new episode of coronavirus disease 2019; lower right: CT scan on the day of discharge consistent with partial healing.
FIG. 2
We started interferon-β (1.2 million units subcutaneously every other day) and remdesivir (200 mg on day 1 and then 100 mg for 4 days after that) with 3 days of methylprednisolone 500 mg followed by dexamethasone 8 mg twice daily continued. Although ATRA and arsenic trioxide continued during the antiviral treatment. He was also evaluated for pulmonary thromboembolism with pulmonary CT-angiography, which was consistent with thromboembolism. We transfused platelets and maintained the platelet count above 50 000/μL, and started enoxaparin (60 units subcutaneously twice daily). After 5 days on mechanical ventilation, O2 saturation began to rise and some evidence of respiratory recovery was seen. On day 8, the patient was extubated. Antibiotics and antifungal treatments were continued for 14 days, then stopped. Dexamethasone was tapered gradually and continuously. By continuing ATRA and arsenic trioxide administration the platelet count increased gradually and the patient became transfusion independent. Six weeks after admission, the patient was discharged with good general condition and without any dependency on oxygen. WBC was 5600/μL, haemoglobin was 10.5 mg/dL and platelets were 145 000/μL at the time of discharge. Anti-coagulant continued after discharge.
Discussion
Up to October 2020, COVID-19 had affected more than 40 million people with more than one million deaths worldwide. Two significant concerns about SARS-CoV-2, the virus that causes COVID-19, are re-infection and prolonged viral shedding [1,2]. Some patients have positive SARS-CoV-2 PCR tests early after the recovery from infection despite antibody production [3]. Some studies have shown that antibody titres begin to drop about 2 months later [4]. The virus may persist in the body in respiratory secretions while the patient has no symptoms; it can spread throughout the body into the different organs such as the spleen or lymph nodes, which cannot be detected by nasopharyngeal swab [5]. It has been suggested that antibodies are produced against virus spike proteins, which can mutate and lead to reduced neutralization [6,7]. During the second infection described here, IgG antibodies were undetectable after the diagnosis, which would be justifiable considering the low burden of disease in the first episode of infection in some patients [8,9]. T-cell immunity may have a pivotal role in long-term protection against the virus by providing targets against the spike protein with helper and cytotoxic T cells [10,11]. During the convalescence period, viral shedding is still ongoing. There is some evidence that patients with immunodeficiency, such as glucocorticoid use, have prolonged viral shedding [12]. In a report from the COCOREC study group in France, they reported on 11 patients with confirmed viral re-infection at least 3 weeks after the first episode. Four of them had a mild relapse and seven of them had severe relapses and were admitted to intensive care. It was suggested that in patients with mild relapse, prolonged exposure and reduced immunity made them susceptible to re-infection. However, in severe relapses, suboptimal control of infection leads to second infection [13,14]. There are several reports of SARS-CoV-2 re-infection with mild clinical pictures or without any symptoms. The latter may be diagnosed with a positive PCR test in which it could be sample contamination or misdiagnosis due to detecting non-infectious RNA. The PCR test cannot differentiate between infectious and non-infectious RNA, so not all test positives will be a clinical relapse [[15], [16], [17], [18]]. Lancman et al. described a 55-year-old woman with acute lymphoblastic leukaemia who was positive for SARS-CoV-2 infection after induction chemotherapy with severe respiratory signs and symptoms. After receiving remdesivir and showing clinical improvement, she became infected again with positive PCR 1 month later after consolidation therapy. Results of the antibody test were negative despite previous positive results. These supported the SARS-CoV-2 re-activation issue because of a short interval between consolidation therapy and PCR positivity [19]. In this paper, we report on a patient with acute myeloid leukaemia who had previously been infected with SARS-CoV-2 with positive IgG serology and negative PCR at the time of admission. However, as he became leukopenic and lymphopenic in the course of treatment, he became infected again with SARS-CoV-2 and became severely symptomatic, which was confirmed by lung imaging and a positive PCR test result. There are some issues concerning re-infection. First, it may be possible that after a first infection, the virus is not fully removed from bodily secretions, the lymphatic system or pulmonary infiltration as in our patient, So it may be quiescent until an immunosuppression event occurs, which it becomes active again. Chemotherapeutic agents that interact with B-cell function, such as anti-CD20 agents, may impact antibody production against SARS-CoV-2. Phillips et al. reported on an individual with acute lymphoblastic leukaemia who had severe COVID-19 before starting induction chemotherapy. He received only steroids and non-myeloablative chemotherapeutic agents until the critical period of infection had passed, then he received a full course of chemotherapy. In their paper Phillips et al. recommended that after passing the critical phase of infection, chemotherapeutic agents could be introduced [20]. However, this needs more attention, as our report and that of Lancman et al. [19] describe new episodes COVID-19 after myeloablative chemotherapy, so starting chemotherapy would not be completely safe. A recently published report from the Memorial Sloan Kettering Cancer Center in New York, demonstrated severe COVID-19 in 20% of patients with cancer and a 12% Case fatality rate. Treatment with immune checkpoint inhibitors predicted both hospitalization and severe disease [21]. A recent report by Choi et al. [22] described a 40-year-old man with antiphospholipid syndrome, who had received immunosuppressive agents because of alveolar haemorrhage. In the course of his first infection with SARS-CoV-2 until his death, he had four episodes of COVID-19, one new infection and three recurrences.
Second, it may be possible that the virus can transform into a new mutational status, which is more virulent [23], or there may be secondary infection with a new viral strain. However, it is necessary to define the exact genome in each course of infection. Nevertheless, because the previous PCR result was negative, it would not possible to compare the genomic study results in the two episodes of COVID-19. In the Case of new mutational status, it could be possible that a new mutation interacts with a different lymphocyte colony and makes them replicative, which would lead to another phase of cytokine release. So, it may be possible that significantly immunocompromised patients can acquire this infection several times. This issue needs further investigations to confirm these observations.
In summary, we reported on a boy with acute myeloid leukaemia M3, who had a previous history of COVID-19. After administration of chemotherapeutic agents he became infected again with positive findings on CT scan and also PCR test. This may be due to re-activation or re-infection, and needs further investigation.
Ethical approval
All procedures performed in this study were in accordance with the ethical standards of the Helsinki declaration. Informed consent was obtained from all individuals.
Conflict of interest
The authors declare that they have no conflict of interest.
Fundings
The authors received no financial support for the research, author-ship and/or publication of the article. | Recovered | ReactionOutcome | CC BY-NC-ND | 33425365 | 19,764,362 | 2021-01 |
What was the outcome of reaction 'Immunosuppression'? | COVID-19 re-infection or persistent infection in patient with acute myeloid leukaemia M3: a mini review.
Coronavirus disease 2019 (COVID-19) pandemic has affected more than 40 million people worldwide. Some patients had episodes of symptom recurrence after the first episode of infection with variable intervals. There are multiple issues and hypotheses about re-infection or re-activation of the virus, especially in immunocompromised patients. In this paper, we present details of an individual with a recent history of COVID-19 who proceeded to acute myeloid leukaemia M3 and immunosuppression by chemotherapy, then we review some recently published articles about possible re-infection or re-activation.
Case history
A 15-year-old boy was referred to our haematology clinic because of pancytopenia (white blood cell count (WBC) 3200/μL, haemoglobin 10.5 mg/dL, platelets 88 000/μL). His mother complained of her son's sudden icteric sclera. He had no past medical, surgical or medication history. One month previously, he had had an episode of coronavirus disease 2019 (COVID-19) with signs and symptoms of cough, dyspnoea and patchy infiltration in the left lung. He had two negative PCR tests. The symptoms then gradually resolved, and only some residual patchy infiltration was visible on lung CT scan. In the physical examination, there were no signs of lymphadenopathies nor of splenomegaly. The PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) was negative, but the antibody test was positive for IgG (33 IU/mL; typically <5 IU/mL) but negative for IgM (3.5 IU/mL; typically <5 IU/mL).
He became a candidate for bone marrow biopsy and aspiration. Results for bone marrow biopsy, aspiration (Fig. 1) and flow cytometry were compatible with acute myeloid leukaemia M3 with positive PML-RARα. After admission, he had no signs or symptoms of active infection, so the chemotherapy regimen started with all-trans retinoic acid (tretinoin; ATRA) (45 mg/m2) and arsenic trioxide (0.15 mg/kg) daily. After about 10 days of treatment, his weight increased by about 10 kg and the WBC count reached 29 000/μL. As with differentiation syndrome, we started dexamethasone 8 mg twice daily and a single dose of idarubicin 12 mg/m2, although he had no sign of respiratory distress. After 3 days, the WBC count decreased to 13 000/μL but then rose again to about 23 000/μL 3 days later, so another single dose of idarubicin 12 mg/m2 was administered. With this second dose, the WBC count dropped to 800/μL, haemoglobin to 7.5 mg/dL and platelets to 15 000/μL. By continuing arsenic trioxide and withholding the ATRA, the WBC count started to decrease. We restarted ATRA 45 mg/m2 and with this decrement, his weight returned to normal.FIG. 1 Bone marrow aspiration shown diffuse infiltration of promyelocytes.
FIG. 1
In the admission course, as he was neutropenic, he became febrile with a temperature of about 39.0°C. He had a cough, shivering and myalgia. We continued ATRA and arsenic trioxide but evaluated him for febrile neutropenia aetiologies. On lung CT scan, a new patchy infiltration was seen in his right lung. Empirical antibiotics (meropenem, vancomycin and levofloxacin) were administered. As the patient's general condition worsened we added the antifungal agent liposomal amphotericin 3 mg/kg to the empirical antibiotics.
After 24 hours, he became severely dyspnoeic, and O2 saturation dropped to 75%. The CT scan showed severe bilateral ground-glass patchy infiltrations compatible with COVID-19 lung involvement (Fig. 2). The patient was intubated and concomitantly a pulmonologist performed a bronchoscopy and took a mini-bronchoalveolar lavage; this was sent for galactomannan and Gram smear, culture and COVID-19 PCR test. After 48 hours, the bronchoalveolar lavage galactomannan was negative, but viral load measured by COVID RT-PCR cycle threshold (CT levels) was 521 868 217 copies/mL.FIG. 2 Upper left: CT scan at first day of admission to hospital; upper right: CT scan showing a new infiltration in the right lower lobe after patient became febrile with neutropenia; lower left: CT scan showing bilateral infiltration suggesting new episode of coronavirus disease 2019; lower right: CT scan on the day of discharge consistent with partial healing.
FIG. 2
We started interferon-β (1.2 million units subcutaneously every other day) and remdesivir (200 mg on day 1 and then 100 mg for 4 days after that) with 3 days of methylprednisolone 500 mg followed by dexamethasone 8 mg twice daily continued. Although ATRA and arsenic trioxide continued during the antiviral treatment. He was also evaluated for pulmonary thromboembolism with pulmonary CT-angiography, which was consistent with thromboembolism. We transfused platelets and maintained the platelet count above 50 000/μL, and started enoxaparin (60 units subcutaneously twice daily). After 5 days on mechanical ventilation, O2 saturation began to rise and some evidence of respiratory recovery was seen. On day 8, the patient was extubated. Antibiotics and antifungal treatments were continued for 14 days, then stopped. Dexamethasone was tapered gradually and continuously. By continuing ATRA and arsenic trioxide administration the platelet count increased gradually and the patient became transfusion independent. Six weeks after admission, the patient was discharged with good general condition and without any dependency on oxygen. WBC was 5600/μL, haemoglobin was 10.5 mg/dL and platelets were 145 000/μL at the time of discharge. Anti-coagulant continued after discharge.
Discussion
Up to October 2020, COVID-19 had affected more than 40 million people with more than one million deaths worldwide. Two significant concerns about SARS-CoV-2, the virus that causes COVID-19, are re-infection and prolonged viral shedding [1,2]. Some patients have positive SARS-CoV-2 PCR tests early after the recovery from infection despite antibody production [3]. Some studies have shown that antibody titres begin to drop about 2 months later [4]. The virus may persist in the body in respiratory secretions while the patient has no symptoms; it can spread throughout the body into the different organs such as the spleen or lymph nodes, which cannot be detected by nasopharyngeal swab [5]. It has been suggested that antibodies are produced against virus spike proteins, which can mutate and lead to reduced neutralization [6,7]. During the second infection described here, IgG antibodies were undetectable after the diagnosis, which would be justifiable considering the low burden of disease in the first episode of infection in some patients [8,9]. T-cell immunity may have a pivotal role in long-term protection against the virus by providing targets against the spike protein with helper and cytotoxic T cells [10,11]. During the convalescence period, viral shedding is still ongoing. There is some evidence that patients with immunodeficiency, such as glucocorticoid use, have prolonged viral shedding [12]. In a report from the COCOREC study group in France, they reported on 11 patients with confirmed viral re-infection at least 3 weeks after the first episode. Four of them had a mild relapse and seven of them had severe relapses and were admitted to intensive care. It was suggested that in patients with mild relapse, prolonged exposure and reduced immunity made them susceptible to re-infection. However, in severe relapses, suboptimal control of infection leads to second infection [13,14]. There are several reports of SARS-CoV-2 re-infection with mild clinical pictures or without any symptoms. The latter may be diagnosed with a positive PCR test in which it could be sample contamination or misdiagnosis due to detecting non-infectious RNA. The PCR test cannot differentiate between infectious and non-infectious RNA, so not all test positives will be a clinical relapse [[15], [16], [17], [18]]. Lancman et al. described a 55-year-old woman with acute lymphoblastic leukaemia who was positive for SARS-CoV-2 infection after induction chemotherapy with severe respiratory signs and symptoms. After receiving remdesivir and showing clinical improvement, she became infected again with positive PCR 1 month later after consolidation therapy. Results of the antibody test were negative despite previous positive results. These supported the SARS-CoV-2 re-activation issue because of a short interval between consolidation therapy and PCR positivity [19]. In this paper, we report on a patient with acute myeloid leukaemia who had previously been infected with SARS-CoV-2 with positive IgG serology and negative PCR at the time of admission. However, as he became leukopenic and lymphopenic in the course of treatment, he became infected again with SARS-CoV-2 and became severely symptomatic, which was confirmed by lung imaging and a positive PCR test result. There are some issues concerning re-infection. First, it may be possible that after a first infection, the virus is not fully removed from bodily secretions, the lymphatic system or pulmonary infiltration as in our patient, So it may be quiescent until an immunosuppression event occurs, which it becomes active again. Chemotherapeutic agents that interact with B-cell function, such as anti-CD20 agents, may impact antibody production against SARS-CoV-2. Phillips et al. reported on an individual with acute lymphoblastic leukaemia who had severe COVID-19 before starting induction chemotherapy. He received only steroids and non-myeloablative chemotherapeutic agents until the critical period of infection had passed, then he received a full course of chemotherapy. In their paper Phillips et al. recommended that after passing the critical phase of infection, chemotherapeutic agents could be introduced [20]. However, this needs more attention, as our report and that of Lancman et al. [19] describe new episodes COVID-19 after myeloablative chemotherapy, so starting chemotherapy would not be completely safe. A recently published report from the Memorial Sloan Kettering Cancer Center in New York, demonstrated severe COVID-19 in 20% of patients with cancer and a 12% Case fatality rate. Treatment with immune checkpoint inhibitors predicted both hospitalization and severe disease [21]. A recent report by Choi et al. [22] described a 40-year-old man with antiphospholipid syndrome, who had received immunosuppressive agents because of alveolar haemorrhage. In the course of his first infection with SARS-CoV-2 until his death, he had four episodes of COVID-19, one new infection and three recurrences.
Second, it may be possible that the virus can transform into a new mutational status, which is more virulent [23], or there may be secondary infection with a new viral strain. However, it is necessary to define the exact genome in each course of infection. Nevertheless, because the previous PCR result was negative, it would not possible to compare the genomic study results in the two episodes of COVID-19. In the Case of new mutational status, it could be possible that a new mutation interacts with a different lymphocyte colony and makes them replicative, which would lead to another phase of cytokine release. So, it may be possible that significantly immunocompromised patients can acquire this infection several times. This issue needs further investigations to confirm these observations.
In summary, we reported on a boy with acute myeloid leukaemia M3, who had a previous history of COVID-19. After administration of chemotherapeutic agents he became infected again with positive findings on CT scan and also PCR test. This may be due to re-activation or re-infection, and needs further investigation.
Ethical approval
All procedures performed in this study were in accordance with the ethical standards of the Helsinki declaration. Informed consent was obtained from all individuals.
Conflict of interest
The authors declare that they have no conflict of interest.
Fundings
The authors received no financial support for the research, author-ship and/or publication of the article. | Recovering | ReactionOutcome | CC BY-NC-ND | 33425365 | 19,660,384 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug effective for unapproved indication'. | A Pilot Trial on the Effect of Levothyroxine on Proteinuria in Patients With Advanced CKD.
Thyroid hormones can directly affect kidney function; elevated levels of thyroid-stimulating hormone (TSH) and chronic kidney disease (CKD) are associated with proteinuria, decreased estimated glomerular filtration rate (eGFR), and progression to end-stage renal disease. Our hypothesis is that in patients with CKD and TSH at levels considered to be in the low subclinical hypothyroidism (SCH) range, lowering TSH with levothyroxine (LVX) improves the clinical parameters of renal function.
This was a double-blind, randomized, pilot clinical trial in patients with proteinuric CKD (eGFR <60 ml/min per 1.73 m2 and proteinuria >150 mg/d) performed at the Hospital Civil de Guadalajara, with the intention of lowering TSH (levels of 1.25-2.5 μIU/l) in patients with TSH (levels of 2.6-9.9 μIU/ml with FT4 in the range of 0.7-1.8 ng/dl). Patients were randomized 1:1 to receive LVX or placebo for 12 weeks. The primary objective was to evaluate absolute levels of proteinuria at the beginning compared to the end of the study and, as a secondary objective, the changes in serum creatinine (sCr), eGFR, cholesterol, triglycerides, low-density lipoprotein (LDL), and blood pressure, and to assess the tolerability and safety of LVX.
Between March and November 2018, a total of 163 patients were assessed for eligibility; 119 patients did not meet the inclusion criteria or were excluded, and 32 patients were randomized. The demographic and clinical characteristics of the 2 study groups were essentially not different. Subjects were 66.87 (SD 12.19) years of age, 62.5% were female, 75% were diabetes mellitus, eGFR was 23.55 (±12.91) ml/min per 1.73 m2, TSH was 5.37 ± 2.13 μIU/ml, proteinuria in 24-hour urine collection was 1.52 ± 1.12, and all of them were taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs). Proteinuria at 12 weeks in the LVX group was 0.89 SD ± 1.28 g/d, and in the placebo group it was 1.35 SD ± 0.85 g/d; when compared to placebo, LVX showed a significant decrease in proteinuria of 1.1 g/d (P = 0.0011). The eGFR in the LVX group showed an improvement of 4 ml/min/1.73 m2 (P = 0.049); in the placebo group, there was a decrease of 1.98 ml/min per 1.73 m2. The sCr, cholesterol, triglycerides, low-density lipoprotein, systolic blood pressure, and diastolic blood pressure were not different between groups. Adverse events were reported in the LVX group in 7.14% of patients and in 11.11% of patients in the placebo group; none left the study because of adverse effects, and there were no serious adverse events.
This single-center, randomized, double-blind, placebo-controlled pilot clinical trial in patients with advanced proteinuric CKD who already used ACEIs or ARBs demonstrated that administering LVX to obtain a TSH range close to 2.5 μIU/ml decreased proteinuria and improved eGFR. Future research is needed to confirm our results and to determine whether our findings generalize to patient groups not explicitly enrolled in this small pilot trial.
Chronic noncommunicable diseases such as obesity, diabetes mellitus, hypertension, and chronic kidney disease (CKD) have become a major public health problem in the Mexican population.1,2 Between 1990 and 2013, the CKD burden rapidly climbed, with age-standardized years of life lost (YLL) and disability-adjusted life-year (DALY) rates increasing more than 130%, the second highest DALY due to CKD in the world.3 The incidence of end-stage renal disease has increased dramatically in parallel with these risk factors.4
Thyroid hormones can directly affect kidney function, and impaired renal function can also contribute to thyroid disorders.5, 6, 7, 8, 9 The prevalence of primary overt, subclinical hypothyroidism (SCH) and low T3 syndrome increases with the progression of CKD.10,11
The prevalence of SCH in patients with an estimated glomerular filtration rate (eGFR) >60 ml/min per 1.73 m2 is 7% and is up to 17.9% in those with an eGFR <60 ml/min per 1.73 m2.11 Thyroid hormone affects the kidney by multiple mechanisms; local hemodynamic changes, decreased renal blood flow, decreased cardiac output, circulating volume, and decreased atrial natriuretic factor contribute to a decrease in renal perfusion with a concomitant reduction in eGFR,5, 6, 7,11, 12, 13 affecting the renin−angiotensin−aldosterone system, glomerular basement membrane, and renal tubular function, and leading to the development of proteinuria through direct effects on megalin and podocytes.8,9
The frequency of proteinuria in patients with normal thyroid function (euthyroid), SCH, and hypothyroidism is 1.29%, 2.2%, and 2.97%, respectively.14 In addition, it has been reported that the progression to end-stage renal disease is more accelerated in patients with SCH than in euthyroid patients,14,15, 16, 17, 18 and there is evidence that high (>3 μIU/ml) and low (<0.5 μIU/ml) thyroid-stimulating hormone (TSH) are associated with higher mortality rates in patients with CKD.19 There is also an association of mortality in patients with CKD and thyroid functional disease due to increased cardiovascular risk,20 particularly in patients on hemodialysis,21, 22, 23 as well as peritoneal dialysis24 and thyroid function disease.
The American Thyroid Guidelines, the American Association of Endocrinology,25 and European Guidelines and Clinical Practice Guidelines26 recommend beginning LVX doses of 0.25 μg and not going above 0.50 μg in patients with high cardiovascular risk,27,28 as patients with CKD have been considered.29
Levothyroxine is usually well tolerated in the general population at standard doses (1.6-18.8 μg/kg). In patients with SCH, overdose symptoms were reported in 10% to 21% of cases, and a Cochrane meta-analysis of thyroid hormone replacement for SCH found no significant adverse events.30
However, many patients with CKD will experience renal progression, despite antiproteinuric treatment.31,32 These observations led to the examination of alternative pathways to delay CKD, with disappointing results so far. The most commonly used antiproteinuric33,34 drugs are angiotensin-converting enzyme inhibitors,35 angiotensin receptor blockers,36 aldosterone antagonists, 37, 38, 39, 40 and, although they are less effective, statins,41,42 allopurinol,43 and vitamin D activators.43, 44, 45, 46, 47, 48
Treatment of SCH with LVX in the general population improves the lipid profile and cardiac function,49, 50, 51 and patients with CKD show improvement in eGFR and serum creatinine (sCr),14,51 but there are no clinical trials in this field in patients with CKD.
Our hypothesis is that in patients with CKD and TSH at levels considered to be in the SCH range, the normalization of TSH with LVX improves the clinical parameters of renal function.
Materials and Methods
We conducted a pilot randomized, single-center, double-blind, placebo-controlled, parallel group, dose-adjusting trial of levothyroxine (LVX) 25 μg administered orally once daily to patients with proteinuric CKD conducted at the Hospital Civil de Guadalajara from March 2018 to 31 January 2019. The study objectives were to evaluate the efficacy and safety of normalizing TSH levels with LVX and to explore the clinical effect of LVX compared with placebo.
The measurement of TSH and FT4 was carried out with the UniCel DxI 800 (Beckman Coulter Inc., Indianapolis, IN) access Immunoassay system by chemiluminescence, with the serum FT4 (assay type 2-step competitive) reportable range of 0.25 to 6 ng/dl (3-2-77.2 pmol/l), analytical sensitivity 0.25 ng/dl (3.2 pmol/l), and serum TSH (assay type 1-step sandwich) reportable range of 0.03 to 100 μIU/ml, which incorporates functionality for the lower limit of detection, analytical sensitivity 0.01 μIU/ml, and 0.03 uIU/ml functional, and all samples were analyzed in a single laboratory.
Patients with CKD (eGFR <60 ml/min per 1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) were eligible if they were >18 years of age or if they had proteinuria >150 mg/24 h. With TSH levels between 2.5 and 10.0 μIU/ml, we chose TSH >2.5 μIU/ml, as there is evidence that there was an association of a decrease in eGFR10,52 with proteinuria,10 and TSH <10.0 μIU/ml excludes clinical hypothyroidism. All patients treated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and without renal replacement therapy who attended the Renal Health Clinic were considered for participation in this pilot clinical trial.
We excluded patients with the following: primary hypothyroidism or preexisting thyroid disease; previous ischemic heart disease within a period of <6 months; arrhythmia; pregnancy; use of drugs that interact with the synthesis of thyroid hormones (Supplementary Table S1); those who did not provide informed consent; those with a serum TSH level <2.5 μIU/ml or >10 μIU/ml; those with a free serum T4 value between 0.6 and 1.8 ng/dl; those with positive anti-thyroid antibodies; and patients weighing <50 kg or >90 kg, because within this weight, all patients will maintain a dosage of 0.3−0.5 μg/kg per day, so it will be easy to prescribe the LVX dose with a narrow error window.
Approval was obtained from the participating site’s Research and Ethics Committee (Hospital CG 034/18 March 2018). Patients provided written informed consent before enrollment in accordance with local and national laws. Conduct and reporting are consistent with the 2010 Consolidated Standards of Reporting Trials (CONSORT) extension for pilot trials.53 The trial was registered in the Clinical Trials Registry (NCT03898622).
Measures of renal function included the eGFR calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation.54 Proteinuria was measured by means of 24-hour urine collection, expressed in grams per day, at the beginning and end of the study. Serum creatinine, serum electrolytes, hemoglobin, albumin, cholesterol, TSH, FT4, and triglycerides were measured at the beginning of the study and every 4 weeks for 4 months.
Using a Web-based randomization system, we randomly assigned participants in a 1:1 ratio. Standard care was defined pragmatically; in both the study intervention and the standard care group, the nephrologist determined all aspects of clinical care, based on standard practice and individual patient needs, independent of the study intervention.
The study consisted of 3 phases. The first phase, with a duration of 8 to 12 weeks, consisted of enrolling patients and collecting demographic and clinical baseline measurements (proteinuria, lipid profile, serum electrolytes, arterial pressure, weight, TSH level, hemoglobin, and serum albumin). The second phase consisted of both groups being treated according to the allocation arm, and the third phase consisted of comparing the variables studied and the data analysis. The dose of LVX has previously been shown to be safe and efficient in adult patients with CKD.14,51
Our primary objective was to evaluate the effect of lowering TSH with the use of LVX or placebo to assess absolute levels at the beginning compared to the end of the study, when proteinuria was measured in urine collected for 24 hours. The secondary objectives were to evaluate the changes in sCr and eGFR and to assess the tolerability and safety of LVX and changes in cholesterol, triglycerides, LDL and blood pressure.
Interventions
The treating nephrologist and the patients were blinded to the study intervention.
If randomized to the intervention arm, the intervention consisted of treatment with oral levothyroxine (LVX) between 0.25 and 0.50 μg according to a dose of 0.3 to 0.5 μg/kg per day during fasting (in the case of taking a drug that interacts with the absorption, use of it was changed according to the hours specified). The dose adjustment was every 4 weeks. Levothyroxine or placebo was adjusted to 25 or 50 μg according to TSH levels (Table 1).Table 1 Dose adjustment of levothyroxine
TSH range Dose adjustment
TSH < 0.5 μIU/ml Suspend the pill
TSH (0.5–1 μIU/ml) Suspend the pill if it is at minimum dose
TSH (1.2–2.4 μIU/ml) Suspend the pill if it is at minimum dose
TSH (2.5–4.3 μIU/ml) Dose 25 μg/d
TSH (4.4–6.1 μIU/ml) Keep dose if 50 μg/d or increase if taking 25 μg/d
TSH (6.2–8 μIU/ml) Keep dose if 50 μg/d or increase if taking 25 μg/d
TSH (8.1–9.9 μIU/ml) Keep dose if 50 μg/d or increase if taking 25 μg/d
TSH, thyroid-stimulating hormone.
All vials (placebo or levothyroxine) presented drugs in one-quarter tablet = 25 μg the first month. In addition, the following months were adjusted according to the TSH range.
Participants allocated to placebo took 1 pill per day, with the same bottle characteristics as patients in the intervention arm, for >12 weeks.
The preparation and packaging of LVX and placebo were carried out by a pharmacist who was not involved in the development of the present study. All patients were followed up every 4 weeks for usual renal health consultation. In addition, the specific aspects of the protocol consisted of monitoring thyroid function for the adjustment of LVX or placebo dose according to the previous dosage adjustment.
To ascertain compliance and adherence to treatment, a record sheet was created with all drug supplied and returned. During the course of the study, the investigator was responsible for providing additional instructions to retrain any subjects who did not comply with the administration of the study drug or with attendance at the required clinical visits.
Adverse events were recorded during the follow-up, which included thyroid profile control tests every 4 weeks. Previously specified adverse effects were reported and followed up, and were rated in intensity according to the Common Terminology Criteria for Adverse Events (CTC) v. 3.0 (1–5), along with the start date and end date, as well as the treatment received.
This protocol was not sponsored or financed by any pharmaceutical company, nor are there any conflicts of interest on the part of the authors.
Statistical Analyses
The sample calculation was at will. The reason for this pilot trial was to investigate areas of uncertainty regarding future definitive randomized clinical trials on the effects of thyroid hormone reduction with levothyroxine on proteinuria in patients with advanced chronic kidney disease based on eGFR and proteinuria. This was a small-scale study conducted to test the plan and method of a research study; this pilot study addresses treatment safety assessments, determination of dose levels and response, and estimation of the effect of treatment and its variance.
The methodology for a clinical trial of superiority was carried out. Parametric continuous variables are given as the mean and SD, and nonparametric continuous variables are reported as medians. Comparisons were made using the Student t test or the Mann−Whitney test. Categorical variables are presented as percentages and were compared using the χ2 test or Fisher exact test. The prespecified threshold for significance was a P value <0.05. All statistical analyses were performed using the statistical programs SPSS version 20 (SPSS IBM Corporation, Armonk, NY) and GraphPad 7 (GraphPad Software, San Diego, CA).
Results
From March to November 2018, a total of 163 patients attended the Renal Health Clinic and were considered for participation. Of the patients, 125 were excluded because 64 did not meet the inclusion criteria, 56 patients decided not to participate, and another 5 did not meet the other specifications. Only 38 patients provided consent to participate. Of these, 6 patients were lost during follow-up, leaving a total of 32 patients (77.2%) to be analyzed. Of those, 14 patients (43.75%) were randomized to the placebo group and 18 (56.25%) to the LVX group (Figure 1).Figure 1 Flowchart during the study period.
Baseline clinical and demographic characteristics are shown in Table 2. Both groups had similar characteristics with respect to sex, age, number of comorbidities, CKD grade, weight, albumin, eGFR, hemoglobin, systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid profile, and proteinuria, except for the statistically higher TSH, sCr and LDL levels in the LVX group. At baseline, the mean (SD) levels of LDL cholesterol were significantly lower in the placebo group than in the LVX group (75.5 ± 19 mg/dl and 102.38 ± 31-42 ng/dl, respectively, P = 0.01). The TSH levels in the placebo group were significantly lower than those in the LVX group (4.46 ± 1.68 μIU/ml and 5.93 ± 2.2 μIU/ml, respectively; P = 0.02). The sCr levels of the placebo group were significantly higher than those of the LVX group (3.05 SD ± 1.65 mg/dl and 2.46 SD ± 1.13 mg/dl, respectively, P = 0.05).Table 2 Demographic and clinical baseline characteristics
Baseline characteristics Placebo (n = 14) Levothyroxine (n = 18) All (N = 32) P value
Sex, n, % female 10 (71.42) 10 (55.55) 20 (62.5) NA
Age, yr, SD 63.85 ± 15 69.22 ± 8.7 66.87 ± 12.19 0.41
Diabetes mellitus 11 (78.57) 13 (72.22) 24 (75) 1.00
Hypertensionn 12 (85.71) 16 (88.88) 28 (87.5) 1.00
Weight, kg, SD 67.90 ± 13.83 67.01 ± 11.32 67.55 ± 12.13 0.88
Obesity (BMI >30 kg/m2) 1 (7.14) 3 (6.6) 4 (12.5) 0.61
CKD G3a (45–59 ml/min per 1.73 m2) 0 3 (16.6) 3 (9.37) 0.23
CKD G3b (30–44 ml/min per 1.73 m2), 2 (14.28) 4 (22.22) 6 (18.75) 0.67
CKD G4 (15–29 ml/min per 1.73 m2) 5 (35.71) 7 (38.88) 12 (37.5) 1.00
CKD G5 (<15 ml/min per /1.73 m2) 7 (50) 4 (22.22) 11 (34.37) 0.14
eGFR (ml/min per 1.73 m2) 18.14 ± 9.96 27.72 ± 13.38 23.55 ± 12.91 0.078
TSH, μIU/ml 4.46 ± 1.68 6.08 ± 2.18 5.37 ± 2.13 0.02
T4L, ng/dl 0.93 ± 0.12 0.99 ± 0.14 0.96 ± 0.13 0.65
Proteinuria grams/d urine collection 1.28 ± 1.28 1.71 ± 1.20 1.52 ± 1.12 0.14
sCr, mg/dl 3.65 ± 1.65 2.46 ± 1.13 2.98 ± 1.51 0.05
Albumin, mg/dl 3.99 ± 0.41 3.8 ± 0.41 3.88 ± 0.42 0.24
Triglycerides, mg/dl 194 ± 75.3 144.66 ± 91.76 172.5 ± 87.71 0.09
Cholesterol, mg/dl 170.57 ± 45.96 165.5 ± 59.67 167.71 ± 54.16 0.67
LDL, mg/dl 75.5 ± 19 102.38 ± 31.42 90.62 ± 29.86 0.01
Hemoglobin, g/dl 11.37 ± 1.21 11.95 ± 1.61 11.72 ± 1.48 0.17
SBP, mm Hg 148.14 ± 27.7 160 ± 19.4 154.81 ± 24.14 0.17
DBP, mm Hg 79 ± 11.72 81.83 ± 8.2 80.59 ± 10 0.60
ACEI or ARB 14 (100) 18 (100) 32 (100) 1.00
Allopurinol 14 (100) 18 (100) 32 (100) 1.00
Statin 14 (100) 18 (100) 32 (100) 1.00
ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensinogen receptor blockers; BMI, body mass index; DBP, diastolic blood pressure; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; G, grade; kg, kilograms; LDL, low-density cholesterol; NA, not available; SBP, systolic blood pressure; sCr, serum creatinine.
Data are n (%) or ±SD, unless otherwise noted.
The primary objective, measured at 3 months of randomization, is presented in Table 3 and Figure 2. A total of 32 patients were analyzed, 14 in the placebo group and 18 in the LVX group, whereas 6 were lost during follow-up. The mean (SD) proteinuria at 3 months in the LVX group was 0.89 ± 1.28 g/d, and in the placebo group 1.35 ± 0.85 g/d. When compared to placebo, LVX showed a significant decrease in proteinuria of 1.1 g/d (P = 0.0011).Table 3 Clinical and laboratory variable changes at the end of the study period (12 weeks), according to the placebo or levothyroxine group
Primary objective Placebo Levothyroxine P value
Proteinuria, g/d +0.2 (−0.4 to 2.1)
(1.35 ± 0.85) −1.1 (−4.1 to 0.9)
(0.89 ± 1.28) 0.0011
Secondary objectives
Changes in eGFR, ml/min per 1.73 m2 −1.96 (−5 to 3)
(16.18 ± 8.37) 4.04 (9.8 to −2)
(31.76 ± 11.9) 0.049
sCr, mg/dl 0.05 (−0.5 to 1.49)
(3.71 ± 1.55) −0.2 (−0.7 to 0.5)
(2.36 ± 1.27) 0.32
Cholesterol, mg/dl −28.46 (107 to 26)
(142.11 ± 44.05) −18 (−57 to 37)
(147.5 ± 30.8) 0.18
Triglycerides, mg/dl −21(−94 to 108)
(173.2 ± 51.46) −14.6 (−286 to 66)
(130 ± 41.79) 0.71
SBP, mm Hg −2.5 (−57 to 35)
(145.64 ± 18.58) −5.5 (−75 to 57)
(154.5 ± 26.38) 0.33
DBP, mm Hg −6.43 (−17 to 14)
(72.57 ± 9.78) −9.06 (−20 to 10)
(72.77 ± 11.51) 0.33
TSH, μIU/ml −0.4 (−3.09 to 1.87)
(3.97 ± 1.77) −3.2 (−6.8 to 1.6)
(3.2 ± 1.5) 0.0032
T4L, ng/dl −0.1 (−0.18 to 0.12)
0.92 ± 0.24 0.05 (−0.38 to 0.4)
1.04 ± 0.21 0.77
Weight, kg 1.63 (−3.5 to 5.5)
(68.96 ± 14.65) −1.05 (−3.5 to 2.1)
(65.86 ± 11.65) 0.20
DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure; sCr, serum creatinine; TSH, thyroid-stimulating hormone.
Figure 2 Proteinuria (in grams per day) at the end of the study period (12 weeks) in the placebo and levothyroxine groups.
The comparative secondary objectives are presented in Table 3 and Figure 3. For the eGFR, the LVX group showed an improvement of 4.04 ml/min per 1.73 m2 (P = 0.049); in the placebo group, there was a decrease of 1.96 ml/min per 1.73 m2. The placebo group showed a decrease in TSH of 0.4 μIU/ml, and the LVX group showed a decrease in TSH of 3.2 μIU/ml (P = 0.0032). When comparing the weight reduction, the LVX arm showed a reduction in weight of −1.05 ± 3.72 kg, whereas the placebo group showed an increase in weight of 1.63 SD ± 5.59 kg (P = 0.20). For sCr, cholesterol, triglycerides, LDL, SBP, and DBP, there were no differences between the groups at 3 months (Figure 3). Adverse effects are shown in Table 4. Urinary tract infection presented in 1 patient in the placebo group (7.14%) and nervousness in 2 patients in the LVX group (11.11%) (relative risk 1.55 95% confidence interval 0.15-15.47, P = 1.0). No patients left the study because of adverse effects. Adverse events were not severe according to the severity scale.Figure 3 Clinical and laboratory variable changes at the end of the study period (12 weeks), according to placebo or levothyroxine group. (a) Serum thyroid-stimulating hormone (TSH); (b) serum FT4; (c) serum creatinine (sCr); (d) estimated glomerular filtration rate (eGFR); (e) serum cholesterol; (f) serum triglycerides; (g) systolic blood pressure (SBP); (h) diastolic blood pressure (DBP); (i) Weight loss (in kilograms). CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.
Table 4 Adverse events during the study period
Group n (%) Outcome
LVX group 1 (7.14) Urinary tract infectiona
Placebo group 2 (11.11) Anxietyb
CI, confidence interval; LVX, levothyroxine; RR, relative risk.
RR = 1.55, 95% CI 0.15–15.47, P = 1.0.
a Urinary tract infection: duration of 5 days, without complications.
b Anxiety: duration of 3 days, without complications.
Discussion
This pilot randomized, single-center, double-blind study in patients with advanced proteinuric CKD demonstrated that administering LVX to obtain a normal TSH range decreased proteinuria and improved eGFR, with few adverse events.
The management of proteinuria in CKD is mainly due to the effects of blocking the renin−angiotensin−aldosterone system (RAAS), such as with ACEIs and ARBs,35,36 and other drugs to a lesser magnitude, such as allopurinol,55 aldosterone antagonists,37, 38, 39, 40 statins,41,42 and calcitriol44, 45, 46, 47; however, despite these treatments, there is still residual proteinuria that contributes to the deterioration of renal function and cardiovascular risk.2 Proteinuria in hypothyroid human beings and rats has been related to RAAS activity,9 blood pressure, and oxidative stress, although it may be a reflection of glomerular hypertension and decreased glomerular filtration rate,5 changes in the management of tubular proteins, or changes in the structure of the glomerular barrier, specifically at the podocyte and megalin.8,9 In our study, the significant decrease in proteinuria of 1.1 g/d in the LVX group could be explained by the normalization of the TSH range. In addition, the antiproteinuric benefit observed with LVX could be explained by the alteration of glomerular pressure due to the negative inotropic effect on the heart, reduction in the circulating intravascular volume, and increase in peripheral resistance, with renal vasoconstriction adding a counterregulatory effect of RAAS, as well as changes at the level of the glomerular, tubular, and podocyte basal membrane.5,10 Higher baseline ranges were observed for TSH, LDL, and sCr in the LVX group, which could explain why the higher the TSH, the greater the effect on proteinuria.14,50,51 It is very important to consider the administration of LVX in patients with CKD and alterations in TSH for a greater benefit in decreasing proteinuria, thus adding the correlation that thyroid hormone in endothelial damage and in cardiovascular risk could also decrease mortality and decrease eGFR.14,19,50,52
In our study, eGFR increased in the LVX group by 4 ml/min per 1.73 m2, compared to that in the placebo group, in which eGFR decreased by 2 ml/min per 1.73 m2. Van Welsem et al.9 reported that the normalization of hypothyroidism after treatment with LVX led to a significant improvement in renal function in a patient with CKD.5 In addition, Shin et al. demonstrated that reaching a TSH goal of 1 to 4.5 μIU/ml with LVX at a dose of 25 to 50 μg/d improved the eGFR +4.31 ± 0.5 ml/min per 1.73 m2.51 Chang et al. used a TSH goal of 1.16-2.86 μIU/ml with a dose of LVX 25 μg/d and obtained an improvement in eGFR +5.77 ml/min per 1.73 m2 (P = 0.015).14
Although previous studies have shown that LVX improves cardiac function, renal function, and dyslipidemia and delays progression of CKD that is already established in patients with SCH, there is still a lack of consensus in the current guidelines on whether to treat SCH in patients with CKD. In particular, little is known about the effect of thyroid hormone replacement on changes in eGFR.21, 22, 23, 24 Some studies exist comparing CKD and thyroid disorders in which normal TSH ranges were maintained and an improvement in the progression of CKD, decreased proteinuria,5,9,13,17 improved lipid profile,37 and lower cardiovascular risk were observed.20 Rhee et al. found, in more than 220,000 patients, that at TSH levels >3 μIU/ml and TSH <0.5 μIU/ml, there is a higher mortality rate in patients with CKD G3.19
There are already studies in which the elevation of TSH is associated with the progression of CKD.14,15 In patients already undergoing renal replacement therapy, such as hemodialysis with elevated TSH, it was associated with mortality,21, 22, 23 similar to peritoneal dialysis.24
We sought to reinforce these benefits of maintaining a range of TSH (<4.5 μIU/ml, considering previous studies in which mortality was associated with TSH >2.5 μIU/ml).19,29 In addition, some authors have reported a greater progression to terminal CKD and mortality in patients with SCH versus euthyroid hypothyroidism.19,20 The American25 and European guidelines27 do not mention the potential benefit of the use of LVX and its impact in patients with CKD and SCH.
Another possibility of improving proteinuria and eGFR is that by decreasing TSH, an increase in catabolism and weight reduction was achieved, eliminating hyperfiltration and proteinuria. It should be mentioned that at the beginning of the study, only 4 patients had a BMI >30 kg/m2, 1 patient from the placebo group and 3 patients from the LVX group (P = 0.61), and the differences in weight loss (in kilograms) at the end of the study were higher in the LVX group than in the placebo group, with an average of −1.05 SD ± 3.72 kg and 1.63 SD ± 5.59 kg, respectively, but the differences were not significant (P = 0.20). Among the other variables relevant to this study, there were no significant changes in BP or HR.
Regarding tolerance, the use of LVX was safe, there were no severe adverse events, and no patient had to discontinue the study drug. However, more patients in the LVX dose adjustment were required (relative risk = 1.55, 95% confidence interval = 0.15−15.47, P = 1.0). In previous studies, no serious adverse effects have been reported when giving LVX to patients with CKD, considering that they are patients with cardiovascular risk.25,26 This information can be interpreted as showing that LVX is a useful treatment in hypothyroidism and that the risk is minimal.28,29
Several limitations need to be acknowledged. This paper presents the results of a small, single-center, randomized controlled pilot clinical trial. As such, estimates of treatment effects may be overoptimistic and/or unique to the population studied. The main analyses did not impute missing data, which, in both the placebo and LVX groups, were assumed to be missing at random. Other limitations of our study include the racial homogeneity of the study population and the short treatment duration (12 weeks). The sustainability of these effects over a longer time period needs to be confirmed in longer-term studies. However, the results demonstrate that the study intervention is feasible and has promising effects on multiple measures of renal function. Another limitation is that TSH levels were different at the time of randomization, although we believe that this had no impact on the final result, as both groups were in ranges of abnormality. Furthermore, there is no objective evidence to suggest that the study population is unique. However, as with all pilot projects, our findings remain exploratory and hypothesis generating.
In conclusion, this single-center, randomized, double-blind, placebo-controlled pilot clinical study in patients with advanced proteinuric CKD who already used ACEIs or ARBs demonstrated that administering LVX to obtain a TSH range close to 2.5 μIU/ml decreased proteinuria and improved eGFR. These findings could encourage the performance of a clinical trial with sufficient statistical power to demonstrate the benefit of normalizing TSH with LVX in patients with CKD.
Disclosure
All the authors declared no competing interests.
Supplementary Material
Supplementary File (Word)
Table S1. Drugs that interact with levothyroxine.
Acknowledgments
Clinical trial registration number: NCT03898622.
Supplementary File (Word)
Table S1. Drugs that interact with levothyroxine. | LEVOTHYROXINE SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33426390 | 18,754,150 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Escherichia urinary tract infection'. | A Pilot Trial on the Effect of Levothyroxine on Proteinuria in Patients With Advanced CKD.
Thyroid hormones can directly affect kidney function; elevated levels of thyroid-stimulating hormone (TSH) and chronic kidney disease (CKD) are associated with proteinuria, decreased estimated glomerular filtration rate (eGFR), and progression to end-stage renal disease. Our hypothesis is that in patients with CKD and TSH at levels considered to be in the low subclinical hypothyroidism (SCH) range, lowering TSH with levothyroxine (LVX) improves the clinical parameters of renal function.
This was a double-blind, randomized, pilot clinical trial in patients with proteinuric CKD (eGFR <60 ml/min per 1.73 m2 and proteinuria >150 mg/d) performed at the Hospital Civil de Guadalajara, with the intention of lowering TSH (levels of 1.25-2.5 μIU/l) in patients with TSH (levels of 2.6-9.9 μIU/ml with FT4 in the range of 0.7-1.8 ng/dl). Patients were randomized 1:1 to receive LVX or placebo for 12 weeks. The primary objective was to evaluate absolute levels of proteinuria at the beginning compared to the end of the study and, as a secondary objective, the changes in serum creatinine (sCr), eGFR, cholesterol, triglycerides, low-density lipoprotein (LDL), and blood pressure, and to assess the tolerability and safety of LVX.
Between March and November 2018, a total of 163 patients were assessed for eligibility; 119 patients did not meet the inclusion criteria or were excluded, and 32 patients were randomized. The demographic and clinical characteristics of the 2 study groups were essentially not different. Subjects were 66.87 (SD 12.19) years of age, 62.5% were female, 75% were diabetes mellitus, eGFR was 23.55 (±12.91) ml/min per 1.73 m2, TSH was 5.37 ± 2.13 μIU/ml, proteinuria in 24-hour urine collection was 1.52 ± 1.12, and all of them were taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs). Proteinuria at 12 weeks in the LVX group was 0.89 SD ± 1.28 g/d, and in the placebo group it was 1.35 SD ± 0.85 g/d; when compared to placebo, LVX showed a significant decrease in proteinuria of 1.1 g/d (P = 0.0011). The eGFR in the LVX group showed an improvement of 4 ml/min/1.73 m2 (P = 0.049); in the placebo group, there was a decrease of 1.98 ml/min per 1.73 m2. The sCr, cholesterol, triglycerides, low-density lipoprotein, systolic blood pressure, and diastolic blood pressure were not different between groups. Adverse events were reported in the LVX group in 7.14% of patients and in 11.11% of patients in the placebo group; none left the study because of adverse effects, and there were no serious adverse events.
This single-center, randomized, double-blind, placebo-controlled pilot clinical trial in patients with advanced proteinuric CKD who already used ACEIs or ARBs demonstrated that administering LVX to obtain a TSH range close to 2.5 μIU/ml decreased proteinuria and improved eGFR. Future research is needed to confirm our results and to determine whether our findings generalize to patient groups not explicitly enrolled in this small pilot trial.
Chronic noncommunicable diseases such as obesity, diabetes mellitus, hypertension, and chronic kidney disease (CKD) have become a major public health problem in the Mexican population.1,2 Between 1990 and 2013, the CKD burden rapidly climbed, with age-standardized years of life lost (YLL) and disability-adjusted life-year (DALY) rates increasing more than 130%, the second highest DALY due to CKD in the world.3 The incidence of end-stage renal disease has increased dramatically in parallel with these risk factors.4
Thyroid hormones can directly affect kidney function, and impaired renal function can also contribute to thyroid disorders.5, 6, 7, 8, 9 The prevalence of primary overt, subclinical hypothyroidism (SCH) and low T3 syndrome increases with the progression of CKD.10,11
The prevalence of SCH in patients with an estimated glomerular filtration rate (eGFR) >60 ml/min per 1.73 m2 is 7% and is up to 17.9% in those with an eGFR <60 ml/min per 1.73 m2.11 Thyroid hormone affects the kidney by multiple mechanisms; local hemodynamic changes, decreased renal blood flow, decreased cardiac output, circulating volume, and decreased atrial natriuretic factor contribute to a decrease in renal perfusion with a concomitant reduction in eGFR,5, 6, 7,11, 12, 13 affecting the renin−angiotensin−aldosterone system, glomerular basement membrane, and renal tubular function, and leading to the development of proteinuria through direct effects on megalin and podocytes.8,9
The frequency of proteinuria in patients with normal thyroid function (euthyroid), SCH, and hypothyroidism is 1.29%, 2.2%, and 2.97%, respectively.14 In addition, it has been reported that the progression to end-stage renal disease is more accelerated in patients with SCH than in euthyroid patients,14,15, 16, 17, 18 and there is evidence that high (>3 μIU/ml) and low (<0.5 μIU/ml) thyroid-stimulating hormone (TSH) are associated with higher mortality rates in patients with CKD.19 There is also an association of mortality in patients with CKD and thyroid functional disease due to increased cardiovascular risk,20 particularly in patients on hemodialysis,21, 22, 23 as well as peritoneal dialysis24 and thyroid function disease.
The American Thyroid Guidelines, the American Association of Endocrinology,25 and European Guidelines and Clinical Practice Guidelines26 recommend beginning LVX doses of 0.25 μg and not going above 0.50 μg in patients with high cardiovascular risk,27,28 as patients with CKD have been considered.29
Levothyroxine is usually well tolerated in the general population at standard doses (1.6-18.8 μg/kg). In patients with SCH, overdose symptoms were reported in 10% to 21% of cases, and a Cochrane meta-analysis of thyroid hormone replacement for SCH found no significant adverse events.30
However, many patients with CKD will experience renal progression, despite antiproteinuric treatment.31,32 These observations led to the examination of alternative pathways to delay CKD, with disappointing results so far. The most commonly used antiproteinuric33,34 drugs are angiotensin-converting enzyme inhibitors,35 angiotensin receptor blockers,36 aldosterone antagonists, 37, 38, 39, 40 and, although they are less effective, statins,41,42 allopurinol,43 and vitamin D activators.43, 44, 45, 46, 47, 48
Treatment of SCH with LVX in the general population improves the lipid profile and cardiac function,49, 50, 51 and patients with CKD show improvement in eGFR and serum creatinine (sCr),14,51 but there are no clinical trials in this field in patients with CKD.
Our hypothesis is that in patients with CKD and TSH at levels considered to be in the SCH range, the normalization of TSH with LVX improves the clinical parameters of renal function.
Materials and Methods
We conducted a pilot randomized, single-center, double-blind, placebo-controlled, parallel group, dose-adjusting trial of levothyroxine (LVX) 25 μg administered orally once daily to patients with proteinuric CKD conducted at the Hospital Civil de Guadalajara from March 2018 to 31 January 2019. The study objectives were to evaluate the efficacy and safety of normalizing TSH levels with LVX and to explore the clinical effect of LVX compared with placebo.
The measurement of TSH and FT4 was carried out with the UniCel DxI 800 (Beckman Coulter Inc., Indianapolis, IN) access Immunoassay system by chemiluminescence, with the serum FT4 (assay type 2-step competitive) reportable range of 0.25 to 6 ng/dl (3-2-77.2 pmol/l), analytical sensitivity 0.25 ng/dl (3.2 pmol/l), and serum TSH (assay type 1-step sandwich) reportable range of 0.03 to 100 μIU/ml, which incorporates functionality for the lower limit of detection, analytical sensitivity 0.01 μIU/ml, and 0.03 uIU/ml functional, and all samples were analyzed in a single laboratory.
Patients with CKD (eGFR <60 ml/min per 1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) were eligible if they were >18 years of age or if they had proteinuria >150 mg/24 h. With TSH levels between 2.5 and 10.0 μIU/ml, we chose TSH >2.5 μIU/ml, as there is evidence that there was an association of a decrease in eGFR10,52 with proteinuria,10 and TSH <10.0 μIU/ml excludes clinical hypothyroidism. All patients treated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and without renal replacement therapy who attended the Renal Health Clinic were considered for participation in this pilot clinical trial.
We excluded patients with the following: primary hypothyroidism or preexisting thyroid disease; previous ischemic heart disease within a period of <6 months; arrhythmia; pregnancy; use of drugs that interact with the synthesis of thyroid hormones (Supplementary Table S1); those who did not provide informed consent; those with a serum TSH level <2.5 μIU/ml or >10 μIU/ml; those with a free serum T4 value between 0.6 and 1.8 ng/dl; those with positive anti-thyroid antibodies; and patients weighing <50 kg or >90 kg, because within this weight, all patients will maintain a dosage of 0.3−0.5 μg/kg per day, so it will be easy to prescribe the LVX dose with a narrow error window.
Approval was obtained from the participating site’s Research and Ethics Committee (Hospital CG 034/18 March 2018). Patients provided written informed consent before enrollment in accordance with local and national laws. Conduct and reporting are consistent with the 2010 Consolidated Standards of Reporting Trials (CONSORT) extension for pilot trials.53 The trial was registered in the Clinical Trials Registry (NCT03898622).
Measures of renal function included the eGFR calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation.54 Proteinuria was measured by means of 24-hour urine collection, expressed in grams per day, at the beginning and end of the study. Serum creatinine, serum electrolytes, hemoglobin, albumin, cholesterol, TSH, FT4, and triglycerides were measured at the beginning of the study and every 4 weeks for 4 months.
Using a Web-based randomization system, we randomly assigned participants in a 1:1 ratio. Standard care was defined pragmatically; in both the study intervention and the standard care group, the nephrologist determined all aspects of clinical care, based on standard practice and individual patient needs, independent of the study intervention.
The study consisted of 3 phases. The first phase, with a duration of 8 to 12 weeks, consisted of enrolling patients and collecting demographic and clinical baseline measurements (proteinuria, lipid profile, serum electrolytes, arterial pressure, weight, TSH level, hemoglobin, and serum albumin). The second phase consisted of both groups being treated according to the allocation arm, and the third phase consisted of comparing the variables studied and the data analysis. The dose of LVX has previously been shown to be safe and efficient in adult patients with CKD.14,51
Our primary objective was to evaluate the effect of lowering TSH with the use of LVX or placebo to assess absolute levels at the beginning compared to the end of the study, when proteinuria was measured in urine collected for 24 hours. The secondary objectives were to evaluate the changes in sCr and eGFR and to assess the tolerability and safety of LVX and changes in cholesterol, triglycerides, LDL and blood pressure.
Interventions
The treating nephrologist and the patients were blinded to the study intervention.
If randomized to the intervention arm, the intervention consisted of treatment with oral levothyroxine (LVX) between 0.25 and 0.50 μg according to a dose of 0.3 to 0.5 μg/kg per day during fasting (in the case of taking a drug that interacts with the absorption, use of it was changed according to the hours specified). The dose adjustment was every 4 weeks. Levothyroxine or placebo was adjusted to 25 or 50 μg according to TSH levels (Table 1).Table 1 Dose adjustment of levothyroxine
TSH range Dose adjustment
TSH < 0.5 μIU/ml Suspend the pill
TSH (0.5–1 μIU/ml) Suspend the pill if it is at minimum dose
TSH (1.2–2.4 μIU/ml) Suspend the pill if it is at minimum dose
TSH (2.5–4.3 μIU/ml) Dose 25 μg/d
TSH (4.4–6.1 μIU/ml) Keep dose if 50 μg/d or increase if taking 25 μg/d
TSH (6.2–8 μIU/ml) Keep dose if 50 μg/d or increase if taking 25 μg/d
TSH (8.1–9.9 μIU/ml) Keep dose if 50 μg/d or increase if taking 25 μg/d
TSH, thyroid-stimulating hormone.
All vials (placebo or levothyroxine) presented drugs in one-quarter tablet = 25 μg the first month. In addition, the following months were adjusted according to the TSH range.
Participants allocated to placebo took 1 pill per day, with the same bottle characteristics as patients in the intervention arm, for >12 weeks.
The preparation and packaging of LVX and placebo were carried out by a pharmacist who was not involved in the development of the present study. All patients were followed up every 4 weeks for usual renal health consultation. In addition, the specific aspects of the protocol consisted of monitoring thyroid function for the adjustment of LVX or placebo dose according to the previous dosage adjustment.
To ascertain compliance and adherence to treatment, a record sheet was created with all drug supplied and returned. During the course of the study, the investigator was responsible for providing additional instructions to retrain any subjects who did not comply with the administration of the study drug or with attendance at the required clinical visits.
Adverse events were recorded during the follow-up, which included thyroid profile control tests every 4 weeks. Previously specified adverse effects were reported and followed up, and were rated in intensity according to the Common Terminology Criteria for Adverse Events (CTC) v. 3.0 (1–5), along with the start date and end date, as well as the treatment received.
This protocol was not sponsored or financed by any pharmaceutical company, nor are there any conflicts of interest on the part of the authors.
Statistical Analyses
The sample calculation was at will. The reason for this pilot trial was to investigate areas of uncertainty regarding future definitive randomized clinical trials on the effects of thyroid hormone reduction with levothyroxine on proteinuria in patients with advanced chronic kidney disease based on eGFR and proteinuria. This was a small-scale study conducted to test the plan and method of a research study; this pilot study addresses treatment safety assessments, determination of dose levels and response, and estimation of the effect of treatment and its variance.
The methodology for a clinical trial of superiority was carried out. Parametric continuous variables are given as the mean and SD, and nonparametric continuous variables are reported as medians. Comparisons were made using the Student t test or the Mann−Whitney test. Categorical variables are presented as percentages and were compared using the χ2 test or Fisher exact test. The prespecified threshold for significance was a P value <0.05. All statistical analyses were performed using the statistical programs SPSS version 20 (SPSS IBM Corporation, Armonk, NY) and GraphPad 7 (GraphPad Software, San Diego, CA).
Results
From March to November 2018, a total of 163 patients attended the Renal Health Clinic and were considered for participation. Of the patients, 125 were excluded because 64 did not meet the inclusion criteria, 56 patients decided not to participate, and another 5 did not meet the other specifications. Only 38 patients provided consent to participate. Of these, 6 patients were lost during follow-up, leaving a total of 32 patients (77.2%) to be analyzed. Of those, 14 patients (43.75%) were randomized to the placebo group and 18 (56.25%) to the LVX group (Figure 1).Figure 1 Flowchart during the study period.
Baseline clinical and demographic characteristics are shown in Table 2. Both groups had similar characteristics with respect to sex, age, number of comorbidities, CKD grade, weight, albumin, eGFR, hemoglobin, systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid profile, and proteinuria, except for the statistically higher TSH, sCr and LDL levels in the LVX group. At baseline, the mean (SD) levels of LDL cholesterol were significantly lower in the placebo group than in the LVX group (75.5 ± 19 mg/dl and 102.38 ± 31-42 ng/dl, respectively, P = 0.01). The TSH levels in the placebo group were significantly lower than those in the LVX group (4.46 ± 1.68 μIU/ml and 5.93 ± 2.2 μIU/ml, respectively; P = 0.02). The sCr levels of the placebo group were significantly higher than those of the LVX group (3.05 SD ± 1.65 mg/dl and 2.46 SD ± 1.13 mg/dl, respectively, P = 0.05).Table 2 Demographic and clinical baseline characteristics
Baseline characteristics Placebo (n = 14) Levothyroxine (n = 18) All (N = 32) P value
Sex, n, % female 10 (71.42) 10 (55.55) 20 (62.5) NA
Age, yr, SD 63.85 ± 15 69.22 ± 8.7 66.87 ± 12.19 0.41
Diabetes mellitus 11 (78.57) 13 (72.22) 24 (75) 1.00
Hypertensionn 12 (85.71) 16 (88.88) 28 (87.5) 1.00
Weight, kg, SD 67.90 ± 13.83 67.01 ± 11.32 67.55 ± 12.13 0.88
Obesity (BMI >30 kg/m2) 1 (7.14) 3 (6.6) 4 (12.5) 0.61
CKD G3a (45–59 ml/min per 1.73 m2) 0 3 (16.6) 3 (9.37) 0.23
CKD G3b (30–44 ml/min per 1.73 m2), 2 (14.28) 4 (22.22) 6 (18.75) 0.67
CKD G4 (15–29 ml/min per 1.73 m2) 5 (35.71) 7 (38.88) 12 (37.5) 1.00
CKD G5 (<15 ml/min per /1.73 m2) 7 (50) 4 (22.22) 11 (34.37) 0.14
eGFR (ml/min per 1.73 m2) 18.14 ± 9.96 27.72 ± 13.38 23.55 ± 12.91 0.078
TSH, μIU/ml 4.46 ± 1.68 6.08 ± 2.18 5.37 ± 2.13 0.02
T4L, ng/dl 0.93 ± 0.12 0.99 ± 0.14 0.96 ± 0.13 0.65
Proteinuria grams/d urine collection 1.28 ± 1.28 1.71 ± 1.20 1.52 ± 1.12 0.14
sCr, mg/dl 3.65 ± 1.65 2.46 ± 1.13 2.98 ± 1.51 0.05
Albumin, mg/dl 3.99 ± 0.41 3.8 ± 0.41 3.88 ± 0.42 0.24
Triglycerides, mg/dl 194 ± 75.3 144.66 ± 91.76 172.5 ± 87.71 0.09
Cholesterol, mg/dl 170.57 ± 45.96 165.5 ± 59.67 167.71 ± 54.16 0.67
LDL, mg/dl 75.5 ± 19 102.38 ± 31.42 90.62 ± 29.86 0.01
Hemoglobin, g/dl 11.37 ± 1.21 11.95 ± 1.61 11.72 ± 1.48 0.17
SBP, mm Hg 148.14 ± 27.7 160 ± 19.4 154.81 ± 24.14 0.17
DBP, mm Hg 79 ± 11.72 81.83 ± 8.2 80.59 ± 10 0.60
ACEI or ARB 14 (100) 18 (100) 32 (100) 1.00
Allopurinol 14 (100) 18 (100) 32 (100) 1.00
Statin 14 (100) 18 (100) 32 (100) 1.00
ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensinogen receptor blockers; BMI, body mass index; DBP, diastolic blood pressure; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; G, grade; kg, kilograms; LDL, low-density cholesterol; NA, not available; SBP, systolic blood pressure; sCr, serum creatinine.
Data are n (%) or ±SD, unless otherwise noted.
The primary objective, measured at 3 months of randomization, is presented in Table 3 and Figure 2. A total of 32 patients were analyzed, 14 in the placebo group and 18 in the LVX group, whereas 6 were lost during follow-up. The mean (SD) proteinuria at 3 months in the LVX group was 0.89 ± 1.28 g/d, and in the placebo group 1.35 ± 0.85 g/d. When compared to placebo, LVX showed a significant decrease in proteinuria of 1.1 g/d (P = 0.0011).Table 3 Clinical and laboratory variable changes at the end of the study period (12 weeks), according to the placebo or levothyroxine group
Primary objective Placebo Levothyroxine P value
Proteinuria, g/d +0.2 (−0.4 to 2.1)
(1.35 ± 0.85) −1.1 (−4.1 to 0.9)
(0.89 ± 1.28) 0.0011
Secondary objectives
Changes in eGFR, ml/min per 1.73 m2 −1.96 (−5 to 3)
(16.18 ± 8.37) 4.04 (9.8 to −2)
(31.76 ± 11.9) 0.049
sCr, mg/dl 0.05 (−0.5 to 1.49)
(3.71 ± 1.55) −0.2 (−0.7 to 0.5)
(2.36 ± 1.27) 0.32
Cholesterol, mg/dl −28.46 (107 to 26)
(142.11 ± 44.05) −18 (−57 to 37)
(147.5 ± 30.8) 0.18
Triglycerides, mg/dl −21(−94 to 108)
(173.2 ± 51.46) −14.6 (−286 to 66)
(130 ± 41.79) 0.71
SBP, mm Hg −2.5 (−57 to 35)
(145.64 ± 18.58) −5.5 (−75 to 57)
(154.5 ± 26.38) 0.33
DBP, mm Hg −6.43 (−17 to 14)
(72.57 ± 9.78) −9.06 (−20 to 10)
(72.77 ± 11.51) 0.33
TSH, μIU/ml −0.4 (−3.09 to 1.87)
(3.97 ± 1.77) −3.2 (−6.8 to 1.6)
(3.2 ± 1.5) 0.0032
T4L, ng/dl −0.1 (−0.18 to 0.12)
0.92 ± 0.24 0.05 (−0.38 to 0.4)
1.04 ± 0.21 0.77
Weight, kg 1.63 (−3.5 to 5.5)
(68.96 ± 14.65) −1.05 (−3.5 to 2.1)
(65.86 ± 11.65) 0.20
DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure; sCr, serum creatinine; TSH, thyroid-stimulating hormone.
Figure 2 Proteinuria (in grams per day) at the end of the study period (12 weeks) in the placebo and levothyroxine groups.
The comparative secondary objectives are presented in Table 3 and Figure 3. For the eGFR, the LVX group showed an improvement of 4.04 ml/min per 1.73 m2 (P = 0.049); in the placebo group, there was a decrease of 1.96 ml/min per 1.73 m2. The placebo group showed a decrease in TSH of 0.4 μIU/ml, and the LVX group showed a decrease in TSH of 3.2 μIU/ml (P = 0.0032). When comparing the weight reduction, the LVX arm showed a reduction in weight of −1.05 ± 3.72 kg, whereas the placebo group showed an increase in weight of 1.63 SD ± 5.59 kg (P = 0.20). For sCr, cholesterol, triglycerides, LDL, SBP, and DBP, there were no differences between the groups at 3 months (Figure 3). Adverse effects are shown in Table 4. Urinary tract infection presented in 1 patient in the placebo group (7.14%) and nervousness in 2 patients in the LVX group (11.11%) (relative risk 1.55 95% confidence interval 0.15-15.47, P = 1.0). No patients left the study because of adverse effects. Adverse events were not severe according to the severity scale.Figure 3 Clinical and laboratory variable changes at the end of the study period (12 weeks), according to placebo or levothyroxine group. (a) Serum thyroid-stimulating hormone (TSH); (b) serum FT4; (c) serum creatinine (sCr); (d) estimated glomerular filtration rate (eGFR); (e) serum cholesterol; (f) serum triglycerides; (g) systolic blood pressure (SBP); (h) diastolic blood pressure (DBP); (i) Weight loss (in kilograms). CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.
Table 4 Adverse events during the study period
Group n (%) Outcome
LVX group 1 (7.14) Urinary tract infectiona
Placebo group 2 (11.11) Anxietyb
CI, confidence interval; LVX, levothyroxine; RR, relative risk.
RR = 1.55, 95% CI 0.15–15.47, P = 1.0.
a Urinary tract infection: duration of 5 days, without complications.
b Anxiety: duration of 3 days, without complications.
Discussion
This pilot randomized, single-center, double-blind study in patients with advanced proteinuric CKD demonstrated that administering LVX to obtain a normal TSH range decreased proteinuria and improved eGFR, with few adverse events.
The management of proteinuria in CKD is mainly due to the effects of blocking the renin−angiotensin−aldosterone system (RAAS), such as with ACEIs and ARBs,35,36 and other drugs to a lesser magnitude, such as allopurinol,55 aldosterone antagonists,37, 38, 39, 40 statins,41,42 and calcitriol44, 45, 46, 47; however, despite these treatments, there is still residual proteinuria that contributes to the deterioration of renal function and cardiovascular risk.2 Proteinuria in hypothyroid human beings and rats has been related to RAAS activity,9 blood pressure, and oxidative stress, although it may be a reflection of glomerular hypertension and decreased glomerular filtration rate,5 changes in the management of tubular proteins, or changes in the structure of the glomerular barrier, specifically at the podocyte and megalin.8,9 In our study, the significant decrease in proteinuria of 1.1 g/d in the LVX group could be explained by the normalization of the TSH range. In addition, the antiproteinuric benefit observed with LVX could be explained by the alteration of glomerular pressure due to the negative inotropic effect on the heart, reduction in the circulating intravascular volume, and increase in peripheral resistance, with renal vasoconstriction adding a counterregulatory effect of RAAS, as well as changes at the level of the glomerular, tubular, and podocyte basal membrane.5,10 Higher baseline ranges were observed for TSH, LDL, and sCr in the LVX group, which could explain why the higher the TSH, the greater the effect on proteinuria.14,50,51 It is very important to consider the administration of LVX in patients with CKD and alterations in TSH for a greater benefit in decreasing proteinuria, thus adding the correlation that thyroid hormone in endothelial damage and in cardiovascular risk could also decrease mortality and decrease eGFR.14,19,50,52
In our study, eGFR increased in the LVX group by 4 ml/min per 1.73 m2, compared to that in the placebo group, in which eGFR decreased by 2 ml/min per 1.73 m2. Van Welsem et al.9 reported that the normalization of hypothyroidism after treatment with LVX led to a significant improvement in renal function in a patient with CKD.5 In addition, Shin et al. demonstrated that reaching a TSH goal of 1 to 4.5 μIU/ml with LVX at a dose of 25 to 50 μg/d improved the eGFR +4.31 ± 0.5 ml/min per 1.73 m2.51 Chang et al. used a TSH goal of 1.16-2.86 μIU/ml with a dose of LVX 25 μg/d and obtained an improvement in eGFR +5.77 ml/min per 1.73 m2 (P = 0.015).14
Although previous studies have shown that LVX improves cardiac function, renal function, and dyslipidemia and delays progression of CKD that is already established in patients with SCH, there is still a lack of consensus in the current guidelines on whether to treat SCH in patients with CKD. In particular, little is known about the effect of thyroid hormone replacement on changes in eGFR.21, 22, 23, 24 Some studies exist comparing CKD and thyroid disorders in which normal TSH ranges were maintained and an improvement in the progression of CKD, decreased proteinuria,5,9,13,17 improved lipid profile,37 and lower cardiovascular risk were observed.20 Rhee et al. found, in more than 220,000 patients, that at TSH levels >3 μIU/ml and TSH <0.5 μIU/ml, there is a higher mortality rate in patients with CKD G3.19
There are already studies in which the elevation of TSH is associated with the progression of CKD.14,15 In patients already undergoing renal replacement therapy, such as hemodialysis with elevated TSH, it was associated with mortality,21, 22, 23 similar to peritoneal dialysis.24
We sought to reinforce these benefits of maintaining a range of TSH (<4.5 μIU/ml, considering previous studies in which mortality was associated with TSH >2.5 μIU/ml).19,29 In addition, some authors have reported a greater progression to terminal CKD and mortality in patients with SCH versus euthyroid hypothyroidism.19,20 The American25 and European guidelines27 do not mention the potential benefit of the use of LVX and its impact in patients with CKD and SCH.
Another possibility of improving proteinuria and eGFR is that by decreasing TSH, an increase in catabolism and weight reduction was achieved, eliminating hyperfiltration and proteinuria. It should be mentioned that at the beginning of the study, only 4 patients had a BMI >30 kg/m2, 1 patient from the placebo group and 3 patients from the LVX group (P = 0.61), and the differences in weight loss (in kilograms) at the end of the study were higher in the LVX group than in the placebo group, with an average of −1.05 SD ± 3.72 kg and 1.63 SD ± 5.59 kg, respectively, but the differences were not significant (P = 0.20). Among the other variables relevant to this study, there were no significant changes in BP or HR.
Regarding tolerance, the use of LVX was safe, there were no severe adverse events, and no patient had to discontinue the study drug. However, more patients in the LVX dose adjustment were required (relative risk = 1.55, 95% confidence interval = 0.15−15.47, P = 1.0). In previous studies, no serious adverse effects have been reported when giving LVX to patients with CKD, considering that they are patients with cardiovascular risk.25,26 This information can be interpreted as showing that LVX is a useful treatment in hypothyroidism and that the risk is minimal.28,29
Several limitations need to be acknowledged. This paper presents the results of a small, single-center, randomized controlled pilot clinical trial. As such, estimates of treatment effects may be overoptimistic and/or unique to the population studied. The main analyses did not impute missing data, which, in both the placebo and LVX groups, were assumed to be missing at random. Other limitations of our study include the racial homogeneity of the study population and the short treatment duration (12 weeks). The sustainability of these effects over a longer time period needs to be confirmed in longer-term studies. However, the results demonstrate that the study intervention is feasible and has promising effects on multiple measures of renal function. Another limitation is that TSH levels were different at the time of randomization, although we believe that this had no impact on the final result, as both groups were in ranges of abnormality. Furthermore, there is no objective evidence to suggest that the study population is unique. However, as with all pilot projects, our findings remain exploratory and hypothesis generating.
In conclusion, this single-center, randomized, double-blind, placebo-controlled pilot clinical study in patients with advanced proteinuric CKD who already used ACEIs or ARBs demonstrated that administering LVX to obtain a TSH range close to 2.5 μIU/ml decreased proteinuria and improved eGFR. These findings could encourage the performance of a clinical trial with sufficient statistical power to demonstrate the benefit of normalizing TSH with LVX in patients with CKD.
Disclosure
All the authors declared no competing interests.
Supplementary Material
Supplementary File (Word)
Table S1. Drugs that interact with levothyroxine.
Acknowledgments
Clinical trial registration number: NCT03898622.
Supplementary File (Word)
Table S1. Drugs that interact with levothyroxine. | LEVOTHYROXINE SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33426390 | 18,754,150 | 2021-01 |
What was the administration route of drug 'LEVOTHYROXINE SODIUM'? | A Pilot Trial on the Effect of Levothyroxine on Proteinuria in Patients With Advanced CKD.
Thyroid hormones can directly affect kidney function; elevated levels of thyroid-stimulating hormone (TSH) and chronic kidney disease (CKD) are associated with proteinuria, decreased estimated glomerular filtration rate (eGFR), and progression to end-stage renal disease. Our hypothesis is that in patients with CKD and TSH at levels considered to be in the low subclinical hypothyroidism (SCH) range, lowering TSH with levothyroxine (LVX) improves the clinical parameters of renal function.
This was a double-blind, randomized, pilot clinical trial in patients with proteinuric CKD (eGFR <60 ml/min per 1.73 m2 and proteinuria >150 mg/d) performed at the Hospital Civil de Guadalajara, with the intention of lowering TSH (levels of 1.25-2.5 μIU/l) in patients with TSH (levels of 2.6-9.9 μIU/ml with FT4 in the range of 0.7-1.8 ng/dl). Patients were randomized 1:1 to receive LVX or placebo for 12 weeks. The primary objective was to evaluate absolute levels of proteinuria at the beginning compared to the end of the study and, as a secondary objective, the changes in serum creatinine (sCr), eGFR, cholesterol, triglycerides, low-density lipoprotein (LDL), and blood pressure, and to assess the tolerability and safety of LVX.
Between March and November 2018, a total of 163 patients were assessed for eligibility; 119 patients did not meet the inclusion criteria or were excluded, and 32 patients were randomized. The demographic and clinical characteristics of the 2 study groups were essentially not different. Subjects were 66.87 (SD 12.19) years of age, 62.5% were female, 75% were diabetes mellitus, eGFR was 23.55 (±12.91) ml/min per 1.73 m2, TSH was 5.37 ± 2.13 μIU/ml, proteinuria in 24-hour urine collection was 1.52 ± 1.12, and all of them were taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs). Proteinuria at 12 weeks in the LVX group was 0.89 SD ± 1.28 g/d, and in the placebo group it was 1.35 SD ± 0.85 g/d; when compared to placebo, LVX showed a significant decrease in proteinuria of 1.1 g/d (P = 0.0011). The eGFR in the LVX group showed an improvement of 4 ml/min/1.73 m2 (P = 0.049); in the placebo group, there was a decrease of 1.98 ml/min per 1.73 m2. The sCr, cholesterol, triglycerides, low-density lipoprotein, systolic blood pressure, and diastolic blood pressure were not different between groups. Adverse events were reported in the LVX group in 7.14% of patients and in 11.11% of patients in the placebo group; none left the study because of adverse effects, and there were no serious adverse events.
This single-center, randomized, double-blind, placebo-controlled pilot clinical trial in patients with advanced proteinuric CKD who already used ACEIs or ARBs demonstrated that administering LVX to obtain a TSH range close to 2.5 μIU/ml decreased proteinuria and improved eGFR. Future research is needed to confirm our results and to determine whether our findings generalize to patient groups not explicitly enrolled in this small pilot trial.
Chronic noncommunicable diseases such as obesity, diabetes mellitus, hypertension, and chronic kidney disease (CKD) have become a major public health problem in the Mexican population.1,2 Between 1990 and 2013, the CKD burden rapidly climbed, with age-standardized years of life lost (YLL) and disability-adjusted life-year (DALY) rates increasing more than 130%, the second highest DALY due to CKD in the world.3 The incidence of end-stage renal disease has increased dramatically in parallel with these risk factors.4
Thyroid hormones can directly affect kidney function, and impaired renal function can also contribute to thyroid disorders.5, 6, 7, 8, 9 The prevalence of primary overt, subclinical hypothyroidism (SCH) and low T3 syndrome increases with the progression of CKD.10,11
The prevalence of SCH in patients with an estimated glomerular filtration rate (eGFR) >60 ml/min per 1.73 m2 is 7% and is up to 17.9% in those with an eGFR <60 ml/min per 1.73 m2.11 Thyroid hormone affects the kidney by multiple mechanisms; local hemodynamic changes, decreased renal blood flow, decreased cardiac output, circulating volume, and decreased atrial natriuretic factor contribute to a decrease in renal perfusion with a concomitant reduction in eGFR,5, 6, 7,11, 12, 13 affecting the renin−angiotensin−aldosterone system, glomerular basement membrane, and renal tubular function, and leading to the development of proteinuria through direct effects on megalin and podocytes.8,9
The frequency of proteinuria in patients with normal thyroid function (euthyroid), SCH, and hypothyroidism is 1.29%, 2.2%, and 2.97%, respectively.14 In addition, it has been reported that the progression to end-stage renal disease is more accelerated in patients with SCH than in euthyroid patients,14,15, 16, 17, 18 and there is evidence that high (>3 μIU/ml) and low (<0.5 μIU/ml) thyroid-stimulating hormone (TSH) are associated with higher mortality rates in patients with CKD.19 There is also an association of mortality in patients with CKD and thyroid functional disease due to increased cardiovascular risk,20 particularly in patients on hemodialysis,21, 22, 23 as well as peritoneal dialysis24 and thyroid function disease.
The American Thyroid Guidelines, the American Association of Endocrinology,25 and European Guidelines and Clinical Practice Guidelines26 recommend beginning LVX doses of 0.25 μg and not going above 0.50 μg in patients with high cardiovascular risk,27,28 as patients with CKD have been considered.29
Levothyroxine is usually well tolerated in the general population at standard doses (1.6-18.8 μg/kg). In patients with SCH, overdose symptoms were reported in 10% to 21% of cases, and a Cochrane meta-analysis of thyroid hormone replacement for SCH found no significant adverse events.30
However, many patients with CKD will experience renal progression, despite antiproteinuric treatment.31,32 These observations led to the examination of alternative pathways to delay CKD, with disappointing results so far. The most commonly used antiproteinuric33,34 drugs are angiotensin-converting enzyme inhibitors,35 angiotensin receptor blockers,36 aldosterone antagonists, 37, 38, 39, 40 and, although they are less effective, statins,41,42 allopurinol,43 and vitamin D activators.43, 44, 45, 46, 47, 48
Treatment of SCH with LVX in the general population improves the lipid profile and cardiac function,49, 50, 51 and patients with CKD show improvement in eGFR and serum creatinine (sCr),14,51 but there are no clinical trials in this field in patients with CKD.
Our hypothesis is that in patients with CKD and TSH at levels considered to be in the SCH range, the normalization of TSH with LVX improves the clinical parameters of renal function.
Materials and Methods
We conducted a pilot randomized, single-center, double-blind, placebo-controlled, parallel group, dose-adjusting trial of levothyroxine (LVX) 25 μg administered orally once daily to patients with proteinuric CKD conducted at the Hospital Civil de Guadalajara from March 2018 to 31 January 2019. The study objectives were to evaluate the efficacy and safety of normalizing TSH levels with LVX and to explore the clinical effect of LVX compared with placebo.
The measurement of TSH and FT4 was carried out with the UniCel DxI 800 (Beckman Coulter Inc., Indianapolis, IN) access Immunoassay system by chemiluminescence, with the serum FT4 (assay type 2-step competitive) reportable range of 0.25 to 6 ng/dl (3-2-77.2 pmol/l), analytical sensitivity 0.25 ng/dl (3.2 pmol/l), and serum TSH (assay type 1-step sandwich) reportable range of 0.03 to 100 μIU/ml, which incorporates functionality for the lower limit of detection, analytical sensitivity 0.01 μIU/ml, and 0.03 uIU/ml functional, and all samples were analyzed in a single laboratory.
Patients with CKD (eGFR <60 ml/min per 1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) were eligible if they were >18 years of age or if they had proteinuria >150 mg/24 h. With TSH levels between 2.5 and 10.0 μIU/ml, we chose TSH >2.5 μIU/ml, as there is evidence that there was an association of a decrease in eGFR10,52 with proteinuria,10 and TSH <10.0 μIU/ml excludes clinical hypothyroidism. All patients treated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and without renal replacement therapy who attended the Renal Health Clinic were considered for participation in this pilot clinical trial.
We excluded patients with the following: primary hypothyroidism or preexisting thyroid disease; previous ischemic heart disease within a period of <6 months; arrhythmia; pregnancy; use of drugs that interact with the synthesis of thyroid hormones (Supplementary Table S1); those who did not provide informed consent; those with a serum TSH level <2.5 μIU/ml or >10 μIU/ml; those with a free serum T4 value between 0.6 and 1.8 ng/dl; those with positive anti-thyroid antibodies; and patients weighing <50 kg or >90 kg, because within this weight, all patients will maintain a dosage of 0.3−0.5 μg/kg per day, so it will be easy to prescribe the LVX dose with a narrow error window.
Approval was obtained from the participating site’s Research and Ethics Committee (Hospital CG 034/18 March 2018). Patients provided written informed consent before enrollment in accordance with local and national laws. Conduct and reporting are consistent with the 2010 Consolidated Standards of Reporting Trials (CONSORT) extension for pilot trials.53 The trial was registered in the Clinical Trials Registry (NCT03898622).
Measures of renal function included the eGFR calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation.54 Proteinuria was measured by means of 24-hour urine collection, expressed in grams per day, at the beginning and end of the study. Serum creatinine, serum electrolytes, hemoglobin, albumin, cholesterol, TSH, FT4, and triglycerides were measured at the beginning of the study and every 4 weeks for 4 months.
Using a Web-based randomization system, we randomly assigned participants in a 1:1 ratio. Standard care was defined pragmatically; in both the study intervention and the standard care group, the nephrologist determined all aspects of clinical care, based on standard practice and individual patient needs, independent of the study intervention.
The study consisted of 3 phases. The first phase, with a duration of 8 to 12 weeks, consisted of enrolling patients and collecting demographic and clinical baseline measurements (proteinuria, lipid profile, serum electrolytes, arterial pressure, weight, TSH level, hemoglobin, and serum albumin). The second phase consisted of both groups being treated according to the allocation arm, and the third phase consisted of comparing the variables studied and the data analysis. The dose of LVX has previously been shown to be safe and efficient in adult patients with CKD.14,51
Our primary objective was to evaluate the effect of lowering TSH with the use of LVX or placebo to assess absolute levels at the beginning compared to the end of the study, when proteinuria was measured in urine collected for 24 hours. The secondary objectives were to evaluate the changes in sCr and eGFR and to assess the tolerability and safety of LVX and changes in cholesterol, triglycerides, LDL and blood pressure.
Interventions
The treating nephrologist and the patients were blinded to the study intervention.
If randomized to the intervention arm, the intervention consisted of treatment with oral levothyroxine (LVX) between 0.25 and 0.50 μg according to a dose of 0.3 to 0.5 μg/kg per day during fasting (in the case of taking a drug that interacts with the absorption, use of it was changed according to the hours specified). The dose adjustment was every 4 weeks. Levothyroxine or placebo was adjusted to 25 or 50 μg according to TSH levels (Table 1).Table 1 Dose adjustment of levothyroxine
TSH range Dose adjustment
TSH < 0.5 μIU/ml Suspend the pill
TSH (0.5–1 μIU/ml) Suspend the pill if it is at minimum dose
TSH (1.2–2.4 μIU/ml) Suspend the pill if it is at minimum dose
TSH (2.5–4.3 μIU/ml) Dose 25 μg/d
TSH (4.4–6.1 μIU/ml) Keep dose if 50 μg/d or increase if taking 25 μg/d
TSH (6.2–8 μIU/ml) Keep dose if 50 μg/d or increase if taking 25 μg/d
TSH (8.1–9.9 μIU/ml) Keep dose if 50 μg/d or increase if taking 25 μg/d
TSH, thyroid-stimulating hormone.
All vials (placebo or levothyroxine) presented drugs in one-quarter tablet = 25 μg the first month. In addition, the following months were adjusted according to the TSH range.
Participants allocated to placebo took 1 pill per day, with the same bottle characteristics as patients in the intervention arm, for >12 weeks.
The preparation and packaging of LVX and placebo were carried out by a pharmacist who was not involved in the development of the present study. All patients were followed up every 4 weeks for usual renal health consultation. In addition, the specific aspects of the protocol consisted of monitoring thyroid function for the adjustment of LVX or placebo dose according to the previous dosage adjustment.
To ascertain compliance and adherence to treatment, a record sheet was created with all drug supplied and returned. During the course of the study, the investigator was responsible for providing additional instructions to retrain any subjects who did not comply with the administration of the study drug or with attendance at the required clinical visits.
Adverse events were recorded during the follow-up, which included thyroid profile control tests every 4 weeks. Previously specified adverse effects were reported and followed up, and were rated in intensity according to the Common Terminology Criteria for Adverse Events (CTC) v. 3.0 (1–5), along with the start date and end date, as well as the treatment received.
This protocol was not sponsored or financed by any pharmaceutical company, nor are there any conflicts of interest on the part of the authors.
Statistical Analyses
The sample calculation was at will. The reason for this pilot trial was to investigate areas of uncertainty regarding future definitive randomized clinical trials on the effects of thyroid hormone reduction with levothyroxine on proteinuria in patients with advanced chronic kidney disease based on eGFR and proteinuria. This was a small-scale study conducted to test the plan and method of a research study; this pilot study addresses treatment safety assessments, determination of dose levels and response, and estimation of the effect of treatment and its variance.
The methodology for a clinical trial of superiority was carried out. Parametric continuous variables are given as the mean and SD, and nonparametric continuous variables are reported as medians. Comparisons were made using the Student t test or the Mann−Whitney test. Categorical variables are presented as percentages and were compared using the χ2 test or Fisher exact test. The prespecified threshold for significance was a P value <0.05. All statistical analyses were performed using the statistical programs SPSS version 20 (SPSS IBM Corporation, Armonk, NY) and GraphPad 7 (GraphPad Software, San Diego, CA).
Results
From March to November 2018, a total of 163 patients attended the Renal Health Clinic and were considered for participation. Of the patients, 125 were excluded because 64 did not meet the inclusion criteria, 56 patients decided not to participate, and another 5 did not meet the other specifications. Only 38 patients provided consent to participate. Of these, 6 patients were lost during follow-up, leaving a total of 32 patients (77.2%) to be analyzed. Of those, 14 patients (43.75%) were randomized to the placebo group and 18 (56.25%) to the LVX group (Figure 1).Figure 1 Flowchart during the study period.
Baseline clinical and demographic characteristics are shown in Table 2. Both groups had similar characteristics with respect to sex, age, number of comorbidities, CKD grade, weight, albumin, eGFR, hemoglobin, systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid profile, and proteinuria, except for the statistically higher TSH, sCr and LDL levels in the LVX group. At baseline, the mean (SD) levels of LDL cholesterol were significantly lower in the placebo group than in the LVX group (75.5 ± 19 mg/dl and 102.38 ± 31-42 ng/dl, respectively, P = 0.01). The TSH levels in the placebo group were significantly lower than those in the LVX group (4.46 ± 1.68 μIU/ml and 5.93 ± 2.2 μIU/ml, respectively; P = 0.02). The sCr levels of the placebo group were significantly higher than those of the LVX group (3.05 SD ± 1.65 mg/dl and 2.46 SD ± 1.13 mg/dl, respectively, P = 0.05).Table 2 Demographic and clinical baseline characteristics
Baseline characteristics Placebo (n = 14) Levothyroxine (n = 18) All (N = 32) P value
Sex, n, % female 10 (71.42) 10 (55.55) 20 (62.5) NA
Age, yr, SD 63.85 ± 15 69.22 ± 8.7 66.87 ± 12.19 0.41
Diabetes mellitus 11 (78.57) 13 (72.22) 24 (75) 1.00
Hypertensionn 12 (85.71) 16 (88.88) 28 (87.5) 1.00
Weight, kg, SD 67.90 ± 13.83 67.01 ± 11.32 67.55 ± 12.13 0.88
Obesity (BMI >30 kg/m2) 1 (7.14) 3 (6.6) 4 (12.5) 0.61
CKD G3a (45–59 ml/min per 1.73 m2) 0 3 (16.6) 3 (9.37) 0.23
CKD G3b (30–44 ml/min per 1.73 m2), 2 (14.28) 4 (22.22) 6 (18.75) 0.67
CKD G4 (15–29 ml/min per 1.73 m2) 5 (35.71) 7 (38.88) 12 (37.5) 1.00
CKD G5 (<15 ml/min per /1.73 m2) 7 (50) 4 (22.22) 11 (34.37) 0.14
eGFR (ml/min per 1.73 m2) 18.14 ± 9.96 27.72 ± 13.38 23.55 ± 12.91 0.078
TSH, μIU/ml 4.46 ± 1.68 6.08 ± 2.18 5.37 ± 2.13 0.02
T4L, ng/dl 0.93 ± 0.12 0.99 ± 0.14 0.96 ± 0.13 0.65
Proteinuria grams/d urine collection 1.28 ± 1.28 1.71 ± 1.20 1.52 ± 1.12 0.14
sCr, mg/dl 3.65 ± 1.65 2.46 ± 1.13 2.98 ± 1.51 0.05
Albumin, mg/dl 3.99 ± 0.41 3.8 ± 0.41 3.88 ± 0.42 0.24
Triglycerides, mg/dl 194 ± 75.3 144.66 ± 91.76 172.5 ± 87.71 0.09
Cholesterol, mg/dl 170.57 ± 45.96 165.5 ± 59.67 167.71 ± 54.16 0.67
LDL, mg/dl 75.5 ± 19 102.38 ± 31.42 90.62 ± 29.86 0.01
Hemoglobin, g/dl 11.37 ± 1.21 11.95 ± 1.61 11.72 ± 1.48 0.17
SBP, mm Hg 148.14 ± 27.7 160 ± 19.4 154.81 ± 24.14 0.17
DBP, mm Hg 79 ± 11.72 81.83 ± 8.2 80.59 ± 10 0.60
ACEI or ARB 14 (100) 18 (100) 32 (100) 1.00
Allopurinol 14 (100) 18 (100) 32 (100) 1.00
Statin 14 (100) 18 (100) 32 (100) 1.00
ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensinogen receptor blockers; BMI, body mass index; DBP, diastolic blood pressure; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; G, grade; kg, kilograms; LDL, low-density cholesterol; NA, not available; SBP, systolic blood pressure; sCr, serum creatinine.
Data are n (%) or ±SD, unless otherwise noted.
The primary objective, measured at 3 months of randomization, is presented in Table 3 and Figure 2. A total of 32 patients were analyzed, 14 in the placebo group and 18 in the LVX group, whereas 6 were lost during follow-up. The mean (SD) proteinuria at 3 months in the LVX group was 0.89 ± 1.28 g/d, and in the placebo group 1.35 ± 0.85 g/d. When compared to placebo, LVX showed a significant decrease in proteinuria of 1.1 g/d (P = 0.0011).Table 3 Clinical and laboratory variable changes at the end of the study period (12 weeks), according to the placebo or levothyroxine group
Primary objective Placebo Levothyroxine P value
Proteinuria, g/d +0.2 (−0.4 to 2.1)
(1.35 ± 0.85) −1.1 (−4.1 to 0.9)
(0.89 ± 1.28) 0.0011
Secondary objectives
Changes in eGFR, ml/min per 1.73 m2 −1.96 (−5 to 3)
(16.18 ± 8.37) 4.04 (9.8 to −2)
(31.76 ± 11.9) 0.049
sCr, mg/dl 0.05 (−0.5 to 1.49)
(3.71 ± 1.55) −0.2 (−0.7 to 0.5)
(2.36 ± 1.27) 0.32
Cholesterol, mg/dl −28.46 (107 to 26)
(142.11 ± 44.05) −18 (−57 to 37)
(147.5 ± 30.8) 0.18
Triglycerides, mg/dl −21(−94 to 108)
(173.2 ± 51.46) −14.6 (−286 to 66)
(130 ± 41.79) 0.71
SBP, mm Hg −2.5 (−57 to 35)
(145.64 ± 18.58) −5.5 (−75 to 57)
(154.5 ± 26.38) 0.33
DBP, mm Hg −6.43 (−17 to 14)
(72.57 ± 9.78) −9.06 (−20 to 10)
(72.77 ± 11.51) 0.33
TSH, μIU/ml −0.4 (−3.09 to 1.87)
(3.97 ± 1.77) −3.2 (−6.8 to 1.6)
(3.2 ± 1.5) 0.0032
T4L, ng/dl −0.1 (−0.18 to 0.12)
0.92 ± 0.24 0.05 (−0.38 to 0.4)
1.04 ± 0.21 0.77
Weight, kg 1.63 (−3.5 to 5.5)
(68.96 ± 14.65) −1.05 (−3.5 to 2.1)
(65.86 ± 11.65) 0.20
DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure; sCr, serum creatinine; TSH, thyroid-stimulating hormone.
Figure 2 Proteinuria (in grams per day) at the end of the study period (12 weeks) in the placebo and levothyroxine groups.
The comparative secondary objectives are presented in Table 3 and Figure 3. For the eGFR, the LVX group showed an improvement of 4.04 ml/min per 1.73 m2 (P = 0.049); in the placebo group, there was a decrease of 1.96 ml/min per 1.73 m2. The placebo group showed a decrease in TSH of 0.4 μIU/ml, and the LVX group showed a decrease in TSH of 3.2 μIU/ml (P = 0.0032). When comparing the weight reduction, the LVX arm showed a reduction in weight of −1.05 ± 3.72 kg, whereas the placebo group showed an increase in weight of 1.63 SD ± 5.59 kg (P = 0.20). For sCr, cholesterol, triglycerides, LDL, SBP, and DBP, there were no differences between the groups at 3 months (Figure 3). Adverse effects are shown in Table 4. Urinary tract infection presented in 1 patient in the placebo group (7.14%) and nervousness in 2 patients in the LVX group (11.11%) (relative risk 1.55 95% confidence interval 0.15-15.47, P = 1.0). No patients left the study because of adverse effects. Adverse events were not severe according to the severity scale.Figure 3 Clinical and laboratory variable changes at the end of the study period (12 weeks), according to placebo or levothyroxine group. (a) Serum thyroid-stimulating hormone (TSH); (b) serum FT4; (c) serum creatinine (sCr); (d) estimated glomerular filtration rate (eGFR); (e) serum cholesterol; (f) serum triglycerides; (g) systolic blood pressure (SBP); (h) diastolic blood pressure (DBP); (i) Weight loss (in kilograms). CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.
Table 4 Adverse events during the study period
Group n (%) Outcome
LVX group 1 (7.14) Urinary tract infectiona
Placebo group 2 (11.11) Anxietyb
CI, confidence interval; LVX, levothyroxine; RR, relative risk.
RR = 1.55, 95% CI 0.15–15.47, P = 1.0.
a Urinary tract infection: duration of 5 days, without complications.
b Anxiety: duration of 3 days, without complications.
Discussion
This pilot randomized, single-center, double-blind study in patients with advanced proteinuric CKD demonstrated that administering LVX to obtain a normal TSH range decreased proteinuria and improved eGFR, with few adverse events.
The management of proteinuria in CKD is mainly due to the effects of blocking the renin−angiotensin−aldosterone system (RAAS), such as with ACEIs and ARBs,35,36 and other drugs to a lesser magnitude, such as allopurinol,55 aldosterone antagonists,37, 38, 39, 40 statins,41,42 and calcitriol44, 45, 46, 47; however, despite these treatments, there is still residual proteinuria that contributes to the deterioration of renal function and cardiovascular risk.2 Proteinuria in hypothyroid human beings and rats has been related to RAAS activity,9 blood pressure, and oxidative stress, although it may be a reflection of glomerular hypertension and decreased glomerular filtration rate,5 changes in the management of tubular proteins, or changes in the structure of the glomerular barrier, specifically at the podocyte and megalin.8,9 In our study, the significant decrease in proteinuria of 1.1 g/d in the LVX group could be explained by the normalization of the TSH range. In addition, the antiproteinuric benefit observed with LVX could be explained by the alteration of glomerular pressure due to the negative inotropic effect on the heart, reduction in the circulating intravascular volume, and increase in peripheral resistance, with renal vasoconstriction adding a counterregulatory effect of RAAS, as well as changes at the level of the glomerular, tubular, and podocyte basal membrane.5,10 Higher baseline ranges were observed for TSH, LDL, and sCr in the LVX group, which could explain why the higher the TSH, the greater the effect on proteinuria.14,50,51 It is very important to consider the administration of LVX in patients with CKD and alterations in TSH for a greater benefit in decreasing proteinuria, thus adding the correlation that thyroid hormone in endothelial damage and in cardiovascular risk could also decrease mortality and decrease eGFR.14,19,50,52
In our study, eGFR increased in the LVX group by 4 ml/min per 1.73 m2, compared to that in the placebo group, in which eGFR decreased by 2 ml/min per 1.73 m2. Van Welsem et al.9 reported that the normalization of hypothyroidism after treatment with LVX led to a significant improvement in renal function in a patient with CKD.5 In addition, Shin et al. demonstrated that reaching a TSH goal of 1 to 4.5 μIU/ml with LVX at a dose of 25 to 50 μg/d improved the eGFR +4.31 ± 0.5 ml/min per 1.73 m2.51 Chang et al. used a TSH goal of 1.16-2.86 μIU/ml with a dose of LVX 25 μg/d and obtained an improvement in eGFR +5.77 ml/min per 1.73 m2 (P = 0.015).14
Although previous studies have shown that LVX improves cardiac function, renal function, and dyslipidemia and delays progression of CKD that is already established in patients with SCH, there is still a lack of consensus in the current guidelines on whether to treat SCH in patients with CKD. In particular, little is known about the effect of thyroid hormone replacement on changes in eGFR.21, 22, 23, 24 Some studies exist comparing CKD and thyroid disorders in which normal TSH ranges were maintained and an improvement in the progression of CKD, decreased proteinuria,5,9,13,17 improved lipid profile,37 and lower cardiovascular risk were observed.20 Rhee et al. found, in more than 220,000 patients, that at TSH levels >3 μIU/ml and TSH <0.5 μIU/ml, there is a higher mortality rate in patients with CKD G3.19
There are already studies in which the elevation of TSH is associated with the progression of CKD.14,15 In patients already undergoing renal replacement therapy, such as hemodialysis with elevated TSH, it was associated with mortality,21, 22, 23 similar to peritoneal dialysis.24
We sought to reinforce these benefits of maintaining a range of TSH (<4.5 μIU/ml, considering previous studies in which mortality was associated with TSH >2.5 μIU/ml).19,29 In addition, some authors have reported a greater progression to terminal CKD and mortality in patients with SCH versus euthyroid hypothyroidism.19,20 The American25 and European guidelines27 do not mention the potential benefit of the use of LVX and its impact in patients with CKD and SCH.
Another possibility of improving proteinuria and eGFR is that by decreasing TSH, an increase in catabolism and weight reduction was achieved, eliminating hyperfiltration and proteinuria. It should be mentioned that at the beginning of the study, only 4 patients had a BMI >30 kg/m2, 1 patient from the placebo group and 3 patients from the LVX group (P = 0.61), and the differences in weight loss (in kilograms) at the end of the study were higher in the LVX group than in the placebo group, with an average of −1.05 SD ± 3.72 kg and 1.63 SD ± 5.59 kg, respectively, but the differences were not significant (P = 0.20). Among the other variables relevant to this study, there were no significant changes in BP or HR.
Regarding tolerance, the use of LVX was safe, there were no severe adverse events, and no patient had to discontinue the study drug. However, more patients in the LVX dose adjustment were required (relative risk = 1.55, 95% confidence interval = 0.15−15.47, P = 1.0). In previous studies, no serious adverse effects have been reported when giving LVX to patients with CKD, considering that they are patients with cardiovascular risk.25,26 This information can be interpreted as showing that LVX is a useful treatment in hypothyroidism and that the risk is minimal.28,29
Several limitations need to be acknowledged. This paper presents the results of a small, single-center, randomized controlled pilot clinical trial. As such, estimates of treatment effects may be overoptimistic and/or unique to the population studied. The main analyses did not impute missing data, which, in both the placebo and LVX groups, were assumed to be missing at random. Other limitations of our study include the racial homogeneity of the study population and the short treatment duration (12 weeks). The sustainability of these effects over a longer time period needs to be confirmed in longer-term studies. However, the results demonstrate that the study intervention is feasible and has promising effects on multiple measures of renal function. Another limitation is that TSH levels were different at the time of randomization, although we believe that this had no impact on the final result, as both groups were in ranges of abnormality. Furthermore, there is no objective evidence to suggest that the study population is unique. However, as with all pilot projects, our findings remain exploratory and hypothesis generating.
In conclusion, this single-center, randomized, double-blind, placebo-controlled pilot clinical study in patients with advanced proteinuric CKD who already used ACEIs or ARBs demonstrated that administering LVX to obtain a TSH range close to 2.5 μIU/ml decreased proteinuria and improved eGFR. These findings could encourage the performance of a clinical trial with sufficient statistical power to demonstrate the benefit of normalizing TSH with LVX in patients with CKD.
Disclosure
All the authors declared no competing interests.
Supplementary Material
Supplementary File (Word)
Table S1. Drugs that interact with levothyroxine.
Acknowledgments
Clinical trial registration number: NCT03898622.
Supplementary File (Word)
Table S1. Drugs that interact with levothyroxine. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33426390 | 18,754,150 | 2021-01 |
What was the dosage of drug 'LEVOTHYROXINE SODIUM'? | A Pilot Trial on the Effect of Levothyroxine on Proteinuria in Patients With Advanced CKD.
Thyroid hormones can directly affect kidney function; elevated levels of thyroid-stimulating hormone (TSH) and chronic kidney disease (CKD) are associated with proteinuria, decreased estimated glomerular filtration rate (eGFR), and progression to end-stage renal disease. Our hypothesis is that in patients with CKD and TSH at levels considered to be in the low subclinical hypothyroidism (SCH) range, lowering TSH with levothyroxine (LVX) improves the clinical parameters of renal function.
This was a double-blind, randomized, pilot clinical trial in patients with proteinuric CKD (eGFR <60 ml/min per 1.73 m2 and proteinuria >150 mg/d) performed at the Hospital Civil de Guadalajara, with the intention of lowering TSH (levels of 1.25-2.5 μIU/l) in patients with TSH (levels of 2.6-9.9 μIU/ml with FT4 in the range of 0.7-1.8 ng/dl). Patients were randomized 1:1 to receive LVX or placebo for 12 weeks. The primary objective was to evaluate absolute levels of proteinuria at the beginning compared to the end of the study and, as a secondary objective, the changes in serum creatinine (sCr), eGFR, cholesterol, triglycerides, low-density lipoprotein (LDL), and blood pressure, and to assess the tolerability and safety of LVX.
Between March and November 2018, a total of 163 patients were assessed for eligibility; 119 patients did not meet the inclusion criteria or were excluded, and 32 patients were randomized. The demographic and clinical characteristics of the 2 study groups were essentially not different. Subjects were 66.87 (SD 12.19) years of age, 62.5% were female, 75% were diabetes mellitus, eGFR was 23.55 (±12.91) ml/min per 1.73 m2, TSH was 5.37 ± 2.13 μIU/ml, proteinuria in 24-hour urine collection was 1.52 ± 1.12, and all of them were taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs). Proteinuria at 12 weeks in the LVX group was 0.89 SD ± 1.28 g/d, and in the placebo group it was 1.35 SD ± 0.85 g/d; when compared to placebo, LVX showed a significant decrease in proteinuria of 1.1 g/d (P = 0.0011). The eGFR in the LVX group showed an improvement of 4 ml/min/1.73 m2 (P = 0.049); in the placebo group, there was a decrease of 1.98 ml/min per 1.73 m2. The sCr, cholesterol, triglycerides, low-density lipoprotein, systolic blood pressure, and diastolic blood pressure were not different between groups. Adverse events were reported in the LVX group in 7.14% of patients and in 11.11% of patients in the placebo group; none left the study because of adverse effects, and there were no serious adverse events.
This single-center, randomized, double-blind, placebo-controlled pilot clinical trial in patients with advanced proteinuric CKD who already used ACEIs or ARBs demonstrated that administering LVX to obtain a TSH range close to 2.5 μIU/ml decreased proteinuria and improved eGFR. Future research is needed to confirm our results and to determine whether our findings generalize to patient groups not explicitly enrolled in this small pilot trial.
Chronic noncommunicable diseases such as obesity, diabetes mellitus, hypertension, and chronic kidney disease (CKD) have become a major public health problem in the Mexican population.1,2 Between 1990 and 2013, the CKD burden rapidly climbed, with age-standardized years of life lost (YLL) and disability-adjusted life-year (DALY) rates increasing more than 130%, the second highest DALY due to CKD in the world.3 The incidence of end-stage renal disease has increased dramatically in parallel with these risk factors.4
Thyroid hormones can directly affect kidney function, and impaired renal function can also contribute to thyroid disorders.5, 6, 7, 8, 9 The prevalence of primary overt, subclinical hypothyroidism (SCH) and low T3 syndrome increases with the progression of CKD.10,11
The prevalence of SCH in patients with an estimated glomerular filtration rate (eGFR) >60 ml/min per 1.73 m2 is 7% and is up to 17.9% in those with an eGFR <60 ml/min per 1.73 m2.11 Thyroid hormone affects the kidney by multiple mechanisms; local hemodynamic changes, decreased renal blood flow, decreased cardiac output, circulating volume, and decreased atrial natriuretic factor contribute to a decrease in renal perfusion with a concomitant reduction in eGFR,5, 6, 7,11, 12, 13 affecting the renin−angiotensin−aldosterone system, glomerular basement membrane, and renal tubular function, and leading to the development of proteinuria through direct effects on megalin and podocytes.8,9
The frequency of proteinuria in patients with normal thyroid function (euthyroid), SCH, and hypothyroidism is 1.29%, 2.2%, and 2.97%, respectively.14 In addition, it has been reported that the progression to end-stage renal disease is more accelerated in patients with SCH than in euthyroid patients,14,15, 16, 17, 18 and there is evidence that high (>3 μIU/ml) and low (<0.5 μIU/ml) thyroid-stimulating hormone (TSH) are associated with higher mortality rates in patients with CKD.19 There is also an association of mortality in patients with CKD and thyroid functional disease due to increased cardiovascular risk,20 particularly in patients on hemodialysis,21, 22, 23 as well as peritoneal dialysis24 and thyroid function disease.
The American Thyroid Guidelines, the American Association of Endocrinology,25 and European Guidelines and Clinical Practice Guidelines26 recommend beginning LVX doses of 0.25 μg and not going above 0.50 μg in patients with high cardiovascular risk,27,28 as patients with CKD have been considered.29
Levothyroxine is usually well tolerated in the general population at standard doses (1.6-18.8 μg/kg). In patients with SCH, overdose symptoms were reported in 10% to 21% of cases, and a Cochrane meta-analysis of thyroid hormone replacement for SCH found no significant adverse events.30
However, many patients with CKD will experience renal progression, despite antiproteinuric treatment.31,32 These observations led to the examination of alternative pathways to delay CKD, with disappointing results so far. The most commonly used antiproteinuric33,34 drugs are angiotensin-converting enzyme inhibitors,35 angiotensin receptor blockers,36 aldosterone antagonists, 37, 38, 39, 40 and, although they are less effective, statins,41,42 allopurinol,43 and vitamin D activators.43, 44, 45, 46, 47, 48
Treatment of SCH with LVX in the general population improves the lipid profile and cardiac function,49, 50, 51 and patients with CKD show improvement in eGFR and serum creatinine (sCr),14,51 but there are no clinical trials in this field in patients with CKD.
Our hypothesis is that in patients with CKD and TSH at levels considered to be in the SCH range, the normalization of TSH with LVX improves the clinical parameters of renal function.
Materials and Methods
We conducted a pilot randomized, single-center, double-blind, placebo-controlled, parallel group, dose-adjusting trial of levothyroxine (LVX) 25 μg administered orally once daily to patients with proteinuric CKD conducted at the Hospital Civil de Guadalajara from March 2018 to 31 January 2019. The study objectives were to evaluate the efficacy and safety of normalizing TSH levels with LVX and to explore the clinical effect of LVX compared with placebo.
The measurement of TSH and FT4 was carried out with the UniCel DxI 800 (Beckman Coulter Inc., Indianapolis, IN) access Immunoassay system by chemiluminescence, with the serum FT4 (assay type 2-step competitive) reportable range of 0.25 to 6 ng/dl (3-2-77.2 pmol/l), analytical sensitivity 0.25 ng/dl (3.2 pmol/l), and serum TSH (assay type 1-step sandwich) reportable range of 0.03 to 100 μIU/ml, which incorporates functionality for the lower limit of detection, analytical sensitivity 0.01 μIU/ml, and 0.03 uIU/ml functional, and all samples were analyzed in a single laboratory.
Patients with CKD (eGFR <60 ml/min per 1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) were eligible if they were >18 years of age or if they had proteinuria >150 mg/24 h. With TSH levels between 2.5 and 10.0 μIU/ml, we chose TSH >2.5 μIU/ml, as there is evidence that there was an association of a decrease in eGFR10,52 with proteinuria,10 and TSH <10.0 μIU/ml excludes clinical hypothyroidism. All patients treated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and without renal replacement therapy who attended the Renal Health Clinic were considered for participation in this pilot clinical trial.
We excluded patients with the following: primary hypothyroidism or preexisting thyroid disease; previous ischemic heart disease within a period of <6 months; arrhythmia; pregnancy; use of drugs that interact with the synthesis of thyroid hormones (Supplementary Table S1); those who did not provide informed consent; those with a serum TSH level <2.5 μIU/ml or >10 μIU/ml; those with a free serum T4 value between 0.6 and 1.8 ng/dl; those with positive anti-thyroid antibodies; and patients weighing <50 kg or >90 kg, because within this weight, all patients will maintain a dosage of 0.3−0.5 μg/kg per day, so it will be easy to prescribe the LVX dose with a narrow error window.
Approval was obtained from the participating site’s Research and Ethics Committee (Hospital CG 034/18 March 2018). Patients provided written informed consent before enrollment in accordance with local and national laws. Conduct and reporting are consistent with the 2010 Consolidated Standards of Reporting Trials (CONSORT) extension for pilot trials.53 The trial was registered in the Clinical Trials Registry (NCT03898622).
Measures of renal function included the eGFR calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation.54 Proteinuria was measured by means of 24-hour urine collection, expressed in grams per day, at the beginning and end of the study. Serum creatinine, serum electrolytes, hemoglobin, albumin, cholesterol, TSH, FT4, and triglycerides were measured at the beginning of the study and every 4 weeks for 4 months.
Using a Web-based randomization system, we randomly assigned participants in a 1:1 ratio. Standard care was defined pragmatically; in both the study intervention and the standard care group, the nephrologist determined all aspects of clinical care, based on standard practice and individual patient needs, independent of the study intervention.
The study consisted of 3 phases. The first phase, with a duration of 8 to 12 weeks, consisted of enrolling patients and collecting demographic and clinical baseline measurements (proteinuria, lipid profile, serum electrolytes, arterial pressure, weight, TSH level, hemoglobin, and serum albumin). The second phase consisted of both groups being treated according to the allocation arm, and the third phase consisted of comparing the variables studied and the data analysis. The dose of LVX has previously been shown to be safe and efficient in adult patients with CKD.14,51
Our primary objective was to evaluate the effect of lowering TSH with the use of LVX or placebo to assess absolute levels at the beginning compared to the end of the study, when proteinuria was measured in urine collected for 24 hours. The secondary objectives were to evaluate the changes in sCr and eGFR and to assess the tolerability and safety of LVX and changes in cholesterol, triglycerides, LDL and blood pressure.
Interventions
The treating nephrologist and the patients were blinded to the study intervention.
If randomized to the intervention arm, the intervention consisted of treatment with oral levothyroxine (LVX) between 0.25 and 0.50 μg according to a dose of 0.3 to 0.5 μg/kg per day during fasting (in the case of taking a drug that interacts with the absorption, use of it was changed according to the hours specified). The dose adjustment was every 4 weeks. Levothyroxine or placebo was adjusted to 25 or 50 μg according to TSH levels (Table 1).Table 1 Dose adjustment of levothyroxine
TSH range Dose adjustment
TSH < 0.5 μIU/ml Suspend the pill
TSH (0.5–1 μIU/ml) Suspend the pill if it is at minimum dose
TSH (1.2–2.4 μIU/ml) Suspend the pill if it is at minimum dose
TSH (2.5–4.3 μIU/ml) Dose 25 μg/d
TSH (4.4–6.1 μIU/ml) Keep dose if 50 μg/d or increase if taking 25 μg/d
TSH (6.2–8 μIU/ml) Keep dose if 50 μg/d or increase if taking 25 μg/d
TSH (8.1–9.9 μIU/ml) Keep dose if 50 μg/d or increase if taking 25 μg/d
TSH, thyroid-stimulating hormone.
All vials (placebo or levothyroxine) presented drugs in one-quarter tablet = 25 μg the first month. In addition, the following months were adjusted according to the TSH range.
Participants allocated to placebo took 1 pill per day, with the same bottle characteristics as patients in the intervention arm, for >12 weeks.
The preparation and packaging of LVX and placebo were carried out by a pharmacist who was not involved in the development of the present study. All patients were followed up every 4 weeks for usual renal health consultation. In addition, the specific aspects of the protocol consisted of monitoring thyroid function for the adjustment of LVX or placebo dose according to the previous dosage adjustment.
To ascertain compliance and adherence to treatment, a record sheet was created with all drug supplied and returned. During the course of the study, the investigator was responsible for providing additional instructions to retrain any subjects who did not comply with the administration of the study drug or with attendance at the required clinical visits.
Adverse events were recorded during the follow-up, which included thyroid profile control tests every 4 weeks. Previously specified adverse effects were reported and followed up, and were rated in intensity according to the Common Terminology Criteria for Adverse Events (CTC) v. 3.0 (1–5), along with the start date and end date, as well as the treatment received.
This protocol was not sponsored or financed by any pharmaceutical company, nor are there any conflicts of interest on the part of the authors.
Statistical Analyses
The sample calculation was at will. The reason for this pilot trial was to investigate areas of uncertainty regarding future definitive randomized clinical trials on the effects of thyroid hormone reduction with levothyroxine on proteinuria in patients with advanced chronic kidney disease based on eGFR and proteinuria. This was a small-scale study conducted to test the plan and method of a research study; this pilot study addresses treatment safety assessments, determination of dose levels and response, and estimation of the effect of treatment and its variance.
The methodology for a clinical trial of superiority was carried out. Parametric continuous variables are given as the mean and SD, and nonparametric continuous variables are reported as medians. Comparisons were made using the Student t test or the Mann−Whitney test. Categorical variables are presented as percentages and were compared using the χ2 test or Fisher exact test. The prespecified threshold for significance was a P value <0.05. All statistical analyses were performed using the statistical programs SPSS version 20 (SPSS IBM Corporation, Armonk, NY) and GraphPad 7 (GraphPad Software, San Diego, CA).
Results
From March to November 2018, a total of 163 patients attended the Renal Health Clinic and were considered for participation. Of the patients, 125 were excluded because 64 did not meet the inclusion criteria, 56 patients decided not to participate, and another 5 did not meet the other specifications. Only 38 patients provided consent to participate. Of these, 6 patients were lost during follow-up, leaving a total of 32 patients (77.2%) to be analyzed. Of those, 14 patients (43.75%) were randomized to the placebo group and 18 (56.25%) to the LVX group (Figure 1).Figure 1 Flowchart during the study period.
Baseline clinical and demographic characteristics are shown in Table 2. Both groups had similar characteristics with respect to sex, age, number of comorbidities, CKD grade, weight, albumin, eGFR, hemoglobin, systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid profile, and proteinuria, except for the statistically higher TSH, sCr and LDL levels in the LVX group. At baseline, the mean (SD) levels of LDL cholesterol were significantly lower in the placebo group than in the LVX group (75.5 ± 19 mg/dl and 102.38 ± 31-42 ng/dl, respectively, P = 0.01). The TSH levels in the placebo group were significantly lower than those in the LVX group (4.46 ± 1.68 μIU/ml and 5.93 ± 2.2 μIU/ml, respectively; P = 0.02). The sCr levels of the placebo group were significantly higher than those of the LVX group (3.05 SD ± 1.65 mg/dl and 2.46 SD ± 1.13 mg/dl, respectively, P = 0.05).Table 2 Demographic and clinical baseline characteristics
Baseline characteristics Placebo (n = 14) Levothyroxine (n = 18) All (N = 32) P value
Sex, n, % female 10 (71.42) 10 (55.55) 20 (62.5) NA
Age, yr, SD 63.85 ± 15 69.22 ± 8.7 66.87 ± 12.19 0.41
Diabetes mellitus 11 (78.57) 13 (72.22) 24 (75) 1.00
Hypertensionn 12 (85.71) 16 (88.88) 28 (87.5) 1.00
Weight, kg, SD 67.90 ± 13.83 67.01 ± 11.32 67.55 ± 12.13 0.88
Obesity (BMI >30 kg/m2) 1 (7.14) 3 (6.6) 4 (12.5) 0.61
CKD G3a (45–59 ml/min per 1.73 m2) 0 3 (16.6) 3 (9.37) 0.23
CKD G3b (30–44 ml/min per 1.73 m2), 2 (14.28) 4 (22.22) 6 (18.75) 0.67
CKD G4 (15–29 ml/min per 1.73 m2) 5 (35.71) 7 (38.88) 12 (37.5) 1.00
CKD G5 (<15 ml/min per /1.73 m2) 7 (50) 4 (22.22) 11 (34.37) 0.14
eGFR (ml/min per 1.73 m2) 18.14 ± 9.96 27.72 ± 13.38 23.55 ± 12.91 0.078
TSH, μIU/ml 4.46 ± 1.68 6.08 ± 2.18 5.37 ± 2.13 0.02
T4L, ng/dl 0.93 ± 0.12 0.99 ± 0.14 0.96 ± 0.13 0.65
Proteinuria grams/d urine collection 1.28 ± 1.28 1.71 ± 1.20 1.52 ± 1.12 0.14
sCr, mg/dl 3.65 ± 1.65 2.46 ± 1.13 2.98 ± 1.51 0.05
Albumin, mg/dl 3.99 ± 0.41 3.8 ± 0.41 3.88 ± 0.42 0.24
Triglycerides, mg/dl 194 ± 75.3 144.66 ± 91.76 172.5 ± 87.71 0.09
Cholesterol, mg/dl 170.57 ± 45.96 165.5 ± 59.67 167.71 ± 54.16 0.67
LDL, mg/dl 75.5 ± 19 102.38 ± 31.42 90.62 ± 29.86 0.01
Hemoglobin, g/dl 11.37 ± 1.21 11.95 ± 1.61 11.72 ± 1.48 0.17
SBP, mm Hg 148.14 ± 27.7 160 ± 19.4 154.81 ± 24.14 0.17
DBP, mm Hg 79 ± 11.72 81.83 ± 8.2 80.59 ± 10 0.60
ACEI or ARB 14 (100) 18 (100) 32 (100) 1.00
Allopurinol 14 (100) 18 (100) 32 (100) 1.00
Statin 14 (100) 18 (100) 32 (100) 1.00
ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensinogen receptor blockers; BMI, body mass index; DBP, diastolic blood pressure; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; G, grade; kg, kilograms; LDL, low-density cholesterol; NA, not available; SBP, systolic blood pressure; sCr, serum creatinine.
Data are n (%) or ±SD, unless otherwise noted.
The primary objective, measured at 3 months of randomization, is presented in Table 3 and Figure 2. A total of 32 patients were analyzed, 14 in the placebo group and 18 in the LVX group, whereas 6 were lost during follow-up. The mean (SD) proteinuria at 3 months in the LVX group was 0.89 ± 1.28 g/d, and in the placebo group 1.35 ± 0.85 g/d. When compared to placebo, LVX showed a significant decrease in proteinuria of 1.1 g/d (P = 0.0011).Table 3 Clinical and laboratory variable changes at the end of the study period (12 weeks), according to the placebo or levothyroxine group
Primary objective Placebo Levothyroxine P value
Proteinuria, g/d +0.2 (−0.4 to 2.1)
(1.35 ± 0.85) −1.1 (−4.1 to 0.9)
(0.89 ± 1.28) 0.0011
Secondary objectives
Changes in eGFR, ml/min per 1.73 m2 −1.96 (−5 to 3)
(16.18 ± 8.37) 4.04 (9.8 to −2)
(31.76 ± 11.9) 0.049
sCr, mg/dl 0.05 (−0.5 to 1.49)
(3.71 ± 1.55) −0.2 (−0.7 to 0.5)
(2.36 ± 1.27) 0.32
Cholesterol, mg/dl −28.46 (107 to 26)
(142.11 ± 44.05) −18 (−57 to 37)
(147.5 ± 30.8) 0.18
Triglycerides, mg/dl −21(−94 to 108)
(173.2 ± 51.46) −14.6 (−286 to 66)
(130 ± 41.79) 0.71
SBP, mm Hg −2.5 (−57 to 35)
(145.64 ± 18.58) −5.5 (−75 to 57)
(154.5 ± 26.38) 0.33
DBP, mm Hg −6.43 (−17 to 14)
(72.57 ± 9.78) −9.06 (−20 to 10)
(72.77 ± 11.51) 0.33
TSH, μIU/ml −0.4 (−3.09 to 1.87)
(3.97 ± 1.77) −3.2 (−6.8 to 1.6)
(3.2 ± 1.5) 0.0032
T4L, ng/dl −0.1 (−0.18 to 0.12)
0.92 ± 0.24 0.05 (−0.38 to 0.4)
1.04 ± 0.21 0.77
Weight, kg 1.63 (−3.5 to 5.5)
(68.96 ± 14.65) −1.05 (−3.5 to 2.1)
(65.86 ± 11.65) 0.20
DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure; sCr, serum creatinine; TSH, thyroid-stimulating hormone.
Figure 2 Proteinuria (in grams per day) at the end of the study period (12 weeks) in the placebo and levothyroxine groups.
The comparative secondary objectives are presented in Table 3 and Figure 3. For the eGFR, the LVX group showed an improvement of 4.04 ml/min per 1.73 m2 (P = 0.049); in the placebo group, there was a decrease of 1.96 ml/min per 1.73 m2. The placebo group showed a decrease in TSH of 0.4 μIU/ml, and the LVX group showed a decrease in TSH of 3.2 μIU/ml (P = 0.0032). When comparing the weight reduction, the LVX arm showed a reduction in weight of −1.05 ± 3.72 kg, whereas the placebo group showed an increase in weight of 1.63 SD ± 5.59 kg (P = 0.20). For sCr, cholesterol, triglycerides, LDL, SBP, and DBP, there were no differences between the groups at 3 months (Figure 3). Adverse effects are shown in Table 4. Urinary tract infection presented in 1 patient in the placebo group (7.14%) and nervousness in 2 patients in the LVX group (11.11%) (relative risk 1.55 95% confidence interval 0.15-15.47, P = 1.0). No patients left the study because of adverse effects. Adverse events were not severe according to the severity scale.Figure 3 Clinical and laboratory variable changes at the end of the study period (12 weeks), according to placebo or levothyroxine group. (a) Serum thyroid-stimulating hormone (TSH); (b) serum FT4; (c) serum creatinine (sCr); (d) estimated glomerular filtration rate (eGFR); (e) serum cholesterol; (f) serum triglycerides; (g) systolic blood pressure (SBP); (h) diastolic blood pressure (DBP); (i) Weight loss (in kilograms). CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.
Table 4 Adverse events during the study period
Group n (%) Outcome
LVX group 1 (7.14) Urinary tract infectiona
Placebo group 2 (11.11) Anxietyb
CI, confidence interval; LVX, levothyroxine; RR, relative risk.
RR = 1.55, 95% CI 0.15–15.47, P = 1.0.
a Urinary tract infection: duration of 5 days, without complications.
b Anxiety: duration of 3 days, without complications.
Discussion
This pilot randomized, single-center, double-blind study in patients with advanced proteinuric CKD demonstrated that administering LVX to obtain a normal TSH range decreased proteinuria and improved eGFR, with few adverse events.
The management of proteinuria in CKD is mainly due to the effects of blocking the renin−angiotensin−aldosterone system (RAAS), such as with ACEIs and ARBs,35,36 and other drugs to a lesser magnitude, such as allopurinol,55 aldosterone antagonists,37, 38, 39, 40 statins,41,42 and calcitriol44, 45, 46, 47; however, despite these treatments, there is still residual proteinuria that contributes to the deterioration of renal function and cardiovascular risk.2 Proteinuria in hypothyroid human beings and rats has been related to RAAS activity,9 blood pressure, and oxidative stress, although it may be a reflection of glomerular hypertension and decreased glomerular filtration rate,5 changes in the management of tubular proteins, or changes in the structure of the glomerular barrier, specifically at the podocyte and megalin.8,9 In our study, the significant decrease in proteinuria of 1.1 g/d in the LVX group could be explained by the normalization of the TSH range. In addition, the antiproteinuric benefit observed with LVX could be explained by the alteration of glomerular pressure due to the negative inotropic effect on the heart, reduction in the circulating intravascular volume, and increase in peripheral resistance, with renal vasoconstriction adding a counterregulatory effect of RAAS, as well as changes at the level of the glomerular, tubular, and podocyte basal membrane.5,10 Higher baseline ranges were observed for TSH, LDL, and sCr in the LVX group, which could explain why the higher the TSH, the greater the effect on proteinuria.14,50,51 It is very important to consider the administration of LVX in patients with CKD and alterations in TSH for a greater benefit in decreasing proteinuria, thus adding the correlation that thyroid hormone in endothelial damage and in cardiovascular risk could also decrease mortality and decrease eGFR.14,19,50,52
In our study, eGFR increased in the LVX group by 4 ml/min per 1.73 m2, compared to that in the placebo group, in which eGFR decreased by 2 ml/min per 1.73 m2. Van Welsem et al.9 reported that the normalization of hypothyroidism after treatment with LVX led to a significant improvement in renal function in a patient with CKD.5 In addition, Shin et al. demonstrated that reaching a TSH goal of 1 to 4.5 μIU/ml with LVX at a dose of 25 to 50 μg/d improved the eGFR +4.31 ± 0.5 ml/min per 1.73 m2.51 Chang et al. used a TSH goal of 1.16-2.86 μIU/ml with a dose of LVX 25 μg/d and obtained an improvement in eGFR +5.77 ml/min per 1.73 m2 (P = 0.015).14
Although previous studies have shown that LVX improves cardiac function, renal function, and dyslipidemia and delays progression of CKD that is already established in patients with SCH, there is still a lack of consensus in the current guidelines on whether to treat SCH in patients with CKD. In particular, little is known about the effect of thyroid hormone replacement on changes in eGFR.21, 22, 23, 24 Some studies exist comparing CKD and thyroid disorders in which normal TSH ranges were maintained and an improvement in the progression of CKD, decreased proteinuria,5,9,13,17 improved lipid profile,37 and lower cardiovascular risk were observed.20 Rhee et al. found, in more than 220,000 patients, that at TSH levels >3 μIU/ml and TSH <0.5 μIU/ml, there is a higher mortality rate in patients with CKD G3.19
There are already studies in which the elevation of TSH is associated with the progression of CKD.14,15 In patients already undergoing renal replacement therapy, such as hemodialysis with elevated TSH, it was associated with mortality,21, 22, 23 similar to peritoneal dialysis.24
We sought to reinforce these benefits of maintaining a range of TSH (<4.5 μIU/ml, considering previous studies in which mortality was associated with TSH >2.5 μIU/ml).19,29 In addition, some authors have reported a greater progression to terminal CKD and mortality in patients with SCH versus euthyroid hypothyroidism.19,20 The American25 and European guidelines27 do not mention the potential benefit of the use of LVX and its impact in patients with CKD and SCH.
Another possibility of improving proteinuria and eGFR is that by decreasing TSH, an increase in catabolism and weight reduction was achieved, eliminating hyperfiltration and proteinuria. It should be mentioned that at the beginning of the study, only 4 patients had a BMI >30 kg/m2, 1 patient from the placebo group and 3 patients from the LVX group (P = 0.61), and the differences in weight loss (in kilograms) at the end of the study were higher in the LVX group than in the placebo group, with an average of −1.05 SD ± 3.72 kg and 1.63 SD ± 5.59 kg, respectively, but the differences were not significant (P = 0.20). Among the other variables relevant to this study, there were no significant changes in BP or HR.
Regarding tolerance, the use of LVX was safe, there were no severe adverse events, and no patient had to discontinue the study drug. However, more patients in the LVX dose adjustment were required (relative risk = 1.55, 95% confidence interval = 0.15−15.47, P = 1.0). In previous studies, no serious adverse effects have been reported when giving LVX to patients with CKD, considering that they are patients with cardiovascular risk.25,26 This information can be interpreted as showing that LVX is a useful treatment in hypothyroidism and that the risk is minimal.28,29
Several limitations need to be acknowledged. This paper presents the results of a small, single-center, randomized controlled pilot clinical trial. As such, estimates of treatment effects may be overoptimistic and/or unique to the population studied. The main analyses did not impute missing data, which, in both the placebo and LVX groups, were assumed to be missing at random. Other limitations of our study include the racial homogeneity of the study population and the short treatment duration (12 weeks). The sustainability of these effects over a longer time period needs to be confirmed in longer-term studies. However, the results demonstrate that the study intervention is feasible and has promising effects on multiple measures of renal function. Another limitation is that TSH levels were different at the time of randomization, although we believe that this had no impact on the final result, as both groups were in ranges of abnormality. Furthermore, there is no objective evidence to suggest that the study population is unique. However, as with all pilot projects, our findings remain exploratory and hypothesis generating.
In conclusion, this single-center, randomized, double-blind, placebo-controlled pilot clinical study in patients with advanced proteinuric CKD who already used ACEIs or ARBs demonstrated that administering LVX to obtain a TSH range close to 2.5 μIU/ml decreased proteinuria and improved eGFR. These findings could encourage the performance of a clinical trial with sufficient statistical power to demonstrate the benefit of normalizing TSH with LVX in patients with CKD.
Disclosure
All the authors declared no competing interests.
Supplementary Material
Supplementary File (Word)
Table S1. Drugs that interact with levothyroxine.
Acknowledgments
Clinical trial registration number: NCT03898622.
Supplementary File (Word)
Table S1. Drugs that interact with levothyroxine. | 25 MCG | DrugDosageText | CC BY-NC-ND | 33426390 | 18,754,150 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Demyelination'. | Renal cell carcinoma with central nervous system demyelination caused by nivolumab.
Central nervous system demyelination caused by immune checkpoint inhibitors is a very rare condition.
A 65-year-old man who received nivolumab for renal cell carcinoma developed abnormal behavior, such as disagreeable speech and sudden anger. Brain-enhanced magnetic resonance imaging revealed multiple lesions with partial contrast effects in the cerebral white matter. We tentatively diagnosed demyelination caused by nivolumab, and performed steroid pulse therapy twice. After that, his symptoms improved. For the next 2 years, his symptoms did not recur, nor did his cancer progress.
Demyelination caused by immune checkpoint inhibitors can be fatal and requires early diagnosis and treatment.
Abbreviations & Acronyms
CNScentral nervous system
CTcomputed tomography
CTCAECommon Terminology Criteria for Adverse Events
ICIimmune checkpoint inhibitor
irAEimmune‐related adverse event
IVIGintravenous immunoglobulin
MRImagnetic resonance imaging
MSmultiple sclerosis
mPSLmethylprednisolone
PD‐1programmed cell death 1
RCCrenal cell carcinoma
Keynote message
Although CNS demyelination owing to ICIs is a rare disorder, it causes neurological symptoms and can be fatal. Early diagnosis and treatment are crucial. Steroids may be required, depending on symptoms.
Introduction
Nivolumab, an anti‐PD‐1 inhibitor, is widely used to treat various cancers, including RCC; however, numerous irAEs have been reported. Neurologic irAEs are relatively rare,
1
especially neurologic irAEs with CNS demyelination. Here, we report an extremely rare case of RCC with CNS demyelination caused by nivolumab.
Case presentation
A 52‐year‐old man underwent a left nephrectomy in another hospital for left RCC in 2004 (pathological diagnosis unknown). He developed left lung metastases in 2010, and started treatment with interferon‐α. Right renal metastasis also appeared in 2010 (Fig. 1a), so he was referred to our hospital and underwent a right partial nephrectomy. Later, he also underwent a left partial pneumonectomy (Fig. 1b,c). The histopathological finding of each excised tissue showed clear cell RCC. In April 2015, he began sunitinib treatment for multiple lung metastases (Fig. 1d,e) (International Metastatic RCC Database Consortium risk group was favorable), but a lumbar spine metastasis was found in February 2016 (Fig. 1f). His medication was switched from sunitinib to axitinib in November 2016. In October 2017, he began taking nivolumab because of the progression of lung metastases and appearance of left hilar lymph node disease (Fig. 1g,h). In January 2018, he received a transarterial embolization for his left hilar lymph node, because of progressive disease. Both the hilar lymph node and lung disease showed durable responses.
Fig. 1 The CT images are shown. An arrow indicates a metastatic lesion. (a) 16‐mm enhanced mass in the lower pole of right kidney; (b) 9‐mm coin lesion in the upper lobe of left lung; (c) 8‐mm coin lesion in the lower lobe of left lung; (d) 8‐mm coin lesion near the hilum of right lung; (e) 5‐mm coin lesion in the middle lobe of right lung; (f) 15‐mm osteolytic lesion in the second lumbar spine; (g) 13‐mm coin lesion in the lower lobe of left lung; (h) 42‐mm left hilar lymph node.
Three days after his 11th nivolumab administration, he began displaying abnormal behavior, such as disagreeable speech and sudden anger. Eleven days later, he also developed a short‐term memory loss and calculation disorder and was hospitalized on the same day. Brain MRI showed multiple lesions, with high signals in T2‐weighted images in his cerebral white matter (Fig. 2a,b). Their open‐ring signs suggested demyelination rather than metastatic tumors (Fig. 2c,d). Demyelination caused by nivolumab was considered to be likely, although we need to rule out infectious diseases, collagen diseases, and MS. His cerebrospinal fluid showed normal glucose, protein, and white blood cell count, presence of oligoclonal bands; normal levels of myelin basic protein, immunoglobulin G, and immunoglobulin A for toxoplasma, and negative JC viral DNA. No malignant cells were found in the cerebrospinal fluid. Most autoantibodies, including anti‐aquaporin 4 antibody, were negative except anti‐nuclear antibody. On the basis of the above examinations, we diagnosed CNS demyelination caused by nivolumab, which was classified as a grade 2 adverse effect in accordance with the CTCAE version 5.0.
Fig. 2 Brain MRI shows high signal in T2‐weighted images and diffusion‐weighted images in the cerebral white matter (arrows: CNS demyelination). (a) T2‐weighted images; (b) diffusion‐weighted images; (c) brain‐enhanced MRI shows an open‐ring sign; (d) enlarged image of panel c.
Nivolumab was ceased and intravenous mPSL (1 g/day) was administered for 3 days from the day of his hospital admission. However, as his neurological symptoms did not greatly improve, we began intravenous mPSL (1 g/day) again for 3 days from the eighth day of hospitalization. He then began to show improvement of abnormal behavior as well as imaging findings. Neurological symptoms, such as disagreeable speech and sudden anger, subsided completely. He was discharged on the 23rd hospital day and fully recovered a short‐term memory loss and calculation disorder 3 months after the onset. No steroid was administered other than intravenous mPSL for a total of 6 days. After 6 months, his brain MRI showed further improvement of multiple lesions in the cerebral white matter (Fig. 3). Nivolumab has been discontinued and neither neurologic symptoms nor progression of RCC have been observed for 26 months without any treatment.
Fig. 3 Brain MRI (T2‐weighted images) taken 6 months after discharge showed further improvement of multiple lesions in the cerebral white matter (arrows: CNS demyelination).
Discussion
A report of 9208 patients treated with ICIs, enrolled in 59 clinical trials, showed that 3.8% of patients were treated with cytotoxic T‐lymphocyte‐associated protein‐4 inhibitor, 6.1% of those with PD‐1 inhibitor and 12.0% of those with both agents had neurologic irAEs.
1
Yet, neurologic irAEs with CNS demyelination are rare conditions. Neurologic irAEs encompass a broad spectrum of neurologic syndromes, including myasthenic syndrome, aseptic meningitis, encephalitis, sensory motor neuropathy, Guillain‐Barré‐like syndromes, painful sensory neuropathy, enteric neuropathy, transverse myelitis, and posterior reversible encephalopathy syndrome.
2
To diagnose neurologic irAEs, infectious diseases, cancer invasion to CNS, paraneoplastic syndrome, and metabolic disorders must be ruled out. Blood tests that include hormone levels, cerebrospinal fluid tests, and brain‐enhanced MRI are essential.
3
In patients with CTCAE grade 1 neurologic symptoms, ICIs should be continued under close observation. Among those with CTCAE grade ≥2 neurological symptoms, administration of corticosteroids equivalent to mPSL (1–4 mg/kg), and discontinuation of ICIs, or treatment such as IVIG, plasma exchange, and steroid pulse are required depending on severity.
2
To our knowledge, only eight cases of CNS demyelination owing to ICIs have been reported, including the present case (Table 1).
4
,
5
,
6
,
7
,
8
,
9
,
10
Our report is the first case of CNS demyelination caused by nivolumab to treat RCC. All other reported patients were treated with steroids except for one patient with no symptoms who was relieved by only discontinuation of nivolumab. IVIG, plasma exchange, and immunosuppressant were added in some cases. In previous reports, most patients with irAEs involving the CNS had onset of symptoms <4 days after administering nivolumab, and symptoms became progressively worse within 2 weeks.
8
Except for one patient with unknown details, all eight patients improved in response to treatment. However, one died from relapsed CNS demyelination, and two died from complications of steroid treatment. As four cases out of eight died, CNS demyelination caused by ICIs can be fatal. We tried the second steroid pulse therapy in the same manner as for MS, which is a CNS demyelinating disease with a clinical picture similar to our case. Since the neurological symptoms were not severe and subsided after the second administration of mPSL, we decided to follow‐up carefully without continuing steroid administration.
Table 1 Review of cases of cerebral nervous system demyelination secondary to treatment with ICIs
Case Author/year Underlying disease Suspected drug Symptom Treatment provided Responsiveness to treatment Outcome
1 Maurice et al.
4
/2015 Melanoma Nivolumab Confusion mPSL After remission, symptoms reappear Died due to demyelinating disease
Nausea IVIG
Vomiting
Apathy
Fixed gaze
Psychomotor slowing
2 Cao et al.
5
/2016 Melanoma Ipilimumab Fatigue mPSL Unknown Died
Memory loss Cyclophosphamide
Vision change
3 Sugiura et al.
6
/2017 Lung cancer Nivolumab Low motivation mPSL Improvement Died due to cytomegalovirus ulcer in the lower intestinal tract
Wobbling
4 Mancone et al.
7
/2018 Melanoma Nivolumab Gait imbalance mPSL Mild improvement Died due to urinary tract infection
Ipilimumab Lower extremity weakness IVIG
5 Zafer et al.
8
/2019 Laryngeal cancer Nivolumab Diffuse generalized slowing mPSL Improvement Survived
IVIG
6 Pillonel et al.
9
/2019 Melanoma Nivolumab No symptom Only discontinue of nivolumab Improvement Survived
7 Duraes et al.
10
/2019 Melanoma Pembrolizumab Distal numbness of the limbs Intravenous steroid Improvement Survived
Weakness with gait impairment Plasma exchange
8 Our case Renal cell Nivolumab
Disagreeable speech
Sudden anger
Memory loss
Calculation disorder
mPSL Improvement Survived
carcinoma
John Wiley & Sons, LtdAn autopsy for a patient with CNS demyelination revealed infiltration of CD8+ T cells into the margin of the demyelinating lesion.
4
Furthermore, a pathway in which CD8+ T cells damaged the myelin sheath has been reported for MS.
11
Furthermore, others have reported that the autopsy of MS patients showed no PD‐1 expression by CD8+ T cells that infiltrate the lesion site.
12
These facts support the hypothesis that the CD8+ T cells whose PD‐1 receptors are inhibited by nivolumab may injure the myelin sheath and cause CNS demyelination.
Conclusion
We experienced a case of RCC with demyelination of the CNS owing to nivolumab. Because this condition may be fatal, early diagnosis and treatment are necessary.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgment
We thank Marla Brunker, from Edanz Group (https://en‐author‐services.edanzgroup.com/), for editing a draft of this manuscript. | NIVOLUMAB | DrugsGivenReaction | CC BY | 33426497 | 15,407,618 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant neoplasm progression'. | Renal cell carcinoma with central nervous system demyelination caused by nivolumab.
Central nervous system demyelination caused by immune checkpoint inhibitors is a very rare condition.
A 65-year-old man who received nivolumab for renal cell carcinoma developed abnormal behavior, such as disagreeable speech and sudden anger. Brain-enhanced magnetic resonance imaging revealed multiple lesions with partial contrast effects in the cerebral white matter. We tentatively diagnosed demyelination caused by nivolumab, and performed steroid pulse therapy twice. After that, his symptoms improved. For the next 2 years, his symptoms did not recur, nor did his cancer progress.
Demyelination caused by immune checkpoint inhibitors can be fatal and requires early diagnosis and treatment.
Abbreviations & Acronyms
CNScentral nervous system
CTcomputed tomography
CTCAECommon Terminology Criteria for Adverse Events
ICIimmune checkpoint inhibitor
irAEimmune‐related adverse event
IVIGintravenous immunoglobulin
MRImagnetic resonance imaging
MSmultiple sclerosis
mPSLmethylprednisolone
PD‐1programmed cell death 1
RCCrenal cell carcinoma
Keynote message
Although CNS demyelination owing to ICIs is a rare disorder, it causes neurological symptoms and can be fatal. Early diagnosis and treatment are crucial. Steroids may be required, depending on symptoms.
Introduction
Nivolumab, an anti‐PD‐1 inhibitor, is widely used to treat various cancers, including RCC; however, numerous irAEs have been reported. Neurologic irAEs are relatively rare,
1
especially neurologic irAEs with CNS demyelination. Here, we report an extremely rare case of RCC with CNS demyelination caused by nivolumab.
Case presentation
A 52‐year‐old man underwent a left nephrectomy in another hospital for left RCC in 2004 (pathological diagnosis unknown). He developed left lung metastases in 2010, and started treatment with interferon‐α. Right renal metastasis also appeared in 2010 (Fig. 1a), so he was referred to our hospital and underwent a right partial nephrectomy. Later, he also underwent a left partial pneumonectomy (Fig. 1b,c). The histopathological finding of each excised tissue showed clear cell RCC. In April 2015, he began sunitinib treatment for multiple lung metastases (Fig. 1d,e) (International Metastatic RCC Database Consortium risk group was favorable), but a lumbar spine metastasis was found in February 2016 (Fig. 1f). His medication was switched from sunitinib to axitinib in November 2016. In October 2017, he began taking nivolumab because of the progression of lung metastases and appearance of left hilar lymph node disease (Fig. 1g,h). In January 2018, he received a transarterial embolization for his left hilar lymph node, because of progressive disease. Both the hilar lymph node and lung disease showed durable responses.
Fig. 1 The CT images are shown. An arrow indicates a metastatic lesion. (a) 16‐mm enhanced mass in the lower pole of right kidney; (b) 9‐mm coin lesion in the upper lobe of left lung; (c) 8‐mm coin lesion in the lower lobe of left lung; (d) 8‐mm coin lesion near the hilum of right lung; (e) 5‐mm coin lesion in the middle lobe of right lung; (f) 15‐mm osteolytic lesion in the second lumbar spine; (g) 13‐mm coin lesion in the lower lobe of left lung; (h) 42‐mm left hilar lymph node.
Three days after his 11th nivolumab administration, he began displaying abnormal behavior, such as disagreeable speech and sudden anger. Eleven days later, he also developed a short‐term memory loss and calculation disorder and was hospitalized on the same day. Brain MRI showed multiple lesions, with high signals in T2‐weighted images in his cerebral white matter (Fig. 2a,b). Their open‐ring signs suggested demyelination rather than metastatic tumors (Fig. 2c,d). Demyelination caused by nivolumab was considered to be likely, although we need to rule out infectious diseases, collagen diseases, and MS. His cerebrospinal fluid showed normal glucose, protein, and white blood cell count, presence of oligoclonal bands; normal levels of myelin basic protein, immunoglobulin G, and immunoglobulin A for toxoplasma, and negative JC viral DNA. No malignant cells were found in the cerebrospinal fluid. Most autoantibodies, including anti‐aquaporin 4 antibody, were negative except anti‐nuclear antibody. On the basis of the above examinations, we diagnosed CNS demyelination caused by nivolumab, which was classified as a grade 2 adverse effect in accordance with the CTCAE version 5.0.
Fig. 2 Brain MRI shows high signal in T2‐weighted images and diffusion‐weighted images in the cerebral white matter (arrows: CNS demyelination). (a) T2‐weighted images; (b) diffusion‐weighted images; (c) brain‐enhanced MRI shows an open‐ring sign; (d) enlarged image of panel c.
Nivolumab was ceased and intravenous mPSL (1 g/day) was administered for 3 days from the day of his hospital admission. However, as his neurological symptoms did not greatly improve, we began intravenous mPSL (1 g/day) again for 3 days from the eighth day of hospitalization. He then began to show improvement of abnormal behavior as well as imaging findings. Neurological symptoms, such as disagreeable speech and sudden anger, subsided completely. He was discharged on the 23rd hospital day and fully recovered a short‐term memory loss and calculation disorder 3 months after the onset. No steroid was administered other than intravenous mPSL for a total of 6 days. After 6 months, his brain MRI showed further improvement of multiple lesions in the cerebral white matter (Fig. 3). Nivolumab has been discontinued and neither neurologic symptoms nor progression of RCC have been observed for 26 months without any treatment.
Fig. 3 Brain MRI (T2‐weighted images) taken 6 months after discharge showed further improvement of multiple lesions in the cerebral white matter (arrows: CNS demyelination).
Discussion
A report of 9208 patients treated with ICIs, enrolled in 59 clinical trials, showed that 3.8% of patients were treated with cytotoxic T‐lymphocyte‐associated protein‐4 inhibitor, 6.1% of those with PD‐1 inhibitor and 12.0% of those with both agents had neurologic irAEs.
1
Yet, neurologic irAEs with CNS demyelination are rare conditions. Neurologic irAEs encompass a broad spectrum of neurologic syndromes, including myasthenic syndrome, aseptic meningitis, encephalitis, sensory motor neuropathy, Guillain‐Barré‐like syndromes, painful sensory neuropathy, enteric neuropathy, transverse myelitis, and posterior reversible encephalopathy syndrome.
2
To diagnose neurologic irAEs, infectious diseases, cancer invasion to CNS, paraneoplastic syndrome, and metabolic disorders must be ruled out. Blood tests that include hormone levels, cerebrospinal fluid tests, and brain‐enhanced MRI are essential.
3
In patients with CTCAE grade 1 neurologic symptoms, ICIs should be continued under close observation. Among those with CTCAE grade ≥2 neurological symptoms, administration of corticosteroids equivalent to mPSL (1–4 mg/kg), and discontinuation of ICIs, or treatment such as IVIG, plasma exchange, and steroid pulse are required depending on severity.
2
To our knowledge, only eight cases of CNS demyelination owing to ICIs have been reported, including the present case (Table 1).
4
,
5
,
6
,
7
,
8
,
9
,
10
Our report is the first case of CNS demyelination caused by nivolumab to treat RCC. All other reported patients were treated with steroids except for one patient with no symptoms who was relieved by only discontinuation of nivolumab. IVIG, plasma exchange, and immunosuppressant were added in some cases. In previous reports, most patients with irAEs involving the CNS had onset of symptoms <4 days after administering nivolumab, and symptoms became progressively worse within 2 weeks.
8
Except for one patient with unknown details, all eight patients improved in response to treatment. However, one died from relapsed CNS demyelination, and two died from complications of steroid treatment. As four cases out of eight died, CNS demyelination caused by ICIs can be fatal. We tried the second steroid pulse therapy in the same manner as for MS, which is a CNS demyelinating disease with a clinical picture similar to our case. Since the neurological symptoms were not severe and subsided after the second administration of mPSL, we decided to follow‐up carefully without continuing steroid administration.
Table 1 Review of cases of cerebral nervous system demyelination secondary to treatment with ICIs
Case Author/year Underlying disease Suspected drug Symptom Treatment provided Responsiveness to treatment Outcome
1 Maurice et al.
4
/2015 Melanoma Nivolumab Confusion mPSL After remission, symptoms reappear Died due to demyelinating disease
Nausea IVIG
Vomiting
Apathy
Fixed gaze
Psychomotor slowing
2 Cao et al.
5
/2016 Melanoma Ipilimumab Fatigue mPSL Unknown Died
Memory loss Cyclophosphamide
Vision change
3 Sugiura et al.
6
/2017 Lung cancer Nivolumab Low motivation mPSL Improvement Died due to cytomegalovirus ulcer in the lower intestinal tract
Wobbling
4 Mancone et al.
7
/2018 Melanoma Nivolumab Gait imbalance mPSL Mild improvement Died due to urinary tract infection
Ipilimumab Lower extremity weakness IVIG
5 Zafer et al.
8
/2019 Laryngeal cancer Nivolumab Diffuse generalized slowing mPSL Improvement Survived
IVIG
6 Pillonel et al.
9
/2019 Melanoma Nivolumab No symptom Only discontinue of nivolumab Improvement Survived
7 Duraes et al.
10
/2019 Melanoma Pembrolizumab Distal numbness of the limbs Intravenous steroid Improvement Survived
Weakness with gait impairment Plasma exchange
8 Our case Renal cell Nivolumab
Disagreeable speech
Sudden anger
Memory loss
Calculation disorder
mPSL Improvement Survived
carcinoma
John Wiley & Sons, LtdAn autopsy for a patient with CNS demyelination revealed infiltration of CD8+ T cells into the margin of the demyelinating lesion.
4
Furthermore, a pathway in which CD8+ T cells damaged the myelin sheath has been reported for MS.
11
Furthermore, others have reported that the autopsy of MS patients showed no PD‐1 expression by CD8+ T cells that infiltrate the lesion site.
12
These facts support the hypothesis that the CD8+ T cells whose PD‐1 receptors are inhibited by nivolumab may injure the myelin sheath and cause CNS demyelination.
Conclusion
We experienced a case of RCC with demyelination of the CNS owing to nivolumab. Because this condition may be fatal, early diagnosis and treatment are necessary.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgment
We thank Marla Brunker, from Edanz Group (https://en‐author‐services.edanzgroup.com/), for editing a draft of this manuscript. | NIVOLUMAB | DrugsGivenReaction | CC BY | 33426497 | 15,407,618 | 2021-01 |
What is the weight of the patient? | Renal cell carcinoma with central nervous system demyelination caused by nivolumab.
Central nervous system demyelination caused by immune checkpoint inhibitors is a very rare condition.
A 65-year-old man who received nivolumab for renal cell carcinoma developed abnormal behavior, such as disagreeable speech and sudden anger. Brain-enhanced magnetic resonance imaging revealed multiple lesions with partial contrast effects in the cerebral white matter. We tentatively diagnosed demyelination caused by nivolumab, and performed steroid pulse therapy twice. After that, his symptoms improved. For the next 2 years, his symptoms did not recur, nor did his cancer progress.
Demyelination caused by immune checkpoint inhibitors can be fatal and requires early diagnosis and treatment.
Abbreviations & Acronyms
CNScentral nervous system
CTcomputed tomography
CTCAECommon Terminology Criteria for Adverse Events
ICIimmune checkpoint inhibitor
irAEimmune‐related adverse event
IVIGintravenous immunoglobulin
MRImagnetic resonance imaging
MSmultiple sclerosis
mPSLmethylprednisolone
PD‐1programmed cell death 1
RCCrenal cell carcinoma
Keynote message
Although CNS demyelination owing to ICIs is a rare disorder, it causes neurological symptoms and can be fatal. Early diagnosis and treatment are crucial. Steroids may be required, depending on symptoms.
Introduction
Nivolumab, an anti‐PD‐1 inhibitor, is widely used to treat various cancers, including RCC; however, numerous irAEs have been reported. Neurologic irAEs are relatively rare,
1
especially neurologic irAEs with CNS demyelination. Here, we report an extremely rare case of RCC with CNS demyelination caused by nivolumab.
Case presentation
A 52‐year‐old man underwent a left nephrectomy in another hospital for left RCC in 2004 (pathological diagnosis unknown). He developed left lung metastases in 2010, and started treatment with interferon‐α. Right renal metastasis also appeared in 2010 (Fig. 1a), so he was referred to our hospital and underwent a right partial nephrectomy. Later, he also underwent a left partial pneumonectomy (Fig. 1b,c). The histopathological finding of each excised tissue showed clear cell RCC. In April 2015, he began sunitinib treatment for multiple lung metastases (Fig. 1d,e) (International Metastatic RCC Database Consortium risk group was favorable), but a lumbar spine metastasis was found in February 2016 (Fig. 1f). His medication was switched from sunitinib to axitinib in November 2016. In October 2017, he began taking nivolumab because of the progression of lung metastases and appearance of left hilar lymph node disease (Fig. 1g,h). In January 2018, he received a transarterial embolization for his left hilar lymph node, because of progressive disease. Both the hilar lymph node and lung disease showed durable responses.
Fig. 1 The CT images are shown. An arrow indicates a metastatic lesion. (a) 16‐mm enhanced mass in the lower pole of right kidney; (b) 9‐mm coin lesion in the upper lobe of left lung; (c) 8‐mm coin lesion in the lower lobe of left lung; (d) 8‐mm coin lesion near the hilum of right lung; (e) 5‐mm coin lesion in the middle lobe of right lung; (f) 15‐mm osteolytic lesion in the second lumbar spine; (g) 13‐mm coin lesion in the lower lobe of left lung; (h) 42‐mm left hilar lymph node.
Three days after his 11th nivolumab administration, he began displaying abnormal behavior, such as disagreeable speech and sudden anger. Eleven days later, he also developed a short‐term memory loss and calculation disorder and was hospitalized on the same day. Brain MRI showed multiple lesions, with high signals in T2‐weighted images in his cerebral white matter (Fig. 2a,b). Their open‐ring signs suggested demyelination rather than metastatic tumors (Fig. 2c,d). Demyelination caused by nivolumab was considered to be likely, although we need to rule out infectious diseases, collagen diseases, and MS. His cerebrospinal fluid showed normal glucose, protein, and white blood cell count, presence of oligoclonal bands; normal levels of myelin basic protein, immunoglobulin G, and immunoglobulin A for toxoplasma, and negative JC viral DNA. No malignant cells were found in the cerebrospinal fluid. Most autoantibodies, including anti‐aquaporin 4 antibody, were negative except anti‐nuclear antibody. On the basis of the above examinations, we diagnosed CNS demyelination caused by nivolumab, which was classified as a grade 2 adverse effect in accordance with the CTCAE version 5.0.
Fig. 2 Brain MRI shows high signal in T2‐weighted images and diffusion‐weighted images in the cerebral white matter (arrows: CNS demyelination). (a) T2‐weighted images; (b) diffusion‐weighted images; (c) brain‐enhanced MRI shows an open‐ring sign; (d) enlarged image of panel c.
Nivolumab was ceased and intravenous mPSL (1 g/day) was administered for 3 days from the day of his hospital admission. However, as his neurological symptoms did not greatly improve, we began intravenous mPSL (1 g/day) again for 3 days from the eighth day of hospitalization. He then began to show improvement of abnormal behavior as well as imaging findings. Neurological symptoms, such as disagreeable speech and sudden anger, subsided completely. He was discharged on the 23rd hospital day and fully recovered a short‐term memory loss and calculation disorder 3 months after the onset. No steroid was administered other than intravenous mPSL for a total of 6 days. After 6 months, his brain MRI showed further improvement of multiple lesions in the cerebral white matter (Fig. 3). Nivolumab has been discontinued and neither neurologic symptoms nor progression of RCC have been observed for 26 months without any treatment.
Fig. 3 Brain MRI (T2‐weighted images) taken 6 months after discharge showed further improvement of multiple lesions in the cerebral white matter (arrows: CNS demyelination).
Discussion
A report of 9208 patients treated with ICIs, enrolled in 59 clinical trials, showed that 3.8% of patients were treated with cytotoxic T‐lymphocyte‐associated protein‐4 inhibitor, 6.1% of those with PD‐1 inhibitor and 12.0% of those with both agents had neurologic irAEs.
1
Yet, neurologic irAEs with CNS demyelination are rare conditions. Neurologic irAEs encompass a broad spectrum of neurologic syndromes, including myasthenic syndrome, aseptic meningitis, encephalitis, sensory motor neuropathy, Guillain‐Barré‐like syndromes, painful sensory neuropathy, enteric neuropathy, transverse myelitis, and posterior reversible encephalopathy syndrome.
2
To diagnose neurologic irAEs, infectious diseases, cancer invasion to CNS, paraneoplastic syndrome, and metabolic disorders must be ruled out. Blood tests that include hormone levels, cerebrospinal fluid tests, and brain‐enhanced MRI are essential.
3
In patients with CTCAE grade 1 neurologic symptoms, ICIs should be continued under close observation. Among those with CTCAE grade ≥2 neurological symptoms, administration of corticosteroids equivalent to mPSL (1–4 mg/kg), and discontinuation of ICIs, or treatment such as IVIG, plasma exchange, and steroid pulse are required depending on severity.
2
To our knowledge, only eight cases of CNS demyelination owing to ICIs have been reported, including the present case (Table 1).
4
,
5
,
6
,
7
,
8
,
9
,
10
Our report is the first case of CNS demyelination caused by nivolumab to treat RCC. All other reported patients were treated with steroids except for one patient with no symptoms who was relieved by only discontinuation of nivolumab. IVIG, plasma exchange, and immunosuppressant were added in some cases. In previous reports, most patients with irAEs involving the CNS had onset of symptoms <4 days after administering nivolumab, and symptoms became progressively worse within 2 weeks.
8
Except for one patient with unknown details, all eight patients improved in response to treatment. However, one died from relapsed CNS demyelination, and two died from complications of steroid treatment. As four cases out of eight died, CNS demyelination caused by ICIs can be fatal. We tried the second steroid pulse therapy in the same manner as for MS, which is a CNS demyelinating disease with a clinical picture similar to our case. Since the neurological symptoms were not severe and subsided after the second administration of mPSL, we decided to follow‐up carefully without continuing steroid administration.
Table 1 Review of cases of cerebral nervous system demyelination secondary to treatment with ICIs
Case Author/year Underlying disease Suspected drug Symptom Treatment provided Responsiveness to treatment Outcome
1 Maurice et al.
4
/2015 Melanoma Nivolumab Confusion mPSL After remission, symptoms reappear Died due to demyelinating disease
Nausea IVIG
Vomiting
Apathy
Fixed gaze
Psychomotor slowing
2 Cao et al.
5
/2016 Melanoma Ipilimumab Fatigue mPSL Unknown Died
Memory loss Cyclophosphamide
Vision change
3 Sugiura et al.
6
/2017 Lung cancer Nivolumab Low motivation mPSL Improvement Died due to cytomegalovirus ulcer in the lower intestinal tract
Wobbling
4 Mancone et al.
7
/2018 Melanoma Nivolumab Gait imbalance mPSL Mild improvement Died due to urinary tract infection
Ipilimumab Lower extremity weakness IVIG
5 Zafer et al.
8
/2019 Laryngeal cancer Nivolumab Diffuse generalized slowing mPSL Improvement Survived
IVIG
6 Pillonel et al.
9
/2019 Melanoma Nivolumab No symptom Only discontinue of nivolumab Improvement Survived
7 Duraes et al.
10
/2019 Melanoma Pembrolizumab Distal numbness of the limbs Intravenous steroid Improvement Survived
Weakness with gait impairment Plasma exchange
8 Our case Renal cell Nivolumab
Disagreeable speech
Sudden anger
Memory loss
Calculation disorder
mPSL Improvement Survived
carcinoma
John Wiley & Sons, LtdAn autopsy for a patient with CNS demyelination revealed infiltration of CD8+ T cells into the margin of the demyelinating lesion.
4
Furthermore, a pathway in which CD8+ T cells damaged the myelin sheath has been reported for MS.
11
Furthermore, others have reported that the autopsy of MS patients showed no PD‐1 expression by CD8+ T cells that infiltrate the lesion site.
12
These facts support the hypothesis that the CD8+ T cells whose PD‐1 receptors are inhibited by nivolumab may injure the myelin sheath and cause CNS demyelination.
Conclusion
We experienced a case of RCC with demyelination of the CNS owing to nivolumab. Because this condition may be fatal, early diagnosis and treatment are necessary.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgment
We thank Marla Brunker, from Edanz Group (https://en‐author‐services.edanzgroup.com/), for editing a draft of this manuscript. | 74 kg. | Weight | CC BY | 33426497 | 15,407,618 | 2021-01 |
What was the administration route of drug 'NIVOLUMAB'? | Renal cell carcinoma with central nervous system demyelination caused by nivolumab.
Central nervous system demyelination caused by immune checkpoint inhibitors is a very rare condition.
A 65-year-old man who received nivolumab for renal cell carcinoma developed abnormal behavior, such as disagreeable speech and sudden anger. Brain-enhanced magnetic resonance imaging revealed multiple lesions with partial contrast effects in the cerebral white matter. We tentatively diagnosed demyelination caused by nivolumab, and performed steroid pulse therapy twice. After that, his symptoms improved. For the next 2 years, his symptoms did not recur, nor did his cancer progress.
Demyelination caused by immune checkpoint inhibitors can be fatal and requires early diagnosis and treatment.
Abbreviations & Acronyms
CNScentral nervous system
CTcomputed tomography
CTCAECommon Terminology Criteria for Adverse Events
ICIimmune checkpoint inhibitor
irAEimmune‐related adverse event
IVIGintravenous immunoglobulin
MRImagnetic resonance imaging
MSmultiple sclerosis
mPSLmethylprednisolone
PD‐1programmed cell death 1
RCCrenal cell carcinoma
Keynote message
Although CNS demyelination owing to ICIs is a rare disorder, it causes neurological symptoms and can be fatal. Early diagnosis and treatment are crucial. Steroids may be required, depending on symptoms.
Introduction
Nivolumab, an anti‐PD‐1 inhibitor, is widely used to treat various cancers, including RCC; however, numerous irAEs have been reported. Neurologic irAEs are relatively rare,
1
especially neurologic irAEs with CNS demyelination. Here, we report an extremely rare case of RCC with CNS demyelination caused by nivolumab.
Case presentation
A 52‐year‐old man underwent a left nephrectomy in another hospital for left RCC in 2004 (pathological diagnosis unknown). He developed left lung metastases in 2010, and started treatment with interferon‐α. Right renal metastasis also appeared in 2010 (Fig. 1a), so he was referred to our hospital and underwent a right partial nephrectomy. Later, he also underwent a left partial pneumonectomy (Fig. 1b,c). The histopathological finding of each excised tissue showed clear cell RCC. In April 2015, he began sunitinib treatment for multiple lung metastases (Fig. 1d,e) (International Metastatic RCC Database Consortium risk group was favorable), but a lumbar spine metastasis was found in February 2016 (Fig. 1f). His medication was switched from sunitinib to axitinib in November 2016. In October 2017, he began taking nivolumab because of the progression of lung metastases and appearance of left hilar lymph node disease (Fig. 1g,h). In January 2018, he received a transarterial embolization for his left hilar lymph node, because of progressive disease. Both the hilar lymph node and lung disease showed durable responses.
Fig. 1 The CT images are shown. An arrow indicates a metastatic lesion. (a) 16‐mm enhanced mass in the lower pole of right kidney; (b) 9‐mm coin lesion in the upper lobe of left lung; (c) 8‐mm coin lesion in the lower lobe of left lung; (d) 8‐mm coin lesion near the hilum of right lung; (e) 5‐mm coin lesion in the middle lobe of right lung; (f) 15‐mm osteolytic lesion in the second lumbar spine; (g) 13‐mm coin lesion in the lower lobe of left lung; (h) 42‐mm left hilar lymph node.
Three days after his 11th nivolumab administration, he began displaying abnormal behavior, such as disagreeable speech and sudden anger. Eleven days later, he also developed a short‐term memory loss and calculation disorder and was hospitalized on the same day. Brain MRI showed multiple lesions, with high signals in T2‐weighted images in his cerebral white matter (Fig. 2a,b). Their open‐ring signs suggested demyelination rather than metastatic tumors (Fig. 2c,d). Demyelination caused by nivolumab was considered to be likely, although we need to rule out infectious diseases, collagen diseases, and MS. His cerebrospinal fluid showed normal glucose, protein, and white blood cell count, presence of oligoclonal bands; normal levels of myelin basic protein, immunoglobulin G, and immunoglobulin A for toxoplasma, and negative JC viral DNA. No malignant cells were found in the cerebrospinal fluid. Most autoantibodies, including anti‐aquaporin 4 antibody, were negative except anti‐nuclear antibody. On the basis of the above examinations, we diagnosed CNS demyelination caused by nivolumab, which was classified as a grade 2 adverse effect in accordance with the CTCAE version 5.0.
Fig. 2 Brain MRI shows high signal in T2‐weighted images and diffusion‐weighted images in the cerebral white matter (arrows: CNS demyelination). (a) T2‐weighted images; (b) diffusion‐weighted images; (c) brain‐enhanced MRI shows an open‐ring sign; (d) enlarged image of panel c.
Nivolumab was ceased and intravenous mPSL (1 g/day) was administered for 3 days from the day of his hospital admission. However, as his neurological symptoms did not greatly improve, we began intravenous mPSL (1 g/day) again for 3 days from the eighth day of hospitalization. He then began to show improvement of abnormal behavior as well as imaging findings. Neurological symptoms, such as disagreeable speech and sudden anger, subsided completely. He was discharged on the 23rd hospital day and fully recovered a short‐term memory loss and calculation disorder 3 months after the onset. No steroid was administered other than intravenous mPSL for a total of 6 days. After 6 months, his brain MRI showed further improvement of multiple lesions in the cerebral white matter (Fig. 3). Nivolumab has been discontinued and neither neurologic symptoms nor progression of RCC have been observed for 26 months without any treatment.
Fig. 3 Brain MRI (T2‐weighted images) taken 6 months after discharge showed further improvement of multiple lesions in the cerebral white matter (arrows: CNS demyelination).
Discussion
A report of 9208 patients treated with ICIs, enrolled in 59 clinical trials, showed that 3.8% of patients were treated with cytotoxic T‐lymphocyte‐associated protein‐4 inhibitor, 6.1% of those with PD‐1 inhibitor and 12.0% of those with both agents had neurologic irAEs.
1
Yet, neurologic irAEs with CNS demyelination are rare conditions. Neurologic irAEs encompass a broad spectrum of neurologic syndromes, including myasthenic syndrome, aseptic meningitis, encephalitis, sensory motor neuropathy, Guillain‐Barré‐like syndromes, painful sensory neuropathy, enteric neuropathy, transverse myelitis, and posterior reversible encephalopathy syndrome.
2
To diagnose neurologic irAEs, infectious diseases, cancer invasion to CNS, paraneoplastic syndrome, and metabolic disorders must be ruled out. Blood tests that include hormone levels, cerebrospinal fluid tests, and brain‐enhanced MRI are essential.
3
In patients with CTCAE grade 1 neurologic symptoms, ICIs should be continued under close observation. Among those with CTCAE grade ≥2 neurological symptoms, administration of corticosteroids equivalent to mPSL (1–4 mg/kg), and discontinuation of ICIs, or treatment such as IVIG, plasma exchange, and steroid pulse are required depending on severity.
2
To our knowledge, only eight cases of CNS demyelination owing to ICIs have been reported, including the present case (Table 1).
4
,
5
,
6
,
7
,
8
,
9
,
10
Our report is the first case of CNS demyelination caused by nivolumab to treat RCC. All other reported patients were treated with steroids except for one patient with no symptoms who was relieved by only discontinuation of nivolumab. IVIG, plasma exchange, and immunosuppressant were added in some cases. In previous reports, most patients with irAEs involving the CNS had onset of symptoms <4 days after administering nivolumab, and symptoms became progressively worse within 2 weeks.
8
Except for one patient with unknown details, all eight patients improved in response to treatment. However, one died from relapsed CNS demyelination, and two died from complications of steroid treatment. As four cases out of eight died, CNS demyelination caused by ICIs can be fatal. We tried the second steroid pulse therapy in the same manner as for MS, which is a CNS demyelinating disease with a clinical picture similar to our case. Since the neurological symptoms were not severe and subsided after the second administration of mPSL, we decided to follow‐up carefully without continuing steroid administration.
Table 1 Review of cases of cerebral nervous system demyelination secondary to treatment with ICIs
Case Author/year Underlying disease Suspected drug Symptom Treatment provided Responsiveness to treatment Outcome
1 Maurice et al.
4
/2015 Melanoma Nivolumab Confusion mPSL After remission, symptoms reappear Died due to demyelinating disease
Nausea IVIG
Vomiting
Apathy
Fixed gaze
Psychomotor slowing
2 Cao et al.
5
/2016 Melanoma Ipilimumab Fatigue mPSL Unknown Died
Memory loss Cyclophosphamide
Vision change
3 Sugiura et al.
6
/2017 Lung cancer Nivolumab Low motivation mPSL Improvement Died due to cytomegalovirus ulcer in the lower intestinal tract
Wobbling
4 Mancone et al.
7
/2018 Melanoma Nivolumab Gait imbalance mPSL Mild improvement Died due to urinary tract infection
Ipilimumab Lower extremity weakness IVIG
5 Zafer et al.
8
/2019 Laryngeal cancer Nivolumab Diffuse generalized slowing mPSL Improvement Survived
IVIG
6 Pillonel et al.
9
/2019 Melanoma Nivolumab No symptom Only discontinue of nivolumab Improvement Survived
7 Duraes et al.
10
/2019 Melanoma Pembrolizumab Distal numbness of the limbs Intravenous steroid Improvement Survived
Weakness with gait impairment Plasma exchange
8 Our case Renal cell Nivolumab
Disagreeable speech
Sudden anger
Memory loss
Calculation disorder
mPSL Improvement Survived
carcinoma
John Wiley & Sons, LtdAn autopsy for a patient with CNS demyelination revealed infiltration of CD8+ T cells into the margin of the demyelinating lesion.
4
Furthermore, a pathway in which CD8+ T cells damaged the myelin sheath has been reported for MS.
11
Furthermore, others have reported that the autopsy of MS patients showed no PD‐1 expression by CD8+ T cells that infiltrate the lesion site.
12
These facts support the hypothesis that the CD8+ T cells whose PD‐1 receptors are inhibited by nivolumab may injure the myelin sheath and cause CNS demyelination.
Conclusion
We experienced a case of RCC with demyelination of the CNS owing to nivolumab. Because this condition may be fatal, early diagnosis and treatment are necessary.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgment
We thank Marla Brunker, from Edanz Group (https://en‐author‐services.edanzgroup.com/), for editing a draft of this manuscript. | Intravenous drip | DrugAdministrationRoute | CC BY | 33426497 | 15,407,618 | 2021-01 |
What was the outcome of reaction 'Demyelination'? | Renal cell carcinoma with central nervous system demyelination caused by nivolumab.
Central nervous system demyelination caused by immune checkpoint inhibitors is a very rare condition.
A 65-year-old man who received nivolumab for renal cell carcinoma developed abnormal behavior, such as disagreeable speech and sudden anger. Brain-enhanced magnetic resonance imaging revealed multiple lesions with partial contrast effects in the cerebral white matter. We tentatively diagnosed demyelination caused by nivolumab, and performed steroid pulse therapy twice. After that, his symptoms improved. For the next 2 years, his symptoms did not recur, nor did his cancer progress.
Demyelination caused by immune checkpoint inhibitors can be fatal and requires early diagnosis and treatment.
Abbreviations & Acronyms
CNScentral nervous system
CTcomputed tomography
CTCAECommon Terminology Criteria for Adverse Events
ICIimmune checkpoint inhibitor
irAEimmune‐related adverse event
IVIGintravenous immunoglobulin
MRImagnetic resonance imaging
MSmultiple sclerosis
mPSLmethylprednisolone
PD‐1programmed cell death 1
RCCrenal cell carcinoma
Keynote message
Although CNS demyelination owing to ICIs is a rare disorder, it causes neurological symptoms and can be fatal. Early diagnosis and treatment are crucial. Steroids may be required, depending on symptoms.
Introduction
Nivolumab, an anti‐PD‐1 inhibitor, is widely used to treat various cancers, including RCC; however, numerous irAEs have been reported. Neurologic irAEs are relatively rare,
1
especially neurologic irAEs with CNS demyelination. Here, we report an extremely rare case of RCC with CNS demyelination caused by nivolumab.
Case presentation
A 52‐year‐old man underwent a left nephrectomy in another hospital for left RCC in 2004 (pathological diagnosis unknown). He developed left lung metastases in 2010, and started treatment with interferon‐α. Right renal metastasis also appeared in 2010 (Fig. 1a), so he was referred to our hospital and underwent a right partial nephrectomy. Later, he also underwent a left partial pneumonectomy (Fig. 1b,c). The histopathological finding of each excised tissue showed clear cell RCC. In April 2015, he began sunitinib treatment for multiple lung metastases (Fig. 1d,e) (International Metastatic RCC Database Consortium risk group was favorable), but a lumbar spine metastasis was found in February 2016 (Fig. 1f). His medication was switched from sunitinib to axitinib in November 2016. In October 2017, he began taking nivolumab because of the progression of lung metastases and appearance of left hilar lymph node disease (Fig. 1g,h). In January 2018, he received a transarterial embolization for his left hilar lymph node, because of progressive disease. Both the hilar lymph node and lung disease showed durable responses.
Fig. 1 The CT images are shown. An arrow indicates a metastatic lesion. (a) 16‐mm enhanced mass in the lower pole of right kidney; (b) 9‐mm coin lesion in the upper lobe of left lung; (c) 8‐mm coin lesion in the lower lobe of left lung; (d) 8‐mm coin lesion near the hilum of right lung; (e) 5‐mm coin lesion in the middle lobe of right lung; (f) 15‐mm osteolytic lesion in the second lumbar spine; (g) 13‐mm coin lesion in the lower lobe of left lung; (h) 42‐mm left hilar lymph node.
Three days after his 11th nivolumab administration, he began displaying abnormal behavior, such as disagreeable speech and sudden anger. Eleven days later, he also developed a short‐term memory loss and calculation disorder and was hospitalized on the same day. Brain MRI showed multiple lesions, with high signals in T2‐weighted images in his cerebral white matter (Fig. 2a,b). Their open‐ring signs suggested demyelination rather than metastatic tumors (Fig. 2c,d). Demyelination caused by nivolumab was considered to be likely, although we need to rule out infectious diseases, collagen diseases, and MS. His cerebrospinal fluid showed normal glucose, protein, and white blood cell count, presence of oligoclonal bands; normal levels of myelin basic protein, immunoglobulin G, and immunoglobulin A for toxoplasma, and negative JC viral DNA. No malignant cells were found in the cerebrospinal fluid. Most autoantibodies, including anti‐aquaporin 4 antibody, were negative except anti‐nuclear antibody. On the basis of the above examinations, we diagnosed CNS demyelination caused by nivolumab, which was classified as a grade 2 adverse effect in accordance with the CTCAE version 5.0.
Fig. 2 Brain MRI shows high signal in T2‐weighted images and diffusion‐weighted images in the cerebral white matter (arrows: CNS demyelination). (a) T2‐weighted images; (b) diffusion‐weighted images; (c) brain‐enhanced MRI shows an open‐ring sign; (d) enlarged image of panel c.
Nivolumab was ceased and intravenous mPSL (1 g/day) was administered for 3 days from the day of his hospital admission. However, as his neurological symptoms did not greatly improve, we began intravenous mPSL (1 g/day) again for 3 days from the eighth day of hospitalization. He then began to show improvement of abnormal behavior as well as imaging findings. Neurological symptoms, such as disagreeable speech and sudden anger, subsided completely. He was discharged on the 23rd hospital day and fully recovered a short‐term memory loss and calculation disorder 3 months after the onset. No steroid was administered other than intravenous mPSL for a total of 6 days. After 6 months, his brain MRI showed further improvement of multiple lesions in the cerebral white matter (Fig. 3). Nivolumab has been discontinued and neither neurologic symptoms nor progression of RCC have been observed for 26 months without any treatment.
Fig. 3 Brain MRI (T2‐weighted images) taken 6 months after discharge showed further improvement of multiple lesions in the cerebral white matter (arrows: CNS demyelination).
Discussion
A report of 9208 patients treated with ICIs, enrolled in 59 clinical trials, showed that 3.8% of patients were treated with cytotoxic T‐lymphocyte‐associated protein‐4 inhibitor, 6.1% of those with PD‐1 inhibitor and 12.0% of those with both agents had neurologic irAEs.
1
Yet, neurologic irAEs with CNS demyelination are rare conditions. Neurologic irAEs encompass a broad spectrum of neurologic syndromes, including myasthenic syndrome, aseptic meningitis, encephalitis, sensory motor neuropathy, Guillain‐Barré‐like syndromes, painful sensory neuropathy, enteric neuropathy, transverse myelitis, and posterior reversible encephalopathy syndrome.
2
To diagnose neurologic irAEs, infectious diseases, cancer invasion to CNS, paraneoplastic syndrome, and metabolic disorders must be ruled out. Blood tests that include hormone levels, cerebrospinal fluid tests, and brain‐enhanced MRI are essential.
3
In patients with CTCAE grade 1 neurologic symptoms, ICIs should be continued under close observation. Among those with CTCAE grade ≥2 neurological symptoms, administration of corticosteroids equivalent to mPSL (1–4 mg/kg), and discontinuation of ICIs, or treatment such as IVIG, plasma exchange, and steroid pulse are required depending on severity.
2
To our knowledge, only eight cases of CNS demyelination owing to ICIs have been reported, including the present case (Table 1).
4
,
5
,
6
,
7
,
8
,
9
,
10
Our report is the first case of CNS demyelination caused by nivolumab to treat RCC. All other reported patients were treated with steroids except for one patient with no symptoms who was relieved by only discontinuation of nivolumab. IVIG, plasma exchange, and immunosuppressant were added in some cases. In previous reports, most patients with irAEs involving the CNS had onset of symptoms <4 days after administering nivolumab, and symptoms became progressively worse within 2 weeks.
8
Except for one patient with unknown details, all eight patients improved in response to treatment. However, one died from relapsed CNS demyelination, and two died from complications of steroid treatment. As four cases out of eight died, CNS demyelination caused by ICIs can be fatal. We tried the second steroid pulse therapy in the same manner as for MS, which is a CNS demyelinating disease with a clinical picture similar to our case. Since the neurological symptoms were not severe and subsided after the second administration of mPSL, we decided to follow‐up carefully without continuing steroid administration.
Table 1 Review of cases of cerebral nervous system demyelination secondary to treatment with ICIs
Case Author/year Underlying disease Suspected drug Symptom Treatment provided Responsiveness to treatment Outcome
1 Maurice et al.
4
/2015 Melanoma Nivolumab Confusion mPSL After remission, symptoms reappear Died due to demyelinating disease
Nausea IVIG
Vomiting
Apathy
Fixed gaze
Psychomotor slowing
2 Cao et al.
5
/2016 Melanoma Ipilimumab Fatigue mPSL Unknown Died
Memory loss Cyclophosphamide
Vision change
3 Sugiura et al.
6
/2017 Lung cancer Nivolumab Low motivation mPSL Improvement Died due to cytomegalovirus ulcer in the lower intestinal tract
Wobbling
4 Mancone et al.
7
/2018 Melanoma Nivolumab Gait imbalance mPSL Mild improvement Died due to urinary tract infection
Ipilimumab Lower extremity weakness IVIG
5 Zafer et al.
8
/2019 Laryngeal cancer Nivolumab Diffuse generalized slowing mPSL Improvement Survived
IVIG
6 Pillonel et al.
9
/2019 Melanoma Nivolumab No symptom Only discontinue of nivolumab Improvement Survived
7 Duraes et al.
10
/2019 Melanoma Pembrolizumab Distal numbness of the limbs Intravenous steroid Improvement Survived
Weakness with gait impairment Plasma exchange
8 Our case Renal cell Nivolumab
Disagreeable speech
Sudden anger
Memory loss
Calculation disorder
mPSL Improvement Survived
carcinoma
John Wiley & Sons, LtdAn autopsy for a patient with CNS demyelination revealed infiltration of CD8+ T cells into the margin of the demyelinating lesion.
4
Furthermore, a pathway in which CD8+ T cells damaged the myelin sheath has been reported for MS.
11
Furthermore, others have reported that the autopsy of MS patients showed no PD‐1 expression by CD8+ T cells that infiltrate the lesion site.
12
These facts support the hypothesis that the CD8+ T cells whose PD‐1 receptors are inhibited by nivolumab may injure the myelin sheath and cause CNS demyelination.
Conclusion
We experienced a case of RCC with demyelination of the CNS owing to nivolumab. Because this condition may be fatal, early diagnosis and treatment are necessary.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgment
We thank Marla Brunker, from Edanz Group (https://en‐author‐services.edanzgroup.com/), for editing a draft of this manuscript. | Not recovered | ReactionOutcome | CC BY | 33426497 | 15,407,618 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug withdrawal syndrome'. | Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.
Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents.
We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database.
After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234).
The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used.
Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.
Introduction
Pharmacological properties of promethazine
Promethazine is a phenothiazine derivative and a histamine (H1) receptor antagonist that is commonly used for symptomatic relief of nausea and vomiting, for allergic conditions, motion sickness and common cold, and for short-term use treatment of insomnia in adults or as a paediatric sedative (EMC, 2019). It also acts as a direct antagonist at muscarinic (M1) and dopamine (D2) receptors (Cookson, 2018; Page et al., 2009; Sharma and Hamelin, 2003). Promethazine hydrochloride is well absorbed from the gastrointestinal tract, with an average of 88% of the dose absorbed after oral administration, and clinical effects appearing within 20 min after intake whilst lasting 4–6 h. The plasma half-life is approximately 7–14 h (Burns and Boyer, 2013). It is classified as a first-generation antihistamine molecule which, compared with second-generation antihistamines, easily penetrates the blood-brain barrier and is associated with adverse effects such as moderate/intense sedation (Jensen et al., 2017). Thus, promethazine might be used in rapid (acute) tranquilization due to its blocking action at H1 and M receptors (Cookson, 2018). Toxicity might result in severe impairment of cognitive and psychomotor functions due to central nervous system (CNS) depression/reduced levels of consciousness, and may cause fatalities (Jensen et al., 2017).
Availability of promethazine
Promethazine is a medicinal product available on its own or in combination with other ingredients, including dextromethorphan, paracetamol and/or expectorants. With regards to promethazine availability, there are wide variations across countries. In fact, in some European countries such as France, Italy and the UK, but also outside Europe, some medicinal products containing promethazine can be purchased over-the-counter (OTC). Promethazine was restricted from an OTC status to prescription only in Denmark as of December 2014. This restriction was partly based on increasing enquiries regarding promethazine exposures to the Danish Poison and Information Centre (DPIC), highlighting its abuse potential and subsequent observations of side-effects after ingestion of standard doses. In Australia, promethazine is available as an OTC medication either alone as a tablet or as a liquid preparation or in combination with paracetamol and codeine phosphate as a syrup (Sharma and Hamelin, 2003). In the USA, some cough preparations containing no more than 200 mg of codeine per 100 mL are considered Schedule V controlled substances (Drug Enforcement Administration (DEA), 2020), purportedly possessing the lowest potential for both misuse and development of a Substance Use Disorder (SUD).
Pharming
Recently, the potential for misuse of medications that are not already controlled has been reported worldwide (Reeves et al., 2015). ‘Pharming’ is a phenomenon involving the non-medical use of prescription (pain relievers, tranquilisers, stimulants, sedatives) and OTC drugs, including cough and cold preparations, particularly those containing dextromethorphan and promethazine (Burns and Boyer, 2013; Jouanjus et al., 2018; Levine, 2007; McCarthy, 2007; National Institute on Drug Abuse (NIDA), 2014). The abuse of these compounds may be facilitated by their easy accessibility, low cost, decreased perception of potential for harm and growing social acceptance (Burns and Boyer, 2013; Levine, 2007; McCarthy, 2007; Substance Abuse Mental Health Services Administration (SAMHSA), 2008). In the current drug abuse scenario, young people/youths have been described abusing with a range of prescription or OTC medicines (Soussan et al., 2018), with these molecules possibly being ingested at high/super-high dosages (Orsolini et al., 2015; Schifano, 2020) and at times in combination with alcohol/remaining recreational substances (Levine, 2007)
Recreational use of promethazine
Centrally acting antihistamines have long been known to induce physical and psychological dependence (Clatts et al., 2010; Gracious et al., 2010; Page et al., 2009; Saatcioglu and Evren, 2005; Thomas et al., 2008). During the past 15 years the abuse of promethazine, especially from OTC and prescription cough and cold medicines and at higher-than-recommended dosages, has been reported (NIDA, 2014). Consistent with this, during the last decade the yearly number of promethazine-related overdose cases in Sweden has increased from 100 to nearly 700 and its sales have increased threefold (Höjer and Tellerup, 2018). Also, according to the 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), antihistamines accounted for the seventh most frequently involved substance in human exposures, resulting in the third type of substance category for rate of exposure increase (Gummin et al., 2019). In Denmark, the number of registered antihistamine exposures increased during 2007–2013, with first-generation antihistamines, specifically promethazine, having been responsible for most exposures and related fatalities (Jensen et al., 2017). Also, in New Zealand a number of promethazine poisoning cases (57/199 patients) were identified from a database of poisoning admissions to a regional toxicology service (Bergman and Wallman, 1998).
Effects
Promethazine reported effects mostly include a range of CNS side effects, such as: confusion; disorientation; drowsiness; cardiovascular symptoms; and respiratory depression (Burns and Boyer, 2013; Höjer and Tellerup, 2018; Page et al., 2009; Tsay et al., 2015). A clear abuse potential has been observed and reported for first-generation antihistamines such as promethazine and cyclizine, due to: calming and sedating effects (Cookson, 2018; Jensen et al., 2017) and enhancement of other co-ingested substances, and especially those interacting with gamma-amino-butyric acid (GABA), opiate and muscarinic acetylcholine receptors (Speeg et al., 1981), leading to hallucinogenic experiences (Clatts et al., 2010; Jensen et al., 2017; Lynch et al., 2015). Indeed, an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility has been described (Burns and Boyer, 2013). In these cases, the mental state alteration is characterised by agitated delirium, with abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia (Agnich et al., 2013; Cowen, 1979; Dollberg et al., 1989; Höjer and Tellerup, 2018; Leak and Carroll, 1967; Page et al., 2009; Scott et al., 2007; Timnak et al., 2004). With the promethazine-codeine cough syrup, ‘euphoric feelings’, ‘relaxation’, ‘slight giddiness and disorienting’, and ‘nice hallucinations’ have been described as well (Bluelight.org [2020]; Erowid.org [2020]). Reported side-effects include drowsiness, fatigue, loss of coordination, constipation and urinary retention (Elwood, 2001).
Vulnerable categories
An increasing trend in abuse of promethazine in co-formulation with some components of OTC cough medications has been reported in young adult populations (Carney et al., 2018; Carr, 2006; Höjer and Tellerup, 2018) since the late 1990s, particularly in the southern USA (Carr, 2006; Elwood, 2001). Codeine and promethazine were recorded as the most requested psychoactive drugs by adolescents/young adults in community pharmacies (Delcourt et al., 2017).
Known by the street names ‘lean’, ‘drank’, ‘barre’, ‘purple stuff’, ‘syrup’ and ‘sizzurp’ (Agnich et al., 2013; NIDA, 2014; Peters et al., 2007), the abuse of promethazine mixed with opioids and other sedatives (e.g. alcohol) in a purple colour drink (‘purple drank’) (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014) has become widely popular (Agnich et al., 2013) after a rap artist/producer created a genre of music, called ‘screw music', inspired by intoxication on codeine and promethazine (Peters et al., 2007). Social media data, e.g. public posts and related hashtags on Instagram, provided additional insights into codeine abuse, depicting its common misuse combined with promethazine and soda/carbonated drinks (Cherian et al., 2018). ‘Purple drank’ has been noted for its euphoric effects and its easy accessibility (Elwood, 2001; Peters et al., 2007). ‘Lean’ creates a distinct (Jakubowski et al., 2018) feeling of euphoria and extreme relaxation (Cookson, 2018), dream-like feelings and a vivid sensation of floating away from the physical body (Peters et al., 2007).
Although at times preferred to other substances, such as benzodiazepines, to treat anxiety and sleep disorders in substance-dependent patients, promethazine has been reported to be misused among people with either opioid dependence (Agnich et al., 2013; Dahlman et al., 2016; Elwood, 2001; Lynch et al., 2015; Shapiro et al., 2013) or a substance abuse condition (Shapiro et al., 2013; Tang et al., 2012). A Hong Kong study reported a total of 63 patients with a diagnosis of cough mixture abuse; 89% were adult males with a mean age of onset of the abuse itself of 20 (±5) years. These subjects had received a diagnosis of substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%) and dysthymia (10%), with most cases having presented with a polysubstance misuse (Tang et al., 2012). Due to the opioid-coformulation, the promethazine-codeine cough mixture might lead to addiction (NIDA, 2014). The mixture may present a high risk of occurrence of near misses due to its central effect of respiratory depression, which is greatly increased by association with alcohol or other CNS depressants, such as sedatives/hypnotics, narcotic analgesics, general anaesthetics and tricyclic antidepressants (Burns and Boyer, 2013; Elwood, 2001; NIDA, 2014; Shapiro et al., 2013; Tsay et al., 2015). The concomitant use of promethazine and other depressant drugs should not be underestimated, as they might together contribute to and/or cause fatalities (Corkery et al., 2020).
Aim of the study
We were interested here in studying how promethazine abuse was reported to the European Medicines Agency (EMA) adverse drug reactions (ADRs) database. We aimed to analyse promethazine misuse/abuse/dependence/withdrawal data. Where possible, in order to have a better understanding, information/data related to diagnosis, concomitant drugs, administration and dosages were also examined.
Methods
Source of data
The EMA through EudraVigilance (EV) manages and analyses information on suspected ADRs to medicines authorised in the European Economic Area (EEA), according to Directive 2001/83/EC and Regulation (EC) No 726/2004 (EMA, 2017). Since November 2017, EV launched extensive Web access to data on suspected ADRs and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research (Postigo et al., 2018). Thus, access to data regarding cases of promethazine abuse, misuse, dependence and withdrawal was obtained by application to the voluntary reporting system of ADRs of the EMA. After 3 months all data comprised all of the ADRs reported during the years from 2003 up to June 2019, presented as large Excel files divided into information sections reporting in a standardised format according to the Medical Dictionary for Regulatory Activities (MedDRA), were sent through a hyperlink (MedDra, 2018). Such listings showed all information related to the ADR, the patient, the drug, the reporter and the diagnosis. An ADR was considered a voluntary and unsolicited communication reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorisation Holders for those ADRs occurring outside the EEA (EMA, 2010). Only ‘suspect’ ADRs were selected, meaning promethazine was considered as ‘suspected’ for the reaction reported. Regarding the content of the ADR, according to the standardised MedDRA Query (SMQ) (MedDRA, 2018), the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, intentional product use issue, substance abuse, substance abuser, substance use and withdrawal syndrome were selected. Those ADRs were defined in accordance with MedDRA in line with previous studies on the EV dataset (Chiappini et al., 2020; MedDRA, 2018; Schifano and Chiappini, 2018a, 2018b; Schifano et al., 2019a, 2019b). Specifically, abuse was here defined as the intentional, non-therapeutic use by a patient or consumer of a product, OTC or prescription, for a perceived reward or desired non-therapeutic effect including, but not limited to, getting high (euphoria) (MedDRA, 2018). Misuse was meant as the intentional use for a therapeutic purpose by a patient or consumer of a product, OTC or prescription, other than as prescribed or not in accordance with the authorised product information (MedDRA, 2018). Finally, non-medical use referred here to the use of a prescription drug, whether obtained by prescription or otherwise, other than in the manner or for the time period prescribed, or by a person for whom the drug was not prescribed (United Nations Office on Drugs and Crime (UNODC), 2013).
Analysis of data
We retrospectively analysed all reported ADRs which were available in the EV database. ADR reports were analysed with respect to age and gender of patient/consumer, source/reporter country (EEA or non-EEA) and reporter qualification (i.e. pharmacist, physician); type of ADR; seriousness (fatal, recovered, resolved outcomes); promethazine dosage; possible concomitant drug(s); and diagnosis/reporter’s comments, if recorded. The descriptive analysis included cases of overdoses, suicides, and fatalities. In the dataset, each case report may refer to one or more reporter; one or more ADR(s); as well as to one or more medicinal product(s). Therefore, a case may be represented by more than one row in the other line listings. The received data files were searched for duplicates by report ID through the ‘EV Local Report Number’, which unequivocally identified an individual case. Thus, the number of suspected ADRs appeared to be different from the number of case reports as one case report might refer to several suspected ADRs. Moreover, the number of patients was different from the number of case reports as a patient might have been described in more than one case. Finally, numbers of ADRs differed from those referring to case reports/single patients since different reporters/senders could have independently flagged the same ADR to the EMA. The descriptive analysis included here a study of the dataset (EMA, 2017) performed through IBM SPSS Statistics software (version 26).
Ethical issues
In compliance with applicable Personal Data Protection legislation (Regulation (EC) No 45/2001 and Regulation (EC) No 1049/2001, the protection of privacy and integrity of individuals was guaranteed, and in order to safeguard the identity of individuals certain data elements, including names/identifiers or country-specific information were not disclosed by the EMA (EMA, 2013, 2017). The study was ethically approved in March 2018 by the University of Hertfordshire Ethics’ Committee, with reference number LMS/PGR/UH/03234.
Results
The dataset obtained reported a total of 11,796 ADRs, correspond-ing to 1,543 single cases recorded during years 2003–2019 (Table 1). Safety reports were all voluntarily submitted, mostly from pharmaceutical companies (1,136/1,543: 73.6%) and regulatory authorities (398/1,543: 25.8%). Reports were irregularly reported over time, with spikes in 2010, 2014 and 2017 (Figure 1). Countries which reported most promethazine-related abuse/misuse/dependence cases included: the USA (805/1,543: 52.10%); Germany (299/1,543: 19.4%); Japan (162/1,543: 10.5%), Sweden (67/1,543: 4.3%), France (43/1,543: 2.8%) and Australia (42/1,543: 2.7%). Out of a total of 1543 cases, ‘suspect’ abuse/misuse/dependence-related cases were 557 (36.1%) and, among them, according to the preferred terms (PTs), most recorded reactions were abuse/misuse-related ADRs (458/557: 82.2%), specifically ‘drug abuse’ (300/557: 53.8%) and ‘intentional product misuse’ (117/557: 21.0%) (Table 1). ‘Suspect’ selected cases and related fatalities annually showed the same trend overall (Figure 1). Most typically, subjects reported were adult (19–64 years) and specifically of the youngest group (19–25 years); males were slightly more frequently recorded than females (M/F: 235/461: 0.51) (Table 1). Where all information was recorded, promethazine was reported as ingested alone in 74 cases, with supratherapeutic dosages, up to 2500 mg, in four cases. In combination with other drugs, most cases were associated with a 100–500 mg promethazine dose, with the maximum dosage recorded having been 8000 mg (Figure 2). The most common administration route was oral (n = 292), although the intramuscular (n = 8) and the parenteral (n = 19) ones were reported as well, see Table 1).
Table 1. Analysis of promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV) during years 2003–2019.
Individual cases (% of total within parentheses)
Total abuse/misuse/dependence cases 1543 Single cases; number of ADRs :11,796
Age range Adult (19–64 years): 648 (648/1,543: 42.0%) - mean age: 31.8 years (SD 26.55–37.05)
Adolescent (10–18 years): 23 (23/1,543: 1.5%) – mean age: 15.9 years (SD 14.3–17.77)
Elderly (>65 years): 25 (25/1,543: 1.6%) – mean age: 72.3 years (SD 70.85–73.7)
Neonatal (hours–days) 14 (14/1,543: 0.9%) – mean age: 24 h (SD 16.6–27.4)
Infant (months–1 year): 7 (7/1,543: 0.45%) – mean age: 10 months (SD 7–13)
Child (<10 years): 4 (4: 1,543: 0.35%) – mean age: 5 years (SD 3.6–6.3)
Unknown: 822 (822/1,543: 53.2%)
Male/female 235/461: 0.51
Most represented abuse/misuse/dependence-related ADRs according to the PTs: 557 (557/1,543: 36.1%)
Abuse-related ADRs 458 (458/557: 82.2%)
Drug abuse 300
Drug abuser 15
Drug diversion 1
Intentional product misuse 117
Intentional product use issue 9
Substance abuse 11
Substance abuser 3
Substance use 2
Dependence-related ADRs 44 (44/557: 7.9%)
Dependence 4
Drug dependence 39
Substance dependence 1
Withdrawal-related ADRs 55 (55/557: 9.8%)
Withdrawal syndrome 19
Drug withdrawal convulsions 1
Drug withdrawal neonatal syndrome 18
Drug withdrawal syndrome 17
Outcome Fatal 310 (310/557: 55.6%)
Unknown 161 (161/557: 28.9%)
Recovered/resolved 55 (55/557: 9.9%)
Recovering/resolving 18 (18/557: 3.3%)
Not recovered/not resolved 13 (13/557: 2.3%)
Promethazine-cases alone 74 (with maximum dosage 2500 mg)
Promethazine-cases with other drugs Most cases (122) were over 100 mg (with maximum dosage 8000 mg)
Most common psychoactive substances used Alcohol: 114
Cocaine: 68
Cannabis: 16
Ketamine: 4
Amphetamine: 1
Most common prescription drugs used Opioids: 1187
Benzodiazepines: 914
Antidepressants: 871
Antipsychotics: 437
Z-drugs: 222
Mood stabilisers: 197
ADR: adverse drug reaction; PTs: preferred terms; SD: standard deviation.
Figure 1. Number of promethazine abuse/misuse/dependence/withdrawal cases reported by year in the EudraVigilance (EV) dataset.
Figure 2. Most represented dosages reported among all promethazine abuse/misuse/dependence/withdrawal cases recorded by the EudraVigilance (EV) dataset.
Concomitantly used drugs recorded were opioids (e.g. oxycodone and fentanyl), benzodiazepines (e.g. diazepam, alprazolam and lorazepam) and antidepressants (e.g. citalopram, venlafaxine and amitriptyline), whilst recreational drugs most represented were alcohol and cocaine (Table 1). Most reported diagnoses, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V; American Psychiatric Association (APA), 2013) related to: mood disorders, e.g. depression/depressed mood/major depression (68 cases) and bipolar disorder (14 cases); anxiety/anxiety disorders (23 cases); alcohol abuse/alcoholic/alcoholism (26 cases); and schizophrenia (14 cases). The outcome of the reactions reported included: ‘fatal’ (n=310/557; 55.6%) and secondarily ‘recovered/resolved’ (n=73; 15.2%) (Table 1). Some 27 cases were related to suicidal or self-harm behaviour, being recorded as ‘suicidal attempt/suicidal ideation’ (n=24), ‘self-injurious ideation’ (n=1), and ‘suicide attempt’ (n=2). Fatalities mostly involved adult females; in these cases, most typical ADRs recorded were ‘drug abuse’ (n=228) and ‘intentional product misuse’ (n=77) (Table 2). Opiates/opioids were the most recorded concomitant drugs (n=356), with methadone being the most represented (n=103), followed by antidepressants (n=221) and benzodiazepines (n=141). Among illicit drugs, heroin appeared to be the most represented (Table 2).
Table 2. Analysis of fatal promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV), 2003–2019.
Fatal cases on abuse/misuse/dependence/withdrawal reactions 310 (310/557 = 55.6%)
Age-range
Adult 303 (97.7%)
Adolescent 7 (2.3%)
Elderly (>65 years) –
Neonatal –
Infant –
Child –
Gender M 103 (33.2%)
F 177 (57.1%)
Unknown 30 (9.7%)
Most recorded PTs
Drug abuse/drug abuser/substance abuse 228/3/6
Intentional product misuse/Intentional product use issue 77/3
Drug dependence 1
Reported death code
Intentional overdose 1
Overdose 4
Completed suicide/suicide 7
Drug toxicity/drug abuse 197
Toxicity to various agents 48
Intentional product misuse 41
Respiratory depression 5
Pneumonia 1
Cardiac arrest 10
Drug dependence 1
Most reported concomitant drugs
Opioids 356
Methadone 103
Dihydrocodeine 1
Codeine 32
Fentanyl 44
Oxycodone 63
Morphine 55
Hydrocodone 33
Hydromorphone 3
Tramadol 22
Antidepressants 221
Duloxetine 1
Escitalopram 1
Sertraline 16
Paroxetine 34
Trazodone 15
Mirtazapine 33
Fluoxetine 24
Venlafaxine 9
Bupropion 1
Amitriptyline 35
Nortriptyline 6
Clomipramine 5
Citalopram 41
Benzodiazepines 141
Lorazepam 3
Temazepam 6
Clonazepam 21
Diazepam 60
Flunitrazepam 1
Brotizolam 1
Alprazolam 42
Midazolam 4
Oxazepam 3
Mood stabilisers 11
Gabapentin 3
Topiramate 8
Antipsychotics 24
Olanzapine 1
Quetiapine 20
Haloperidol 1
Amisulpride 1
Levomepromazine 1
Z-drugs 39
Zolpidem 37
Zopiclone 2
Illicit drugs
Amphetamine 15
Cocaine 40
Heroin 52
Alcohol 26
PTs: preferred terms.
Discussion
Non-medical prescription drug use is a globally recognised problem, with severe adverse consequences. The current study provides a large amount of descriptive data highlighting that promethazine can be taken at high dosages, through non-approved administration routes, and in a setting of polydrug use (Hughes et al., 2016; Novak et al., 2016).
Promethazine misuse has been increasingly recorded since the early 2000s, consistently with data from US poison centres reporting antihistamine exposures rising in the period 2007–2013 (Jensen et al., 2017). This is not surprising, since the pharmacodynamic properties of promethazine underpins its sought-after central effects. In 2014, e.g. the highest peak here, the increase in promethazine misuse reporting was solely driven by the USA (245/245 cases; 100%). This may have been associated with intense media attention to the subject in that year (TMZ, 2014). The increments reported in 2010, 2014 and 2017 were then followed by decrements, which may have been related to not only reporting variabilities, but also to differences in sales of antihistamines following local/national drug abuse prevention campaigns (Klein-Schwartz, 2017). Overall, the USA appeared here to be the country most involved in reporting of promethazine ADRs. Several reasons may help in explaining this, including healthcare professionals’ awareness of prescription/OTC drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Lynch et al., 2015; Manchikanti et al., 2006; NIDA, 2014; Tsay et al., 2015) which, in turn, may have facilitated pharmacovigilance reporting. According to an 11-year period of the US National Poison Centers’ database, the annual rate of promethazine abuse/misuse per 100,000 US population doubled over time (Tsay et al., 2015). In the USA, promethazine abuse/misuse has been described in teenagers and young adults (Peters et al., 2003), methadone maintenance patients, heroin users and opioid-prescribed chronic pain patients (Lynch et al., 2015; Shapiro et al., 2013).
Consistent with previous observations (Agnich et al., 2013; Burns and Boyer, 2013; Carr, 2006; Elwood, 2001; Höjer and Tellerup, 2018; NIDA, 2014; Page et al., 2009; Parker et al., 2013; Peters et al., 2007), most recorded ADRs related here to either ‘drug abuse’ and ‘intentional product misuse’, involving young adult (19–25 years) males. Although considered a vulnerable category with respect to prescription drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014; Peters et al., 2007), adolescents (10–18 years) were here reported in only a minority (23/1543:1.5%) of cases.
Several drugs were here associated with promethazine, although opiates/opioids were the most represented molecules in related fatalities. This combination might intensify effects such as sedation and analgesia (Burns and Boyer, 2013; Lynch et al., 2015; Shapiro et al., 2013), and in the 1950s the association was medically used to reduce the dosage of opiates/opioids (McGee and Weiss, 1956). However, due to a range of adverse effects (Lynch et al., 2015) including lack of data supporting clinical efficacy (Richter and Burk, 1992) and an enhanced addiction potential of opioids (Lynch et al., 2015; Peters et al., 2007; Shapiro et al., 2013), the combination of promethazine/opioids has declined in popularity.
So far, the recreational intake of promethazine with opioids has been typically reported in cough mixtures containing codeine (Casati et al., 2012; Clatts et al., 2010; Elwood, 2001; Foley et al., 2015; Peters et al., 2007). However, current EMA data suggest that, apart from methadone, oxycodone and fentanyl were the most typical opiates/opiates identified in association with promethazine, possibly due to their recent popularity, especially in the USA (Manchikanti et al., 2018; Rose, 2018). In the promethazine fatalities (e.g. 310 cases) dataset analysed, codeine, fentanyl and oxycodone were respectively reported in 32, 44 and 63 cases. Consistent with current data, a concomitant use of opioids and promethazine has been described in various subpopulations, such as methadone maintenance patients, injecting drug users and chronic pain patients (Banta-Green et al., 2005; Lynch et al., 2015; Shapiro et al., 2013; Shields et al., 2007; Van Hout and Norman, 2016). Overall, there is now a high level of awareness of the abuse potential of antihistamine/opioid-containing products (Hou et al., 2011; Hughes et al., 1999; Wazaify et al., 2005). Hence, some countries are limiting both the medication pack size levels and the quantities of drugs sold in a single transaction, whilst also promoting non-injectable and non-inhaling formulations and changing some formulations’ OTC status (Cooper, 2013; Foley et al., 2015; Van Hout and Norman, 2016).
Benzodiazepines (e.g. diazepam, alprazolam and lorazepam) were here also frequently recorded, suggesting sedative synergistic effects in combination with promethazine (Lynch et al., 2015), and hence an increased risk of untoward clinical issues (McLellan and Turner, 2010). Other prescription drug categories recorded included antidepressants (most typically: citalopram and amitriptyline, respectively in 149/557 and 95/557 cases), which is consistent with the most typically recorded diagnoses, e.g. depressive (68 cases); bipolar (14 cases); and anxiety (23 cases) disorders. It is also possible that antidepressants were here ingested in combination with promethazine for sleep induction purposes. It is a reason for concern that promethazine ADRs, either alone or in combination, resulted in either fatal (50.6%) or ‘recovered/resolved’ outcomes (22.2%). This is consistent with previous promethazine misuse/abuse data, reporting both adverse clinical outcomes and high frequency of healthcare facility treatment (Bergman and Wallman, 1998; Ichikura et al., 2016; McLellan and Turner, 2010; Tsay et al., 2015). A list of possibly misused substances which might reinforce promethazine psychoactive effects and possibly increase its toxicity is included in Table 3.
Table 3. List of substances recorded in the literature as used in association with promethazine in order to increase its effects; prescription drugs are recorded according to the Neuroscience-based Nomenclature description (Nutt and Blier, 2016).
Psychoactive substances
Description Mode of action Examples Effects
Alcohol (Burns and Boyer, 2013; Jensen et al., 2017) CNS depressant effects ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, relaxation, ‘slight giddiness and disorienting’ and ‘nice hallucination’.
It may increase, prolong or intensify promethazine sedative effect. It should be avoided in patients receiving promethazine.
Heroin and other illicit opioids (Dahlman et al., 2016; Tsay et al., 2015) Opioid depressant effects It may increase, prolong, or intensify promethazine sedative effect.
Prescription drugs
Categories Mode of action Examples Effects
Drugs for insomnia (Burns and Boyer, 2013) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Z-drugs: zaleplon, zolpidem, zopiclone, eszopiclone They may increase, prolong or intensify promethazine sedative effect.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Drugs for anxiety (Burns and Boyer, 2013; Lynch et al., 2015) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, lorazepam, oxazepam They may increase, prolong or intensify promethazine sedative action.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Dextrometorphan (Tsay et al., 2015) At high doses, acting as NMDA-receptor antagonist; dextrometorphan and its potent metabolite dextrorphan inhibit the excitatory amino acid and neurotransmitter glutamate in the brain, determining hallucinogenic and dissociative activities, which are recreationally searched It might be combined with promethazine in cough-suppressant formulation Dextrometorphan neurobehavioural effects are dose-related, starting from a mild to moderate stimulation with restlessness and euphoria (100–200 mg), to a dissociated state characterised by hallucinations, paranoia, perceptual distortions, delusional beliefs, ataxia and out-of-body experiences (‘robo-ing’/‘robo-copping’/‘robo-tripping’) (>1000 mg). In overdosage they might increase promethazine effects.
Drugs for depression (Burns and Boyer, 2013; Jensen et al., 2017): TCA Multimodal action: reuptake inhibitor (SERT and NET), receptor antagonist (5-HT2) Amitriptyline Promethazine may increase, prolong or intensify their sedative effect. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Anticholinergic drugs Antagonist at cholinergic receptors Hyoscine butyl bromide/scopolamine (Burns and Boyer, 2013) Together with promethazine an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility may be seen. A typical mental status alteration with a dose-dependent agitated delirium characterised by abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia, has been described. These molecules should be avoided or administered in reduced dosage to patients receiving promethazine.
Prescription opioids
Codeine (Burns and Boyer, 2013; Jouanjus et al., 2018; Lynch et al., 2015; O Reilly et al., 2015; Shapiro et al., 2013) ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, elation, analgesia and ‘liking’, with increased potential of addiction. Overdosage of codeine might determine respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne–Stokes respiration and cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Opiate overdosage, particularly by the intravenous route, may be associated with apnoea, circulatory collapse, cardiac arrest and death. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Other opioid analgesics (Burns and Boyer, 2013; Dahlman et al., 2016; Lynch et al., 2015; Shapiro et al., 2013) Methadone They may increase, prolong or intensify promethazine sedative effects. Opioids should be avoided or administered in reduced dosage to patients receiving promethazine.
The addiction potential of opioids might be enhanced. Also, increasing life-threatening events, such as respiratory depression, overdose and prolongation of the QT interval, might be responsible for drug-related fatalities.
5-HT2: serotonin-2 receptor; CNS: central nervous system; D2: dopamine 2 receptor; GABA: gamma-amino-butyric acid; H1: histamine 1 receptor; NE: norepinephrine; NET: norepinephrine transporter; NMDA: N-methyl-D-aspartate; SERT: serotonin transporter; SSRI: selective-serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
Finally, among abuse-related cases, neonates, infants and children were here reported as well. This is consistent with cases of unexpected infant deaths associated with use of cold medications, poor socioeconomic conditions (Rimsza and Newberry, 2008) and/or accidental ingestion (McLellan and Turner, 2010).
Limitations
One of the limitations was given here by the descriptive nature of the study. Indeed, a comparator molecule, for a disproportionality analysis (Chiappini and Schifano, 2016; Schifano and Chiappini, 2018b) to be carried out, was not available due to data access limitations (EMA, 2017; Postigo et al., 2018). Furthermore, current data did not appear to show an increasing trend of abuse or misuse across the years. Since proper denominator figures (e.g. data on worldwide promethazine prescriptions) are not available, it was unclear if what observed was a substantial number of cases, indicative of clinically meaningful abuse potential, or a passing trend for promethazine misuse by a very small number of individuals. However, consistent with previous suggestions (Montastruc et al, 2011), the value of the current study was that its rationale was driven by a proper, detailed, pharmacodynamic hypothesis established on the basic properties of promethazine. Similar to remaining pharmacovigilance datasets (EMA, 2010; Evoy et al., 2019; Schifano and Chiappini, 2018a; Schifano et al., 2019a, 2019b; Schwan et al., 2010), focussing on the analysis of voluntary adverse events, a further limitation was given here by reliance on self-reporting and the likelihood of missing data occurrence. Moreover, although healthcare professionals have a main role in detection, assessment and spontaneous reporting of ADRs (Belton, 1997; Khalili et al., 2012), specific abuse/misuse/dependence issues relating to promethazine may have been underestimated, with only the most serious cases having been reported, hence the high rates of promethazine fatalities here recorded. Furthermore, although patients and their carers are allowed indeed to flag up an ADR, it is unlikely that they have spontaneously reported misusing events. Other factors, such as increased knowledge of promethazine misuse/abuse, may have resulted here in outcome reporting bias. There was also a potential for duplicate reports, with the same report submitted by the consumer, the healthcare professional and by the manufacturer as well, causing skewed study results. This may occur when a healthcare professional reported the same suspected ADR to both the national Regulatory Authority and the Marketing Authorisation Holder and they both reported subsequently to EV. However, the EV local report number which was here considered unequivocally identified an individual case. In addition, whilst this study represents one of the largest sample of promethazine abuse events published to date, the overall number of events is still relatively small, potentially limiting external validity. Case reports of suspected ADRs alone are not always sufficient to prove that a certain suspected reaction has indeed been caused by a specific medicine. This could be a symptom of another illness, or it could be associated with another medicinal product taken by the patient at the same time. The suspected ADRs were here presented using the PTs of the MedDRA Dictionary (Postigo et al., 2018). Thus, any case report should be considered together with all available data including case reports worldwide, clinical trials, epidemiological studies and toxicological investigations, in order to allow for robust conclusions. Finally, case reports reflect the information as provided to EV by the reporter, and not all data fields were completed for all reports.
Conclusion
To the best of our understanding, the current study described in detail the largest sample ever of abuse, misuse and dependence issues related to promethazine, whilst focussing on a large multinational dataset, such as the EV. The substantial number of promethazine-related events identified over the years represents a pharmacovigilance signal which needs to be better investigated (Montastruc et al., 2011). Although the observed trend of promethazine abuse and misuse, especially in young adults, is not a new phenomenon, further details of the issue have been here provided and future studies will optimally identify the related risk factors, with these measures enabling policymakers and regulators to take action to detect and prevent such misusing practices (Jouanjus et al., 2019). A multicomponent approach is recommended, including monitoring drug utilisation, tracking users’ posts on social media, and exploring healthcare databases; this will enable performing proactive and effective post-marketing surveillance and pharmacovigilance approaches. This has proved to be a relevant, efficient and accurate strategy, for example with gabapentinoids, which have recently been rescheduled in the UK (Borg et al., 2011; Eickhoff et al., 2012; Jouanjus et al., 2019; Novak et al., 2016; Parker et al., 2013; Schifano and Chiappini, 2019; Throckmorton et al., 2018). In this context, the role of the Web is rapidly spreading, playing a significant role in the marketing, sale and distribution of drugs, hence facilitating continuous changes in drug scenarios (Orsolini et al., 2017). Indeed, over the last 10 years access to online pharmacies to purchase medicinal compounds has increased (Desai, 2016; Monteith and Glenn, 2018). On the other hand, professionals access the Web to gather data on emerging trends of drug abuse (Deluca et al., 2002; Orsolini et al., 2015; Schifano, 2020; Schifano et al., 2003).
OTC and prescription drug misuse is perceived to be a significantly under-recognised issue affecting a range of vulnerable individuals (Coombes and Cooper, 2019). However, controlling the problem of OTC misuse and abuse might be challenging, due to the need for achieving high levels of consumer safety whilst not restricting access to OTC products for those who continue to use them safely.
Staff training should be evaluated, in order for pharmacists to self-monitor care and use of medicines, to educate patients and intervene/support those experiencing problematic drug use (Elwood, 2001; GPC, 2019; Tobin et al., 2013; Wells et al., 2018). Record-keeping (Hou et al., 2011) and real time monitoring (Cairns et al., 2016) could be a method of restricting access to some OTC drugs and prevent ‘shopping’ from one pharmacy to another, and where these measures would result to be ineffective, regulatory interventions, e.g. drug re-scheduling, might be useful (Marsden et al., 2019; McDonough, 2016; Peacock et al., 2019). Also, prevention and early education on substance abuse in young teenagers are critical (Levine, 2007; Marsden et al., 2019). Finally, appropriate and specific clinical guidelines for the treatment of misuse, abuse and dependence on prescription or OTC drugs should be implemented (Fingleton et al., 2019).
The review and study design were developed by SC, FS, JMC and AG. SC drafted the first version of the manuscript with input from all authors. All authors contributed to the interpretation of the data analysis and the further drafting of the manuscript and approved the final version.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FS was a member of the UK Advisory Council on the Misuse Drugs (ACMD) from 2011–2019; and is currently an EMA Advisory board (psychiatry) member. JMC is a member of the ACMD’s Novel Psychoactive Substances and Technical Committees. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
ORCID iDs: Stefania Chiappini https://orcid.org/0000-0002-6810-1540
John Martin Corkery https://orcid.org/0000-0002-3849-817X | PROMETHAZINE HYDROCHLORIDE, TRAMADOL HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33427017 | 18,928,797 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Overdose'. | Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.
Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents.
We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database.
After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234).
The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used.
Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.
Introduction
Pharmacological properties of promethazine
Promethazine is a phenothiazine derivative and a histamine (H1) receptor antagonist that is commonly used for symptomatic relief of nausea and vomiting, for allergic conditions, motion sickness and common cold, and for short-term use treatment of insomnia in adults or as a paediatric sedative (EMC, 2019). It also acts as a direct antagonist at muscarinic (M1) and dopamine (D2) receptors (Cookson, 2018; Page et al., 2009; Sharma and Hamelin, 2003). Promethazine hydrochloride is well absorbed from the gastrointestinal tract, with an average of 88% of the dose absorbed after oral administration, and clinical effects appearing within 20 min after intake whilst lasting 4–6 h. The plasma half-life is approximately 7–14 h (Burns and Boyer, 2013). It is classified as a first-generation antihistamine molecule which, compared with second-generation antihistamines, easily penetrates the blood-brain barrier and is associated with adverse effects such as moderate/intense sedation (Jensen et al., 2017). Thus, promethazine might be used in rapid (acute) tranquilization due to its blocking action at H1 and M receptors (Cookson, 2018). Toxicity might result in severe impairment of cognitive and psychomotor functions due to central nervous system (CNS) depression/reduced levels of consciousness, and may cause fatalities (Jensen et al., 2017).
Availability of promethazine
Promethazine is a medicinal product available on its own or in combination with other ingredients, including dextromethorphan, paracetamol and/or expectorants. With regards to promethazine availability, there are wide variations across countries. In fact, in some European countries such as France, Italy and the UK, but also outside Europe, some medicinal products containing promethazine can be purchased over-the-counter (OTC). Promethazine was restricted from an OTC status to prescription only in Denmark as of December 2014. This restriction was partly based on increasing enquiries regarding promethazine exposures to the Danish Poison and Information Centre (DPIC), highlighting its abuse potential and subsequent observations of side-effects after ingestion of standard doses. In Australia, promethazine is available as an OTC medication either alone as a tablet or as a liquid preparation or in combination with paracetamol and codeine phosphate as a syrup (Sharma and Hamelin, 2003). In the USA, some cough preparations containing no more than 200 mg of codeine per 100 mL are considered Schedule V controlled substances (Drug Enforcement Administration (DEA), 2020), purportedly possessing the lowest potential for both misuse and development of a Substance Use Disorder (SUD).
Pharming
Recently, the potential for misuse of medications that are not already controlled has been reported worldwide (Reeves et al., 2015). ‘Pharming’ is a phenomenon involving the non-medical use of prescription (pain relievers, tranquilisers, stimulants, sedatives) and OTC drugs, including cough and cold preparations, particularly those containing dextromethorphan and promethazine (Burns and Boyer, 2013; Jouanjus et al., 2018; Levine, 2007; McCarthy, 2007; National Institute on Drug Abuse (NIDA), 2014). The abuse of these compounds may be facilitated by their easy accessibility, low cost, decreased perception of potential for harm and growing social acceptance (Burns and Boyer, 2013; Levine, 2007; McCarthy, 2007; Substance Abuse Mental Health Services Administration (SAMHSA), 2008). In the current drug abuse scenario, young people/youths have been described abusing with a range of prescription or OTC medicines (Soussan et al., 2018), with these molecules possibly being ingested at high/super-high dosages (Orsolini et al., 2015; Schifano, 2020) and at times in combination with alcohol/remaining recreational substances (Levine, 2007)
Recreational use of promethazine
Centrally acting antihistamines have long been known to induce physical and psychological dependence (Clatts et al., 2010; Gracious et al., 2010; Page et al., 2009; Saatcioglu and Evren, 2005; Thomas et al., 2008). During the past 15 years the abuse of promethazine, especially from OTC and prescription cough and cold medicines and at higher-than-recommended dosages, has been reported (NIDA, 2014). Consistent with this, during the last decade the yearly number of promethazine-related overdose cases in Sweden has increased from 100 to nearly 700 and its sales have increased threefold (Höjer and Tellerup, 2018). Also, according to the 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), antihistamines accounted for the seventh most frequently involved substance in human exposures, resulting in the third type of substance category for rate of exposure increase (Gummin et al., 2019). In Denmark, the number of registered antihistamine exposures increased during 2007–2013, with first-generation antihistamines, specifically promethazine, having been responsible for most exposures and related fatalities (Jensen et al., 2017). Also, in New Zealand a number of promethazine poisoning cases (57/199 patients) were identified from a database of poisoning admissions to a regional toxicology service (Bergman and Wallman, 1998).
Effects
Promethazine reported effects mostly include a range of CNS side effects, such as: confusion; disorientation; drowsiness; cardiovascular symptoms; and respiratory depression (Burns and Boyer, 2013; Höjer and Tellerup, 2018; Page et al., 2009; Tsay et al., 2015). A clear abuse potential has been observed and reported for first-generation antihistamines such as promethazine and cyclizine, due to: calming and sedating effects (Cookson, 2018; Jensen et al., 2017) and enhancement of other co-ingested substances, and especially those interacting with gamma-amino-butyric acid (GABA), opiate and muscarinic acetylcholine receptors (Speeg et al., 1981), leading to hallucinogenic experiences (Clatts et al., 2010; Jensen et al., 2017; Lynch et al., 2015). Indeed, an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility has been described (Burns and Boyer, 2013). In these cases, the mental state alteration is characterised by agitated delirium, with abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia (Agnich et al., 2013; Cowen, 1979; Dollberg et al., 1989; Höjer and Tellerup, 2018; Leak and Carroll, 1967; Page et al., 2009; Scott et al., 2007; Timnak et al., 2004). With the promethazine-codeine cough syrup, ‘euphoric feelings’, ‘relaxation’, ‘slight giddiness and disorienting’, and ‘nice hallucinations’ have been described as well (Bluelight.org [2020]; Erowid.org [2020]). Reported side-effects include drowsiness, fatigue, loss of coordination, constipation and urinary retention (Elwood, 2001).
Vulnerable categories
An increasing trend in abuse of promethazine in co-formulation with some components of OTC cough medications has been reported in young adult populations (Carney et al., 2018; Carr, 2006; Höjer and Tellerup, 2018) since the late 1990s, particularly in the southern USA (Carr, 2006; Elwood, 2001). Codeine and promethazine were recorded as the most requested psychoactive drugs by adolescents/young adults in community pharmacies (Delcourt et al., 2017).
Known by the street names ‘lean’, ‘drank’, ‘barre’, ‘purple stuff’, ‘syrup’ and ‘sizzurp’ (Agnich et al., 2013; NIDA, 2014; Peters et al., 2007), the abuse of promethazine mixed with opioids and other sedatives (e.g. alcohol) in a purple colour drink (‘purple drank’) (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014) has become widely popular (Agnich et al., 2013) after a rap artist/producer created a genre of music, called ‘screw music', inspired by intoxication on codeine and promethazine (Peters et al., 2007). Social media data, e.g. public posts and related hashtags on Instagram, provided additional insights into codeine abuse, depicting its common misuse combined with promethazine and soda/carbonated drinks (Cherian et al., 2018). ‘Purple drank’ has been noted for its euphoric effects and its easy accessibility (Elwood, 2001; Peters et al., 2007). ‘Lean’ creates a distinct (Jakubowski et al., 2018) feeling of euphoria and extreme relaxation (Cookson, 2018), dream-like feelings and a vivid sensation of floating away from the physical body (Peters et al., 2007).
Although at times preferred to other substances, such as benzodiazepines, to treat anxiety and sleep disorders in substance-dependent patients, promethazine has been reported to be misused among people with either opioid dependence (Agnich et al., 2013; Dahlman et al., 2016; Elwood, 2001; Lynch et al., 2015; Shapiro et al., 2013) or a substance abuse condition (Shapiro et al., 2013; Tang et al., 2012). A Hong Kong study reported a total of 63 patients with a diagnosis of cough mixture abuse; 89% were adult males with a mean age of onset of the abuse itself of 20 (±5) years. These subjects had received a diagnosis of substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%) and dysthymia (10%), with most cases having presented with a polysubstance misuse (Tang et al., 2012). Due to the opioid-coformulation, the promethazine-codeine cough mixture might lead to addiction (NIDA, 2014). The mixture may present a high risk of occurrence of near misses due to its central effect of respiratory depression, which is greatly increased by association with alcohol or other CNS depressants, such as sedatives/hypnotics, narcotic analgesics, general anaesthetics and tricyclic antidepressants (Burns and Boyer, 2013; Elwood, 2001; NIDA, 2014; Shapiro et al., 2013; Tsay et al., 2015). The concomitant use of promethazine and other depressant drugs should not be underestimated, as they might together contribute to and/or cause fatalities (Corkery et al., 2020).
Aim of the study
We were interested here in studying how promethazine abuse was reported to the European Medicines Agency (EMA) adverse drug reactions (ADRs) database. We aimed to analyse promethazine misuse/abuse/dependence/withdrawal data. Where possible, in order to have a better understanding, information/data related to diagnosis, concomitant drugs, administration and dosages were also examined.
Methods
Source of data
The EMA through EudraVigilance (EV) manages and analyses information on suspected ADRs to medicines authorised in the European Economic Area (EEA), according to Directive 2001/83/EC and Regulation (EC) No 726/2004 (EMA, 2017). Since November 2017, EV launched extensive Web access to data on suspected ADRs and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research (Postigo et al., 2018). Thus, access to data regarding cases of promethazine abuse, misuse, dependence and withdrawal was obtained by application to the voluntary reporting system of ADRs of the EMA. After 3 months all data comprised all of the ADRs reported during the years from 2003 up to June 2019, presented as large Excel files divided into information sections reporting in a standardised format according to the Medical Dictionary for Regulatory Activities (MedDRA), were sent through a hyperlink (MedDra, 2018). Such listings showed all information related to the ADR, the patient, the drug, the reporter and the diagnosis. An ADR was considered a voluntary and unsolicited communication reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorisation Holders for those ADRs occurring outside the EEA (EMA, 2010). Only ‘suspect’ ADRs were selected, meaning promethazine was considered as ‘suspected’ for the reaction reported. Regarding the content of the ADR, according to the standardised MedDRA Query (SMQ) (MedDRA, 2018), the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, intentional product use issue, substance abuse, substance abuser, substance use and withdrawal syndrome were selected. Those ADRs were defined in accordance with MedDRA in line with previous studies on the EV dataset (Chiappini et al., 2020; MedDRA, 2018; Schifano and Chiappini, 2018a, 2018b; Schifano et al., 2019a, 2019b). Specifically, abuse was here defined as the intentional, non-therapeutic use by a patient or consumer of a product, OTC or prescription, for a perceived reward or desired non-therapeutic effect including, but not limited to, getting high (euphoria) (MedDRA, 2018). Misuse was meant as the intentional use for a therapeutic purpose by a patient or consumer of a product, OTC or prescription, other than as prescribed or not in accordance with the authorised product information (MedDRA, 2018). Finally, non-medical use referred here to the use of a prescription drug, whether obtained by prescription or otherwise, other than in the manner or for the time period prescribed, or by a person for whom the drug was not prescribed (United Nations Office on Drugs and Crime (UNODC), 2013).
Analysis of data
We retrospectively analysed all reported ADRs which were available in the EV database. ADR reports were analysed with respect to age and gender of patient/consumer, source/reporter country (EEA or non-EEA) and reporter qualification (i.e. pharmacist, physician); type of ADR; seriousness (fatal, recovered, resolved outcomes); promethazine dosage; possible concomitant drug(s); and diagnosis/reporter’s comments, if recorded. The descriptive analysis included cases of overdoses, suicides, and fatalities. In the dataset, each case report may refer to one or more reporter; one or more ADR(s); as well as to one or more medicinal product(s). Therefore, a case may be represented by more than one row in the other line listings. The received data files were searched for duplicates by report ID through the ‘EV Local Report Number’, which unequivocally identified an individual case. Thus, the number of suspected ADRs appeared to be different from the number of case reports as one case report might refer to several suspected ADRs. Moreover, the number of patients was different from the number of case reports as a patient might have been described in more than one case. Finally, numbers of ADRs differed from those referring to case reports/single patients since different reporters/senders could have independently flagged the same ADR to the EMA. The descriptive analysis included here a study of the dataset (EMA, 2017) performed through IBM SPSS Statistics software (version 26).
Ethical issues
In compliance with applicable Personal Data Protection legislation (Regulation (EC) No 45/2001 and Regulation (EC) No 1049/2001, the protection of privacy and integrity of individuals was guaranteed, and in order to safeguard the identity of individuals certain data elements, including names/identifiers or country-specific information were not disclosed by the EMA (EMA, 2013, 2017). The study was ethically approved in March 2018 by the University of Hertfordshire Ethics’ Committee, with reference number LMS/PGR/UH/03234.
Results
The dataset obtained reported a total of 11,796 ADRs, correspond-ing to 1,543 single cases recorded during years 2003–2019 (Table 1). Safety reports were all voluntarily submitted, mostly from pharmaceutical companies (1,136/1,543: 73.6%) and regulatory authorities (398/1,543: 25.8%). Reports were irregularly reported over time, with spikes in 2010, 2014 and 2017 (Figure 1). Countries which reported most promethazine-related abuse/misuse/dependence cases included: the USA (805/1,543: 52.10%); Germany (299/1,543: 19.4%); Japan (162/1,543: 10.5%), Sweden (67/1,543: 4.3%), France (43/1,543: 2.8%) and Australia (42/1,543: 2.7%). Out of a total of 1543 cases, ‘suspect’ abuse/misuse/dependence-related cases were 557 (36.1%) and, among them, according to the preferred terms (PTs), most recorded reactions were abuse/misuse-related ADRs (458/557: 82.2%), specifically ‘drug abuse’ (300/557: 53.8%) and ‘intentional product misuse’ (117/557: 21.0%) (Table 1). ‘Suspect’ selected cases and related fatalities annually showed the same trend overall (Figure 1). Most typically, subjects reported were adult (19–64 years) and specifically of the youngest group (19–25 years); males were slightly more frequently recorded than females (M/F: 235/461: 0.51) (Table 1). Where all information was recorded, promethazine was reported as ingested alone in 74 cases, with supratherapeutic dosages, up to 2500 mg, in four cases. In combination with other drugs, most cases were associated with a 100–500 mg promethazine dose, with the maximum dosage recorded having been 8000 mg (Figure 2). The most common administration route was oral (n = 292), although the intramuscular (n = 8) and the parenteral (n = 19) ones were reported as well, see Table 1).
Table 1. Analysis of promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV) during years 2003–2019.
Individual cases (% of total within parentheses)
Total abuse/misuse/dependence cases 1543 Single cases; number of ADRs :11,796
Age range Adult (19–64 years): 648 (648/1,543: 42.0%) - mean age: 31.8 years (SD 26.55–37.05)
Adolescent (10–18 years): 23 (23/1,543: 1.5%) – mean age: 15.9 years (SD 14.3–17.77)
Elderly (>65 years): 25 (25/1,543: 1.6%) – mean age: 72.3 years (SD 70.85–73.7)
Neonatal (hours–days) 14 (14/1,543: 0.9%) – mean age: 24 h (SD 16.6–27.4)
Infant (months–1 year): 7 (7/1,543: 0.45%) – mean age: 10 months (SD 7–13)
Child (<10 years): 4 (4: 1,543: 0.35%) – mean age: 5 years (SD 3.6–6.3)
Unknown: 822 (822/1,543: 53.2%)
Male/female 235/461: 0.51
Most represented abuse/misuse/dependence-related ADRs according to the PTs: 557 (557/1,543: 36.1%)
Abuse-related ADRs 458 (458/557: 82.2%)
Drug abuse 300
Drug abuser 15
Drug diversion 1
Intentional product misuse 117
Intentional product use issue 9
Substance abuse 11
Substance abuser 3
Substance use 2
Dependence-related ADRs 44 (44/557: 7.9%)
Dependence 4
Drug dependence 39
Substance dependence 1
Withdrawal-related ADRs 55 (55/557: 9.8%)
Withdrawal syndrome 19
Drug withdrawal convulsions 1
Drug withdrawal neonatal syndrome 18
Drug withdrawal syndrome 17
Outcome Fatal 310 (310/557: 55.6%)
Unknown 161 (161/557: 28.9%)
Recovered/resolved 55 (55/557: 9.9%)
Recovering/resolving 18 (18/557: 3.3%)
Not recovered/not resolved 13 (13/557: 2.3%)
Promethazine-cases alone 74 (with maximum dosage 2500 mg)
Promethazine-cases with other drugs Most cases (122) were over 100 mg (with maximum dosage 8000 mg)
Most common psychoactive substances used Alcohol: 114
Cocaine: 68
Cannabis: 16
Ketamine: 4
Amphetamine: 1
Most common prescription drugs used Opioids: 1187
Benzodiazepines: 914
Antidepressants: 871
Antipsychotics: 437
Z-drugs: 222
Mood stabilisers: 197
ADR: adverse drug reaction; PTs: preferred terms; SD: standard deviation.
Figure 1. Number of promethazine abuse/misuse/dependence/withdrawal cases reported by year in the EudraVigilance (EV) dataset.
Figure 2. Most represented dosages reported among all promethazine abuse/misuse/dependence/withdrawal cases recorded by the EudraVigilance (EV) dataset.
Concomitantly used drugs recorded were opioids (e.g. oxycodone and fentanyl), benzodiazepines (e.g. diazepam, alprazolam and lorazepam) and antidepressants (e.g. citalopram, venlafaxine and amitriptyline), whilst recreational drugs most represented were alcohol and cocaine (Table 1). Most reported diagnoses, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V; American Psychiatric Association (APA), 2013) related to: mood disorders, e.g. depression/depressed mood/major depression (68 cases) and bipolar disorder (14 cases); anxiety/anxiety disorders (23 cases); alcohol abuse/alcoholic/alcoholism (26 cases); and schizophrenia (14 cases). The outcome of the reactions reported included: ‘fatal’ (n=310/557; 55.6%) and secondarily ‘recovered/resolved’ (n=73; 15.2%) (Table 1). Some 27 cases were related to suicidal or self-harm behaviour, being recorded as ‘suicidal attempt/suicidal ideation’ (n=24), ‘self-injurious ideation’ (n=1), and ‘suicide attempt’ (n=2). Fatalities mostly involved adult females; in these cases, most typical ADRs recorded were ‘drug abuse’ (n=228) and ‘intentional product misuse’ (n=77) (Table 2). Opiates/opioids were the most recorded concomitant drugs (n=356), with methadone being the most represented (n=103), followed by antidepressants (n=221) and benzodiazepines (n=141). Among illicit drugs, heroin appeared to be the most represented (Table 2).
Table 2. Analysis of fatal promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV), 2003–2019.
Fatal cases on abuse/misuse/dependence/withdrawal reactions 310 (310/557 = 55.6%)
Age-range
Adult 303 (97.7%)
Adolescent 7 (2.3%)
Elderly (>65 years) –
Neonatal –
Infant –
Child –
Gender M 103 (33.2%)
F 177 (57.1%)
Unknown 30 (9.7%)
Most recorded PTs
Drug abuse/drug abuser/substance abuse 228/3/6
Intentional product misuse/Intentional product use issue 77/3
Drug dependence 1
Reported death code
Intentional overdose 1
Overdose 4
Completed suicide/suicide 7
Drug toxicity/drug abuse 197
Toxicity to various agents 48
Intentional product misuse 41
Respiratory depression 5
Pneumonia 1
Cardiac arrest 10
Drug dependence 1
Most reported concomitant drugs
Opioids 356
Methadone 103
Dihydrocodeine 1
Codeine 32
Fentanyl 44
Oxycodone 63
Morphine 55
Hydrocodone 33
Hydromorphone 3
Tramadol 22
Antidepressants 221
Duloxetine 1
Escitalopram 1
Sertraline 16
Paroxetine 34
Trazodone 15
Mirtazapine 33
Fluoxetine 24
Venlafaxine 9
Bupropion 1
Amitriptyline 35
Nortriptyline 6
Clomipramine 5
Citalopram 41
Benzodiazepines 141
Lorazepam 3
Temazepam 6
Clonazepam 21
Diazepam 60
Flunitrazepam 1
Brotizolam 1
Alprazolam 42
Midazolam 4
Oxazepam 3
Mood stabilisers 11
Gabapentin 3
Topiramate 8
Antipsychotics 24
Olanzapine 1
Quetiapine 20
Haloperidol 1
Amisulpride 1
Levomepromazine 1
Z-drugs 39
Zolpidem 37
Zopiclone 2
Illicit drugs
Amphetamine 15
Cocaine 40
Heroin 52
Alcohol 26
PTs: preferred terms.
Discussion
Non-medical prescription drug use is a globally recognised problem, with severe adverse consequences. The current study provides a large amount of descriptive data highlighting that promethazine can be taken at high dosages, through non-approved administration routes, and in a setting of polydrug use (Hughes et al., 2016; Novak et al., 2016).
Promethazine misuse has been increasingly recorded since the early 2000s, consistently with data from US poison centres reporting antihistamine exposures rising in the period 2007–2013 (Jensen et al., 2017). This is not surprising, since the pharmacodynamic properties of promethazine underpins its sought-after central effects. In 2014, e.g. the highest peak here, the increase in promethazine misuse reporting was solely driven by the USA (245/245 cases; 100%). This may have been associated with intense media attention to the subject in that year (TMZ, 2014). The increments reported in 2010, 2014 and 2017 were then followed by decrements, which may have been related to not only reporting variabilities, but also to differences in sales of antihistamines following local/national drug abuse prevention campaigns (Klein-Schwartz, 2017). Overall, the USA appeared here to be the country most involved in reporting of promethazine ADRs. Several reasons may help in explaining this, including healthcare professionals’ awareness of prescription/OTC drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Lynch et al., 2015; Manchikanti et al., 2006; NIDA, 2014; Tsay et al., 2015) which, in turn, may have facilitated pharmacovigilance reporting. According to an 11-year period of the US National Poison Centers’ database, the annual rate of promethazine abuse/misuse per 100,000 US population doubled over time (Tsay et al., 2015). In the USA, promethazine abuse/misuse has been described in teenagers and young adults (Peters et al., 2003), methadone maintenance patients, heroin users and opioid-prescribed chronic pain patients (Lynch et al., 2015; Shapiro et al., 2013).
Consistent with previous observations (Agnich et al., 2013; Burns and Boyer, 2013; Carr, 2006; Elwood, 2001; Höjer and Tellerup, 2018; NIDA, 2014; Page et al., 2009; Parker et al., 2013; Peters et al., 2007), most recorded ADRs related here to either ‘drug abuse’ and ‘intentional product misuse’, involving young adult (19–25 years) males. Although considered a vulnerable category with respect to prescription drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014; Peters et al., 2007), adolescents (10–18 years) were here reported in only a minority (23/1543:1.5%) of cases.
Several drugs were here associated with promethazine, although opiates/opioids were the most represented molecules in related fatalities. This combination might intensify effects such as sedation and analgesia (Burns and Boyer, 2013; Lynch et al., 2015; Shapiro et al., 2013), and in the 1950s the association was medically used to reduce the dosage of opiates/opioids (McGee and Weiss, 1956). However, due to a range of adverse effects (Lynch et al., 2015) including lack of data supporting clinical efficacy (Richter and Burk, 1992) and an enhanced addiction potential of opioids (Lynch et al., 2015; Peters et al., 2007; Shapiro et al., 2013), the combination of promethazine/opioids has declined in popularity.
So far, the recreational intake of promethazine with opioids has been typically reported in cough mixtures containing codeine (Casati et al., 2012; Clatts et al., 2010; Elwood, 2001; Foley et al., 2015; Peters et al., 2007). However, current EMA data suggest that, apart from methadone, oxycodone and fentanyl were the most typical opiates/opiates identified in association with promethazine, possibly due to their recent popularity, especially in the USA (Manchikanti et al., 2018; Rose, 2018). In the promethazine fatalities (e.g. 310 cases) dataset analysed, codeine, fentanyl and oxycodone were respectively reported in 32, 44 and 63 cases. Consistent with current data, a concomitant use of opioids and promethazine has been described in various subpopulations, such as methadone maintenance patients, injecting drug users and chronic pain patients (Banta-Green et al., 2005; Lynch et al., 2015; Shapiro et al., 2013; Shields et al., 2007; Van Hout and Norman, 2016). Overall, there is now a high level of awareness of the abuse potential of antihistamine/opioid-containing products (Hou et al., 2011; Hughes et al., 1999; Wazaify et al., 2005). Hence, some countries are limiting both the medication pack size levels and the quantities of drugs sold in a single transaction, whilst also promoting non-injectable and non-inhaling formulations and changing some formulations’ OTC status (Cooper, 2013; Foley et al., 2015; Van Hout and Norman, 2016).
Benzodiazepines (e.g. diazepam, alprazolam and lorazepam) were here also frequently recorded, suggesting sedative synergistic effects in combination with promethazine (Lynch et al., 2015), and hence an increased risk of untoward clinical issues (McLellan and Turner, 2010). Other prescription drug categories recorded included antidepressants (most typically: citalopram and amitriptyline, respectively in 149/557 and 95/557 cases), which is consistent with the most typically recorded diagnoses, e.g. depressive (68 cases); bipolar (14 cases); and anxiety (23 cases) disorders. It is also possible that antidepressants were here ingested in combination with promethazine for sleep induction purposes. It is a reason for concern that promethazine ADRs, either alone or in combination, resulted in either fatal (50.6%) or ‘recovered/resolved’ outcomes (22.2%). This is consistent with previous promethazine misuse/abuse data, reporting both adverse clinical outcomes and high frequency of healthcare facility treatment (Bergman and Wallman, 1998; Ichikura et al., 2016; McLellan and Turner, 2010; Tsay et al., 2015). A list of possibly misused substances which might reinforce promethazine psychoactive effects and possibly increase its toxicity is included in Table 3.
Table 3. List of substances recorded in the literature as used in association with promethazine in order to increase its effects; prescription drugs are recorded according to the Neuroscience-based Nomenclature description (Nutt and Blier, 2016).
Psychoactive substances
Description Mode of action Examples Effects
Alcohol (Burns and Boyer, 2013; Jensen et al., 2017) CNS depressant effects ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, relaxation, ‘slight giddiness and disorienting’ and ‘nice hallucination’.
It may increase, prolong or intensify promethazine sedative effect. It should be avoided in patients receiving promethazine.
Heroin and other illicit opioids (Dahlman et al., 2016; Tsay et al., 2015) Opioid depressant effects It may increase, prolong, or intensify promethazine sedative effect.
Prescription drugs
Categories Mode of action Examples Effects
Drugs for insomnia (Burns and Boyer, 2013) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Z-drugs: zaleplon, zolpidem, zopiclone, eszopiclone They may increase, prolong or intensify promethazine sedative effect.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Drugs for anxiety (Burns and Boyer, 2013; Lynch et al., 2015) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, lorazepam, oxazepam They may increase, prolong or intensify promethazine sedative action.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Dextrometorphan (Tsay et al., 2015) At high doses, acting as NMDA-receptor antagonist; dextrometorphan and its potent metabolite dextrorphan inhibit the excitatory amino acid and neurotransmitter glutamate in the brain, determining hallucinogenic and dissociative activities, which are recreationally searched It might be combined with promethazine in cough-suppressant formulation Dextrometorphan neurobehavioural effects are dose-related, starting from a mild to moderate stimulation with restlessness and euphoria (100–200 mg), to a dissociated state characterised by hallucinations, paranoia, perceptual distortions, delusional beliefs, ataxia and out-of-body experiences (‘robo-ing’/‘robo-copping’/‘robo-tripping’) (>1000 mg). In overdosage they might increase promethazine effects.
Drugs for depression (Burns and Boyer, 2013; Jensen et al., 2017): TCA Multimodal action: reuptake inhibitor (SERT and NET), receptor antagonist (5-HT2) Amitriptyline Promethazine may increase, prolong or intensify their sedative effect. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Anticholinergic drugs Antagonist at cholinergic receptors Hyoscine butyl bromide/scopolamine (Burns and Boyer, 2013) Together with promethazine an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility may be seen. A typical mental status alteration with a dose-dependent agitated delirium characterised by abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia, has been described. These molecules should be avoided or administered in reduced dosage to patients receiving promethazine.
Prescription opioids
Codeine (Burns and Boyer, 2013; Jouanjus et al., 2018; Lynch et al., 2015; O Reilly et al., 2015; Shapiro et al., 2013) ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, elation, analgesia and ‘liking’, with increased potential of addiction. Overdosage of codeine might determine respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne–Stokes respiration and cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Opiate overdosage, particularly by the intravenous route, may be associated with apnoea, circulatory collapse, cardiac arrest and death. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Other opioid analgesics (Burns and Boyer, 2013; Dahlman et al., 2016; Lynch et al., 2015; Shapiro et al., 2013) Methadone They may increase, prolong or intensify promethazine sedative effects. Opioids should be avoided or administered in reduced dosage to patients receiving promethazine.
The addiction potential of opioids might be enhanced. Also, increasing life-threatening events, such as respiratory depression, overdose and prolongation of the QT interval, might be responsible for drug-related fatalities.
5-HT2: serotonin-2 receptor; CNS: central nervous system; D2: dopamine 2 receptor; GABA: gamma-amino-butyric acid; H1: histamine 1 receptor; NE: norepinephrine; NET: norepinephrine transporter; NMDA: N-methyl-D-aspartate; SERT: serotonin transporter; SSRI: selective-serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
Finally, among abuse-related cases, neonates, infants and children were here reported as well. This is consistent with cases of unexpected infant deaths associated with use of cold medications, poor socioeconomic conditions (Rimsza and Newberry, 2008) and/or accidental ingestion (McLellan and Turner, 2010).
Limitations
One of the limitations was given here by the descriptive nature of the study. Indeed, a comparator molecule, for a disproportionality analysis (Chiappini and Schifano, 2016; Schifano and Chiappini, 2018b) to be carried out, was not available due to data access limitations (EMA, 2017; Postigo et al., 2018). Furthermore, current data did not appear to show an increasing trend of abuse or misuse across the years. Since proper denominator figures (e.g. data on worldwide promethazine prescriptions) are not available, it was unclear if what observed was a substantial number of cases, indicative of clinically meaningful abuse potential, or a passing trend for promethazine misuse by a very small number of individuals. However, consistent with previous suggestions (Montastruc et al, 2011), the value of the current study was that its rationale was driven by a proper, detailed, pharmacodynamic hypothesis established on the basic properties of promethazine. Similar to remaining pharmacovigilance datasets (EMA, 2010; Evoy et al., 2019; Schifano and Chiappini, 2018a; Schifano et al., 2019a, 2019b; Schwan et al., 2010), focussing on the analysis of voluntary adverse events, a further limitation was given here by reliance on self-reporting and the likelihood of missing data occurrence. Moreover, although healthcare professionals have a main role in detection, assessment and spontaneous reporting of ADRs (Belton, 1997; Khalili et al., 2012), specific abuse/misuse/dependence issues relating to promethazine may have been underestimated, with only the most serious cases having been reported, hence the high rates of promethazine fatalities here recorded. Furthermore, although patients and their carers are allowed indeed to flag up an ADR, it is unlikely that they have spontaneously reported misusing events. Other factors, such as increased knowledge of promethazine misuse/abuse, may have resulted here in outcome reporting bias. There was also a potential for duplicate reports, with the same report submitted by the consumer, the healthcare professional and by the manufacturer as well, causing skewed study results. This may occur when a healthcare professional reported the same suspected ADR to both the national Regulatory Authority and the Marketing Authorisation Holder and they both reported subsequently to EV. However, the EV local report number which was here considered unequivocally identified an individual case. In addition, whilst this study represents one of the largest sample of promethazine abuse events published to date, the overall number of events is still relatively small, potentially limiting external validity. Case reports of suspected ADRs alone are not always sufficient to prove that a certain suspected reaction has indeed been caused by a specific medicine. This could be a symptom of another illness, or it could be associated with another medicinal product taken by the patient at the same time. The suspected ADRs were here presented using the PTs of the MedDRA Dictionary (Postigo et al., 2018). Thus, any case report should be considered together with all available data including case reports worldwide, clinical trials, epidemiological studies and toxicological investigations, in order to allow for robust conclusions. Finally, case reports reflect the information as provided to EV by the reporter, and not all data fields were completed for all reports.
Conclusion
To the best of our understanding, the current study described in detail the largest sample ever of abuse, misuse and dependence issues related to promethazine, whilst focussing on a large multinational dataset, such as the EV. The substantial number of promethazine-related events identified over the years represents a pharmacovigilance signal which needs to be better investigated (Montastruc et al., 2011). Although the observed trend of promethazine abuse and misuse, especially in young adults, is not a new phenomenon, further details of the issue have been here provided and future studies will optimally identify the related risk factors, with these measures enabling policymakers and regulators to take action to detect and prevent such misusing practices (Jouanjus et al., 2019). A multicomponent approach is recommended, including monitoring drug utilisation, tracking users’ posts on social media, and exploring healthcare databases; this will enable performing proactive and effective post-marketing surveillance and pharmacovigilance approaches. This has proved to be a relevant, efficient and accurate strategy, for example with gabapentinoids, which have recently been rescheduled in the UK (Borg et al., 2011; Eickhoff et al., 2012; Jouanjus et al., 2019; Novak et al., 2016; Parker et al., 2013; Schifano and Chiappini, 2019; Throckmorton et al., 2018). In this context, the role of the Web is rapidly spreading, playing a significant role in the marketing, sale and distribution of drugs, hence facilitating continuous changes in drug scenarios (Orsolini et al., 2017). Indeed, over the last 10 years access to online pharmacies to purchase medicinal compounds has increased (Desai, 2016; Monteith and Glenn, 2018). On the other hand, professionals access the Web to gather data on emerging trends of drug abuse (Deluca et al., 2002; Orsolini et al., 2015; Schifano, 2020; Schifano et al., 2003).
OTC and prescription drug misuse is perceived to be a significantly under-recognised issue affecting a range of vulnerable individuals (Coombes and Cooper, 2019). However, controlling the problem of OTC misuse and abuse might be challenging, due to the need for achieving high levels of consumer safety whilst not restricting access to OTC products for those who continue to use them safely.
Staff training should be evaluated, in order for pharmacists to self-monitor care and use of medicines, to educate patients and intervene/support those experiencing problematic drug use (Elwood, 2001; GPC, 2019; Tobin et al., 2013; Wells et al., 2018). Record-keeping (Hou et al., 2011) and real time monitoring (Cairns et al., 2016) could be a method of restricting access to some OTC drugs and prevent ‘shopping’ from one pharmacy to another, and where these measures would result to be ineffective, regulatory interventions, e.g. drug re-scheduling, might be useful (Marsden et al., 2019; McDonough, 2016; Peacock et al., 2019). Also, prevention and early education on substance abuse in young teenagers are critical (Levine, 2007; Marsden et al., 2019). Finally, appropriate and specific clinical guidelines for the treatment of misuse, abuse and dependence on prescription or OTC drugs should be implemented (Fingleton et al., 2019).
The review and study design were developed by SC, FS, JMC and AG. SC drafted the first version of the manuscript with input from all authors. All authors contributed to the interpretation of the data analysis and the further drafting of the manuscript and approved the final version.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FS was a member of the UK Advisory Council on the Misuse Drugs (ACMD) from 2011–2019; and is currently an EMA Advisory board (psychiatry) member. JMC is a member of the ACMD’s Novel Psychoactive Substances and Technical Committees. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
ORCID iDs: Stefania Chiappini https://orcid.org/0000-0002-6810-1540
John Martin Corkery https://orcid.org/0000-0002-3849-817X | PROMETHAZINE HYDROCHLORIDE, TRAMADOL HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33427017 | 18,928,797 | 2021-06 |
What was the outcome of reaction 'Cardiac arrest'? | Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.
Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents.
We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database.
After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234).
The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used.
Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.
Introduction
Pharmacological properties of promethazine
Promethazine is a phenothiazine derivative and a histamine (H1) receptor antagonist that is commonly used for symptomatic relief of nausea and vomiting, for allergic conditions, motion sickness and common cold, and for short-term use treatment of insomnia in adults or as a paediatric sedative (EMC, 2019). It also acts as a direct antagonist at muscarinic (M1) and dopamine (D2) receptors (Cookson, 2018; Page et al., 2009; Sharma and Hamelin, 2003). Promethazine hydrochloride is well absorbed from the gastrointestinal tract, with an average of 88% of the dose absorbed after oral administration, and clinical effects appearing within 20 min after intake whilst lasting 4–6 h. The plasma half-life is approximately 7–14 h (Burns and Boyer, 2013). It is classified as a first-generation antihistamine molecule which, compared with second-generation antihistamines, easily penetrates the blood-brain barrier and is associated with adverse effects such as moderate/intense sedation (Jensen et al., 2017). Thus, promethazine might be used in rapid (acute) tranquilization due to its blocking action at H1 and M receptors (Cookson, 2018). Toxicity might result in severe impairment of cognitive and psychomotor functions due to central nervous system (CNS) depression/reduced levels of consciousness, and may cause fatalities (Jensen et al., 2017).
Availability of promethazine
Promethazine is a medicinal product available on its own or in combination with other ingredients, including dextromethorphan, paracetamol and/or expectorants. With regards to promethazine availability, there are wide variations across countries. In fact, in some European countries such as France, Italy and the UK, but also outside Europe, some medicinal products containing promethazine can be purchased over-the-counter (OTC). Promethazine was restricted from an OTC status to prescription only in Denmark as of December 2014. This restriction was partly based on increasing enquiries regarding promethazine exposures to the Danish Poison and Information Centre (DPIC), highlighting its abuse potential and subsequent observations of side-effects after ingestion of standard doses. In Australia, promethazine is available as an OTC medication either alone as a tablet or as a liquid preparation or in combination with paracetamol and codeine phosphate as a syrup (Sharma and Hamelin, 2003). In the USA, some cough preparations containing no more than 200 mg of codeine per 100 mL are considered Schedule V controlled substances (Drug Enforcement Administration (DEA), 2020), purportedly possessing the lowest potential for both misuse and development of a Substance Use Disorder (SUD).
Pharming
Recently, the potential for misuse of medications that are not already controlled has been reported worldwide (Reeves et al., 2015). ‘Pharming’ is a phenomenon involving the non-medical use of prescription (pain relievers, tranquilisers, stimulants, sedatives) and OTC drugs, including cough and cold preparations, particularly those containing dextromethorphan and promethazine (Burns and Boyer, 2013; Jouanjus et al., 2018; Levine, 2007; McCarthy, 2007; National Institute on Drug Abuse (NIDA), 2014). The abuse of these compounds may be facilitated by their easy accessibility, low cost, decreased perception of potential for harm and growing social acceptance (Burns and Boyer, 2013; Levine, 2007; McCarthy, 2007; Substance Abuse Mental Health Services Administration (SAMHSA), 2008). In the current drug abuse scenario, young people/youths have been described abusing with a range of prescription or OTC medicines (Soussan et al., 2018), with these molecules possibly being ingested at high/super-high dosages (Orsolini et al., 2015; Schifano, 2020) and at times in combination with alcohol/remaining recreational substances (Levine, 2007)
Recreational use of promethazine
Centrally acting antihistamines have long been known to induce physical and psychological dependence (Clatts et al., 2010; Gracious et al., 2010; Page et al., 2009; Saatcioglu and Evren, 2005; Thomas et al., 2008). During the past 15 years the abuse of promethazine, especially from OTC and prescription cough and cold medicines and at higher-than-recommended dosages, has been reported (NIDA, 2014). Consistent with this, during the last decade the yearly number of promethazine-related overdose cases in Sweden has increased from 100 to nearly 700 and its sales have increased threefold (Höjer and Tellerup, 2018). Also, according to the 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), antihistamines accounted for the seventh most frequently involved substance in human exposures, resulting in the third type of substance category for rate of exposure increase (Gummin et al., 2019). In Denmark, the number of registered antihistamine exposures increased during 2007–2013, with first-generation antihistamines, specifically promethazine, having been responsible for most exposures and related fatalities (Jensen et al., 2017). Also, in New Zealand a number of promethazine poisoning cases (57/199 patients) were identified from a database of poisoning admissions to a regional toxicology service (Bergman and Wallman, 1998).
Effects
Promethazine reported effects mostly include a range of CNS side effects, such as: confusion; disorientation; drowsiness; cardiovascular symptoms; and respiratory depression (Burns and Boyer, 2013; Höjer and Tellerup, 2018; Page et al., 2009; Tsay et al., 2015). A clear abuse potential has been observed and reported for first-generation antihistamines such as promethazine and cyclizine, due to: calming and sedating effects (Cookson, 2018; Jensen et al., 2017) and enhancement of other co-ingested substances, and especially those interacting with gamma-amino-butyric acid (GABA), opiate and muscarinic acetylcholine receptors (Speeg et al., 1981), leading to hallucinogenic experiences (Clatts et al., 2010; Jensen et al., 2017; Lynch et al., 2015). Indeed, an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility has been described (Burns and Boyer, 2013). In these cases, the mental state alteration is characterised by agitated delirium, with abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia (Agnich et al., 2013; Cowen, 1979; Dollberg et al., 1989; Höjer and Tellerup, 2018; Leak and Carroll, 1967; Page et al., 2009; Scott et al., 2007; Timnak et al., 2004). With the promethazine-codeine cough syrup, ‘euphoric feelings’, ‘relaxation’, ‘slight giddiness and disorienting’, and ‘nice hallucinations’ have been described as well (Bluelight.org [2020]; Erowid.org [2020]). Reported side-effects include drowsiness, fatigue, loss of coordination, constipation and urinary retention (Elwood, 2001).
Vulnerable categories
An increasing trend in abuse of promethazine in co-formulation with some components of OTC cough medications has been reported in young adult populations (Carney et al., 2018; Carr, 2006; Höjer and Tellerup, 2018) since the late 1990s, particularly in the southern USA (Carr, 2006; Elwood, 2001). Codeine and promethazine were recorded as the most requested psychoactive drugs by adolescents/young adults in community pharmacies (Delcourt et al., 2017).
Known by the street names ‘lean’, ‘drank’, ‘barre’, ‘purple stuff’, ‘syrup’ and ‘sizzurp’ (Agnich et al., 2013; NIDA, 2014; Peters et al., 2007), the abuse of promethazine mixed with opioids and other sedatives (e.g. alcohol) in a purple colour drink (‘purple drank’) (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014) has become widely popular (Agnich et al., 2013) after a rap artist/producer created a genre of music, called ‘screw music', inspired by intoxication on codeine and promethazine (Peters et al., 2007). Social media data, e.g. public posts and related hashtags on Instagram, provided additional insights into codeine abuse, depicting its common misuse combined with promethazine and soda/carbonated drinks (Cherian et al., 2018). ‘Purple drank’ has been noted for its euphoric effects and its easy accessibility (Elwood, 2001; Peters et al., 2007). ‘Lean’ creates a distinct (Jakubowski et al., 2018) feeling of euphoria and extreme relaxation (Cookson, 2018), dream-like feelings and a vivid sensation of floating away from the physical body (Peters et al., 2007).
Although at times preferred to other substances, such as benzodiazepines, to treat anxiety and sleep disorders in substance-dependent patients, promethazine has been reported to be misused among people with either opioid dependence (Agnich et al., 2013; Dahlman et al., 2016; Elwood, 2001; Lynch et al., 2015; Shapiro et al., 2013) or a substance abuse condition (Shapiro et al., 2013; Tang et al., 2012). A Hong Kong study reported a total of 63 patients with a diagnosis of cough mixture abuse; 89% were adult males with a mean age of onset of the abuse itself of 20 (±5) years. These subjects had received a diagnosis of substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%) and dysthymia (10%), with most cases having presented with a polysubstance misuse (Tang et al., 2012). Due to the opioid-coformulation, the promethazine-codeine cough mixture might lead to addiction (NIDA, 2014). The mixture may present a high risk of occurrence of near misses due to its central effect of respiratory depression, which is greatly increased by association with alcohol or other CNS depressants, such as sedatives/hypnotics, narcotic analgesics, general anaesthetics and tricyclic antidepressants (Burns and Boyer, 2013; Elwood, 2001; NIDA, 2014; Shapiro et al., 2013; Tsay et al., 2015). The concomitant use of promethazine and other depressant drugs should not be underestimated, as they might together contribute to and/or cause fatalities (Corkery et al., 2020).
Aim of the study
We were interested here in studying how promethazine abuse was reported to the European Medicines Agency (EMA) adverse drug reactions (ADRs) database. We aimed to analyse promethazine misuse/abuse/dependence/withdrawal data. Where possible, in order to have a better understanding, information/data related to diagnosis, concomitant drugs, administration and dosages were also examined.
Methods
Source of data
The EMA through EudraVigilance (EV) manages and analyses information on suspected ADRs to medicines authorised in the European Economic Area (EEA), according to Directive 2001/83/EC and Regulation (EC) No 726/2004 (EMA, 2017). Since November 2017, EV launched extensive Web access to data on suspected ADRs and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research (Postigo et al., 2018). Thus, access to data regarding cases of promethazine abuse, misuse, dependence and withdrawal was obtained by application to the voluntary reporting system of ADRs of the EMA. After 3 months all data comprised all of the ADRs reported during the years from 2003 up to June 2019, presented as large Excel files divided into information sections reporting in a standardised format according to the Medical Dictionary for Regulatory Activities (MedDRA), were sent through a hyperlink (MedDra, 2018). Such listings showed all information related to the ADR, the patient, the drug, the reporter and the diagnosis. An ADR was considered a voluntary and unsolicited communication reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorisation Holders for those ADRs occurring outside the EEA (EMA, 2010). Only ‘suspect’ ADRs were selected, meaning promethazine was considered as ‘suspected’ for the reaction reported. Regarding the content of the ADR, according to the standardised MedDRA Query (SMQ) (MedDRA, 2018), the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, intentional product use issue, substance abuse, substance abuser, substance use and withdrawal syndrome were selected. Those ADRs were defined in accordance with MedDRA in line with previous studies on the EV dataset (Chiappini et al., 2020; MedDRA, 2018; Schifano and Chiappini, 2018a, 2018b; Schifano et al., 2019a, 2019b). Specifically, abuse was here defined as the intentional, non-therapeutic use by a patient or consumer of a product, OTC or prescription, for a perceived reward or desired non-therapeutic effect including, but not limited to, getting high (euphoria) (MedDRA, 2018). Misuse was meant as the intentional use for a therapeutic purpose by a patient or consumer of a product, OTC or prescription, other than as prescribed or not in accordance with the authorised product information (MedDRA, 2018). Finally, non-medical use referred here to the use of a prescription drug, whether obtained by prescription or otherwise, other than in the manner or for the time period prescribed, or by a person for whom the drug was not prescribed (United Nations Office on Drugs and Crime (UNODC), 2013).
Analysis of data
We retrospectively analysed all reported ADRs which were available in the EV database. ADR reports were analysed with respect to age and gender of patient/consumer, source/reporter country (EEA or non-EEA) and reporter qualification (i.e. pharmacist, physician); type of ADR; seriousness (fatal, recovered, resolved outcomes); promethazine dosage; possible concomitant drug(s); and diagnosis/reporter’s comments, if recorded. The descriptive analysis included cases of overdoses, suicides, and fatalities. In the dataset, each case report may refer to one or more reporter; one or more ADR(s); as well as to one or more medicinal product(s). Therefore, a case may be represented by more than one row in the other line listings. The received data files were searched for duplicates by report ID through the ‘EV Local Report Number’, which unequivocally identified an individual case. Thus, the number of suspected ADRs appeared to be different from the number of case reports as one case report might refer to several suspected ADRs. Moreover, the number of patients was different from the number of case reports as a patient might have been described in more than one case. Finally, numbers of ADRs differed from those referring to case reports/single patients since different reporters/senders could have independently flagged the same ADR to the EMA. The descriptive analysis included here a study of the dataset (EMA, 2017) performed through IBM SPSS Statistics software (version 26).
Ethical issues
In compliance with applicable Personal Data Protection legislation (Regulation (EC) No 45/2001 and Regulation (EC) No 1049/2001, the protection of privacy and integrity of individuals was guaranteed, and in order to safeguard the identity of individuals certain data elements, including names/identifiers or country-specific information were not disclosed by the EMA (EMA, 2013, 2017). The study was ethically approved in March 2018 by the University of Hertfordshire Ethics’ Committee, with reference number LMS/PGR/UH/03234.
Results
The dataset obtained reported a total of 11,796 ADRs, correspond-ing to 1,543 single cases recorded during years 2003–2019 (Table 1). Safety reports were all voluntarily submitted, mostly from pharmaceutical companies (1,136/1,543: 73.6%) and regulatory authorities (398/1,543: 25.8%). Reports were irregularly reported over time, with spikes in 2010, 2014 and 2017 (Figure 1). Countries which reported most promethazine-related abuse/misuse/dependence cases included: the USA (805/1,543: 52.10%); Germany (299/1,543: 19.4%); Japan (162/1,543: 10.5%), Sweden (67/1,543: 4.3%), France (43/1,543: 2.8%) and Australia (42/1,543: 2.7%). Out of a total of 1543 cases, ‘suspect’ abuse/misuse/dependence-related cases were 557 (36.1%) and, among them, according to the preferred terms (PTs), most recorded reactions were abuse/misuse-related ADRs (458/557: 82.2%), specifically ‘drug abuse’ (300/557: 53.8%) and ‘intentional product misuse’ (117/557: 21.0%) (Table 1). ‘Suspect’ selected cases and related fatalities annually showed the same trend overall (Figure 1). Most typically, subjects reported were adult (19–64 years) and specifically of the youngest group (19–25 years); males were slightly more frequently recorded than females (M/F: 235/461: 0.51) (Table 1). Where all information was recorded, promethazine was reported as ingested alone in 74 cases, with supratherapeutic dosages, up to 2500 mg, in four cases. In combination with other drugs, most cases were associated with a 100–500 mg promethazine dose, with the maximum dosage recorded having been 8000 mg (Figure 2). The most common administration route was oral (n = 292), although the intramuscular (n = 8) and the parenteral (n = 19) ones were reported as well, see Table 1).
Table 1. Analysis of promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV) during years 2003–2019.
Individual cases (% of total within parentheses)
Total abuse/misuse/dependence cases 1543 Single cases; number of ADRs :11,796
Age range Adult (19–64 years): 648 (648/1,543: 42.0%) - mean age: 31.8 years (SD 26.55–37.05)
Adolescent (10–18 years): 23 (23/1,543: 1.5%) – mean age: 15.9 years (SD 14.3–17.77)
Elderly (>65 years): 25 (25/1,543: 1.6%) – mean age: 72.3 years (SD 70.85–73.7)
Neonatal (hours–days) 14 (14/1,543: 0.9%) – mean age: 24 h (SD 16.6–27.4)
Infant (months–1 year): 7 (7/1,543: 0.45%) – mean age: 10 months (SD 7–13)
Child (<10 years): 4 (4: 1,543: 0.35%) – mean age: 5 years (SD 3.6–6.3)
Unknown: 822 (822/1,543: 53.2%)
Male/female 235/461: 0.51
Most represented abuse/misuse/dependence-related ADRs according to the PTs: 557 (557/1,543: 36.1%)
Abuse-related ADRs 458 (458/557: 82.2%)
Drug abuse 300
Drug abuser 15
Drug diversion 1
Intentional product misuse 117
Intentional product use issue 9
Substance abuse 11
Substance abuser 3
Substance use 2
Dependence-related ADRs 44 (44/557: 7.9%)
Dependence 4
Drug dependence 39
Substance dependence 1
Withdrawal-related ADRs 55 (55/557: 9.8%)
Withdrawal syndrome 19
Drug withdrawal convulsions 1
Drug withdrawal neonatal syndrome 18
Drug withdrawal syndrome 17
Outcome Fatal 310 (310/557: 55.6%)
Unknown 161 (161/557: 28.9%)
Recovered/resolved 55 (55/557: 9.9%)
Recovering/resolving 18 (18/557: 3.3%)
Not recovered/not resolved 13 (13/557: 2.3%)
Promethazine-cases alone 74 (with maximum dosage 2500 mg)
Promethazine-cases with other drugs Most cases (122) were over 100 mg (with maximum dosage 8000 mg)
Most common psychoactive substances used Alcohol: 114
Cocaine: 68
Cannabis: 16
Ketamine: 4
Amphetamine: 1
Most common prescription drugs used Opioids: 1187
Benzodiazepines: 914
Antidepressants: 871
Antipsychotics: 437
Z-drugs: 222
Mood stabilisers: 197
ADR: adverse drug reaction; PTs: preferred terms; SD: standard deviation.
Figure 1. Number of promethazine abuse/misuse/dependence/withdrawal cases reported by year in the EudraVigilance (EV) dataset.
Figure 2. Most represented dosages reported among all promethazine abuse/misuse/dependence/withdrawal cases recorded by the EudraVigilance (EV) dataset.
Concomitantly used drugs recorded were opioids (e.g. oxycodone and fentanyl), benzodiazepines (e.g. diazepam, alprazolam and lorazepam) and antidepressants (e.g. citalopram, venlafaxine and amitriptyline), whilst recreational drugs most represented were alcohol and cocaine (Table 1). Most reported diagnoses, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V; American Psychiatric Association (APA), 2013) related to: mood disorders, e.g. depression/depressed mood/major depression (68 cases) and bipolar disorder (14 cases); anxiety/anxiety disorders (23 cases); alcohol abuse/alcoholic/alcoholism (26 cases); and schizophrenia (14 cases). The outcome of the reactions reported included: ‘fatal’ (n=310/557; 55.6%) and secondarily ‘recovered/resolved’ (n=73; 15.2%) (Table 1). Some 27 cases were related to suicidal or self-harm behaviour, being recorded as ‘suicidal attempt/suicidal ideation’ (n=24), ‘self-injurious ideation’ (n=1), and ‘suicide attempt’ (n=2). Fatalities mostly involved adult females; in these cases, most typical ADRs recorded were ‘drug abuse’ (n=228) and ‘intentional product misuse’ (n=77) (Table 2). Opiates/opioids were the most recorded concomitant drugs (n=356), with methadone being the most represented (n=103), followed by antidepressants (n=221) and benzodiazepines (n=141). Among illicit drugs, heroin appeared to be the most represented (Table 2).
Table 2. Analysis of fatal promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV), 2003–2019.
Fatal cases on abuse/misuse/dependence/withdrawal reactions 310 (310/557 = 55.6%)
Age-range
Adult 303 (97.7%)
Adolescent 7 (2.3%)
Elderly (>65 years) –
Neonatal –
Infant –
Child –
Gender M 103 (33.2%)
F 177 (57.1%)
Unknown 30 (9.7%)
Most recorded PTs
Drug abuse/drug abuser/substance abuse 228/3/6
Intentional product misuse/Intentional product use issue 77/3
Drug dependence 1
Reported death code
Intentional overdose 1
Overdose 4
Completed suicide/suicide 7
Drug toxicity/drug abuse 197
Toxicity to various agents 48
Intentional product misuse 41
Respiratory depression 5
Pneumonia 1
Cardiac arrest 10
Drug dependence 1
Most reported concomitant drugs
Opioids 356
Methadone 103
Dihydrocodeine 1
Codeine 32
Fentanyl 44
Oxycodone 63
Morphine 55
Hydrocodone 33
Hydromorphone 3
Tramadol 22
Antidepressants 221
Duloxetine 1
Escitalopram 1
Sertraline 16
Paroxetine 34
Trazodone 15
Mirtazapine 33
Fluoxetine 24
Venlafaxine 9
Bupropion 1
Amitriptyline 35
Nortriptyline 6
Clomipramine 5
Citalopram 41
Benzodiazepines 141
Lorazepam 3
Temazepam 6
Clonazepam 21
Diazepam 60
Flunitrazepam 1
Brotizolam 1
Alprazolam 42
Midazolam 4
Oxazepam 3
Mood stabilisers 11
Gabapentin 3
Topiramate 8
Antipsychotics 24
Olanzapine 1
Quetiapine 20
Haloperidol 1
Amisulpride 1
Levomepromazine 1
Z-drugs 39
Zolpidem 37
Zopiclone 2
Illicit drugs
Amphetamine 15
Cocaine 40
Heroin 52
Alcohol 26
PTs: preferred terms.
Discussion
Non-medical prescription drug use is a globally recognised problem, with severe adverse consequences. The current study provides a large amount of descriptive data highlighting that promethazine can be taken at high dosages, through non-approved administration routes, and in a setting of polydrug use (Hughes et al., 2016; Novak et al., 2016).
Promethazine misuse has been increasingly recorded since the early 2000s, consistently with data from US poison centres reporting antihistamine exposures rising in the period 2007–2013 (Jensen et al., 2017). This is not surprising, since the pharmacodynamic properties of promethazine underpins its sought-after central effects. In 2014, e.g. the highest peak here, the increase in promethazine misuse reporting was solely driven by the USA (245/245 cases; 100%). This may have been associated with intense media attention to the subject in that year (TMZ, 2014). The increments reported in 2010, 2014 and 2017 were then followed by decrements, which may have been related to not only reporting variabilities, but also to differences in sales of antihistamines following local/national drug abuse prevention campaigns (Klein-Schwartz, 2017). Overall, the USA appeared here to be the country most involved in reporting of promethazine ADRs. Several reasons may help in explaining this, including healthcare professionals’ awareness of prescription/OTC drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Lynch et al., 2015; Manchikanti et al., 2006; NIDA, 2014; Tsay et al., 2015) which, in turn, may have facilitated pharmacovigilance reporting. According to an 11-year period of the US National Poison Centers’ database, the annual rate of promethazine abuse/misuse per 100,000 US population doubled over time (Tsay et al., 2015). In the USA, promethazine abuse/misuse has been described in teenagers and young adults (Peters et al., 2003), methadone maintenance patients, heroin users and opioid-prescribed chronic pain patients (Lynch et al., 2015; Shapiro et al., 2013).
Consistent with previous observations (Agnich et al., 2013; Burns and Boyer, 2013; Carr, 2006; Elwood, 2001; Höjer and Tellerup, 2018; NIDA, 2014; Page et al., 2009; Parker et al., 2013; Peters et al., 2007), most recorded ADRs related here to either ‘drug abuse’ and ‘intentional product misuse’, involving young adult (19–25 years) males. Although considered a vulnerable category with respect to prescription drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014; Peters et al., 2007), adolescents (10–18 years) were here reported in only a minority (23/1543:1.5%) of cases.
Several drugs were here associated with promethazine, although opiates/opioids were the most represented molecules in related fatalities. This combination might intensify effects such as sedation and analgesia (Burns and Boyer, 2013; Lynch et al., 2015; Shapiro et al., 2013), and in the 1950s the association was medically used to reduce the dosage of opiates/opioids (McGee and Weiss, 1956). However, due to a range of adverse effects (Lynch et al., 2015) including lack of data supporting clinical efficacy (Richter and Burk, 1992) and an enhanced addiction potential of opioids (Lynch et al., 2015; Peters et al., 2007; Shapiro et al., 2013), the combination of promethazine/opioids has declined in popularity.
So far, the recreational intake of promethazine with opioids has been typically reported in cough mixtures containing codeine (Casati et al., 2012; Clatts et al., 2010; Elwood, 2001; Foley et al., 2015; Peters et al., 2007). However, current EMA data suggest that, apart from methadone, oxycodone and fentanyl were the most typical opiates/opiates identified in association with promethazine, possibly due to their recent popularity, especially in the USA (Manchikanti et al., 2018; Rose, 2018). In the promethazine fatalities (e.g. 310 cases) dataset analysed, codeine, fentanyl and oxycodone were respectively reported in 32, 44 and 63 cases. Consistent with current data, a concomitant use of opioids and promethazine has been described in various subpopulations, such as methadone maintenance patients, injecting drug users and chronic pain patients (Banta-Green et al., 2005; Lynch et al., 2015; Shapiro et al., 2013; Shields et al., 2007; Van Hout and Norman, 2016). Overall, there is now a high level of awareness of the abuse potential of antihistamine/opioid-containing products (Hou et al., 2011; Hughes et al., 1999; Wazaify et al., 2005). Hence, some countries are limiting both the medication pack size levels and the quantities of drugs sold in a single transaction, whilst also promoting non-injectable and non-inhaling formulations and changing some formulations’ OTC status (Cooper, 2013; Foley et al., 2015; Van Hout and Norman, 2016).
Benzodiazepines (e.g. diazepam, alprazolam and lorazepam) were here also frequently recorded, suggesting sedative synergistic effects in combination with promethazine (Lynch et al., 2015), and hence an increased risk of untoward clinical issues (McLellan and Turner, 2010). Other prescription drug categories recorded included antidepressants (most typically: citalopram and amitriptyline, respectively in 149/557 and 95/557 cases), which is consistent with the most typically recorded diagnoses, e.g. depressive (68 cases); bipolar (14 cases); and anxiety (23 cases) disorders. It is also possible that antidepressants were here ingested in combination with promethazine for sleep induction purposes. It is a reason for concern that promethazine ADRs, either alone or in combination, resulted in either fatal (50.6%) or ‘recovered/resolved’ outcomes (22.2%). This is consistent with previous promethazine misuse/abuse data, reporting both adverse clinical outcomes and high frequency of healthcare facility treatment (Bergman and Wallman, 1998; Ichikura et al., 2016; McLellan and Turner, 2010; Tsay et al., 2015). A list of possibly misused substances which might reinforce promethazine psychoactive effects and possibly increase its toxicity is included in Table 3.
Table 3. List of substances recorded in the literature as used in association with promethazine in order to increase its effects; prescription drugs are recorded according to the Neuroscience-based Nomenclature description (Nutt and Blier, 2016).
Psychoactive substances
Description Mode of action Examples Effects
Alcohol (Burns and Boyer, 2013; Jensen et al., 2017) CNS depressant effects ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, relaxation, ‘slight giddiness and disorienting’ and ‘nice hallucination’.
It may increase, prolong or intensify promethazine sedative effect. It should be avoided in patients receiving promethazine.
Heroin and other illicit opioids (Dahlman et al., 2016; Tsay et al., 2015) Opioid depressant effects It may increase, prolong, or intensify promethazine sedative effect.
Prescription drugs
Categories Mode of action Examples Effects
Drugs for insomnia (Burns and Boyer, 2013) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Z-drugs: zaleplon, zolpidem, zopiclone, eszopiclone They may increase, prolong or intensify promethazine sedative effect.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Drugs for anxiety (Burns and Boyer, 2013; Lynch et al., 2015) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, lorazepam, oxazepam They may increase, prolong or intensify promethazine sedative action.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Dextrometorphan (Tsay et al., 2015) At high doses, acting as NMDA-receptor antagonist; dextrometorphan and its potent metabolite dextrorphan inhibit the excitatory amino acid and neurotransmitter glutamate in the brain, determining hallucinogenic and dissociative activities, which are recreationally searched It might be combined with promethazine in cough-suppressant formulation Dextrometorphan neurobehavioural effects are dose-related, starting from a mild to moderate stimulation with restlessness and euphoria (100–200 mg), to a dissociated state characterised by hallucinations, paranoia, perceptual distortions, delusional beliefs, ataxia and out-of-body experiences (‘robo-ing’/‘robo-copping’/‘robo-tripping’) (>1000 mg). In overdosage they might increase promethazine effects.
Drugs for depression (Burns and Boyer, 2013; Jensen et al., 2017): TCA Multimodal action: reuptake inhibitor (SERT and NET), receptor antagonist (5-HT2) Amitriptyline Promethazine may increase, prolong or intensify their sedative effect. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Anticholinergic drugs Antagonist at cholinergic receptors Hyoscine butyl bromide/scopolamine (Burns and Boyer, 2013) Together with promethazine an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility may be seen. A typical mental status alteration with a dose-dependent agitated delirium characterised by abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia, has been described. These molecules should be avoided or administered in reduced dosage to patients receiving promethazine.
Prescription opioids
Codeine (Burns and Boyer, 2013; Jouanjus et al., 2018; Lynch et al., 2015; O Reilly et al., 2015; Shapiro et al., 2013) ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, elation, analgesia and ‘liking’, with increased potential of addiction. Overdosage of codeine might determine respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne–Stokes respiration and cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Opiate overdosage, particularly by the intravenous route, may be associated with apnoea, circulatory collapse, cardiac arrest and death. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Other opioid analgesics (Burns and Boyer, 2013; Dahlman et al., 2016; Lynch et al., 2015; Shapiro et al., 2013) Methadone They may increase, prolong or intensify promethazine sedative effects. Opioids should be avoided or administered in reduced dosage to patients receiving promethazine.
The addiction potential of opioids might be enhanced. Also, increasing life-threatening events, such as respiratory depression, overdose and prolongation of the QT interval, might be responsible for drug-related fatalities.
5-HT2: serotonin-2 receptor; CNS: central nervous system; D2: dopamine 2 receptor; GABA: gamma-amino-butyric acid; H1: histamine 1 receptor; NE: norepinephrine; NET: norepinephrine transporter; NMDA: N-methyl-D-aspartate; SERT: serotonin transporter; SSRI: selective-serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
Finally, among abuse-related cases, neonates, infants and children were here reported as well. This is consistent with cases of unexpected infant deaths associated with use of cold medications, poor socioeconomic conditions (Rimsza and Newberry, 2008) and/or accidental ingestion (McLellan and Turner, 2010).
Limitations
One of the limitations was given here by the descriptive nature of the study. Indeed, a comparator molecule, for a disproportionality analysis (Chiappini and Schifano, 2016; Schifano and Chiappini, 2018b) to be carried out, was not available due to data access limitations (EMA, 2017; Postigo et al., 2018). Furthermore, current data did not appear to show an increasing trend of abuse or misuse across the years. Since proper denominator figures (e.g. data on worldwide promethazine prescriptions) are not available, it was unclear if what observed was a substantial number of cases, indicative of clinically meaningful abuse potential, or a passing trend for promethazine misuse by a very small number of individuals. However, consistent with previous suggestions (Montastruc et al, 2011), the value of the current study was that its rationale was driven by a proper, detailed, pharmacodynamic hypothesis established on the basic properties of promethazine. Similar to remaining pharmacovigilance datasets (EMA, 2010; Evoy et al., 2019; Schifano and Chiappini, 2018a; Schifano et al., 2019a, 2019b; Schwan et al., 2010), focussing on the analysis of voluntary adverse events, a further limitation was given here by reliance on self-reporting and the likelihood of missing data occurrence. Moreover, although healthcare professionals have a main role in detection, assessment and spontaneous reporting of ADRs (Belton, 1997; Khalili et al., 2012), specific abuse/misuse/dependence issues relating to promethazine may have been underestimated, with only the most serious cases having been reported, hence the high rates of promethazine fatalities here recorded. Furthermore, although patients and their carers are allowed indeed to flag up an ADR, it is unlikely that they have spontaneously reported misusing events. Other factors, such as increased knowledge of promethazine misuse/abuse, may have resulted here in outcome reporting bias. There was also a potential for duplicate reports, with the same report submitted by the consumer, the healthcare professional and by the manufacturer as well, causing skewed study results. This may occur when a healthcare professional reported the same suspected ADR to both the national Regulatory Authority and the Marketing Authorisation Holder and they both reported subsequently to EV. However, the EV local report number which was here considered unequivocally identified an individual case. In addition, whilst this study represents one of the largest sample of promethazine abuse events published to date, the overall number of events is still relatively small, potentially limiting external validity. Case reports of suspected ADRs alone are not always sufficient to prove that a certain suspected reaction has indeed been caused by a specific medicine. This could be a symptom of another illness, or it could be associated with another medicinal product taken by the patient at the same time. The suspected ADRs were here presented using the PTs of the MedDRA Dictionary (Postigo et al., 2018). Thus, any case report should be considered together with all available data including case reports worldwide, clinical trials, epidemiological studies and toxicological investigations, in order to allow for robust conclusions. Finally, case reports reflect the information as provided to EV by the reporter, and not all data fields were completed for all reports.
Conclusion
To the best of our understanding, the current study described in detail the largest sample ever of abuse, misuse and dependence issues related to promethazine, whilst focussing on a large multinational dataset, such as the EV. The substantial number of promethazine-related events identified over the years represents a pharmacovigilance signal which needs to be better investigated (Montastruc et al., 2011). Although the observed trend of promethazine abuse and misuse, especially in young adults, is not a new phenomenon, further details of the issue have been here provided and future studies will optimally identify the related risk factors, with these measures enabling policymakers and regulators to take action to detect and prevent such misusing practices (Jouanjus et al., 2019). A multicomponent approach is recommended, including monitoring drug utilisation, tracking users’ posts on social media, and exploring healthcare databases; this will enable performing proactive and effective post-marketing surveillance and pharmacovigilance approaches. This has proved to be a relevant, efficient and accurate strategy, for example with gabapentinoids, which have recently been rescheduled in the UK (Borg et al., 2011; Eickhoff et al., 2012; Jouanjus et al., 2019; Novak et al., 2016; Parker et al., 2013; Schifano and Chiappini, 2019; Throckmorton et al., 2018). In this context, the role of the Web is rapidly spreading, playing a significant role in the marketing, sale and distribution of drugs, hence facilitating continuous changes in drug scenarios (Orsolini et al., 2017). Indeed, over the last 10 years access to online pharmacies to purchase medicinal compounds has increased (Desai, 2016; Monteith and Glenn, 2018). On the other hand, professionals access the Web to gather data on emerging trends of drug abuse (Deluca et al., 2002; Orsolini et al., 2015; Schifano, 2020; Schifano et al., 2003).
OTC and prescription drug misuse is perceived to be a significantly under-recognised issue affecting a range of vulnerable individuals (Coombes and Cooper, 2019). However, controlling the problem of OTC misuse and abuse might be challenging, due to the need for achieving high levels of consumer safety whilst not restricting access to OTC products for those who continue to use them safely.
Staff training should be evaluated, in order for pharmacists to self-monitor care and use of medicines, to educate patients and intervene/support those experiencing problematic drug use (Elwood, 2001; GPC, 2019; Tobin et al., 2013; Wells et al., 2018). Record-keeping (Hou et al., 2011) and real time monitoring (Cairns et al., 2016) could be a method of restricting access to some OTC drugs and prevent ‘shopping’ from one pharmacy to another, and where these measures would result to be ineffective, regulatory interventions, e.g. drug re-scheduling, might be useful (Marsden et al., 2019; McDonough, 2016; Peacock et al., 2019). Also, prevention and early education on substance abuse in young teenagers are critical (Levine, 2007; Marsden et al., 2019). Finally, appropriate and specific clinical guidelines for the treatment of misuse, abuse and dependence on prescription or OTC drugs should be implemented (Fingleton et al., 2019).
The review and study design were developed by SC, FS, JMC and AG. SC drafted the first version of the manuscript with input from all authors. All authors contributed to the interpretation of the data analysis and the further drafting of the manuscript and approved the final version.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FS was a member of the UK Advisory Council on the Misuse Drugs (ACMD) from 2011–2019; and is currently an EMA Advisory board (psychiatry) member. JMC is a member of the ACMD’s Novel Psychoactive Substances and Technical Committees. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
ORCID iDs: Stefania Chiappini https://orcid.org/0000-0002-6810-1540
John Martin Corkery https://orcid.org/0000-0002-3849-817X | Fatal | ReactionOutcome | CC BY | 33427017 | 18,928,797 | 2021-06 |
What was the outcome of reaction 'Completed suicide'? | Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.
Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents.
We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database.
After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234).
The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used.
Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.
Introduction
Pharmacological properties of promethazine
Promethazine is a phenothiazine derivative and a histamine (H1) receptor antagonist that is commonly used for symptomatic relief of nausea and vomiting, for allergic conditions, motion sickness and common cold, and for short-term use treatment of insomnia in adults or as a paediatric sedative (EMC, 2019). It also acts as a direct antagonist at muscarinic (M1) and dopamine (D2) receptors (Cookson, 2018; Page et al., 2009; Sharma and Hamelin, 2003). Promethazine hydrochloride is well absorbed from the gastrointestinal tract, with an average of 88% of the dose absorbed after oral administration, and clinical effects appearing within 20 min after intake whilst lasting 4–6 h. The plasma half-life is approximately 7–14 h (Burns and Boyer, 2013). It is classified as a first-generation antihistamine molecule which, compared with second-generation antihistamines, easily penetrates the blood-brain barrier and is associated with adverse effects such as moderate/intense sedation (Jensen et al., 2017). Thus, promethazine might be used in rapid (acute) tranquilization due to its blocking action at H1 and M receptors (Cookson, 2018). Toxicity might result in severe impairment of cognitive and psychomotor functions due to central nervous system (CNS) depression/reduced levels of consciousness, and may cause fatalities (Jensen et al., 2017).
Availability of promethazine
Promethazine is a medicinal product available on its own or in combination with other ingredients, including dextromethorphan, paracetamol and/or expectorants. With regards to promethazine availability, there are wide variations across countries. In fact, in some European countries such as France, Italy and the UK, but also outside Europe, some medicinal products containing promethazine can be purchased over-the-counter (OTC). Promethazine was restricted from an OTC status to prescription only in Denmark as of December 2014. This restriction was partly based on increasing enquiries regarding promethazine exposures to the Danish Poison and Information Centre (DPIC), highlighting its abuse potential and subsequent observations of side-effects after ingestion of standard doses. In Australia, promethazine is available as an OTC medication either alone as a tablet or as a liquid preparation or in combination with paracetamol and codeine phosphate as a syrup (Sharma and Hamelin, 2003). In the USA, some cough preparations containing no more than 200 mg of codeine per 100 mL are considered Schedule V controlled substances (Drug Enforcement Administration (DEA), 2020), purportedly possessing the lowest potential for both misuse and development of a Substance Use Disorder (SUD).
Pharming
Recently, the potential for misuse of medications that are not already controlled has been reported worldwide (Reeves et al., 2015). ‘Pharming’ is a phenomenon involving the non-medical use of prescription (pain relievers, tranquilisers, stimulants, sedatives) and OTC drugs, including cough and cold preparations, particularly those containing dextromethorphan and promethazine (Burns and Boyer, 2013; Jouanjus et al., 2018; Levine, 2007; McCarthy, 2007; National Institute on Drug Abuse (NIDA), 2014). The abuse of these compounds may be facilitated by their easy accessibility, low cost, decreased perception of potential for harm and growing social acceptance (Burns and Boyer, 2013; Levine, 2007; McCarthy, 2007; Substance Abuse Mental Health Services Administration (SAMHSA), 2008). In the current drug abuse scenario, young people/youths have been described abusing with a range of prescription or OTC medicines (Soussan et al., 2018), with these molecules possibly being ingested at high/super-high dosages (Orsolini et al., 2015; Schifano, 2020) and at times in combination with alcohol/remaining recreational substances (Levine, 2007)
Recreational use of promethazine
Centrally acting antihistamines have long been known to induce physical and psychological dependence (Clatts et al., 2010; Gracious et al., 2010; Page et al., 2009; Saatcioglu and Evren, 2005; Thomas et al., 2008). During the past 15 years the abuse of promethazine, especially from OTC and prescription cough and cold medicines and at higher-than-recommended dosages, has been reported (NIDA, 2014). Consistent with this, during the last decade the yearly number of promethazine-related overdose cases in Sweden has increased from 100 to nearly 700 and its sales have increased threefold (Höjer and Tellerup, 2018). Also, according to the 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), antihistamines accounted for the seventh most frequently involved substance in human exposures, resulting in the third type of substance category for rate of exposure increase (Gummin et al., 2019). In Denmark, the number of registered antihistamine exposures increased during 2007–2013, with first-generation antihistamines, specifically promethazine, having been responsible for most exposures and related fatalities (Jensen et al., 2017). Also, in New Zealand a number of promethazine poisoning cases (57/199 patients) were identified from a database of poisoning admissions to a regional toxicology service (Bergman and Wallman, 1998).
Effects
Promethazine reported effects mostly include a range of CNS side effects, such as: confusion; disorientation; drowsiness; cardiovascular symptoms; and respiratory depression (Burns and Boyer, 2013; Höjer and Tellerup, 2018; Page et al., 2009; Tsay et al., 2015). A clear abuse potential has been observed and reported for first-generation antihistamines such as promethazine and cyclizine, due to: calming and sedating effects (Cookson, 2018; Jensen et al., 2017) and enhancement of other co-ingested substances, and especially those interacting with gamma-amino-butyric acid (GABA), opiate and muscarinic acetylcholine receptors (Speeg et al., 1981), leading to hallucinogenic experiences (Clatts et al., 2010; Jensen et al., 2017; Lynch et al., 2015). Indeed, an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility has been described (Burns and Boyer, 2013). In these cases, the mental state alteration is characterised by agitated delirium, with abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia (Agnich et al., 2013; Cowen, 1979; Dollberg et al., 1989; Höjer and Tellerup, 2018; Leak and Carroll, 1967; Page et al., 2009; Scott et al., 2007; Timnak et al., 2004). With the promethazine-codeine cough syrup, ‘euphoric feelings’, ‘relaxation’, ‘slight giddiness and disorienting’, and ‘nice hallucinations’ have been described as well (Bluelight.org [2020]; Erowid.org [2020]). Reported side-effects include drowsiness, fatigue, loss of coordination, constipation and urinary retention (Elwood, 2001).
Vulnerable categories
An increasing trend in abuse of promethazine in co-formulation with some components of OTC cough medications has been reported in young adult populations (Carney et al., 2018; Carr, 2006; Höjer and Tellerup, 2018) since the late 1990s, particularly in the southern USA (Carr, 2006; Elwood, 2001). Codeine and promethazine were recorded as the most requested psychoactive drugs by adolescents/young adults in community pharmacies (Delcourt et al., 2017).
Known by the street names ‘lean’, ‘drank’, ‘barre’, ‘purple stuff’, ‘syrup’ and ‘sizzurp’ (Agnich et al., 2013; NIDA, 2014; Peters et al., 2007), the abuse of promethazine mixed with opioids and other sedatives (e.g. alcohol) in a purple colour drink (‘purple drank’) (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014) has become widely popular (Agnich et al., 2013) after a rap artist/producer created a genre of music, called ‘screw music', inspired by intoxication on codeine and promethazine (Peters et al., 2007). Social media data, e.g. public posts and related hashtags on Instagram, provided additional insights into codeine abuse, depicting its common misuse combined with promethazine and soda/carbonated drinks (Cherian et al., 2018). ‘Purple drank’ has been noted for its euphoric effects and its easy accessibility (Elwood, 2001; Peters et al., 2007). ‘Lean’ creates a distinct (Jakubowski et al., 2018) feeling of euphoria and extreme relaxation (Cookson, 2018), dream-like feelings and a vivid sensation of floating away from the physical body (Peters et al., 2007).
Although at times preferred to other substances, such as benzodiazepines, to treat anxiety and sleep disorders in substance-dependent patients, promethazine has been reported to be misused among people with either opioid dependence (Agnich et al., 2013; Dahlman et al., 2016; Elwood, 2001; Lynch et al., 2015; Shapiro et al., 2013) or a substance abuse condition (Shapiro et al., 2013; Tang et al., 2012). A Hong Kong study reported a total of 63 patients with a diagnosis of cough mixture abuse; 89% were adult males with a mean age of onset of the abuse itself of 20 (±5) years. These subjects had received a diagnosis of substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%) and dysthymia (10%), with most cases having presented with a polysubstance misuse (Tang et al., 2012). Due to the opioid-coformulation, the promethazine-codeine cough mixture might lead to addiction (NIDA, 2014). The mixture may present a high risk of occurrence of near misses due to its central effect of respiratory depression, which is greatly increased by association with alcohol or other CNS depressants, such as sedatives/hypnotics, narcotic analgesics, general anaesthetics and tricyclic antidepressants (Burns and Boyer, 2013; Elwood, 2001; NIDA, 2014; Shapiro et al., 2013; Tsay et al., 2015). The concomitant use of promethazine and other depressant drugs should not be underestimated, as they might together contribute to and/or cause fatalities (Corkery et al., 2020).
Aim of the study
We were interested here in studying how promethazine abuse was reported to the European Medicines Agency (EMA) adverse drug reactions (ADRs) database. We aimed to analyse promethazine misuse/abuse/dependence/withdrawal data. Where possible, in order to have a better understanding, information/data related to diagnosis, concomitant drugs, administration and dosages were also examined.
Methods
Source of data
The EMA through EudraVigilance (EV) manages and analyses information on suspected ADRs to medicines authorised in the European Economic Area (EEA), according to Directive 2001/83/EC and Regulation (EC) No 726/2004 (EMA, 2017). Since November 2017, EV launched extensive Web access to data on suspected ADRs and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research (Postigo et al., 2018). Thus, access to data regarding cases of promethazine abuse, misuse, dependence and withdrawal was obtained by application to the voluntary reporting system of ADRs of the EMA. After 3 months all data comprised all of the ADRs reported during the years from 2003 up to June 2019, presented as large Excel files divided into information sections reporting in a standardised format according to the Medical Dictionary for Regulatory Activities (MedDRA), were sent through a hyperlink (MedDra, 2018). Such listings showed all information related to the ADR, the patient, the drug, the reporter and the diagnosis. An ADR was considered a voluntary and unsolicited communication reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorisation Holders for those ADRs occurring outside the EEA (EMA, 2010). Only ‘suspect’ ADRs were selected, meaning promethazine was considered as ‘suspected’ for the reaction reported. Regarding the content of the ADR, according to the standardised MedDRA Query (SMQ) (MedDRA, 2018), the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, intentional product use issue, substance abuse, substance abuser, substance use and withdrawal syndrome were selected. Those ADRs were defined in accordance with MedDRA in line with previous studies on the EV dataset (Chiappini et al., 2020; MedDRA, 2018; Schifano and Chiappini, 2018a, 2018b; Schifano et al., 2019a, 2019b). Specifically, abuse was here defined as the intentional, non-therapeutic use by a patient or consumer of a product, OTC or prescription, for a perceived reward or desired non-therapeutic effect including, but not limited to, getting high (euphoria) (MedDRA, 2018). Misuse was meant as the intentional use for a therapeutic purpose by a patient or consumer of a product, OTC or prescription, other than as prescribed or not in accordance with the authorised product information (MedDRA, 2018). Finally, non-medical use referred here to the use of a prescription drug, whether obtained by prescription or otherwise, other than in the manner or for the time period prescribed, or by a person for whom the drug was not prescribed (United Nations Office on Drugs and Crime (UNODC), 2013).
Analysis of data
We retrospectively analysed all reported ADRs which were available in the EV database. ADR reports were analysed with respect to age and gender of patient/consumer, source/reporter country (EEA or non-EEA) and reporter qualification (i.e. pharmacist, physician); type of ADR; seriousness (fatal, recovered, resolved outcomes); promethazine dosage; possible concomitant drug(s); and diagnosis/reporter’s comments, if recorded. The descriptive analysis included cases of overdoses, suicides, and fatalities. In the dataset, each case report may refer to one or more reporter; one or more ADR(s); as well as to one or more medicinal product(s). Therefore, a case may be represented by more than one row in the other line listings. The received data files were searched for duplicates by report ID through the ‘EV Local Report Number’, which unequivocally identified an individual case. Thus, the number of suspected ADRs appeared to be different from the number of case reports as one case report might refer to several suspected ADRs. Moreover, the number of patients was different from the number of case reports as a patient might have been described in more than one case. Finally, numbers of ADRs differed from those referring to case reports/single patients since different reporters/senders could have independently flagged the same ADR to the EMA. The descriptive analysis included here a study of the dataset (EMA, 2017) performed through IBM SPSS Statistics software (version 26).
Ethical issues
In compliance with applicable Personal Data Protection legislation (Regulation (EC) No 45/2001 and Regulation (EC) No 1049/2001, the protection of privacy and integrity of individuals was guaranteed, and in order to safeguard the identity of individuals certain data elements, including names/identifiers or country-specific information were not disclosed by the EMA (EMA, 2013, 2017). The study was ethically approved in March 2018 by the University of Hertfordshire Ethics’ Committee, with reference number LMS/PGR/UH/03234.
Results
The dataset obtained reported a total of 11,796 ADRs, correspond-ing to 1,543 single cases recorded during years 2003–2019 (Table 1). Safety reports were all voluntarily submitted, mostly from pharmaceutical companies (1,136/1,543: 73.6%) and regulatory authorities (398/1,543: 25.8%). Reports were irregularly reported over time, with spikes in 2010, 2014 and 2017 (Figure 1). Countries which reported most promethazine-related abuse/misuse/dependence cases included: the USA (805/1,543: 52.10%); Germany (299/1,543: 19.4%); Japan (162/1,543: 10.5%), Sweden (67/1,543: 4.3%), France (43/1,543: 2.8%) and Australia (42/1,543: 2.7%). Out of a total of 1543 cases, ‘suspect’ abuse/misuse/dependence-related cases were 557 (36.1%) and, among them, according to the preferred terms (PTs), most recorded reactions were abuse/misuse-related ADRs (458/557: 82.2%), specifically ‘drug abuse’ (300/557: 53.8%) and ‘intentional product misuse’ (117/557: 21.0%) (Table 1). ‘Suspect’ selected cases and related fatalities annually showed the same trend overall (Figure 1). Most typically, subjects reported were adult (19–64 years) and specifically of the youngest group (19–25 years); males were slightly more frequently recorded than females (M/F: 235/461: 0.51) (Table 1). Where all information was recorded, promethazine was reported as ingested alone in 74 cases, with supratherapeutic dosages, up to 2500 mg, in four cases. In combination with other drugs, most cases were associated with a 100–500 mg promethazine dose, with the maximum dosage recorded having been 8000 mg (Figure 2). The most common administration route was oral (n = 292), although the intramuscular (n = 8) and the parenteral (n = 19) ones were reported as well, see Table 1).
Table 1. Analysis of promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV) during years 2003–2019.
Individual cases (% of total within parentheses)
Total abuse/misuse/dependence cases 1543 Single cases; number of ADRs :11,796
Age range Adult (19–64 years): 648 (648/1,543: 42.0%) - mean age: 31.8 years (SD 26.55–37.05)
Adolescent (10–18 years): 23 (23/1,543: 1.5%) – mean age: 15.9 years (SD 14.3–17.77)
Elderly (>65 years): 25 (25/1,543: 1.6%) – mean age: 72.3 years (SD 70.85–73.7)
Neonatal (hours–days) 14 (14/1,543: 0.9%) – mean age: 24 h (SD 16.6–27.4)
Infant (months–1 year): 7 (7/1,543: 0.45%) – mean age: 10 months (SD 7–13)
Child (<10 years): 4 (4: 1,543: 0.35%) – mean age: 5 years (SD 3.6–6.3)
Unknown: 822 (822/1,543: 53.2%)
Male/female 235/461: 0.51
Most represented abuse/misuse/dependence-related ADRs according to the PTs: 557 (557/1,543: 36.1%)
Abuse-related ADRs 458 (458/557: 82.2%)
Drug abuse 300
Drug abuser 15
Drug diversion 1
Intentional product misuse 117
Intentional product use issue 9
Substance abuse 11
Substance abuser 3
Substance use 2
Dependence-related ADRs 44 (44/557: 7.9%)
Dependence 4
Drug dependence 39
Substance dependence 1
Withdrawal-related ADRs 55 (55/557: 9.8%)
Withdrawal syndrome 19
Drug withdrawal convulsions 1
Drug withdrawal neonatal syndrome 18
Drug withdrawal syndrome 17
Outcome Fatal 310 (310/557: 55.6%)
Unknown 161 (161/557: 28.9%)
Recovered/resolved 55 (55/557: 9.9%)
Recovering/resolving 18 (18/557: 3.3%)
Not recovered/not resolved 13 (13/557: 2.3%)
Promethazine-cases alone 74 (with maximum dosage 2500 mg)
Promethazine-cases with other drugs Most cases (122) were over 100 mg (with maximum dosage 8000 mg)
Most common psychoactive substances used Alcohol: 114
Cocaine: 68
Cannabis: 16
Ketamine: 4
Amphetamine: 1
Most common prescription drugs used Opioids: 1187
Benzodiazepines: 914
Antidepressants: 871
Antipsychotics: 437
Z-drugs: 222
Mood stabilisers: 197
ADR: adverse drug reaction; PTs: preferred terms; SD: standard deviation.
Figure 1. Number of promethazine abuse/misuse/dependence/withdrawal cases reported by year in the EudraVigilance (EV) dataset.
Figure 2. Most represented dosages reported among all promethazine abuse/misuse/dependence/withdrawal cases recorded by the EudraVigilance (EV) dataset.
Concomitantly used drugs recorded were opioids (e.g. oxycodone and fentanyl), benzodiazepines (e.g. diazepam, alprazolam and lorazepam) and antidepressants (e.g. citalopram, venlafaxine and amitriptyline), whilst recreational drugs most represented were alcohol and cocaine (Table 1). Most reported diagnoses, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V; American Psychiatric Association (APA), 2013) related to: mood disorders, e.g. depression/depressed mood/major depression (68 cases) and bipolar disorder (14 cases); anxiety/anxiety disorders (23 cases); alcohol abuse/alcoholic/alcoholism (26 cases); and schizophrenia (14 cases). The outcome of the reactions reported included: ‘fatal’ (n=310/557; 55.6%) and secondarily ‘recovered/resolved’ (n=73; 15.2%) (Table 1). Some 27 cases were related to suicidal or self-harm behaviour, being recorded as ‘suicidal attempt/suicidal ideation’ (n=24), ‘self-injurious ideation’ (n=1), and ‘suicide attempt’ (n=2). Fatalities mostly involved adult females; in these cases, most typical ADRs recorded were ‘drug abuse’ (n=228) and ‘intentional product misuse’ (n=77) (Table 2). Opiates/opioids were the most recorded concomitant drugs (n=356), with methadone being the most represented (n=103), followed by antidepressants (n=221) and benzodiazepines (n=141). Among illicit drugs, heroin appeared to be the most represented (Table 2).
Table 2. Analysis of fatal promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV), 2003–2019.
Fatal cases on abuse/misuse/dependence/withdrawal reactions 310 (310/557 = 55.6%)
Age-range
Adult 303 (97.7%)
Adolescent 7 (2.3%)
Elderly (>65 years) –
Neonatal –
Infant –
Child –
Gender M 103 (33.2%)
F 177 (57.1%)
Unknown 30 (9.7%)
Most recorded PTs
Drug abuse/drug abuser/substance abuse 228/3/6
Intentional product misuse/Intentional product use issue 77/3
Drug dependence 1
Reported death code
Intentional overdose 1
Overdose 4
Completed suicide/suicide 7
Drug toxicity/drug abuse 197
Toxicity to various agents 48
Intentional product misuse 41
Respiratory depression 5
Pneumonia 1
Cardiac arrest 10
Drug dependence 1
Most reported concomitant drugs
Opioids 356
Methadone 103
Dihydrocodeine 1
Codeine 32
Fentanyl 44
Oxycodone 63
Morphine 55
Hydrocodone 33
Hydromorphone 3
Tramadol 22
Antidepressants 221
Duloxetine 1
Escitalopram 1
Sertraline 16
Paroxetine 34
Trazodone 15
Mirtazapine 33
Fluoxetine 24
Venlafaxine 9
Bupropion 1
Amitriptyline 35
Nortriptyline 6
Clomipramine 5
Citalopram 41
Benzodiazepines 141
Lorazepam 3
Temazepam 6
Clonazepam 21
Diazepam 60
Flunitrazepam 1
Brotizolam 1
Alprazolam 42
Midazolam 4
Oxazepam 3
Mood stabilisers 11
Gabapentin 3
Topiramate 8
Antipsychotics 24
Olanzapine 1
Quetiapine 20
Haloperidol 1
Amisulpride 1
Levomepromazine 1
Z-drugs 39
Zolpidem 37
Zopiclone 2
Illicit drugs
Amphetamine 15
Cocaine 40
Heroin 52
Alcohol 26
PTs: preferred terms.
Discussion
Non-medical prescription drug use is a globally recognised problem, with severe adverse consequences. The current study provides a large amount of descriptive data highlighting that promethazine can be taken at high dosages, through non-approved administration routes, and in a setting of polydrug use (Hughes et al., 2016; Novak et al., 2016).
Promethazine misuse has been increasingly recorded since the early 2000s, consistently with data from US poison centres reporting antihistamine exposures rising in the period 2007–2013 (Jensen et al., 2017). This is not surprising, since the pharmacodynamic properties of promethazine underpins its sought-after central effects. In 2014, e.g. the highest peak here, the increase in promethazine misuse reporting was solely driven by the USA (245/245 cases; 100%). This may have been associated with intense media attention to the subject in that year (TMZ, 2014). The increments reported in 2010, 2014 and 2017 were then followed by decrements, which may have been related to not only reporting variabilities, but also to differences in sales of antihistamines following local/national drug abuse prevention campaigns (Klein-Schwartz, 2017). Overall, the USA appeared here to be the country most involved in reporting of promethazine ADRs. Several reasons may help in explaining this, including healthcare professionals’ awareness of prescription/OTC drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Lynch et al., 2015; Manchikanti et al., 2006; NIDA, 2014; Tsay et al., 2015) which, in turn, may have facilitated pharmacovigilance reporting. According to an 11-year period of the US National Poison Centers’ database, the annual rate of promethazine abuse/misuse per 100,000 US population doubled over time (Tsay et al., 2015). In the USA, promethazine abuse/misuse has been described in teenagers and young adults (Peters et al., 2003), methadone maintenance patients, heroin users and opioid-prescribed chronic pain patients (Lynch et al., 2015; Shapiro et al., 2013).
Consistent with previous observations (Agnich et al., 2013; Burns and Boyer, 2013; Carr, 2006; Elwood, 2001; Höjer and Tellerup, 2018; NIDA, 2014; Page et al., 2009; Parker et al., 2013; Peters et al., 2007), most recorded ADRs related here to either ‘drug abuse’ and ‘intentional product misuse’, involving young adult (19–25 years) males. Although considered a vulnerable category with respect to prescription drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014; Peters et al., 2007), adolescents (10–18 years) were here reported in only a minority (23/1543:1.5%) of cases.
Several drugs were here associated with promethazine, although opiates/opioids were the most represented molecules in related fatalities. This combination might intensify effects such as sedation and analgesia (Burns and Boyer, 2013; Lynch et al., 2015; Shapiro et al., 2013), and in the 1950s the association was medically used to reduce the dosage of opiates/opioids (McGee and Weiss, 1956). However, due to a range of adverse effects (Lynch et al., 2015) including lack of data supporting clinical efficacy (Richter and Burk, 1992) and an enhanced addiction potential of opioids (Lynch et al., 2015; Peters et al., 2007; Shapiro et al., 2013), the combination of promethazine/opioids has declined in popularity.
So far, the recreational intake of promethazine with opioids has been typically reported in cough mixtures containing codeine (Casati et al., 2012; Clatts et al., 2010; Elwood, 2001; Foley et al., 2015; Peters et al., 2007). However, current EMA data suggest that, apart from methadone, oxycodone and fentanyl were the most typical opiates/opiates identified in association with promethazine, possibly due to their recent popularity, especially in the USA (Manchikanti et al., 2018; Rose, 2018). In the promethazine fatalities (e.g. 310 cases) dataset analysed, codeine, fentanyl and oxycodone were respectively reported in 32, 44 and 63 cases. Consistent with current data, a concomitant use of opioids and promethazine has been described in various subpopulations, such as methadone maintenance patients, injecting drug users and chronic pain patients (Banta-Green et al., 2005; Lynch et al., 2015; Shapiro et al., 2013; Shields et al., 2007; Van Hout and Norman, 2016). Overall, there is now a high level of awareness of the abuse potential of antihistamine/opioid-containing products (Hou et al., 2011; Hughes et al., 1999; Wazaify et al., 2005). Hence, some countries are limiting both the medication pack size levels and the quantities of drugs sold in a single transaction, whilst also promoting non-injectable and non-inhaling formulations and changing some formulations’ OTC status (Cooper, 2013; Foley et al., 2015; Van Hout and Norman, 2016).
Benzodiazepines (e.g. diazepam, alprazolam and lorazepam) were here also frequently recorded, suggesting sedative synergistic effects in combination with promethazine (Lynch et al., 2015), and hence an increased risk of untoward clinical issues (McLellan and Turner, 2010). Other prescription drug categories recorded included antidepressants (most typically: citalopram and amitriptyline, respectively in 149/557 and 95/557 cases), which is consistent with the most typically recorded diagnoses, e.g. depressive (68 cases); bipolar (14 cases); and anxiety (23 cases) disorders. It is also possible that antidepressants were here ingested in combination with promethazine for sleep induction purposes. It is a reason for concern that promethazine ADRs, either alone or in combination, resulted in either fatal (50.6%) or ‘recovered/resolved’ outcomes (22.2%). This is consistent with previous promethazine misuse/abuse data, reporting both adverse clinical outcomes and high frequency of healthcare facility treatment (Bergman and Wallman, 1998; Ichikura et al., 2016; McLellan and Turner, 2010; Tsay et al., 2015). A list of possibly misused substances which might reinforce promethazine psychoactive effects and possibly increase its toxicity is included in Table 3.
Table 3. List of substances recorded in the literature as used in association with promethazine in order to increase its effects; prescription drugs are recorded according to the Neuroscience-based Nomenclature description (Nutt and Blier, 2016).
Psychoactive substances
Description Mode of action Examples Effects
Alcohol (Burns and Boyer, 2013; Jensen et al., 2017) CNS depressant effects ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, relaxation, ‘slight giddiness and disorienting’ and ‘nice hallucination’.
It may increase, prolong or intensify promethazine sedative effect. It should be avoided in patients receiving promethazine.
Heroin and other illicit opioids (Dahlman et al., 2016; Tsay et al., 2015) Opioid depressant effects It may increase, prolong, or intensify promethazine sedative effect.
Prescription drugs
Categories Mode of action Examples Effects
Drugs for insomnia (Burns and Boyer, 2013) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Z-drugs: zaleplon, zolpidem, zopiclone, eszopiclone They may increase, prolong or intensify promethazine sedative effect.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Drugs for anxiety (Burns and Boyer, 2013; Lynch et al., 2015) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, lorazepam, oxazepam They may increase, prolong or intensify promethazine sedative action.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Dextrometorphan (Tsay et al., 2015) At high doses, acting as NMDA-receptor antagonist; dextrometorphan and its potent metabolite dextrorphan inhibit the excitatory amino acid and neurotransmitter glutamate in the brain, determining hallucinogenic and dissociative activities, which are recreationally searched It might be combined with promethazine in cough-suppressant formulation Dextrometorphan neurobehavioural effects are dose-related, starting from a mild to moderate stimulation with restlessness and euphoria (100–200 mg), to a dissociated state characterised by hallucinations, paranoia, perceptual distortions, delusional beliefs, ataxia and out-of-body experiences (‘robo-ing’/‘robo-copping’/‘robo-tripping’) (>1000 mg). In overdosage they might increase promethazine effects.
Drugs for depression (Burns and Boyer, 2013; Jensen et al., 2017): TCA Multimodal action: reuptake inhibitor (SERT and NET), receptor antagonist (5-HT2) Amitriptyline Promethazine may increase, prolong or intensify their sedative effect. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Anticholinergic drugs Antagonist at cholinergic receptors Hyoscine butyl bromide/scopolamine (Burns and Boyer, 2013) Together with promethazine an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility may be seen. A typical mental status alteration with a dose-dependent agitated delirium characterised by abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia, has been described. These molecules should be avoided or administered in reduced dosage to patients receiving promethazine.
Prescription opioids
Codeine (Burns and Boyer, 2013; Jouanjus et al., 2018; Lynch et al., 2015; O Reilly et al., 2015; Shapiro et al., 2013) ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, elation, analgesia and ‘liking’, with increased potential of addiction. Overdosage of codeine might determine respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne–Stokes respiration and cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Opiate overdosage, particularly by the intravenous route, may be associated with apnoea, circulatory collapse, cardiac arrest and death. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Other opioid analgesics (Burns and Boyer, 2013; Dahlman et al., 2016; Lynch et al., 2015; Shapiro et al., 2013) Methadone They may increase, prolong or intensify promethazine sedative effects. Opioids should be avoided or administered in reduced dosage to patients receiving promethazine.
The addiction potential of opioids might be enhanced. Also, increasing life-threatening events, such as respiratory depression, overdose and prolongation of the QT interval, might be responsible for drug-related fatalities.
5-HT2: serotonin-2 receptor; CNS: central nervous system; D2: dopamine 2 receptor; GABA: gamma-amino-butyric acid; H1: histamine 1 receptor; NE: norepinephrine; NET: norepinephrine transporter; NMDA: N-methyl-D-aspartate; SERT: serotonin transporter; SSRI: selective-serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
Finally, among abuse-related cases, neonates, infants and children were here reported as well. This is consistent with cases of unexpected infant deaths associated with use of cold medications, poor socioeconomic conditions (Rimsza and Newberry, 2008) and/or accidental ingestion (McLellan and Turner, 2010).
Limitations
One of the limitations was given here by the descriptive nature of the study. Indeed, a comparator molecule, for a disproportionality analysis (Chiappini and Schifano, 2016; Schifano and Chiappini, 2018b) to be carried out, was not available due to data access limitations (EMA, 2017; Postigo et al., 2018). Furthermore, current data did not appear to show an increasing trend of abuse or misuse across the years. Since proper denominator figures (e.g. data on worldwide promethazine prescriptions) are not available, it was unclear if what observed was a substantial number of cases, indicative of clinically meaningful abuse potential, or a passing trend for promethazine misuse by a very small number of individuals. However, consistent with previous suggestions (Montastruc et al, 2011), the value of the current study was that its rationale was driven by a proper, detailed, pharmacodynamic hypothesis established on the basic properties of promethazine. Similar to remaining pharmacovigilance datasets (EMA, 2010; Evoy et al., 2019; Schifano and Chiappini, 2018a; Schifano et al., 2019a, 2019b; Schwan et al., 2010), focussing on the analysis of voluntary adverse events, a further limitation was given here by reliance on self-reporting and the likelihood of missing data occurrence. Moreover, although healthcare professionals have a main role in detection, assessment and spontaneous reporting of ADRs (Belton, 1997; Khalili et al., 2012), specific abuse/misuse/dependence issues relating to promethazine may have been underestimated, with only the most serious cases having been reported, hence the high rates of promethazine fatalities here recorded. Furthermore, although patients and their carers are allowed indeed to flag up an ADR, it is unlikely that they have spontaneously reported misusing events. Other factors, such as increased knowledge of promethazine misuse/abuse, may have resulted here in outcome reporting bias. There was also a potential for duplicate reports, with the same report submitted by the consumer, the healthcare professional and by the manufacturer as well, causing skewed study results. This may occur when a healthcare professional reported the same suspected ADR to both the national Regulatory Authority and the Marketing Authorisation Holder and they both reported subsequently to EV. However, the EV local report number which was here considered unequivocally identified an individual case. In addition, whilst this study represents one of the largest sample of promethazine abuse events published to date, the overall number of events is still relatively small, potentially limiting external validity. Case reports of suspected ADRs alone are not always sufficient to prove that a certain suspected reaction has indeed been caused by a specific medicine. This could be a symptom of another illness, or it could be associated with another medicinal product taken by the patient at the same time. The suspected ADRs were here presented using the PTs of the MedDRA Dictionary (Postigo et al., 2018). Thus, any case report should be considered together with all available data including case reports worldwide, clinical trials, epidemiological studies and toxicological investigations, in order to allow for robust conclusions. Finally, case reports reflect the information as provided to EV by the reporter, and not all data fields were completed for all reports.
Conclusion
To the best of our understanding, the current study described in detail the largest sample ever of abuse, misuse and dependence issues related to promethazine, whilst focussing on a large multinational dataset, such as the EV. The substantial number of promethazine-related events identified over the years represents a pharmacovigilance signal which needs to be better investigated (Montastruc et al., 2011). Although the observed trend of promethazine abuse and misuse, especially in young adults, is not a new phenomenon, further details of the issue have been here provided and future studies will optimally identify the related risk factors, with these measures enabling policymakers and regulators to take action to detect and prevent such misusing practices (Jouanjus et al., 2019). A multicomponent approach is recommended, including monitoring drug utilisation, tracking users’ posts on social media, and exploring healthcare databases; this will enable performing proactive and effective post-marketing surveillance and pharmacovigilance approaches. This has proved to be a relevant, efficient and accurate strategy, for example with gabapentinoids, which have recently been rescheduled in the UK (Borg et al., 2011; Eickhoff et al., 2012; Jouanjus et al., 2019; Novak et al., 2016; Parker et al., 2013; Schifano and Chiappini, 2019; Throckmorton et al., 2018). In this context, the role of the Web is rapidly spreading, playing a significant role in the marketing, sale and distribution of drugs, hence facilitating continuous changes in drug scenarios (Orsolini et al., 2017). Indeed, over the last 10 years access to online pharmacies to purchase medicinal compounds has increased (Desai, 2016; Monteith and Glenn, 2018). On the other hand, professionals access the Web to gather data on emerging trends of drug abuse (Deluca et al., 2002; Orsolini et al., 2015; Schifano, 2020; Schifano et al., 2003).
OTC and prescription drug misuse is perceived to be a significantly under-recognised issue affecting a range of vulnerable individuals (Coombes and Cooper, 2019). However, controlling the problem of OTC misuse and abuse might be challenging, due to the need for achieving high levels of consumer safety whilst not restricting access to OTC products for those who continue to use them safely.
Staff training should be evaluated, in order for pharmacists to self-monitor care and use of medicines, to educate patients and intervene/support those experiencing problematic drug use (Elwood, 2001; GPC, 2019; Tobin et al., 2013; Wells et al., 2018). Record-keeping (Hou et al., 2011) and real time monitoring (Cairns et al., 2016) could be a method of restricting access to some OTC drugs and prevent ‘shopping’ from one pharmacy to another, and where these measures would result to be ineffective, regulatory interventions, e.g. drug re-scheduling, might be useful (Marsden et al., 2019; McDonough, 2016; Peacock et al., 2019). Also, prevention and early education on substance abuse in young teenagers are critical (Levine, 2007; Marsden et al., 2019). Finally, appropriate and specific clinical guidelines for the treatment of misuse, abuse and dependence on prescription or OTC drugs should be implemented (Fingleton et al., 2019).
The review and study design were developed by SC, FS, JMC and AG. SC drafted the first version of the manuscript with input from all authors. All authors contributed to the interpretation of the data analysis and the further drafting of the manuscript and approved the final version.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FS was a member of the UK Advisory Council on the Misuse Drugs (ACMD) from 2011–2019; and is currently an EMA Advisory board (psychiatry) member. JMC is a member of the ACMD’s Novel Psychoactive Substances and Technical Committees. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
ORCID iDs: Stefania Chiappini https://orcid.org/0000-0002-6810-1540
John Martin Corkery https://orcid.org/0000-0002-3849-817X | Fatal | ReactionOutcome | CC BY | 33427017 | 18,928,797 | 2021-06 |
What was the outcome of reaction 'Drug abuse'? | Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.
Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents.
We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database.
After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234).
The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used.
Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.
Introduction
Pharmacological properties of promethazine
Promethazine is a phenothiazine derivative and a histamine (H1) receptor antagonist that is commonly used for symptomatic relief of nausea and vomiting, for allergic conditions, motion sickness and common cold, and for short-term use treatment of insomnia in adults or as a paediatric sedative (EMC, 2019). It also acts as a direct antagonist at muscarinic (M1) and dopamine (D2) receptors (Cookson, 2018; Page et al., 2009; Sharma and Hamelin, 2003). Promethazine hydrochloride is well absorbed from the gastrointestinal tract, with an average of 88% of the dose absorbed after oral administration, and clinical effects appearing within 20 min after intake whilst lasting 4–6 h. The plasma half-life is approximately 7–14 h (Burns and Boyer, 2013). It is classified as a first-generation antihistamine molecule which, compared with second-generation antihistamines, easily penetrates the blood-brain barrier and is associated with adverse effects such as moderate/intense sedation (Jensen et al., 2017). Thus, promethazine might be used in rapid (acute) tranquilization due to its blocking action at H1 and M receptors (Cookson, 2018). Toxicity might result in severe impairment of cognitive and psychomotor functions due to central nervous system (CNS) depression/reduced levels of consciousness, and may cause fatalities (Jensen et al., 2017).
Availability of promethazine
Promethazine is a medicinal product available on its own or in combination with other ingredients, including dextromethorphan, paracetamol and/or expectorants. With regards to promethazine availability, there are wide variations across countries. In fact, in some European countries such as France, Italy and the UK, but also outside Europe, some medicinal products containing promethazine can be purchased over-the-counter (OTC). Promethazine was restricted from an OTC status to prescription only in Denmark as of December 2014. This restriction was partly based on increasing enquiries regarding promethazine exposures to the Danish Poison and Information Centre (DPIC), highlighting its abuse potential and subsequent observations of side-effects after ingestion of standard doses. In Australia, promethazine is available as an OTC medication either alone as a tablet or as a liquid preparation or in combination with paracetamol and codeine phosphate as a syrup (Sharma and Hamelin, 2003). In the USA, some cough preparations containing no more than 200 mg of codeine per 100 mL are considered Schedule V controlled substances (Drug Enforcement Administration (DEA), 2020), purportedly possessing the lowest potential for both misuse and development of a Substance Use Disorder (SUD).
Pharming
Recently, the potential for misuse of medications that are not already controlled has been reported worldwide (Reeves et al., 2015). ‘Pharming’ is a phenomenon involving the non-medical use of prescription (pain relievers, tranquilisers, stimulants, sedatives) and OTC drugs, including cough and cold preparations, particularly those containing dextromethorphan and promethazine (Burns and Boyer, 2013; Jouanjus et al., 2018; Levine, 2007; McCarthy, 2007; National Institute on Drug Abuse (NIDA), 2014). The abuse of these compounds may be facilitated by their easy accessibility, low cost, decreased perception of potential for harm and growing social acceptance (Burns and Boyer, 2013; Levine, 2007; McCarthy, 2007; Substance Abuse Mental Health Services Administration (SAMHSA), 2008). In the current drug abuse scenario, young people/youths have been described abusing with a range of prescription or OTC medicines (Soussan et al., 2018), with these molecules possibly being ingested at high/super-high dosages (Orsolini et al., 2015; Schifano, 2020) and at times in combination with alcohol/remaining recreational substances (Levine, 2007)
Recreational use of promethazine
Centrally acting antihistamines have long been known to induce physical and psychological dependence (Clatts et al., 2010; Gracious et al., 2010; Page et al., 2009; Saatcioglu and Evren, 2005; Thomas et al., 2008). During the past 15 years the abuse of promethazine, especially from OTC and prescription cough and cold medicines and at higher-than-recommended dosages, has been reported (NIDA, 2014). Consistent with this, during the last decade the yearly number of promethazine-related overdose cases in Sweden has increased from 100 to nearly 700 and its sales have increased threefold (Höjer and Tellerup, 2018). Also, according to the 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), antihistamines accounted for the seventh most frequently involved substance in human exposures, resulting in the third type of substance category for rate of exposure increase (Gummin et al., 2019). In Denmark, the number of registered antihistamine exposures increased during 2007–2013, with first-generation antihistamines, specifically promethazine, having been responsible for most exposures and related fatalities (Jensen et al., 2017). Also, in New Zealand a number of promethazine poisoning cases (57/199 patients) were identified from a database of poisoning admissions to a regional toxicology service (Bergman and Wallman, 1998).
Effects
Promethazine reported effects mostly include a range of CNS side effects, such as: confusion; disorientation; drowsiness; cardiovascular symptoms; and respiratory depression (Burns and Boyer, 2013; Höjer and Tellerup, 2018; Page et al., 2009; Tsay et al., 2015). A clear abuse potential has been observed and reported for first-generation antihistamines such as promethazine and cyclizine, due to: calming and sedating effects (Cookson, 2018; Jensen et al., 2017) and enhancement of other co-ingested substances, and especially those interacting with gamma-amino-butyric acid (GABA), opiate and muscarinic acetylcholine receptors (Speeg et al., 1981), leading to hallucinogenic experiences (Clatts et al., 2010; Jensen et al., 2017; Lynch et al., 2015). Indeed, an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility has been described (Burns and Boyer, 2013). In these cases, the mental state alteration is characterised by agitated delirium, with abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia (Agnich et al., 2013; Cowen, 1979; Dollberg et al., 1989; Höjer and Tellerup, 2018; Leak and Carroll, 1967; Page et al., 2009; Scott et al., 2007; Timnak et al., 2004). With the promethazine-codeine cough syrup, ‘euphoric feelings’, ‘relaxation’, ‘slight giddiness and disorienting’, and ‘nice hallucinations’ have been described as well (Bluelight.org [2020]; Erowid.org [2020]). Reported side-effects include drowsiness, fatigue, loss of coordination, constipation and urinary retention (Elwood, 2001).
Vulnerable categories
An increasing trend in abuse of promethazine in co-formulation with some components of OTC cough medications has been reported in young adult populations (Carney et al., 2018; Carr, 2006; Höjer and Tellerup, 2018) since the late 1990s, particularly in the southern USA (Carr, 2006; Elwood, 2001). Codeine and promethazine were recorded as the most requested psychoactive drugs by adolescents/young adults in community pharmacies (Delcourt et al., 2017).
Known by the street names ‘lean’, ‘drank’, ‘barre’, ‘purple stuff’, ‘syrup’ and ‘sizzurp’ (Agnich et al., 2013; NIDA, 2014; Peters et al., 2007), the abuse of promethazine mixed with opioids and other sedatives (e.g. alcohol) in a purple colour drink (‘purple drank’) (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014) has become widely popular (Agnich et al., 2013) after a rap artist/producer created a genre of music, called ‘screw music', inspired by intoxication on codeine and promethazine (Peters et al., 2007). Social media data, e.g. public posts and related hashtags on Instagram, provided additional insights into codeine abuse, depicting its common misuse combined with promethazine and soda/carbonated drinks (Cherian et al., 2018). ‘Purple drank’ has been noted for its euphoric effects and its easy accessibility (Elwood, 2001; Peters et al., 2007). ‘Lean’ creates a distinct (Jakubowski et al., 2018) feeling of euphoria and extreme relaxation (Cookson, 2018), dream-like feelings and a vivid sensation of floating away from the physical body (Peters et al., 2007).
Although at times preferred to other substances, such as benzodiazepines, to treat anxiety and sleep disorders in substance-dependent patients, promethazine has been reported to be misused among people with either opioid dependence (Agnich et al., 2013; Dahlman et al., 2016; Elwood, 2001; Lynch et al., 2015; Shapiro et al., 2013) or a substance abuse condition (Shapiro et al., 2013; Tang et al., 2012). A Hong Kong study reported a total of 63 patients with a diagnosis of cough mixture abuse; 89% were adult males with a mean age of onset of the abuse itself of 20 (±5) years. These subjects had received a diagnosis of substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%) and dysthymia (10%), with most cases having presented with a polysubstance misuse (Tang et al., 2012). Due to the opioid-coformulation, the promethazine-codeine cough mixture might lead to addiction (NIDA, 2014). The mixture may present a high risk of occurrence of near misses due to its central effect of respiratory depression, which is greatly increased by association with alcohol or other CNS depressants, such as sedatives/hypnotics, narcotic analgesics, general anaesthetics and tricyclic antidepressants (Burns and Boyer, 2013; Elwood, 2001; NIDA, 2014; Shapiro et al., 2013; Tsay et al., 2015). The concomitant use of promethazine and other depressant drugs should not be underestimated, as they might together contribute to and/or cause fatalities (Corkery et al., 2020).
Aim of the study
We were interested here in studying how promethazine abuse was reported to the European Medicines Agency (EMA) adverse drug reactions (ADRs) database. We aimed to analyse promethazine misuse/abuse/dependence/withdrawal data. Where possible, in order to have a better understanding, information/data related to diagnosis, concomitant drugs, administration and dosages were also examined.
Methods
Source of data
The EMA through EudraVigilance (EV) manages and analyses information on suspected ADRs to medicines authorised in the European Economic Area (EEA), according to Directive 2001/83/EC and Regulation (EC) No 726/2004 (EMA, 2017). Since November 2017, EV launched extensive Web access to data on suspected ADRs and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research (Postigo et al., 2018). Thus, access to data regarding cases of promethazine abuse, misuse, dependence and withdrawal was obtained by application to the voluntary reporting system of ADRs of the EMA. After 3 months all data comprised all of the ADRs reported during the years from 2003 up to June 2019, presented as large Excel files divided into information sections reporting in a standardised format according to the Medical Dictionary for Regulatory Activities (MedDRA), were sent through a hyperlink (MedDra, 2018). Such listings showed all information related to the ADR, the patient, the drug, the reporter and the diagnosis. An ADR was considered a voluntary and unsolicited communication reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorisation Holders for those ADRs occurring outside the EEA (EMA, 2010). Only ‘suspect’ ADRs were selected, meaning promethazine was considered as ‘suspected’ for the reaction reported. Regarding the content of the ADR, according to the standardised MedDRA Query (SMQ) (MedDRA, 2018), the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, intentional product use issue, substance abuse, substance abuser, substance use and withdrawal syndrome were selected. Those ADRs were defined in accordance with MedDRA in line with previous studies on the EV dataset (Chiappini et al., 2020; MedDRA, 2018; Schifano and Chiappini, 2018a, 2018b; Schifano et al., 2019a, 2019b). Specifically, abuse was here defined as the intentional, non-therapeutic use by a patient or consumer of a product, OTC or prescription, for a perceived reward or desired non-therapeutic effect including, but not limited to, getting high (euphoria) (MedDRA, 2018). Misuse was meant as the intentional use for a therapeutic purpose by a patient or consumer of a product, OTC or prescription, other than as prescribed or not in accordance with the authorised product information (MedDRA, 2018). Finally, non-medical use referred here to the use of a prescription drug, whether obtained by prescription or otherwise, other than in the manner or for the time period prescribed, or by a person for whom the drug was not prescribed (United Nations Office on Drugs and Crime (UNODC), 2013).
Analysis of data
We retrospectively analysed all reported ADRs which were available in the EV database. ADR reports were analysed with respect to age and gender of patient/consumer, source/reporter country (EEA or non-EEA) and reporter qualification (i.e. pharmacist, physician); type of ADR; seriousness (fatal, recovered, resolved outcomes); promethazine dosage; possible concomitant drug(s); and diagnosis/reporter’s comments, if recorded. The descriptive analysis included cases of overdoses, suicides, and fatalities. In the dataset, each case report may refer to one or more reporter; one or more ADR(s); as well as to one or more medicinal product(s). Therefore, a case may be represented by more than one row in the other line listings. The received data files were searched for duplicates by report ID through the ‘EV Local Report Number’, which unequivocally identified an individual case. Thus, the number of suspected ADRs appeared to be different from the number of case reports as one case report might refer to several suspected ADRs. Moreover, the number of patients was different from the number of case reports as a patient might have been described in more than one case. Finally, numbers of ADRs differed from those referring to case reports/single patients since different reporters/senders could have independently flagged the same ADR to the EMA. The descriptive analysis included here a study of the dataset (EMA, 2017) performed through IBM SPSS Statistics software (version 26).
Ethical issues
In compliance with applicable Personal Data Protection legislation (Regulation (EC) No 45/2001 and Regulation (EC) No 1049/2001, the protection of privacy and integrity of individuals was guaranteed, and in order to safeguard the identity of individuals certain data elements, including names/identifiers or country-specific information were not disclosed by the EMA (EMA, 2013, 2017). The study was ethically approved in March 2018 by the University of Hertfordshire Ethics’ Committee, with reference number LMS/PGR/UH/03234.
Results
The dataset obtained reported a total of 11,796 ADRs, correspond-ing to 1,543 single cases recorded during years 2003–2019 (Table 1). Safety reports were all voluntarily submitted, mostly from pharmaceutical companies (1,136/1,543: 73.6%) and regulatory authorities (398/1,543: 25.8%). Reports were irregularly reported over time, with spikes in 2010, 2014 and 2017 (Figure 1). Countries which reported most promethazine-related abuse/misuse/dependence cases included: the USA (805/1,543: 52.10%); Germany (299/1,543: 19.4%); Japan (162/1,543: 10.5%), Sweden (67/1,543: 4.3%), France (43/1,543: 2.8%) and Australia (42/1,543: 2.7%). Out of a total of 1543 cases, ‘suspect’ abuse/misuse/dependence-related cases were 557 (36.1%) and, among them, according to the preferred terms (PTs), most recorded reactions were abuse/misuse-related ADRs (458/557: 82.2%), specifically ‘drug abuse’ (300/557: 53.8%) and ‘intentional product misuse’ (117/557: 21.0%) (Table 1). ‘Suspect’ selected cases and related fatalities annually showed the same trend overall (Figure 1). Most typically, subjects reported were adult (19–64 years) and specifically of the youngest group (19–25 years); males were slightly more frequently recorded than females (M/F: 235/461: 0.51) (Table 1). Where all information was recorded, promethazine was reported as ingested alone in 74 cases, with supratherapeutic dosages, up to 2500 mg, in four cases. In combination with other drugs, most cases were associated with a 100–500 mg promethazine dose, with the maximum dosage recorded having been 8000 mg (Figure 2). The most common administration route was oral (n = 292), although the intramuscular (n = 8) and the parenteral (n = 19) ones were reported as well, see Table 1).
Table 1. Analysis of promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV) during years 2003–2019.
Individual cases (% of total within parentheses)
Total abuse/misuse/dependence cases 1543 Single cases; number of ADRs :11,796
Age range Adult (19–64 years): 648 (648/1,543: 42.0%) - mean age: 31.8 years (SD 26.55–37.05)
Adolescent (10–18 years): 23 (23/1,543: 1.5%) – mean age: 15.9 years (SD 14.3–17.77)
Elderly (>65 years): 25 (25/1,543: 1.6%) – mean age: 72.3 years (SD 70.85–73.7)
Neonatal (hours–days) 14 (14/1,543: 0.9%) – mean age: 24 h (SD 16.6–27.4)
Infant (months–1 year): 7 (7/1,543: 0.45%) – mean age: 10 months (SD 7–13)
Child (<10 years): 4 (4: 1,543: 0.35%) – mean age: 5 years (SD 3.6–6.3)
Unknown: 822 (822/1,543: 53.2%)
Male/female 235/461: 0.51
Most represented abuse/misuse/dependence-related ADRs according to the PTs: 557 (557/1,543: 36.1%)
Abuse-related ADRs 458 (458/557: 82.2%)
Drug abuse 300
Drug abuser 15
Drug diversion 1
Intentional product misuse 117
Intentional product use issue 9
Substance abuse 11
Substance abuser 3
Substance use 2
Dependence-related ADRs 44 (44/557: 7.9%)
Dependence 4
Drug dependence 39
Substance dependence 1
Withdrawal-related ADRs 55 (55/557: 9.8%)
Withdrawal syndrome 19
Drug withdrawal convulsions 1
Drug withdrawal neonatal syndrome 18
Drug withdrawal syndrome 17
Outcome Fatal 310 (310/557: 55.6%)
Unknown 161 (161/557: 28.9%)
Recovered/resolved 55 (55/557: 9.9%)
Recovering/resolving 18 (18/557: 3.3%)
Not recovered/not resolved 13 (13/557: 2.3%)
Promethazine-cases alone 74 (with maximum dosage 2500 mg)
Promethazine-cases with other drugs Most cases (122) were over 100 mg (with maximum dosage 8000 mg)
Most common psychoactive substances used Alcohol: 114
Cocaine: 68
Cannabis: 16
Ketamine: 4
Amphetamine: 1
Most common prescription drugs used Opioids: 1187
Benzodiazepines: 914
Antidepressants: 871
Antipsychotics: 437
Z-drugs: 222
Mood stabilisers: 197
ADR: adverse drug reaction; PTs: preferred terms; SD: standard deviation.
Figure 1. Number of promethazine abuse/misuse/dependence/withdrawal cases reported by year in the EudraVigilance (EV) dataset.
Figure 2. Most represented dosages reported among all promethazine abuse/misuse/dependence/withdrawal cases recorded by the EudraVigilance (EV) dataset.
Concomitantly used drugs recorded were opioids (e.g. oxycodone and fentanyl), benzodiazepines (e.g. diazepam, alprazolam and lorazepam) and antidepressants (e.g. citalopram, venlafaxine and amitriptyline), whilst recreational drugs most represented were alcohol and cocaine (Table 1). Most reported diagnoses, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V; American Psychiatric Association (APA), 2013) related to: mood disorders, e.g. depression/depressed mood/major depression (68 cases) and bipolar disorder (14 cases); anxiety/anxiety disorders (23 cases); alcohol abuse/alcoholic/alcoholism (26 cases); and schizophrenia (14 cases). The outcome of the reactions reported included: ‘fatal’ (n=310/557; 55.6%) and secondarily ‘recovered/resolved’ (n=73; 15.2%) (Table 1). Some 27 cases were related to suicidal or self-harm behaviour, being recorded as ‘suicidal attempt/suicidal ideation’ (n=24), ‘self-injurious ideation’ (n=1), and ‘suicide attempt’ (n=2). Fatalities mostly involved adult females; in these cases, most typical ADRs recorded were ‘drug abuse’ (n=228) and ‘intentional product misuse’ (n=77) (Table 2). Opiates/opioids were the most recorded concomitant drugs (n=356), with methadone being the most represented (n=103), followed by antidepressants (n=221) and benzodiazepines (n=141). Among illicit drugs, heroin appeared to be the most represented (Table 2).
Table 2. Analysis of fatal promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV), 2003–2019.
Fatal cases on abuse/misuse/dependence/withdrawal reactions 310 (310/557 = 55.6%)
Age-range
Adult 303 (97.7%)
Adolescent 7 (2.3%)
Elderly (>65 years) –
Neonatal –
Infant –
Child –
Gender M 103 (33.2%)
F 177 (57.1%)
Unknown 30 (9.7%)
Most recorded PTs
Drug abuse/drug abuser/substance abuse 228/3/6
Intentional product misuse/Intentional product use issue 77/3
Drug dependence 1
Reported death code
Intentional overdose 1
Overdose 4
Completed suicide/suicide 7
Drug toxicity/drug abuse 197
Toxicity to various agents 48
Intentional product misuse 41
Respiratory depression 5
Pneumonia 1
Cardiac arrest 10
Drug dependence 1
Most reported concomitant drugs
Opioids 356
Methadone 103
Dihydrocodeine 1
Codeine 32
Fentanyl 44
Oxycodone 63
Morphine 55
Hydrocodone 33
Hydromorphone 3
Tramadol 22
Antidepressants 221
Duloxetine 1
Escitalopram 1
Sertraline 16
Paroxetine 34
Trazodone 15
Mirtazapine 33
Fluoxetine 24
Venlafaxine 9
Bupropion 1
Amitriptyline 35
Nortriptyline 6
Clomipramine 5
Citalopram 41
Benzodiazepines 141
Lorazepam 3
Temazepam 6
Clonazepam 21
Diazepam 60
Flunitrazepam 1
Brotizolam 1
Alprazolam 42
Midazolam 4
Oxazepam 3
Mood stabilisers 11
Gabapentin 3
Topiramate 8
Antipsychotics 24
Olanzapine 1
Quetiapine 20
Haloperidol 1
Amisulpride 1
Levomepromazine 1
Z-drugs 39
Zolpidem 37
Zopiclone 2
Illicit drugs
Amphetamine 15
Cocaine 40
Heroin 52
Alcohol 26
PTs: preferred terms.
Discussion
Non-medical prescription drug use is a globally recognised problem, with severe adverse consequences. The current study provides a large amount of descriptive data highlighting that promethazine can be taken at high dosages, through non-approved administration routes, and in a setting of polydrug use (Hughes et al., 2016; Novak et al., 2016).
Promethazine misuse has been increasingly recorded since the early 2000s, consistently with data from US poison centres reporting antihistamine exposures rising in the period 2007–2013 (Jensen et al., 2017). This is not surprising, since the pharmacodynamic properties of promethazine underpins its sought-after central effects. In 2014, e.g. the highest peak here, the increase in promethazine misuse reporting was solely driven by the USA (245/245 cases; 100%). This may have been associated with intense media attention to the subject in that year (TMZ, 2014). The increments reported in 2010, 2014 and 2017 were then followed by decrements, which may have been related to not only reporting variabilities, but also to differences in sales of antihistamines following local/national drug abuse prevention campaigns (Klein-Schwartz, 2017). Overall, the USA appeared here to be the country most involved in reporting of promethazine ADRs. Several reasons may help in explaining this, including healthcare professionals’ awareness of prescription/OTC drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Lynch et al., 2015; Manchikanti et al., 2006; NIDA, 2014; Tsay et al., 2015) which, in turn, may have facilitated pharmacovigilance reporting. According to an 11-year period of the US National Poison Centers’ database, the annual rate of promethazine abuse/misuse per 100,000 US population doubled over time (Tsay et al., 2015). In the USA, promethazine abuse/misuse has been described in teenagers and young adults (Peters et al., 2003), methadone maintenance patients, heroin users and opioid-prescribed chronic pain patients (Lynch et al., 2015; Shapiro et al., 2013).
Consistent with previous observations (Agnich et al., 2013; Burns and Boyer, 2013; Carr, 2006; Elwood, 2001; Höjer and Tellerup, 2018; NIDA, 2014; Page et al., 2009; Parker et al., 2013; Peters et al., 2007), most recorded ADRs related here to either ‘drug abuse’ and ‘intentional product misuse’, involving young adult (19–25 years) males. Although considered a vulnerable category with respect to prescription drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014; Peters et al., 2007), adolescents (10–18 years) were here reported in only a minority (23/1543:1.5%) of cases.
Several drugs were here associated with promethazine, although opiates/opioids were the most represented molecules in related fatalities. This combination might intensify effects such as sedation and analgesia (Burns and Boyer, 2013; Lynch et al., 2015; Shapiro et al., 2013), and in the 1950s the association was medically used to reduce the dosage of opiates/opioids (McGee and Weiss, 1956). However, due to a range of adverse effects (Lynch et al., 2015) including lack of data supporting clinical efficacy (Richter and Burk, 1992) and an enhanced addiction potential of opioids (Lynch et al., 2015; Peters et al., 2007; Shapiro et al., 2013), the combination of promethazine/opioids has declined in popularity.
So far, the recreational intake of promethazine with opioids has been typically reported in cough mixtures containing codeine (Casati et al., 2012; Clatts et al., 2010; Elwood, 2001; Foley et al., 2015; Peters et al., 2007). However, current EMA data suggest that, apart from methadone, oxycodone and fentanyl were the most typical opiates/opiates identified in association with promethazine, possibly due to their recent popularity, especially in the USA (Manchikanti et al., 2018; Rose, 2018). In the promethazine fatalities (e.g. 310 cases) dataset analysed, codeine, fentanyl and oxycodone were respectively reported in 32, 44 and 63 cases. Consistent with current data, a concomitant use of opioids and promethazine has been described in various subpopulations, such as methadone maintenance patients, injecting drug users and chronic pain patients (Banta-Green et al., 2005; Lynch et al., 2015; Shapiro et al., 2013; Shields et al., 2007; Van Hout and Norman, 2016). Overall, there is now a high level of awareness of the abuse potential of antihistamine/opioid-containing products (Hou et al., 2011; Hughes et al., 1999; Wazaify et al., 2005). Hence, some countries are limiting both the medication pack size levels and the quantities of drugs sold in a single transaction, whilst also promoting non-injectable and non-inhaling formulations and changing some formulations’ OTC status (Cooper, 2013; Foley et al., 2015; Van Hout and Norman, 2016).
Benzodiazepines (e.g. diazepam, alprazolam and lorazepam) were here also frequently recorded, suggesting sedative synergistic effects in combination with promethazine (Lynch et al., 2015), and hence an increased risk of untoward clinical issues (McLellan and Turner, 2010). Other prescription drug categories recorded included antidepressants (most typically: citalopram and amitriptyline, respectively in 149/557 and 95/557 cases), which is consistent with the most typically recorded diagnoses, e.g. depressive (68 cases); bipolar (14 cases); and anxiety (23 cases) disorders. It is also possible that antidepressants were here ingested in combination with promethazine for sleep induction purposes. It is a reason for concern that promethazine ADRs, either alone or in combination, resulted in either fatal (50.6%) or ‘recovered/resolved’ outcomes (22.2%). This is consistent with previous promethazine misuse/abuse data, reporting both adverse clinical outcomes and high frequency of healthcare facility treatment (Bergman and Wallman, 1998; Ichikura et al., 2016; McLellan and Turner, 2010; Tsay et al., 2015). A list of possibly misused substances which might reinforce promethazine psychoactive effects and possibly increase its toxicity is included in Table 3.
Table 3. List of substances recorded in the literature as used in association with promethazine in order to increase its effects; prescription drugs are recorded according to the Neuroscience-based Nomenclature description (Nutt and Blier, 2016).
Psychoactive substances
Description Mode of action Examples Effects
Alcohol (Burns and Boyer, 2013; Jensen et al., 2017) CNS depressant effects ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, relaxation, ‘slight giddiness and disorienting’ and ‘nice hallucination’.
It may increase, prolong or intensify promethazine sedative effect. It should be avoided in patients receiving promethazine.
Heroin and other illicit opioids (Dahlman et al., 2016; Tsay et al., 2015) Opioid depressant effects It may increase, prolong, or intensify promethazine sedative effect.
Prescription drugs
Categories Mode of action Examples Effects
Drugs for insomnia (Burns and Boyer, 2013) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Z-drugs: zaleplon, zolpidem, zopiclone, eszopiclone They may increase, prolong or intensify promethazine sedative effect.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Drugs for anxiety (Burns and Boyer, 2013; Lynch et al., 2015) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, lorazepam, oxazepam They may increase, prolong or intensify promethazine sedative action.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Dextrometorphan (Tsay et al., 2015) At high doses, acting as NMDA-receptor antagonist; dextrometorphan and its potent metabolite dextrorphan inhibit the excitatory amino acid and neurotransmitter glutamate in the brain, determining hallucinogenic and dissociative activities, which are recreationally searched It might be combined with promethazine in cough-suppressant formulation Dextrometorphan neurobehavioural effects are dose-related, starting from a mild to moderate stimulation with restlessness and euphoria (100–200 mg), to a dissociated state characterised by hallucinations, paranoia, perceptual distortions, delusional beliefs, ataxia and out-of-body experiences (‘robo-ing’/‘robo-copping’/‘robo-tripping’) (>1000 mg). In overdosage they might increase promethazine effects.
Drugs for depression (Burns and Boyer, 2013; Jensen et al., 2017): TCA Multimodal action: reuptake inhibitor (SERT and NET), receptor antagonist (5-HT2) Amitriptyline Promethazine may increase, prolong or intensify their sedative effect. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Anticholinergic drugs Antagonist at cholinergic receptors Hyoscine butyl bromide/scopolamine (Burns and Boyer, 2013) Together with promethazine an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility may be seen. A typical mental status alteration with a dose-dependent agitated delirium characterised by abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia, has been described. These molecules should be avoided or administered in reduced dosage to patients receiving promethazine.
Prescription opioids
Codeine (Burns and Boyer, 2013; Jouanjus et al., 2018; Lynch et al., 2015; O Reilly et al., 2015; Shapiro et al., 2013) ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, elation, analgesia and ‘liking’, with increased potential of addiction. Overdosage of codeine might determine respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne–Stokes respiration and cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Opiate overdosage, particularly by the intravenous route, may be associated with apnoea, circulatory collapse, cardiac arrest and death. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Other opioid analgesics (Burns and Boyer, 2013; Dahlman et al., 2016; Lynch et al., 2015; Shapiro et al., 2013) Methadone They may increase, prolong or intensify promethazine sedative effects. Opioids should be avoided or administered in reduced dosage to patients receiving promethazine.
The addiction potential of opioids might be enhanced. Also, increasing life-threatening events, such as respiratory depression, overdose and prolongation of the QT interval, might be responsible for drug-related fatalities.
5-HT2: serotonin-2 receptor; CNS: central nervous system; D2: dopamine 2 receptor; GABA: gamma-amino-butyric acid; H1: histamine 1 receptor; NE: norepinephrine; NET: norepinephrine transporter; NMDA: N-methyl-D-aspartate; SERT: serotonin transporter; SSRI: selective-serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
Finally, among abuse-related cases, neonates, infants and children were here reported as well. This is consistent with cases of unexpected infant deaths associated with use of cold medications, poor socioeconomic conditions (Rimsza and Newberry, 2008) and/or accidental ingestion (McLellan and Turner, 2010).
Limitations
One of the limitations was given here by the descriptive nature of the study. Indeed, a comparator molecule, for a disproportionality analysis (Chiappini and Schifano, 2016; Schifano and Chiappini, 2018b) to be carried out, was not available due to data access limitations (EMA, 2017; Postigo et al., 2018). Furthermore, current data did not appear to show an increasing trend of abuse or misuse across the years. Since proper denominator figures (e.g. data on worldwide promethazine prescriptions) are not available, it was unclear if what observed was a substantial number of cases, indicative of clinically meaningful abuse potential, or a passing trend for promethazine misuse by a very small number of individuals. However, consistent with previous suggestions (Montastruc et al, 2011), the value of the current study was that its rationale was driven by a proper, detailed, pharmacodynamic hypothesis established on the basic properties of promethazine. Similar to remaining pharmacovigilance datasets (EMA, 2010; Evoy et al., 2019; Schifano and Chiappini, 2018a; Schifano et al., 2019a, 2019b; Schwan et al., 2010), focussing on the analysis of voluntary adverse events, a further limitation was given here by reliance on self-reporting and the likelihood of missing data occurrence. Moreover, although healthcare professionals have a main role in detection, assessment and spontaneous reporting of ADRs (Belton, 1997; Khalili et al., 2012), specific abuse/misuse/dependence issues relating to promethazine may have been underestimated, with only the most serious cases having been reported, hence the high rates of promethazine fatalities here recorded. Furthermore, although patients and their carers are allowed indeed to flag up an ADR, it is unlikely that they have spontaneously reported misusing events. Other factors, such as increased knowledge of promethazine misuse/abuse, may have resulted here in outcome reporting bias. There was also a potential for duplicate reports, with the same report submitted by the consumer, the healthcare professional and by the manufacturer as well, causing skewed study results. This may occur when a healthcare professional reported the same suspected ADR to both the national Regulatory Authority and the Marketing Authorisation Holder and they both reported subsequently to EV. However, the EV local report number which was here considered unequivocally identified an individual case. In addition, whilst this study represents one of the largest sample of promethazine abuse events published to date, the overall number of events is still relatively small, potentially limiting external validity. Case reports of suspected ADRs alone are not always sufficient to prove that a certain suspected reaction has indeed been caused by a specific medicine. This could be a symptom of another illness, or it could be associated with another medicinal product taken by the patient at the same time. The suspected ADRs were here presented using the PTs of the MedDRA Dictionary (Postigo et al., 2018). Thus, any case report should be considered together with all available data including case reports worldwide, clinical trials, epidemiological studies and toxicological investigations, in order to allow for robust conclusions. Finally, case reports reflect the information as provided to EV by the reporter, and not all data fields were completed for all reports.
Conclusion
To the best of our understanding, the current study described in detail the largest sample ever of abuse, misuse and dependence issues related to promethazine, whilst focussing on a large multinational dataset, such as the EV. The substantial number of promethazine-related events identified over the years represents a pharmacovigilance signal which needs to be better investigated (Montastruc et al., 2011). Although the observed trend of promethazine abuse and misuse, especially in young adults, is not a new phenomenon, further details of the issue have been here provided and future studies will optimally identify the related risk factors, with these measures enabling policymakers and regulators to take action to detect and prevent such misusing practices (Jouanjus et al., 2019). A multicomponent approach is recommended, including monitoring drug utilisation, tracking users’ posts on social media, and exploring healthcare databases; this will enable performing proactive and effective post-marketing surveillance and pharmacovigilance approaches. This has proved to be a relevant, efficient and accurate strategy, for example with gabapentinoids, which have recently been rescheduled in the UK (Borg et al., 2011; Eickhoff et al., 2012; Jouanjus et al., 2019; Novak et al., 2016; Parker et al., 2013; Schifano and Chiappini, 2019; Throckmorton et al., 2018). In this context, the role of the Web is rapidly spreading, playing a significant role in the marketing, sale and distribution of drugs, hence facilitating continuous changes in drug scenarios (Orsolini et al., 2017). Indeed, over the last 10 years access to online pharmacies to purchase medicinal compounds has increased (Desai, 2016; Monteith and Glenn, 2018). On the other hand, professionals access the Web to gather data on emerging trends of drug abuse (Deluca et al., 2002; Orsolini et al., 2015; Schifano, 2020; Schifano et al., 2003).
OTC and prescription drug misuse is perceived to be a significantly under-recognised issue affecting a range of vulnerable individuals (Coombes and Cooper, 2019). However, controlling the problem of OTC misuse and abuse might be challenging, due to the need for achieving high levels of consumer safety whilst not restricting access to OTC products for those who continue to use them safely.
Staff training should be evaluated, in order for pharmacists to self-monitor care and use of medicines, to educate patients and intervene/support those experiencing problematic drug use (Elwood, 2001; GPC, 2019; Tobin et al., 2013; Wells et al., 2018). Record-keeping (Hou et al., 2011) and real time monitoring (Cairns et al., 2016) could be a method of restricting access to some OTC drugs and prevent ‘shopping’ from one pharmacy to another, and where these measures would result to be ineffective, regulatory interventions, e.g. drug re-scheduling, might be useful (Marsden et al., 2019; McDonough, 2016; Peacock et al., 2019). Also, prevention and early education on substance abuse in young teenagers are critical (Levine, 2007; Marsden et al., 2019). Finally, appropriate and specific clinical guidelines for the treatment of misuse, abuse and dependence on prescription or OTC drugs should be implemented (Fingleton et al., 2019).
The review and study design were developed by SC, FS, JMC and AG. SC drafted the first version of the manuscript with input from all authors. All authors contributed to the interpretation of the data analysis and the further drafting of the manuscript and approved the final version.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FS was a member of the UK Advisory Council on the Misuse Drugs (ACMD) from 2011–2019; and is currently an EMA Advisory board (psychiatry) member. JMC is a member of the ACMD’s Novel Psychoactive Substances and Technical Committees. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
ORCID iDs: Stefania Chiappini https://orcid.org/0000-0002-6810-1540
John Martin Corkery https://orcid.org/0000-0002-3849-817X | Fatal | ReactionOutcome | CC BY | 33427017 | 18,928,797 | 2021-06 |
What was the outcome of reaction 'Drug dependence'? | Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.
Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents.
We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database.
After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234).
The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used.
Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.
Introduction
Pharmacological properties of promethazine
Promethazine is a phenothiazine derivative and a histamine (H1) receptor antagonist that is commonly used for symptomatic relief of nausea and vomiting, for allergic conditions, motion sickness and common cold, and for short-term use treatment of insomnia in adults or as a paediatric sedative (EMC, 2019). It also acts as a direct antagonist at muscarinic (M1) and dopamine (D2) receptors (Cookson, 2018; Page et al., 2009; Sharma and Hamelin, 2003). Promethazine hydrochloride is well absorbed from the gastrointestinal tract, with an average of 88% of the dose absorbed after oral administration, and clinical effects appearing within 20 min after intake whilst lasting 4–6 h. The plasma half-life is approximately 7–14 h (Burns and Boyer, 2013). It is classified as a first-generation antihistamine molecule which, compared with second-generation antihistamines, easily penetrates the blood-brain barrier and is associated with adverse effects such as moderate/intense sedation (Jensen et al., 2017). Thus, promethazine might be used in rapid (acute) tranquilization due to its blocking action at H1 and M receptors (Cookson, 2018). Toxicity might result in severe impairment of cognitive and psychomotor functions due to central nervous system (CNS) depression/reduced levels of consciousness, and may cause fatalities (Jensen et al., 2017).
Availability of promethazine
Promethazine is a medicinal product available on its own or in combination with other ingredients, including dextromethorphan, paracetamol and/or expectorants. With regards to promethazine availability, there are wide variations across countries. In fact, in some European countries such as France, Italy and the UK, but also outside Europe, some medicinal products containing promethazine can be purchased over-the-counter (OTC). Promethazine was restricted from an OTC status to prescription only in Denmark as of December 2014. This restriction was partly based on increasing enquiries regarding promethazine exposures to the Danish Poison and Information Centre (DPIC), highlighting its abuse potential and subsequent observations of side-effects after ingestion of standard doses. In Australia, promethazine is available as an OTC medication either alone as a tablet or as a liquid preparation or in combination with paracetamol and codeine phosphate as a syrup (Sharma and Hamelin, 2003). In the USA, some cough preparations containing no more than 200 mg of codeine per 100 mL are considered Schedule V controlled substances (Drug Enforcement Administration (DEA), 2020), purportedly possessing the lowest potential for both misuse and development of a Substance Use Disorder (SUD).
Pharming
Recently, the potential for misuse of medications that are not already controlled has been reported worldwide (Reeves et al., 2015). ‘Pharming’ is a phenomenon involving the non-medical use of prescription (pain relievers, tranquilisers, stimulants, sedatives) and OTC drugs, including cough and cold preparations, particularly those containing dextromethorphan and promethazine (Burns and Boyer, 2013; Jouanjus et al., 2018; Levine, 2007; McCarthy, 2007; National Institute on Drug Abuse (NIDA), 2014). The abuse of these compounds may be facilitated by their easy accessibility, low cost, decreased perception of potential for harm and growing social acceptance (Burns and Boyer, 2013; Levine, 2007; McCarthy, 2007; Substance Abuse Mental Health Services Administration (SAMHSA), 2008). In the current drug abuse scenario, young people/youths have been described abusing with a range of prescription or OTC medicines (Soussan et al., 2018), with these molecules possibly being ingested at high/super-high dosages (Orsolini et al., 2015; Schifano, 2020) and at times in combination with alcohol/remaining recreational substances (Levine, 2007)
Recreational use of promethazine
Centrally acting antihistamines have long been known to induce physical and psychological dependence (Clatts et al., 2010; Gracious et al., 2010; Page et al., 2009; Saatcioglu and Evren, 2005; Thomas et al., 2008). During the past 15 years the abuse of promethazine, especially from OTC and prescription cough and cold medicines and at higher-than-recommended dosages, has been reported (NIDA, 2014). Consistent with this, during the last decade the yearly number of promethazine-related overdose cases in Sweden has increased from 100 to nearly 700 and its sales have increased threefold (Höjer and Tellerup, 2018). Also, according to the 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), antihistamines accounted for the seventh most frequently involved substance in human exposures, resulting in the third type of substance category for rate of exposure increase (Gummin et al., 2019). In Denmark, the number of registered antihistamine exposures increased during 2007–2013, with first-generation antihistamines, specifically promethazine, having been responsible for most exposures and related fatalities (Jensen et al., 2017). Also, in New Zealand a number of promethazine poisoning cases (57/199 patients) were identified from a database of poisoning admissions to a regional toxicology service (Bergman and Wallman, 1998).
Effects
Promethazine reported effects mostly include a range of CNS side effects, such as: confusion; disorientation; drowsiness; cardiovascular symptoms; and respiratory depression (Burns and Boyer, 2013; Höjer and Tellerup, 2018; Page et al., 2009; Tsay et al., 2015). A clear abuse potential has been observed and reported for first-generation antihistamines such as promethazine and cyclizine, due to: calming and sedating effects (Cookson, 2018; Jensen et al., 2017) and enhancement of other co-ingested substances, and especially those interacting with gamma-amino-butyric acid (GABA), opiate and muscarinic acetylcholine receptors (Speeg et al., 1981), leading to hallucinogenic experiences (Clatts et al., 2010; Jensen et al., 2017; Lynch et al., 2015). Indeed, an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility has been described (Burns and Boyer, 2013). In these cases, the mental state alteration is characterised by agitated delirium, with abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia (Agnich et al., 2013; Cowen, 1979; Dollberg et al., 1989; Höjer and Tellerup, 2018; Leak and Carroll, 1967; Page et al., 2009; Scott et al., 2007; Timnak et al., 2004). With the promethazine-codeine cough syrup, ‘euphoric feelings’, ‘relaxation’, ‘slight giddiness and disorienting’, and ‘nice hallucinations’ have been described as well (Bluelight.org [2020]; Erowid.org [2020]). Reported side-effects include drowsiness, fatigue, loss of coordination, constipation and urinary retention (Elwood, 2001).
Vulnerable categories
An increasing trend in abuse of promethazine in co-formulation with some components of OTC cough medications has been reported in young adult populations (Carney et al., 2018; Carr, 2006; Höjer and Tellerup, 2018) since the late 1990s, particularly in the southern USA (Carr, 2006; Elwood, 2001). Codeine and promethazine were recorded as the most requested psychoactive drugs by adolescents/young adults in community pharmacies (Delcourt et al., 2017).
Known by the street names ‘lean’, ‘drank’, ‘barre’, ‘purple stuff’, ‘syrup’ and ‘sizzurp’ (Agnich et al., 2013; NIDA, 2014; Peters et al., 2007), the abuse of promethazine mixed with opioids and other sedatives (e.g. alcohol) in a purple colour drink (‘purple drank’) (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014) has become widely popular (Agnich et al., 2013) after a rap artist/producer created a genre of music, called ‘screw music', inspired by intoxication on codeine and promethazine (Peters et al., 2007). Social media data, e.g. public posts and related hashtags on Instagram, provided additional insights into codeine abuse, depicting its common misuse combined with promethazine and soda/carbonated drinks (Cherian et al., 2018). ‘Purple drank’ has been noted for its euphoric effects and its easy accessibility (Elwood, 2001; Peters et al., 2007). ‘Lean’ creates a distinct (Jakubowski et al., 2018) feeling of euphoria and extreme relaxation (Cookson, 2018), dream-like feelings and a vivid sensation of floating away from the physical body (Peters et al., 2007).
Although at times preferred to other substances, such as benzodiazepines, to treat anxiety and sleep disorders in substance-dependent patients, promethazine has been reported to be misused among people with either opioid dependence (Agnich et al., 2013; Dahlman et al., 2016; Elwood, 2001; Lynch et al., 2015; Shapiro et al., 2013) or a substance abuse condition (Shapiro et al., 2013; Tang et al., 2012). A Hong Kong study reported a total of 63 patients with a diagnosis of cough mixture abuse; 89% were adult males with a mean age of onset of the abuse itself of 20 (±5) years. These subjects had received a diagnosis of substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%) and dysthymia (10%), with most cases having presented with a polysubstance misuse (Tang et al., 2012). Due to the opioid-coformulation, the promethazine-codeine cough mixture might lead to addiction (NIDA, 2014). The mixture may present a high risk of occurrence of near misses due to its central effect of respiratory depression, which is greatly increased by association with alcohol or other CNS depressants, such as sedatives/hypnotics, narcotic analgesics, general anaesthetics and tricyclic antidepressants (Burns and Boyer, 2013; Elwood, 2001; NIDA, 2014; Shapiro et al., 2013; Tsay et al., 2015). The concomitant use of promethazine and other depressant drugs should not be underestimated, as they might together contribute to and/or cause fatalities (Corkery et al., 2020).
Aim of the study
We were interested here in studying how promethazine abuse was reported to the European Medicines Agency (EMA) adverse drug reactions (ADRs) database. We aimed to analyse promethazine misuse/abuse/dependence/withdrawal data. Where possible, in order to have a better understanding, information/data related to diagnosis, concomitant drugs, administration and dosages were also examined.
Methods
Source of data
The EMA through EudraVigilance (EV) manages and analyses information on suspected ADRs to medicines authorised in the European Economic Area (EEA), according to Directive 2001/83/EC and Regulation (EC) No 726/2004 (EMA, 2017). Since November 2017, EV launched extensive Web access to data on suspected ADRs and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research (Postigo et al., 2018). Thus, access to data regarding cases of promethazine abuse, misuse, dependence and withdrawal was obtained by application to the voluntary reporting system of ADRs of the EMA. After 3 months all data comprised all of the ADRs reported during the years from 2003 up to June 2019, presented as large Excel files divided into information sections reporting in a standardised format according to the Medical Dictionary for Regulatory Activities (MedDRA), were sent through a hyperlink (MedDra, 2018). Such listings showed all information related to the ADR, the patient, the drug, the reporter and the diagnosis. An ADR was considered a voluntary and unsolicited communication reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorisation Holders for those ADRs occurring outside the EEA (EMA, 2010). Only ‘suspect’ ADRs were selected, meaning promethazine was considered as ‘suspected’ for the reaction reported. Regarding the content of the ADR, according to the standardised MedDRA Query (SMQ) (MedDRA, 2018), the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, intentional product use issue, substance abuse, substance abuser, substance use and withdrawal syndrome were selected. Those ADRs were defined in accordance with MedDRA in line with previous studies on the EV dataset (Chiappini et al., 2020; MedDRA, 2018; Schifano and Chiappini, 2018a, 2018b; Schifano et al., 2019a, 2019b). Specifically, abuse was here defined as the intentional, non-therapeutic use by a patient or consumer of a product, OTC or prescription, for a perceived reward or desired non-therapeutic effect including, but not limited to, getting high (euphoria) (MedDRA, 2018). Misuse was meant as the intentional use for a therapeutic purpose by a patient or consumer of a product, OTC or prescription, other than as prescribed or not in accordance with the authorised product information (MedDRA, 2018). Finally, non-medical use referred here to the use of a prescription drug, whether obtained by prescription or otherwise, other than in the manner or for the time period prescribed, or by a person for whom the drug was not prescribed (United Nations Office on Drugs and Crime (UNODC), 2013).
Analysis of data
We retrospectively analysed all reported ADRs which were available in the EV database. ADR reports were analysed with respect to age and gender of patient/consumer, source/reporter country (EEA or non-EEA) and reporter qualification (i.e. pharmacist, physician); type of ADR; seriousness (fatal, recovered, resolved outcomes); promethazine dosage; possible concomitant drug(s); and diagnosis/reporter’s comments, if recorded. The descriptive analysis included cases of overdoses, suicides, and fatalities. In the dataset, each case report may refer to one or more reporter; one or more ADR(s); as well as to one or more medicinal product(s). Therefore, a case may be represented by more than one row in the other line listings. The received data files were searched for duplicates by report ID through the ‘EV Local Report Number’, which unequivocally identified an individual case. Thus, the number of suspected ADRs appeared to be different from the number of case reports as one case report might refer to several suspected ADRs. Moreover, the number of patients was different from the number of case reports as a patient might have been described in more than one case. Finally, numbers of ADRs differed from those referring to case reports/single patients since different reporters/senders could have independently flagged the same ADR to the EMA. The descriptive analysis included here a study of the dataset (EMA, 2017) performed through IBM SPSS Statistics software (version 26).
Ethical issues
In compliance with applicable Personal Data Protection legislation (Regulation (EC) No 45/2001 and Regulation (EC) No 1049/2001, the protection of privacy and integrity of individuals was guaranteed, and in order to safeguard the identity of individuals certain data elements, including names/identifiers or country-specific information were not disclosed by the EMA (EMA, 2013, 2017). The study was ethically approved in March 2018 by the University of Hertfordshire Ethics’ Committee, with reference number LMS/PGR/UH/03234.
Results
The dataset obtained reported a total of 11,796 ADRs, correspond-ing to 1,543 single cases recorded during years 2003–2019 (Table 1). Safety reports were all voluntarily submitted, mostly from pharmaceutical companies (1,136/1,543: 73.6%) and regulatory authorities (398/1,543: 25.8%). Reports were irregularly reported over time, with spikes in 2010, 2014 and 2017 (Figure 1). Countries which reported most promethazine-related abuse/misuse/dependence cases included: the USA (805/1,543: 52.10%); Germany (299/1,543: 19.4%); Japan (162/1,543: 10.5%), Sweden (67/1,543: 4.3%), France (43/1,543: 2.8%) and Australia (42/1,543: 2.7%). Out of a total of 1543 cases, ‘suspect’ abuse/misuse/dependence-related cases were 557 (36.1%) and, among them, according to the preferred terms (PTs), most recorded reactions were abuse/misuse-related ADRs (458/557: 82.2%), specifically ‘drug abuse’ (300/557: 53.8%) and ‘intentional product misuse’ (117/557: 21.0%) (Table 1). ‘Suspect’ selected cases and related fatalities annually showed the same trend overall (Figure 1). Most typically, subjects reported were adult (19–64 years) and specifically of the youngest group (19–25 years); males were slightly more frequently recorded than females (M/F: 235/461: 0.51) (Table 1). Where all information was recorded, promethazine was reported as ingested alone in 74 cases, with supratherapeutic dosages, up to 2500 mg, in four cases. In combination with other drugs, most cases were associated with a 100–500 mg promethazine dose, with the maximum dosage recorded having been 8000 mg (Figure 2). The most common administration route was oral (n = 292), although the intramuscular (n = 8) and the parenteral (n = 19) ones were reported as well, see Table 1).
Table 1. Analysis of promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV) during years 2003–2019.
Individual cases (% of total within parentheses)
Total abuse/misuse/dependence cases 1543 Single cases; number of ADRs :11,796
Age range Adult (19–64 years): 648 (648/1,543: 42.0%) - mean age: 31.8 years (SD 26.55–37.05)
Adolescent (10–18 years): 23 (23/1,543: 1.5%) – mean age: 15.9 years (SD 14.3–17.77)
Elderly (>65 years): 25 (25/1,543: 1.6%) – mean age: 72.3 years (SD 70.85–73.7)
Neonatal (hours–days) 14 (14/1,543: 0.9%) – mean age: 24 h (SD 16.6–27.4)
Infant (months–1 year): 7 (7/1,543: 0.45%) – mean age: 10 months (SD 7–13)
Child (<10 years): 4 (4: 1,543: 0.35%) – mean age: 5 years (SD 3.6–6.3)
Unknown: 822 (822/1,543: 53.2%)
Male/female 235/461: 0.51
Most represented abuse/misuse/dependence-related ADRs according to the PTs: 557 (557/1,543: 36.1%)
Abuse-related ADRs 458 (458/557: 82.2%)
Drug abuse 300
Drug abuser 15
Drug diversion 1
Intentional product misuse 117
Intentional product use issue 9
Substance abuse 11
Substance abuser 3
Substance use 2
Dependence-related ADRs 44 (44/557: 7.9%)
Dependence 4
Drug dependence 39
Substance dependence 1
Withdrawal-related ADRs 55 (55/557: 9.8%)
Withdrawal syndrome 19
Drug withdrawal convulsions 1
Drug withdrawal neonatal syndrome 18
Drug withdrawal syndrome 17
Outcome Fatal 310 (310/557: 55.6%)
Unknown 161 (161/557: 28.9%)
Recovered/resolved 55 (55/557: 9.9%)
Recovering/resolving 18 (18/557: 3.3%)
Not recovered/not resolved 13 (13/557: 2.3%)
Promethazine-cases alone 74 (with maximum dosage 2500 mg)
Promethazine-cases with other drugs Most cases (122) were over 100 mg (with maximum dosage 8000 mg)
Most common psychoactive substances used Alcohol: 114
Cocaine: 68
Cannabis: 16
Ketamine: 4
Amphetamine: 1
Most common prescription drugs used Opioids: 1187
Benzodiazepines: 914
Antidepressants: 871
Antipsychotics: 437
Z-drugs: 222
Mood stabilisers: 197
ADR: adverse drug reaction; PTs: preferred terms; SD: standard deviation.
Figure 1. Number of promethazine abuse/misuse/dependence/withdrawal cases reported by year in the EudraVigilance (EV) dataset.
Figure 2. Most represented dosages reported among all promethazine abuse/misuse/dependence/withdrawal cases recorded by the EudraVigilance (EV) dataset.
Concomitantly used drugs recorded were opioids (e.g. oxycodone and fentanyl), benzodiazepines (e.g. diazepam, alprazolam and lorazepam) and antidepressants (e.g. citalopram, venlafaxine and amitriptyline), whilst recreational drugs most represented were alcohol and cocaine (Table 1). Most reported diagnoses, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V; American Psychiatric Association (APA), 2013) related to: mood disorders, e.g. depression/depressed mood/major depression (68 cases) and bipolar disorder (14 cases); anxiety/anxiety disorders (23 cases); alcohol abuse/alcoholic/alcoholism (26 cases); and schizophrenia (14 cases). The outcome of the reactions reported included: ‘fatal’ (n=310/557; 55.6%) and secondarily ‘recovered/resolved’ (n=73; 15.2%) (Table 1). Some 27 cases were related to suicidal or self-harm behaviour, being recorded as ‘suicidal attempt/suicidal ideation’ (n=24), ‘self-injurious ideation’ (n=1), and ‘suicide attempt’ (n=2). Fatalities mostly involved adult females; in these cases, most typical ADRs recorded were ‘drug abuse’ (n=228) and ‘intentional product misuse’ (n=77) (Table 2). Opiates/opioids were the most recorded concomitant drugs (n=356), with methadone being the most represented (n=103), followed by antidepressants (n=221) and benzodiazepines (n=141). Among illicit drugs, heroin appeared to be the most represented (Table 2).
Table 2. Analysis of fatal promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV), 2003–2019.
Fatal cases on abuse/misuse/dependence/withdrawal reactions 310 (310/557 = 55.6%)
Age-range
Adult 303 (97.7%)
Adolescent 7 (2.3%)
Elderly (>65 years) –
Neonatal –
Infant –
Child –
Gender M 103 (33.2%)
F 177 (57.1%)
Unknown 30 (9.7%)
Most recorded PTs
Drug abuse/drug abuser/substance abuse 228/3/6
Intentional product misuse/Intentional product use issue 77/3
Drug dependence 1
Reported death code
Intentional overdose 1
Overdose 4
Completed suicide/suicide 7
Drug toxicity/drug abuse 197
Toxicity to various agents 48
Intentional product misuse 41
Respiratory depression 5
Pneumonia 1
Cardiac arrest 10
Drug dependence 1
Most reported concomitant drugs
Opioids 356
Methadone 103
Dihydrocodeine 1
Codeine 32
Fentanyl 44
Oxycodone 63
Morphine 55
Hydrocodone 33
Hydromorphone 3
Tramadol 22
Antidepressants 221
Duloxetine 1
Escitalopram 1
Sertraline 16
Paroxetine 34
Trazodone 15
Mirtazapine 33
Fluoxetine 24
Venlafaxine 9
Bupropion 1
Amitriptyline 35
Nortriptyline 6
Clomipramine 5
Citalopram 41
Benzodiazepines 141
Lorazepam 3
Temazepam 6
Clonazepam 21
Diazepam 60
Flunitrazepam 1
Brotizolam 1
Alprazolam 42
Midazolam 4
Oxazepam 3
Mood stabilisers 11
Gabapentin 3
Topiramate 8
Antipsychotics 24
Olanzapine 1
Quetiapine 20
Haloperidol 1
Amisulpride 1
Levomepromazine 1
Z-drugs 39
Zolpidem 37
Zopiclone 2
Illicit drugs
Amphetamine 15
Cocaine 40
Heroin 52
Alcohol 26
PTs: preferred terms.
Discussion
Non-medical prescription drug use is a globally recognised problem, with severe adverse consequences. The current study provides a large amount of descriptive data highlighting that promethazine can be taken at high dosages, through non-approved administration routes, and in a setting of polydrug use (Hughes et al., 2016; Novak et al., 2016).
Promethazine misuse has been increasingly recorded since the early 2000s, consistently with data from US poison centres reporting antihistamine exposures rising in the period 2007–2013 (Jensen et al., 2017). This is not surprising, since the pharmacodynamic properties of promethazine underpins its sought-after central effects. In 2014, e.g. the highest peak here, the increase in promethazine misuse reporting was solely driven by the USA (245/245 cases; 100%). This may have been associated with intense media attention to the subject in that year (TMZ, 2014). The increments reported in 2010, 2014 and 2017 were then followed by decrements, which may have been related to not only reporting variabilities, but also to differences in sales of antihistamines following local/national drug abuse prevention campaigns (Klein-Schwartz, 2017). Overall, the USA appeared here to be the country most involved in reporting of promethazine ADRs. Several reasons may help in explaining this, including healthcare professionals’ awareness of prescription/OTC drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Lynch et al., 2015; Manchikanti et al., 2006; NIDA, 2014; Tsay et al., 2015) which, in turn, may have facilitated pharmacovigilance reporting. According to an 11-year period of the US National Poison Centers’ database, the annual rate of promethazine abuse/misuse per 100,000 US population doubled over time (Tsay et al., 2015). In the USA, promethazine abuse/misuse has been described in teenagers and young adults (Peters et al., 2003), methadone maintenance patients, heroin users and opioid-prescribed chronic pain patients (Lynch et al., 2015; Shapiro et al., 2013).
Consistent with previous observations (Agnich et al., 2013; Burns and Boyer, 2013; Carr, 2006; Elwood, 2001; Höjer and Tellerup, 2018; NIDA, 2014; Page et al., 2009; Parker et al., 2013; Peters et al., 2007), most recorded ADRs related here to either ‘drug abuse’ and ‘intentional product misuse’, involving young adult (19–25 years) males. Although considered a vulnerable category with respect to prescription drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014; Peters et al., 2007), adolescents (10–18 years) were here reported in only a minority (23/1543:1.5%) of cases.
Several drugs were here associated with promethazine, although opiates/opioids were the most represented molecules in related fatalities. This combination might intensify effects such as sedation and analgesia (Burns and Boyer, 2013; Lynch et al., 2015; Shapiro et al., 2013), and in the 1950s the association was medically used to reduce the dosage of opiates/opioids (McGee and Weiss, 1956). However, due to a range of adverse effects (Lynch et al., 2015) including lack of data supporting clinical efficacy (Richter and Burk, 1992) and an enhanced addiction potential of opioids (Lynch et al., 2015; Peters et al., 2007; Shapiro et al., 2013), the combination of promethazine/opioids has declined in popularity.
So far, the recreational intake of promethazine with opioids has been typically reported in cough mixtures containing codeine (Casati et al., 2012; Clatts et al., 2010; Elwood, 2001; Foley et al., 2015; Peters et al., 2007). However, current EMA data suggest that, apart from methadone, oxycodone and fentanyl were the most typical opiates/opiates identified in association with promethazine, possibly due to their recent popularity, especially in the USA (Manchikanti et al., 2018; Rose, 2018). In the promethazine fatalities (e.g. 310 cases) dataset analysed, codeine, fentanyl and oxycodone were respectively reported in 32, 44 and 63 cases. Consistent with current data, a concomitant use of opioids and promethazine has been described in various subpopulations, such as methadone maintenance patients, injecting drug users and chronic pain patients (Banta-Green et al., 2005; Lynch et al., 2015; Shapiro et al., 2013; Shields et al., 2007; Van Hout and Norman, 2016). Overall, there is now a high level of awareness of the abuse potential of antihistamine/opioid-containing products (Hou et al., 2011; Hughes et al., 1999; Wazaify et al., 2005). Hence, some countries are limiting both the medication pack size levels and the quantities of drugs sold in a single transaction, whilst also promoting non-injectable and non-inhaling formulations and changing some formulations’ OTC status (Cooper, 2013; Foley et al., 2015; Van Hout and Norman, 2016).
Benzodiazepines (e.g. diazepam, alprazolam and lorazepam) were here also frequently recorded, suggesting sedative synergistic effects in combination with promethazine (Lynch et al., 2015), and hence an increased risk of untoward clinical issues (McLellan and Turner, 2010). Other prescription drug categories recorded included antidepressants (most typically: citalopram and amitriptyline, respectively in 149/557 and 95/557 cases), which is consistent with the most typically recorded diagnoses, e.g. depressive (68 cases); bipolar (14 cases); and anxiety (23 cases) disorders. It is also possible that antidepressants were here ingested in combination with promethazine for sleep induction purposes. It is a reason for concern that promethazine ADRs, either alone or in combination, resulted in either fatal (50.6%) or ‘recovered/resolved’ outcomes (22.2%). This is consistent with previous promethazine misuse/abuse data, reporting both adverse clinical outcomes and high frequency of healthcare facility treatment (Bergman and Wallman, 1998; Ichikura et al., 2016; McLellan and Turner, 2010; Tsay et al., 2015). A list of possibly misused substances which might reinforce promethazine psychoactive effects and possibly increase its toxicity is included in Table 3.
Table 3. List of substances recorded in the literature as used in association with promethazine in order to increase its effects; prescription drugs are recorded according to the Neuroscience-based Nomenclature description (Nutt and Blier, 2016).
Psychoactive substances
Description Mode of action Examples Effects
Alcohol (Burns and Boyer, 2013; Jensen et al., 2017) CNS depressant effects ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, relaxation, ‘slight giddiness and disorienting’ and ‘nice hallucination’.
It may increase, prolong or intensify promethazine sedative effect. It should be avoided in patients receiving promethazine.
Heroin and other illicit opioids (Dahlman et al., 2016; Tsay et al., 2015) Opioid depressant effects It may increase, prolong, or intensify promethazine sedative effect.
Prescription drugs
Categories Mode of action Examples Effects
Drugs for insomnia (Burns and Boyer, 2013) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Z-drugs: zaleplon, zolpidem, zopiclone, eszopiclone They may increase, prolong or intensify promethazine sedative effect.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Drugs for anxiety (Burns and Boyer, 2013; Lynch et al., 2015) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, lorazepam, oxazepam They may increase, prolong or intensify promethazine sedative action.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Dextrometorphan (Tsay et al., 2015) At high doses, acting as NMDA-receptor antagonist; dextrometorphan and its potent metabolite dextrorphan inhibit the excitatory amino acid and neurotransmitter glutamate in the brain, determining hallucinogenic and dissociative activities, which are recreationally searched It might be combined with promethazine in cough-suppressant formulation Dextrometorphan neurobehavioural effects are dose-related, starting from a mild to moderate stimulation with restlessness and euphoria (100–200 mg), to a dissociated state characterised by hallucinations, paranoia, perceptual distortions, delusional beliefs, ataxia and out-of-body experiences (‘robo-ing’/‘robo-copping’/‘robo-tripping’) (>1000 mg). In overdosage they might increase promethazine effects.
Drugs for depression (Burns and Boyer, 2013; Jensen et al., 2017): TCA Multimodal action: reuptake inhibitor (SERT and NET), receptor antagonist (5-HT2) Amitriptyline Promethazine may increase, prolong or intensify their sedative effect. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Anticholinergic drugs Antagonist at cholinergic receptors Hyoscine butyl bromide/scopolamine (Burns and Boyer, 2013) Together with promethazine an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility may be seen. A typical mental status alteration with a dose-dependent agitated delirium characterised by abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia, has been described. These molecules should be avoided or administered in reduced dosage to patients receiving promethazine.
Prescription opioids
Codeine (Burns and Boyer, 2013; Jouanjus et al., 2018; Lynch et al., 2015; O Reilly et al., 2015; Shapiro et al., 2013) ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, elation, analgesia and ‘liking’, with increased potential of addiction. Overdosage of codeine might determine respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne–Stokes respiration and cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Opiate overdosage, particularly by the intravenous route, may be associated with apnoea, circulatory collapse, cardiac arrest and death. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Other opioid analgesics (Burns and Boyer, 2013; Dahlman et al., 2016; Lynch et al., 2015; Shapiro et al., 2013) Methadone They may increase, prolong or intensify promethazine sedative effects. Opioids should be avoided or administered in reduced dosage to patients receiving promethazine.
The addiction potential of opioids might be enhanced. Also, increasing life-threatening events, such as respiratory depression, overdose and prolongation of the QT interval, might be responsible for drug-related fatalities.
5-HT2: serotonin-2 receptor; CNS: central nervous system; D2: dopamine 2 receptor; GABA: gamma-amino-butyric acid; H1: histamine 1 receptor; NE: norepinephrine; NET: norepinephrine transporter; NMDA: N-methyl-D-aspartate; SERT: serotonin transporter; SSRI: selective-serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
Finally, among abuse-related cases, neonates, infants and children were here reported as well. This is consistent with cases of unexpected infant deaths associated with use of cold medications, poor socioeconomic conditions (Rimsza and Newberry, 2008) and/or accidental ingestion (McLellan and Turner, 2010).
Limitations
One of the limitations was given here by the descriptive nature of the study. Indeed, a comparator molecule, for a disproportionality analysis (Chiappini and Schifano, 2016; Schifano and Chiappini, 2018b) to be carried out, was not available due to data access limitations (EMA, 2017; Postigo et al., 2018). Furthermore, current data did not appear to show an increasing trend of abuse or misuse across the years. Since proper denominator figures (e.g. data on worldwide promethazine prescriptions) are not available, it was unclear if what observed was a substantial number of cases, indicative of clinically meaningful abuse potential, or a passing trend for promethazine misuse by a very small number of individuals. However, consistent with previous suggestions (Montastruc et al, 2011), the value of the current study was that its rationale was driven by a proper, detailed, pharmacodynamic hypothesis established on the basic properties of promethazine. Similar to remaining pharmacovigilance datasets (EMA, 2010; Evoy et al., 2019; Schifano and Chiappini, 2018a; Schifano et al., 2019a, 2019b; Schwan et al., 2010), focussing on the analysis of voluntary adverse events, a further limitation was given here by reliance on self-reporting and the likelihood of missing data occurrence. Moreover, although healthcare professionals have a main role in detection, assessment and spontaneous reporting of ADRs (Belton, 1997; Khalili et al., 2012), specific abuse/misuse/dependence issues relating to promethazine may have been underestimated, with only the most serious cases having been reported, hence the high rates of promethazine fatalities here recorded. Furthermore, although patients and their carers are allowed indeed to flag up an ADR, it is unlikely that they have spontaneously reported misusing events. Other factors, such as increased knowledge of promethazine misuse/abuse, may have resulted here in outcome reporting bias. There was also a potential for duplicate reports, with the same report submitted by the consumer, the healthcare professional and by the manufacturer as well, causing skewed study results. This may occur when a healthcare professional reported the same suspected ADR to both the national Regulatory Authority and the Marketing Authorisation Holder and they both reported subsequently to EV. However, the EV local report number which was here considered unequivocally identified an individual case. In addition, whilst this study represents one of the largest sample of promethazine abuse events published to date, the overall number of events is still relatively small, potentially limiting external validity. Case reports of suspected ADRs alone are not always sufficient to prove that a certain suspected reaction has indeed been caused by a specific medicine. This could be a symptom of another illness, or it could be associated with another medicinal product taken by the patient at the same time. The suspected ADRs were here presented using the PTs of the MedDRA Dictionary (Postigo et al., 2018). Thus, any case report should be considered together with all available data including case reports worldwide, clinical trials, epidemiological studies and toxicological investigations, in order to allow for robust conclusions. Finally, case reports reflect the information as provided to EV by the reporter, and not all data fields were completed for all reports.
Conclusion
To the best of our understanding, the current study described in detail the largest sample ever of abuse, misuse and dependence issues related to promethazine, whilst focussing on a large multinational dataset, such as the EV. The substantial number of promethazine-related events identified over the years represents a pharmacovigilance signal which needs to be better investigated (Montastruc et al., 2011). Although the observed trend of promethazine abuse and misuse, especially in young adults, is not a new phenomenon, further details of the issue have been here provided and future studies will optimally identify the related risk factors, with these measures enabling policymakers and regulators to take action to detect and prevent such misusing practices (Jouanjus et al., 2019). A multicomponent approach is recommended, including monitoring drug utilisation, tracking users’ posts on social media, and exploring healthcare databases; this will enable performing proactive and effective post-marketing surveillance and pharmacovigilance approaches. This has proved to be a relevant, efficient and accurate strategy, for example with gabapentinoids, which have recently been rescheduled in the UK (Borg et al., 2011; Eickhoff et al., 2012; Jouanjus et al., 2019; Novak et al., 2016; Parker et al., 2013; Schifano and Chiappini, 2019; Throckmorton et al., 2018). In this context, the role of the Web is rapidly spreading, playing a significant role in the marketing, sale and distribution of drugs, hence facilitating continuous changes in drug scenarios (Orsolini et al., 2017). Indeed, over the last 10 years access to online pharmacies to purchase medicinal compounds has increased (Desai, 2016; Monteith and Glenn, 2018). On the other hand, professionals access the Web to gather data on emerging trends of drug abuse (Deluca et al., 2002; Orsolini et al., 2015; Schifano, 2020; Schifano et al., 2003).
OTC and prescription drug misuse is perceived to be a significantly under-recognised issue affecting a range of vulnerable individuals (Coombes and Cooper, 2019). However, controlling the problem of OTC misuse and abuse might be challenging, due to the need for achieving high levels of consumer safety whilst not restricting access to OTC products for those who continue to use them safely.
Staff training should be evaluated, in order for pharmacists to self-monitor care and use of medicines, to educate patients and intervene/support those experiencing problematic drug use (Elwood, 2001; GPC, 2019; Tobin et al., 2013; Wells et al., 2018). Record-keeping (Hou et al., 2011) and real time monitoring (Cairns et al., 2016) could be a method of restricting access to some OTC drugs and prevent ‘shopping’ from one pharmacy to another, and where these measures would result to be ineffective, regulatory interventions, e.g. drug re-scheduling, might be useful (Marsden et al., 2019; McDonough, 2016; Peacock et al., 2019). Also, prevention and early education on substance abuse in young teenagers are critical (Levine, 2007; Marsden et al., 2019). Finally, appropriate and specific clinical guidelines for the treatment of misuse, abuse and dependence on prescription or OTC drugs should be implemented (Fingleton et al., 2019).
The review and study design were developed by SC, FS, JMC and AG. SC drafted the first version of the manuscript with input from all authors. All authors contributed to the interpretation of the data analysis and the further drafting of the manuscript and approved the final version.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FS was a member of the UK Advisory Council on the Misuse Drugs (ACMD) from 2011–2019; and is currently an EMA Advisory board (psychiatry) member. JMC is a member of the ACMD’s Novel Psychoactive Substances and Technical Committees. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
ORCID iDs: Stefania Chiappini https://orcid.org/0000-0002-6810-1540
John Martin Corkery https://orcid.org/0000-0002-3849-817X | Fatal | ReactionOutcome | CC BY | 33427017 | 18,928,797 | 2021-06 |
What was the outcome of reaction 'Drug withdrawal syndrome'? | Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.
Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents.
We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database.
After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234).
The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used.
Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.
Introduction
Pharmacological properties of promethazine
Promethazine is a phenothiazine derivative and a histamine (H1) receptor antagonist that is commonly used for symptomatic relief of nausea and vomiting, for allergic conditions, motion sickness and common cold, and for short-term use treatment of insomnia in adults or as a paediatric sedative (EMC, 2019). It also acts as a direct antagonist at muscarinic (M1) and dopamine (D2) receptors (Cookson, 2018; Page et al., 2009; Sharma and Hamelin, 2003). Promethazine hydrochloride is well absorbed from the gastrointestinal tract, with an average of 88% of the dose absorbed after oral administration, and clinical effects appearing within 20 min after intake whilst lasting 4–6 h. The plasma half-life is approximately 7–14 h (Burns and Boyer, 2013). It is classified as a first-generation antihistamine molecule which, compared with second-generation antihistamines, easily penetrates the blood-brain barrier and is associated with adverse effects such as moderate/intense sedation (Jensen et al., 2017). Thus, promethazine might be used in rapid (acute) tranquilization due to its blocking action at H1 and M receptors (Cookson, 2018). Toxicity might result in severe impairment of cognitive and psychomotor functions due to central nervous system (CNS) depression/reduced levels of consciousness, and may cause fatalities (Jensen et al., 2017).
Availability of promethazine
Promethazine is a medicinal product available on its own or in combination with other ingredients, including dextromethorphan, paracetamol and/or expectorants. With regards to promethazine availability, there are wide variations across countries. In fact, in some European countries such as France, Italy and the UK, but also outside Europe, some medicinal products containing promethazine can be purchased over-the-counter (OTC). Promethazine was restricted from an OTC status to prescription only in Denmark as of December 2014. This restriction was partly based on increasing enquiries regarding promethazine exposures to the Danish Poison and Information Centre (DPIC), highlighting its abuse potential and subsequent observations of side-effects after ingestion of standard doses. In Australia, promethazine is available as an OTC medication either alone as a tablet or as a liquid preparation or in combination with paracetamol and codeine phosphate as a syrup (Sharma and Hamelin, 2003). In the USA, some cough preparations containing no more than 200 mg of codeine per 100 mL are considered Schedule V controlled substances (Drug Enforcement Administration (DEA), 2020), purportedly possessing the lowest potential for both misuse and development of a Substance Use Disorder (SUD).
Pharming
Recently, the potential for misuse of medications that are not already controlled has been reported worldwide (Reeves et al., 2015). ‘Pharming’ is a phenomenon involving the non-medical use of prescription (pain relievers, tranquilisers, stimulants, sedatives) and OTC drugs, including cough and cold preparations, particularly those containing dextromethorphan and promethazine (Burns and Boyer, 2013; Jouanjus et al., 2018; Levine, 2007; McCarthy, 2007; National Institute on Drug Abuse (NIDA), 2014). The abuse of these compounds may be facilitated by their easy accessibility, low cost, decreased perception of potential for harm and growing social acceptance (Burns and Boyer, 2013; Levine, 2007; McCarthy, 2007; Substance Abuse Mental Health Services Administration (SAMHSA), 2008). In the current drug abuse scenario, young people/youths have been described abusing with a range of prescription or OTC medicines (Soussan et al., 2018), with these molecules possibly being ingested at high/super-high dosages (Orsolini et al., 2015; Schifano, 2020) and at times in combination with alcohol/remaining recreational substances (Levine, 2007)
Recreational use of promethazine
Centrally acting antihistamines have long been known to induce physical and psychological dependence (Clatts et al., 2010; Gracious et al., 2010; Page et al., 2009; Saatcioglu and Evren, 2005; Thomas et al., 2008). During the past 15 years the abuse of promethazine, especially from OTC and prescription cough and cold medicines and at higher-than-recommended dosages, has been reported (NIDA, 2014). Consistent with this, during the last decade the yearly number of promethazine-related overdose cases in Sweden has increased from 100 to nearly 700 and its sales have increased threefold (Höjer and Tellerup, 2018). Also, according to the 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), antihistamines accounted for the seventh most frequently involved substance in human exposures, resulting in the third type of substance category for rate of exposure increase (Gummin et al., 2019). In Denmark, the number of registered antihistamine exposures increased during 2007–2013, with first-generation antihistamines, specifically promethazine, having been responsible for most exposures and related fatalities (Jensen et al., 2017). Also, in New Zealand a number of promethazine poisoning cases (57/199 patients) were identified from a database of poisoning admissions to a regional toxicology service (Bergman and Wallman, 1998).
Effects
Promethazine reported effects mostly include a range of CNS side effects, such as: confusion; disorientation; drowsiness; cardiovascular symptoms; and respiratory depression (Burns and Boyer, 2013; Höjer and Tellerup, 2018; Page et al., 2009; Tsay et al., 2015). A clear abuse potential has been observed and reported for first-generation antihistamines such as promethazine and cyclizine, due to: calming and sedating effects (Cookson, 2018; Jensen et al., 2017) and enhancement of other co-ingested substances, and especially those interacting with gamma-amino-butyric acid (GABA), opiate and muscarinic acetylcholine receptors (Speeg et al., 1981), leading to hallucinogenic experiences (Clatts et al., 2010; Jensen et al., 2017; Lynch et al., 2015). Indeed, an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility has been described (Burns and Boyer, 2013). In these cases, the mental state alteration is characterised by agitated delirium, with abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia (Agnich et al., 2013; Cowen, 1979; Dollberg et al., 1989; Höjer and Tellerup, 2018; Leak and Carroll, 1967; Page et al., 2009; Scott et al., 2007; Timnak et al., 2004). With the promethazine-codeine cough syrup, ‘euphoric feelings’, ‘relaxation’, ‘slight giddiness and disorienting’, and ‘nice hallucinations’ have been described as well (Bluelight.org [2020]; Erowid.org [2020]). Reported side-effects include drowsiness, fatigue, loss of coordination, constipation and urinary retention (Elwood, 2001).
Vulnerable categories
An increasing trend in abuse of promethazine in co-formulation with some components of OTC cough medications has been reported in young adult populations (Carney et al., 2018; Carr, 2006; Höjer and Tellerup, 2018) since the late 1990s, particularly in the southern USA (Carr, 2006; Elwood, 2001). Codeine and promethazine were recorded as the most requested psychoactive drugs by adolescents/young adults in community pharmacies (Delcourt et al., 2017).
Known by the street names ‘lean’, ‘drank’, ‘barre’, ‘purple stuff’, ‘syrup’ and ‘sizzurp’ (Agnich et al., 2013; NIDA, 2014; Peters et al., 2007), the abuse of promethazine mixed with opioids and other sedatives (e.g. alcohol) in a purple colour drink (‘purple drank’) (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014) has become widely popular (Agnich et al., 2013) after a rap artist/producer created a genre of music, called ‘screw music', inspired by intoxication on codeine and promethazine (Peters et al., 2007). Social media data, e.g. public posts and related hashtags on Instagram, provided additional insights into codeine abuse, depicting its common misuse combined with promethazine and soda/carbonated drinks (Cherian et al., 2018). ‘Purple drank’ has been noted for its euphoric effects and its easy accessibility (Elwood, 2001; Peters et al., 2007). ‘Lean’ creates a distinct (Jakubowski et al., 2018) feeling of euphoria and extreme relaxation (Cookson, 2018), dream-like feelings and a vivid sensation of floating away from the physical body (Peters et al., 2007).
Although at times preferred to other substances, such as benzodiazepines, to treat anxiety and sleep disorders in substance-dependent patients, promethazine has been reported to be misused among people with either opioid dependence (Agnich et al., 2013; Dahlman et al., 2016; Elwood, 2001; Lynch et al., 2015; Shapiro et al., 2013) or a substance abuse condition (Shapiro et al., 2013; Tang et al., 2012). A Hong Kong study reported a total of 63 patients with a diagnosis of cough mixture abuse; 89% were adult males with a mean age of onset of the abuse itself of 20 (±5) years. These subjects had received a diagnosis of substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%) and dysthymia (10%), with most cases having presented with a polysubstance misuse (Tang et al., 2012). Due to the opioid-coformulation, the promethazine-codeine cough mixture might lead to addiction (NIDA, 2014). The mixture may present a high risk of occurrence of near misses due to its central effect of respiratory depression, which is greatly increased by association with alcohol or other CNS depressants, such as sedatives/hypnotics, narcotic analgesics, general anaesthetics and tricyclic antidepressants (Burns and Boyer, 2013; Elwood, 2001; NIDA, 2014; Shapiro et al., 2013; Tsay et al., 2015). The concomitant use of promethazine and other depressant drugs should not be underestimated, as they might together contribute to and/or cause fatalities (Corkery et al., 2020).
Aim of the study
We were interested here in studying how promethazine abuse was reported to the European Medicines Agency (EMA) adverse drug reactions (ADRs) database. We aimed to analyse promethazine misuse/abuse/dependence/withdrawal data. Where possible, in order to have a better understanding, information/data related to diagnosis, concomitant drugs, administration and dosages were also examined.
Methods
Source of data
The EMA through EudraVigilance (EV) manages and analyses information on suspected ADRs to medicines authorised in the European Economic Area (EEA), according to Directive 2001/83/EC and Regulation (EC) No 726/2004 (EMA, 2017). Since November 2017, EV launched extensive Web access to data on suspected ADRs and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research (Postigo et al., 2018). Thus, access to data regarding cases of promethazine abuse, misuse, dependence and withdrawal was obtained by application to the voluntary reporting system of ADRs of the EMA. After 3 months all data comprised all of the ADRs reported during the years from 2003 up to June 2019, presented as large Excel files divided into information sections reporting in a standardised format according to the Medical Dictionary for Regulatory Activities (MedDRA), were sent through a hyperlink (MedDra, 2018). Such listings showed all information related to the ADR, the patient, the drug, the reporter and the diagnosis. An ADR was considered a voluntary and unsolicited communication reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorisation Holders for those ADRs occurring outside the EEA (EMA, 2010). Only ‘suspect’ ADRs were selected, meaning promethazine was considered as ‘suspected’ for the reaction reported. Regarding the content of the ADR, according to the standardised MedDRA Query (SMQ) (MedDRA, 2018), the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, intentional product use issue, substance abuse, substance abuser, substance use and withdrawal syndrome were selected. Those ADRs were defined in accordance with MedDRA in line with previous studies on the EV dataset (Chiappini et al., 2020; MedDRA, 2018; Schifano and Chiappini, 2018a, 2018b; Schifano et al., 2019a, 2019b). Specifically, abuse was here defined as the intentional, non-therapeutic use by a patient or consumer of a product, OTC or prescription, for a perceived reward or desired non-therapeutic effect including, but not limited to, getting high (euphoria) (MedDRA, 2018). Misuse was meant as the intentional use for a therapeutic purpose by a patient or consumer of a product, OTC or prescription, other than as prescribed or not in accordance with the authorised product information (MedDRA, 2018). Finally, non-medical use referred here to the use of a prescription drug, whether obtained by prescription or otherwise, other than in the manner or for the time period prescribed, or by a person for whom the drug was not prescribed (United Nations Office on Drugs and Crime (UNODC), 2013).
Analysis of data
We retrospectively analysed all reported ADRs which were available in the EV database. ADR reports were analysed with respect to age and gender of patient/consumer, source/reporter country (EEA or non-EEA) and reporter qualification (i.e. pharmacist, physician); type of ADR; seriousness (fatal, recovered, resolved outcomes); promethazine dosage; possible concomitant drug(s); and diagnosis/reporter’s comments, if recorded. The descriptive analysis included cases of overdoses, suicides, and fatalities. In the dataset, each case report may refer to one or more reporter; one or more ADR(s); as well as to one or more medicinal product(s). Therefore, a case may be represented by more than one row in the other line listings. The received data files were searched for duplicates by report ID through the ‘EV Local Report Number’, which unequivocally identified an individual case. Thus, the number of suspected ADRs appeared to be different from the number of case reports as one case report might refer to several suspected ADRs. Moreover, the number of patients was different from the number of case reports as a patient might have been described in more than one case. Finally, numbers of ADRs differed from those referring to case reports/single patients since different reporters/senders could have independently flagged the same ADR to the EMA. The descriptive analysis included here a study of the dataset (EMA, 2017) performed through IBM SPSS Statistics software (version 26).
Ethical issues
In compliance with applicable Personal Data Protection legislation (Regulation (EC) No 45/2001 and Regulation (EC) No 1049/2001, the protection of privacy and integrity of individuals was guaranteed, and in order to safeguard the identity of individuals certain data elements, including names/identifiers or country-specific information were not disclosed by the EMA (EMA, 2013, 2017). The study was ethically approved in March 2018 by the University of Hertfordshire Ethics’ Committee, with reference number LMS/PGR/UH/03234.
Results
The dataset obtained reported a total of 11,796 ADRs, correspond-ing to 1,543 single cases recorded during years 2003–2019 (Table 1). Safety reports were all voluntarily submitted, mostly from pharmaceutical companies (1,136/1,543: 73.6%) and regulatory authorities (398/1,543: 25.8%). Reports were irregularly reported over time, with spikes in 2010, 2014 and 2017 (Figure 1). Countries which reported most promethazine-related abuse/misuse/dependence cases included: the USA (805/1,543: 52.10%); Germany (299/1,543: 19.4%); Japan (162/1,543: 10.5%), Sweden (67/1,543: 4.3%), France (43/1,543: 2.8%) and Australia (42/1,543: 2.7%). Out of a total of 1543 cases, ‘suspect’ abuse/misuse/dependence-related cases were 557 (36.1%) and, among them, according to the preferred terms (PTs), most recorded reactions were abuse/misuse-related ADRs (458/557: 82.2%), specifically ‘drug abuse’ (300/557: 53.8%) and ‘intentional product misuse’ (117/557: 21.0%) (Table 1). ‘Suspect’ selected cases and related fatalities annually showed the same trend overall (Figure 1). Most typically, subjects reported were adult (19–64 years) and specifically of the youngest group (19–25 years); males were slightly more frequently recorded than females (M/F: 235/461: 0.51) (Table 1). Where all information was recorded, promethazine was reported as ingested alone in 74 cases, with supratherapeutic dosages, up to 2500 mg, in four cases. In combination with other drugs, most cases were associated with a 100–500 mg promethazine dose, with the maximum dosage recorded having been 8000 mg (Figure 2). The most common administration route was oral (n = 292), although the intramuscular (n = 8) and the parenteral (n = 19) ones were reported as well, see Table 1).
Table 1. Analysis of promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV) during years 2003–2019.
Individual cases (% of total within parentheses)
Total abuse/misuse/dependence cases 1543 Single cases; number of ADRs :11,796
Age range Adult (19–64 years): 648 (648/1,543: 42.0%) - mean age: 31.8 years (SD 26.55–37.05)
Adolescent (10–18 years): 23 (23/1,543: 1.5%) – mean age: 15.9 years (SD 14.3–17.77)
Elderly (>65 years): 25 (25/1,543: 1.6%) – mean age: 72.3 years (SD 70.85–73.7)
Neonatal (hours–days) 14 (14/1,543: 0.9%) – mean age: 24 h (SD 16.6–27.4)
Infant (months–1 year): 7 (7/1,543: 0.45%) – mean age: 10 months (SD 7–13)
Child (<10 years): 4 (4: 1,543: 0.35%) – mean age: 5 years (SD 3.6–6.3)
Unknown: 822 (822/1,543: 53.2%)
Male/female 235/461: 0.51
Most represented abuse/misuse/dependence-related ADRs according to the PTs: 557 (557/1,543: 36.1%)
Abuse-related ADRs 458 (458/557: 82.2%)
Drug abuse 300
Drug abuser 15
Drug diversion 1
Intentional product misuse 117
Intentional product use issue 9
Substance abuse 11
Substance abuser 3
Substance use 2
Dependence-related ADRs 44 (44/557: 7.9%)
Dependence 4
Drug dependence 39
Substance dependence 1
Withdrawal-related ADRs 55 (55/557: 9.8%)
Withdrawal syndrome 19
Drug withdrawal convulsions 1
Drug withdrawal neonatal syndrome 18
Drug withdrawal syndrome 17
Outcome Fatal 310 (310/557: 55.6%)
Unknown 161 (161/557: 28.9%)
Recovered/resolved 55 (55/557: 9.9%)
Recovering/resolving 18 (18/557: 3.3%)
Not recovered/not resolved 13 (13/557: 2.3%)
Promethazine-cases alone 74 (with maximum dosage 2500 mg)
Promethazine-cases with other drugs Most cases (122) were over 100 mg (with maximum dosage 8000 mg)
Most common psychoactive substances used Alcohol: 114
Cocaine: 68
Cannabis: 16
Ketamine: 4
Amphetamine: 1
Most common prescription drugs used Opioids: 1187
Benzodiazepines: 914
Antidepressants: 871
Antipsychotics: 437
Z-drugs: 222
Mood stabilisers: 197
ADR: adverse drug reaction; PTs: preferred terms; SD: standard deviation.
Figure 1. Number of promethazine abuse/misuse/dependence/withdrawal cases reported by year in the EudraVigilance (EV) dataset.
Figure 2. Most represented dosages reported among all promethazine abuse/misuse/dependence/withdrawal cases recorded by the EudraVigilance (EV) dataset.
Concomitantly used drugs recorded were opioids (e.g. oxycodone and fentanyl), benzodiazepines (e.g. diazepam, alprazolam and lorazepam) and antidepressants (e.g. citalopram, venlafaxine and amitriptyline), whilst recreational drugs most represented were alcohol and cocaine (Table 1). Most reported diagnoses, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V; American Psychiatric Association (APA), 2013) related to: mood disorders, e.g. depression/depressed mood/major depression (68 cases) and bipolar disorder (14 cases); anxiety/anxiety disorders (23 cases); alcohol abuse/alcoholic/alcoholism (26 cases); and schizophrenia (14 cases). The outcome of the reactions reported included: ‘fatal’ (n=310/557; 55.6%) and secondarily ‘recovered/resolved’ (n=73; 15.2%) (Table 1). Some 27 cases were related to suicidal or self-harm behaviour, being recorded as ‘suicidal attempt/suicidal ideation’ (n=24), ‘self-injurious ideation’ (n=1), and ‘suicide attempt’ (n=2). Fatalities mostly involved adult females; in these cases, most typical ADRs recorded were ‘drug abuse’ (n=228) and ‘intentional product misuse’ (n=77) (Table 2). Opiates/opioids were the most recorded concomitant drugs (n=356), with methadone being the most represented (n=103), followed by antidepressants (n=221) and benzodiazepines (n=141). Among illicit drugs, heroin appeared to be the most represented (Table 2).
Table 2. Analysis of fatal promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV), 2003–2019.
Fatal cases on abuse/misuse/dependence/withdrawal reactions 310 (310/557 = 55.6%)
Age-range
Adult 303 (97.7%)
Adolescent 7 (2.3%)
Elderly (>65 years) –
Neonatal –
Infant –
Child –
Gender M 103 (33.2%)
F 177 (57.1%)
Unknown 30 (9.7%)
Most recorded PTs
Drug abuse/drug abuser/substance abuse 228/3/6
Intentional product misuse/Intentional product use issue 77/3
Drug dependence 1
Reported death code
Intentional overdose 1
Overdose 4
Completed suicide/suicide 7
Drug toxicity/drug abuse 197
Toxicity to various agents 48
Intentional product misuse 41
Respiratory depression 5
Pneumonia 1
Cardiac arrest 10
Drug dependence 1
Most reported concomitant drugs
Opioids 356
Methadone 103
Dihydrocodeine 1
Codeine 32
Fentanyl 44
Oxycodone 63
Morphine 55
Hydrocodone 33
Hydromorphone 3
Tramadol 22
Antidepressants 221
Duloxetine 1
Escitalopram 1
Sertraline 16
Paroxetine 34
Trazodone 15
Mirtazapine 33
Fluoxetine 24
Venlafaxine 9
Bupropion 1
Amitriptyline 35
Nortriptyline 6
Clomipramine 5
Citalopram 41
Benzodiazepines 141
Lorazepam 3
Temazepam 6
Clonazepam 21
Diazepam 60
Flunitrazepam 1
Brotizolam 1
Alprazolam 42
Midazolam 4
Oxazepam 3
Mood stabilisers 11
Gabapentin 3
Topiramate 8
Antipsychotics 24
Olanzapine 1
Quetiapine 20
Haloperidol 1
Amisulpride 1
Levomepromazine 1
Z-drugs 39
Zolpidem 37
Zopiclone 2
Illicit drugs
Amphetamine 15
Cocaine 40
Heroin 52
Alcohol 26
PTs: preferred terms.
Discussion
Non-medical prescription drug use is a globally recognised problem, with severe adverse consequences. The current study provides a large amount of descriptive data highlighting that promethazine can be taken at high dosages, through non-approved administration routes, and in a setting of polydrug use (Hughes et al., 2016; Novak et al., 2016).
Promethazine misuse has been increasingly recorded since the early 2000s, consistently with data from US poison centres reporting antihistamine exposures rising in the period 2007–2013 (Jensen et al., 2017). This is not surprising, since the pharmacodynamic properties of promethazine underpins its sought-after central effects. In 2014, e.g. the highest peak here, the increase in promethazine misuse reporting was solely driven by the USA (245/245 cases; 100%). This may have been associated with intense media attention to the subject in that year (TMZ, 2014). The increments reported in 2010, 2014 and 2017 were then followed by decrements, which may have been related to not only reporting variabilities, but also to differences in sales of antihistamines following local/national drug abuse prevention campaigns (Klein-Schwartz, 2017). Overall, the USA appeared here to be the country most involved in reporting of promethazine ADRs. Several reasons may help in explaining this, including healthcare professionals’ awareness of prescription/OTC drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Lynch et al., 2015; Manchikanti et al., 2006; NIDA, 2014; Tsay et al., 2015) which, in turn, may have facilitated pharmacovigilance reporting. According to an 11-year period of the US National Poison Centers’ database, the annual rate of promethazine abuse/misuse per 100,000 US population doubled over time (Tsay et al., 2015). In the USA, promethazine abuse/misuse has been described in teenagers and young adults (Peters et al., 2003), methadone maintenance patients, heroin users and opioid-prescribed chronic pain patients (Lynch et al., 2015; Shapiro et al., 2013).
Consistent with previous observations (Agnich et al., 2013; Burns and Boyer, 2013; Carr, 2006; Elwood, 2001; Höjer and Tellerup, 2018; NIDA, 2014; Page et al., 2009; Parker et al., 2013; Peters et al., 2007), most recorded ADRs related here to either ‘drug abuse’ and ‘intentional product misuse’, involving young adult (19–25 years) males. Although considered a vulnerable category with respect to prescription drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014; Peters et al., 2007), adolescents (10–18 years) were here reported in only a minority (23/1543:1.5%) of cases.
Several drugs were here associated with promethazine, although opiates/opioids were the most represented molecules in related fatalities. This combination might intensify effects such as sedation and analgesia (Burns and Boyer, 2013; Lynch et al., 2015; Shapiro et al., 2013), and in the 1950s the association was medically used to reduce the dosage of opiates/opioids (McGee and Weiss, 1956). However, due to a range of adverse effects (Lynch et al., 2015) including lack of data supporting clinical efficacy (Richter and Burk, 1992) and an enhanced addiction potential of opioids (Lynch et al., 2015; Peters et al., 2007; Shapiro et al., 2013), the combination of promethazine/opioids has declined in popularity.
So far, the recreational intake of promethazine with opioids has been typically reported in cough mixtures containing codeine (Casati et al., 2012; Clatts et al., 2010; Elwood, 2001; Foley et al., 2015; Peters et al., 2007). However, current EMA data suggest that, apart from methadone, oxycodone and fentanyl were the most typical opiates/opiates identified in association with promethazine, possibly due to their recent popularity, especially in the USA (Manchikanti et al., 2018; Rose, 2018). In the promethazine fatalities (e.g. 310 cases) dataset analysed, codeine, fentanyl and oxycodone were respectively reported in 32, 44 and 63 cases. Consistent with current data, a concomitant use of opioids and promethazine has been described in various subpopulations, such as methadone maintenance patients, injecting drug users and chronic pain patients (Banta-Green et al., 2005; Lynch et al., 2015; Shapiro et al., 2013; Shields et al., 2007; Van Hout and Norman, 2016). Overall, there is now a high level of awareness of the abuse potential of antihistamine/opioid-containing products (Hou et al., 2011; Hughes et al., 1999; Wazaify et al., 2005). Hence, some countries are limiting both the medication pack size levels and the quantities of drugs sold in a single transaction, whilst also promoting non-injectable and non-inhaling formulations and changing some formulations’ OTC status (Cooper, 2013; Foley et al., 2015; Van Hout and Norman, 2016).
Benzodiazepines (e.g. diazepam, alprazolam and lorazepam) were here also frequently recorded, suggesting sedative synergistic effects in combination with promethazine (Lynch et al., 2015), and hence an increased risk of untoward clinical issues (McLellan and Turner, 2010). Other prescription drug categories recorded included antidepressants (most typically: citalopram and amitriptyline, respectively in 149/557 and 95/557 cases), which is consistent with the most typically recorded diagnoses, e.g. depressive (68 cases); bipolar (14 cases); and anxiety (23 cases) disorders. It is also possible that antidepressants were here ingested in combination with promethazine for sleep induction purposes. It is a reason for concern that promethazine ADRs, either alone or in combination, resulted in either fatal (50.6%) or ‘recovered/resolved’ outcomes (22.2%). This is consistent with previous promethazine misuse/abuse data, reporting both adverse clinical outcomes and high frequency of healthcare facility treatment (Bergman and Wallman, 1998; Ichikura et al., 2016; McLellan and Turner, 2010; Tsay et al., 2015). A list of possibly misused substances which might reinforce promethazine psychoactive effects and possibly increase its toxicity is included in Table 3.
Table 3. List of substances recorded in the literature as used in association with promethazine in order to increase its effects; prescription drugs are recorded according to the Neuroscience-based Nomenclature description (Nutt and Blier, 2016).
Psychoactive substances
Description Mode of action Examples Effects
Alcohol (Burns and Boyer, 2013; Jensen et al., 2017) CNS depressant effects ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, relaxation, ‘slight giddiness and disorienting’ and ‘nice hallucination’.
It may increase, prolong or intensify promethazine sedative effect. It should be avoided in patients receiving promethazine.
Heroin and other illicit opioids (Dahlman et al., 2016; Tsay et al., 2015) Opioid depressant effects It may increase, prolong, or intensify promethazine sedative effect.
Prescription drugs
Categories Mode of action Examples Effects
Drugs for insomnia (Burns and Boyer, 2013) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Z-drugs: zaleplon, zolpidem, zopiclone, eszopiclone They may increase, prolong or intensify promethazine sedative effect.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Drugs for anxiety (Burns and Boyer, 2013; Lynch et al., 2015) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, lorazepam, oxazepam They may increase, prolong or intensify promethazine sedative action.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Dextrometorphan (Tsay et al., 2015) At high doses, acting as NMDA-receptor antagonist; dextrometorphan and its potent metabolite dextrorphan inhibit the excitatory amino acid and neurotransmitter glutamate in the brain, determining hallucinogenic and dissociative activities, which are recreationally searched It might be combined with promethazine in cough-suppressant formulation Dextrometorphan neurobehavioural effects are dose-related, starting from a mild to moderate stimulation with restlessness and euphoria (100–200 mg), to a dissociated state characterised by hallucinations, paranoia, perceptual distortions, delusional beliefs, ataxia and out-of-body experiences (‘robo-ing’/‘robo-copping’/‘robo-tripping’) (>1000 mg). In overdosage they might increase promethazine effects.
Drugs for depression (Burns and Boyer, 2013; Jensen et al., 2017): TCA Multimodal action: reuptake inhibitor (SERT and NET), receptor antagonist (5-HT2) Amitriptyline Promethazine may increase, prolong or intensify their sedative effect. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Anticholinergic drugs Antagonist at cholinergic receptors Hyoscine butyl bromide/scopolamine (Burns and Boyer, 2013) Together with promethazine an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility may be seen. A typical mental status alteration with a dose-dependent agitated delirium characterised by abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia, has been described. These molecules should be avoided or administered in reduced dosage to patients receiving promethazine.
Prescription opioids
Codeine (Burns and Boyer, 2013; Jouanjus et al., 2018; Lynch et al., 2015; O Reilly et al., 2015; Shapiro et al., 2013) ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, elation, analgesia and ‘liking’, with increased potential of addiction. Overdosage of codeine might determine respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne–Stokes respiration and cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Opiate overdosage, particularly by the intravenous route, may be associated with apnoea, circulatory collapse, cardiac arrest and death. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Other opioid analgesics (Burns and Boyer, 2013; Dahlman et al., 2016; Lynch et al., 2015; Shapiro et al., 2013) Methadone They may increase, prolong or intensify promethazine sedative effects. Opioids should be avoided or administered in reduced dosage to patients receiving promethazine.
The addiction potential of opioids might be enhanced. Also, increasing life-threatening events, such as respiratory depression, overdose and prolongation of the QT interval, might be responsible for drug-related fatalities.
5-HT2: serotonin-2 receptor; CNS: central nervous system; D2: dopamine 2 receptor; GABA: gamma-amino-butyric acid; H1: histamine 1 receptor; NE: norepinephrine; NET: norepinephrine transporter; NMDA: N-methyl-D-aspartate; SERT: serotonin transporter; SSRI: selective-serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
Finally, among abuse-related cases, neonates, infants and children were here reported as well. This is consistent with cases of unexpected infant deaths associated with use of cold medications, poor socioeconomic conditions (Rimsza and Newberry, 2008) and/or accidental ingestion (McLellan and Turner, 2010).
Limitations
One of the limitations was given here by the descriptive nature of the study. Indeed, a comparator molecule, for a disproportionality analysis (Chiappini and Schifano, 2016; Schifano and Chiappini, 2018b) to be carried out, was not available due to data access limitations (EMA, 2017; Postigo et al., 2018). Furthermore, current data did not appear to show an increasing trend of abuse or misuse across the years. Since proper denominator figures (e.g. data on worldwide promethazine prescriptions) are not available, it was unclear if what observed was a substantial number of cases, indicative of clinically meaningful abuse potential, or a passing trend for promethazine misuse by a very small number of individuals. However, consistent with previous suggestions (Montastruc et al, 2011), the value of the current study was that its rationale was driven by a proper, detailed, pharmacodynamic hypothesis established on the basic properties of promethazine. Similar to remaining pharmacovigilance datasets (EMA, 2010; Evoy et al., 2019; Schifano and Chiappini, 2018a; Schifano et al., 2019a, 2019b; Schwan et al., 2010), focussing on the analysis of voluntary adverse events, a further limitation was given here by reliance on self-reporting and the likelihood of missing data occurrence. Moreover, although healthcare professionals have a main role in detection, assessment and spontaneous reporting of ADRs (Belton, 1997; Khalili et al., 2012), specific abuse/misuse/dependence issues relating to promethazine may have been underestimated, with only the most serious cases having been reported, hence the high rates of promethazine fatalities here recorded. Furthermore, although patients and their carers are allowed indeed to flag up an ADR, it is unlikely that they have spontaneously reported misusing events. Other factors, such as increased knowledge of promethazine misuse/abuse, may have resulted here in outcome reporting bias. There was also a potential for duplicate reports, with the same report submitted by the consumer, the healthcare professional and by the manufacturer as well, causing skewed study results. This may occur when a healthcare professional reported the same suspected ADR to both the national Regulatory Authority and the Marketing Authorisation Holder and they both reported subsequently to EV. However, the EV local report number which was here considered unequivocally identified an individual case. In addition, whilst this study represents one of the largest sample of promethazine abuse events published to date, the overall number of events is still relatively small, potentially limiting external validity. Case reports of suspected ADRs alone are not always sufficient to prove that a certain suspected reaction has indeed been caused by a specific medicine. This could be a symptom of another illness, or it could be associated with another medicinal product taken by the patient at the same time. The suspected ADRs were here presented using the PTs of the MedDRA Dictionary (Postigo et al., 2018). Thus, any case report should be considered together with all available data including case reports worldwide, clinical trials, epidemiological studies and toxicological investigations, in order to allow for robust conclusions. Finally, case reports reflect the information as provided to EV by the reporter, and not all data fields were completed for all reports.
Conclusion
To the best of our understanding, the current study described in detail the largest sample ever of abuse, misuse and dependence issues related to promethazine, whilst focussing on a large multinational dataset, such as the EV. The substantial number of promethazine-related events identified over the years represents a pharmacovigilance signal which needs to be better investigated (Montastruc et al., 2011). Although the observed trend of promethazine abuse and misuse, especially in young adults, is not a new phenomenon, further details of the issue have been here provided and future studies will optimally identify the related risk factors, with these measures enabling policymakers and regulators to take action to detect and prevent such misusing practices (Jouanjus et al., 2019). A multicomponent approach is recommended, including monitoring drug utilisation, tracking users’ posts on social media, and exploring healthcare databases; this will enable performing proactive and effective post-marketing surveillance and pharmacovigilance approaches. This has proved to be a relevant, efficient and accurate strategy, for example with gabapentinoids, which have recently been rescheduled in the UK (Borg et al., 2011; Eickhoff et al., 2012; Jouanjus et al., 2019; Novak et al., 2016; Parker et al., 2013; Schifano and Chiappini, 2019; Throckmorton et al., 2018). In this context, the role of the Web is rapidly spreading, playing a significant role in the marketing, sale and distribution of drugs, hence facilitating continuous changes in drug scenarios (Orsolini et al., 2017). Indeed, over the last 10 years access to online pharmacies to purchase medicinal compounds has increased (Desai, 2016; Monteith and Glenn, 2018). On the other hand, professionals access the Web to gather data on emerging trends of drug abuse (Deluca et al., 2002; Orsolini et al., 2015; Schifano, 2020; Schifano et al., 2003).
OTC and prescription drug misuse is perceived to be a significantly under-recognised issue affecting a range of vulnerable individuals (Coombes and Cooper, 2019). However, controlling the problem of OTC misuse and abuse might be challenging, due to the need for achieving high levels of consumer safety whilst not restricting access to OTC products for those who continue to use them safely.
Staff training should be evaluated, in order for pharmacists to self-monitor care and use of medicines, to educate patients and intervene/support those experiencing problematic drug use (Elwood, 2001; GPC, 2019; Tobin et al., 2013; Wells et al., 2018). Record-keeping (Hou et al., 2011) and real time monitoring (Cairns et al., 2016) could be a method of restricting access to some OTC drugs and prevent ‘shopping’ from one pharmacy to another, and where these measures would result to be ineffective, regulatory interventions, e.g. drug re-scheduling, might be useful (Marsden et al., 2019; McDonough, 2016; Peacock et al., 2019). Also, prevention and early education on substance abuse in young teenagers are critical (Levine, 2007; Marsden et al., 2019). Finally, appropriate and specific clinical guidelines for the treatment of misuse, abuse and dependence on prescription or OTC drugs should be implemented (Fingleton et al., 2019).
The review and study design were developed by SC, FS, JMC and AG. SC drafted the first version of the manuscript with input from all authors. All authors contributed to the interpretation of the data analysis and the further drafting of the manuscript and approved the final version.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FS was a member of the UK Advisory Council on the Misuse Drugs (ACMD) from 2011–2019; and is currently an EMA Advisory board (psychiatry) member. JMC is a member of the ACMD’s Novel Psychoactive Substances and Technical Committees. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
ORCID iDs: Stefania Chiappini https://orcid.org/0000-0002-6810-1540
John Martin Corkery https://orcid.org/0000-0002-3849-817X | Fatal | ReactionOutcome | CC BY | 33427017 | 18,928,797 | 2021-06 |
What was the outcome of reaction 'Intentional overdose'? | Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.
Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents.
We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database.
After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234).
The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used.
Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.
Introduction
Pharmacological properties of promethazine
Promethazine is a phenothiazine derivative and a histamine (H1) receptor antagonist that is commonly used for symptomatic relief of nausea and vomiting, for allergic conditions, motion sickness and common cold, and for short-term use treatment of insomnia in adults or as a paediatric sedative (EMC, 2019). It also acts as a direct antagonist at muscarinic (M1) and dopamine (D2) receptors (Cookson, 2018; Page et al., 2009; Sharma and Hamelin, 2003). Promethazine hydrochloride is well absorbed from the gastrointestinal tract, with an average of 88% of the dose absorbed after oral administration, and clinical effects appearing within 20 min after intake whilst lasting 4–6 h. The plasma half-life is approximately 7–14 h (Burns and Boyer, 2013). It is classified as a first-generation antihistamine molecule which, compared with second-generation antihistamines, easily penetrates the blood-brain barrier and is associated with adverse effects such as moderate/intense sedation (Jensen et al., 2017). Thus, promethazine might be used in rapid (acute) tranquilization due to its blocking action at H1 and M receptors (Cookson, 2018). Toxicity might result in severe impairment of cognitive and psychomotor functions due to central nervous system (CNS) depression/reduced levels of consciousness, and may cause fatalities (Jensen et al., 2017).
Availability of promethazine
Promethazine is a medicinal product available on its own or in combination with other ingredients, including dextromethorphan, paracetamol and/or expectorants. With regards to promethazine availability, there are wide variations across countries. In fact, in some European countries such as France, Italy and the UK, but also outside Europe, some medicinal products containing promethazine can be purchased over-the-counter (OTC). Promethazine was restricted from an OTC status to prescription only in Denmark as of December 2014. This restriction was partly based on increasing enquiries regarding promethazine exposures to the Danish Poison and Information Centre (DPIC), highlighting its abuse potential and subsequent observations of side-effects after ingestion of standard doses. In Australia, promethazine is available as an OTC medication either alone as a tablet or as a liquid preparation or in combination with paracetamol and codeine phosphate as a syrup (Sharma and Hamelin, 2003). In the USA, some cough preparations containing no more than 200 mg of codeine per 100 mL are considered Schedule V controlled substances (Drug Enforcement Administration (DEA), 2020), purportedly possessing the lowest potential for both misuse and development of a Substance Use Disorder (SUD).
Pharming
Recently, the potential for misuse of medications that are not already controlled has been reported worldwide (Reeves et al., 2015). ‘Pharming’ is a phenomenon involving the non-medical use of prescription (pain relievers, tranquilisers, stimulants, sedatives) and OTC drugs, including cough and cold preparations, particularly those containing dextromethorphan and promethazine (Burns and Boyer, 2013; Jouanjus et al., 2018; Levine, 2007; McCarthy, 2007; National Institute on Drug Abuse (NIDA), 2014). The abuse of these compounds may be facilitated by their easy accessibility, low cost, decreased perception of potential for harm and growing social acceptance (Burns and Boyer, 2013; Levine, 2007; McCarthy, 2007; Substance Abuse Mental Health Services Administration (SAMHSA), 2008). In the current drug abuse scenario, young people/youths have been described abusing with a range of prescription or OTC medicines (Soussan et al., 2018), with these molecules possibly being ingested at high/super-high dosages (Orsolini et al., 2015; Schifano, 2020) and at times in combination with alcohol/remaining recreational substances (Levine, 2007)
Recreational use of promethazine
Centrally acting antihistamines have long been known to induce physical and psychological dependence (Clatts et al., 2010; Gracious et al., 2010; Page et al., 2009; Saatcioglu and Evren, 2005; Thomas et al., 2008). During the past 15 years the abuse of promethazine, especially from OTC and prescription cough and cold medicines and at higher-than-recommended dosages, has been reported (NIDA, 2014). Consistent with this, during the last decade the yearly number of promethazine-related overdose cases in Sweden has increased from 100 to nearly 700 and its sales have increased threefold (Höjer and Tellerup, 2018). Also, according to the 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), antihistamines accounted for the seventh most frequently involved substance in human exposures, resulting in the third type of substance category for rate of exposure increase (Gummin et al., 2019). In Denmark, the number of registered antihistamine exposures increased during 2007–2013, with first-generation antihistamines, specifically promethazine, having been responsible for most exposures and related fatalities (Jensen et al., 2017). Also, in New Zealand a number of promethazine poisoning cases (57/199 patients) were identified from a database of poisoning admissions to a regional toxicology service (Bergman and Wallman, 1998).
Effects
Promethazine reported effects mostly include a range of CNS side effects, such as: confusion; disorientation; drowsiness; cardiovascular symptoms; and respiratory depression (Burns and Boyer, 2013; Höjer and Tellerup, 2018; Page et al., 2009; Tsay et al., 2015). A clear abuse potential has been observed and reported for first-generation antihistamines such as promethazine and cyclizine, due to: calming and sedating effects (Cookson, 2018; Jensen et al., 2017) and enhancement of other co-ingested substances, and especially those interacting with gamma-amino-butyric acid (GABA), opiate and muscarinic acetylcholine receptors (Speeg et al., 1981), leading to hallucinogenic experiences (Clatts et al., 2010; Jensen et al., 2017; Lynch et al., 2015). Indeed, an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility has been described (Burns and Boyer, 2013). In these cases, the mental state alteration is characterised by agitated delirium, with abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia (Agnich et al., 2013; Cowen, 1979; Dollberg et al., 1989; Höjer and Tellerup, 2018; Leak and Carroll, 1967; Page et al., 2009; Scott et al., 2007; Timnak et al., 2004). With the promethazine-codeine cough syrup, ‘euphoric feelings’, ‘relaxation’, ‘slight giddiness and disorienting’, and ‘nice hallucinations’ have been described as well (Bluelight.org [2020]; Erowid.org [2020]). Reported side-effects include drowsiness, fatigue, loss of coordination, constipation and urinary retention (Elwood, 2001).
Vulnerable categories
An increasing trend in abuse of promethazine in co-formulation with some components of OTC cough medications has been reported in young adult populations (Carney et al., 2018; Carr, 2006; Höjer and Tellerup, 2018) since the late 1990s, particularly in the southern USA (Carr, 2006; Elwood, 2001). Codeine and promethazine were recorded as the most requested psychoactive drugs by adolescents/young adults in community pharmacies (Delcourt et al., 2017).
Known by the street names ‘lean’, ‘drank’, ‘barre’, ‘purple stuff’, ‘syrup’ and ‘sizzurp’ (Agnich et al., 2013; NIDA, 2014; Peters et al., 2007), the abuse of promethazine mixed with opioids and other sedatives (e.g. alcohol) in a purple colour drink (‘purple drank’) (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014) has become widely popular (Agnich et al., 2013) after a rap artist/producer created a genre of music, called ‘screw music', inspired by intoxication on codeine and promethazine (Peters et al., 2007). Social media data, e.g. public posts and related hashtags on Instagram, provided additional insights into codeine abuse, depicting its common misuse combined with promethazine and soda/carbonated drinks (Cherian et al., 2018). ‘Purple drank’ has been noted for its euphoric effects and its easy accessibility (Elwood, 2001; Peters et al., 2007). ‘Lean’ creates a distinct (Jakubowski et al., 2018) feeling of euphoria and extreme relaxation (Cookson, 2018), dream-like feelings and a vivid sensation of floating away from the physical body (Peters et al., 2007).
Although at times preferred to other substances, such as benzodiazepines, to treat anxiety and sleep disorders in substance-dependent patients, promethazine has been reported to be misused among people with either opioid dependence (Agnich et al., 2013; Dahlman et al., 2016; Elwood, 2001; Lynch et al., 2015; Shapiro et al., 2013) or a substance abuse condition (Shapiro et al., 2013; Tang et al., 2012). A Hong Kong study reported a total of 63 patients with a diagnosis of cough mixture abuse; 89% were adult males with a mean age of onset of the abuse itself of 20 (±5) years. These subjects had received a diagnosis of substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%) and dysthymia (10%), with most cases having presented with a polysubstance misuse (Tang et al., 2012). Due to the opioid-coformulation, the promethazine-codeine cough mixture might lead to addiction (NIDA, 2014). The mixture may present a high risk of occurrence of near misses due to its central effect of respiratory depression, which is greatly increased by association with alcohol or other CNS depressants, such as sedatives/hypnotics, narcotic analgesics, general anaesthetics and tricyclic antidepressants (Burns and Boyer, 2013; Elwood, 2001; NIDA, 2014; Shapiro et al., 2013; Tsay et al., 2015). The concomitant use of promethazine and other depressant drugs should not be underestimated, as they might together contribute to and/or cause fatalities (Corkery et al., 2020).
Aim of the study
We were interested here in studying how promethazine abuse was reported to the European Medicines Agency (EMA) adverse drug reactions (ADRs) database. We aimed to analyse promethazine misuse/abuse/dependence/withdrawal data. Where possible, in order to have a better understanding, information/data related to diagnosis, concomitant drugs, administration and dosages were also examined.
Methods
Source of data
The EMA through EudraVigilance (EV) manages and analyses information on suspected ADRs to medicines authorised in the European Economic Area (EEA), according to Directive 2001/83/EC and Regulation (EC) No 726/2004 (EMA, 2017). Since November 2017, EV launched extensive Web access to data on suspected ADRs and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research (Postigo et al., 2018). Thus, access to data regarding cases of promethazine abuse, misuse, dependence and withdrawal was obtained by application to the voluntary reporting system of ADRs of the EMA. After 3 months all data comprised all of the ADRs reported during the years from 2003 up to June 2019, presented as large Excel files divided into information sections reporting in a standardised format according to the Medical Dictionary for Regulatory Activities (MedDRA), were sent through a hyperlink (MedDra, 2018). Such listings showed all information related to the ADR, the patient, the drug, the reporter and the diagnosis. An ADR was considered a voluntary and unsolicited communication reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorisation Holders for those ADRs occurring outside the EEA (EMA, 2010). Only ‘suspect’ ADRs were selected, meaning promethazine was considered as ‘suspected’ for the reaction reported. Regarding the content of the ADR, according to the standardised MedDRA Query (SMQ) (MedDRA, 2018), the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, intentional product use issue, substance abuse, substance abuser, substance use and withdrawal syndrome were selected. Those ADRs were defined in accordance with MedDRA in line with previous studies on the EV dataset (Chiappini et al., 2020; MedDRA, 2018; Schifano and Chiappini, 2018a, 2018b; Schifano et al., 2019a, 2019b). Specifically, abuse was here defined as the intentional, non-therapeutic use by a patient or consumer of a product, OTC or prescription, for a perceived reward or desired non-therapeutic effect including, but not limited to, getting high (euphoria) (MedDRA, 2018). Misuse was meant as the intentional use for a therapeutic purpose by a patient or consumer of a product, OTC or prescription, other than as prescribed or not in accordance with the authorised product information (MedDRA, 2018). Finally, non-medical use referred here to the use of a prescription drug, whether obtained by prescription or otherwise, other than in the manner or for the time period prescribed, or by a person for whom the drug was not prescribed (United Nations Office on Drugs and Crime (UNODC), 2013).
Analysis of data
We retrospectively analysed all reported ADRs which were available in the EV database. ADR reports were analysed with respect to age and gender of patient/consumer, source/reporter country (EEA or non-EEA) and reporter qualification (i.e. pharmacist, physician); type of ADR; seriousness (fatal, recovered, resolved outcomes); promethazine dosage; possible concomitant drug(s); and diagnosis/reporter’s comments, if recorded. The descriptive analysis included cases of overdoses, suicides, and fatalities. In the dataset, each case report may refer to one or more reporter; one or more ADR(s); as well as to one or more medicinal product(s). Therefore, a case may be represented by more than one row in the other line listings. The received data files were searched for duplicates by report ID through the ‘EV Local Report Number’, which unequivocally identified an individual case. Thus, the number of suspected ADRs appeared to be different from the number of case reports as one case report might refer to several suspected ADRs. Moreover, the number of patients was different from the number of case reports as a patient might have been described in more than one case. Finally, numbers of ADRs differed from those referring to case reports/single patients since different reporters/senders could have independently flagged the same ADR to the EMA. The descriptive analysis included here a study of the dataset (EMA, 2017) performed through IBM SPSS Statistics software (version 26).
Ethical issues
In compliance with applicable Personal Data Protection legislation (Regulation (EC) No 45/2001 and Regulation (EC) No 1049/2001, the protection of privacy and integrity of individuals was guaranteed, and in order to safeguard the identity of individuals certain data elements, including names/identifiers or country-specific information were not disclosed by the EMA (EMA, 2013, 2017). The study was ethically approved in March 2018 by the University of Hertfordshire Ethics’ Committee, with reference number LMS/PGR/UH/03234.
Results
The dataset obtained reported a total of 11,796 ADRs, correspond-ing to 1,543 single cases recorded during years 2003–2019 (Table 1). Safety reports were all voluntarily submitted, mostly from pharmaceutical companies (1,136/1,543: 73.6%) and regulatory authorities (398/1,543: 25.8%). Reports were irregularly reported over time, with spikes in 2010, 2014 and 2017 (Figure 1). Countries which reported most promethazine-related abuse/misuse/dependence cases included: the USA (805/1,543: 52.10%); Germany (299/1,543: 19.4%); Japan (162/1,543: 10.5%), Sweden (67/1,543: 4.3%), France (43/1,543: 2.8%) and Australia (42/1,543: 2.7%). Out of a total of 1543 cases, ‘suspect’ abuse/misuse/dependence-related cases were 557 (36.1%) and, among them, according to the preferred terms (PTs), most recorded reactions were abuse/misuse-related ADRs (458/557: 82.2%), specifically ‘drug abuse’ (300/557: 53.8%) and ‘intentional product misuse’ (117/557: 21.0%) (Table 1). ‘Suspect’ selected cases and related fatalities annually showed the same trend overall (Figure 1). Most typically, subjects reported were adult (19–64 years) and specifically of the youngest group (19–25 years); males were slightly more frequently recorded than females (M/F: 235/461: 0.51) (Table 1). Where all information was recorded, promethazine was reported as ingested alone in 74 cases, with supratherapeutic dosages, up to 2500 mg, in four cases. In combination with other drugs, most cases were associated with a 100–500 mg promethazine dose, with the maximum dosage recorded having been 8000 mg (Figure 2). The most common administration route was oral (n = 292), although the intramuscular (n = 8) and the parenteral (n = 19) ones were reported as well, see Table 1).
Table 1. Analysis of promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV) during years 2003–2019.
Individual cases (% of total within parentheses)
Total abuse/misuse/dependence cases 1543 Single cases; number of ADRs :11,796
Age range Adult (19–64 years): 648 (648/1,543: 42.0%) - mean age: 31.8 years (SD 26.55–37.05)
Adolescent (10–18 years): 23 (23/1,543: 1.5%) – mean age: 15.9 years (SD 14.3–17.77)
Elderly (>65 years): 25 (25/1,543: 1.6%) – mean age: 72.3 years (SD 70.85–73.7)
Neonatal (hours–days) 14 (14/1,543: 0.9%) – mean age: 24 h (SD 16.6–27.4)
Infant (months–1 year): 7 (7/1,543: 0.45%) – mean age: 10 months (SD 7–13)
Child (<10 years): 4 (4: 1,543: 0.35%) – mean age: 5 years (SD 3.6–6.3)
Unknown: 822 (822/1,543: 53.2%)
Male/female 235/461: 0.51
Most represented abuse/misuse/dependence-related ADRs according to the PTs: 557 (557/1,543: 36.1%)
Abuse-related ADRs 458 (458/557: 82.2%)
Drug abuse 300
Drug abuser 15
Drug diversion 1
Intentional product misuse 117
Intentional product use issue 9
Substance abuse 11
Substance abuser 3
Substance use 2
Dependence-related ADRs 44 (44/557: 7.9%)
Dependence 4
Drug dependence 39
Substance dependence 1
Withdrawal-related ADRs 55 (55/557: 9.8%)
Withdrawal syndrome 19
Drug withdrawal convulsions 1
Drug withdrawal neonatal syndrome 18
Drug withdrawal syndrome 17
Outcome Fatal 310 (310/557: 55.6%)
Unknown 161 (161/557: 28.9%)
Recovered/resolved 55 (55/557: 9.9%)
Recovering/resolving 18 (18/557: 3.3%)
Not recovered/not resolved 13 (13/557: 2.3%)
Promethazine-cases alone 74 (with maximum dosage 2500 mg)
Promethazine-cases with other drugs Most cases (122) were over 100 mg (with maximum dosage 8000 mg)
Most common psychoactive substances used Alcohol: 114
Cocaine: 68
Cannabis: 16
Ketamine: 4
Amphetamine: 1
Most common prescription drugs used Opioids: 1187
Benzodiazepines: 914
Antidepressants: 871
Antipsychotics: 437
Z-drugs: 222
Mood stabilisers: 197
ADR: adverse drug reaction; PTs: preferred terms; SD: standard deviation.
Figure 1. Number of promethazine abuse/misuse/dependence/withdrawal cases reported by year in the EudraVigilance (EV) dataset.
Figure 2. Most represented dosages reported among all promethazine abuse/misuse/dependence/withdrawal cases recorded by the EudraVigilance (EV) dataset.
Concomitantly used drugs recorded were opioids (e.g. oxycodone and fentanyl), benzodiazepines (e.g. diazepam, alprazolam and lorazepam) and antidepressants (e.g. citalopram, venlafaxine and amitriptyline), whilst recreational drugs most represented were alcohol and cocaine (Table 1). Most reported diagnoses, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V; American Psychiatric Association (APA), 2013) related to: mood disorders, e.g. depression/depressed mood/major depression (68 cases) and bipolar disorder (14 cases); anxiety/anxiety disorders (23 cases); alcohol abuse/alcoholic/alcoholism (26 cases); and schizophrenia (14 cases). The outcome of the reactions reported included: ‘fatal’ (n=310/557; 55.6%) and secondarily ‘recovered/resolved’ (n=73; 15.2%) (Table 1). Some 27 cases were related to suicidal or self-harm behaviour, being recorded as ‘suicidal attempt/suicidal ideation’ (n=24), ‘self-injurious ideation’ (n=1), and ‘suicide attempt’ (n=2). Fatalities mostly involved adult females; in these cases, most typical ADRs recorded were ‘drug abuse’ (n=228) and ‘intentional product misuse’ (n=77) (Table 2). Opiates/opioids were the most recorded concomitant drugs (n=356), with methadone being the most represented (n=103), followed by antidepressants (n=221) and benzodiazepines (n=141). Among illicit drugs, heroin appeared to be the most represented (Table 2).
Table 2. Analysis of fatal promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV), 2003–2019.
Fatal cases on abuse/misuse/dependence/withdrawal reactions 310 (310/557 = 55.6%)
Age-range
Adult 303 (97.7%)
Adolescent 7 (2.3%)
Elderly (>65 years) –
Neonatal –
Infant –
Child –
Gender M 103 (33.2%)
F 177 (57.1%)
Unknown 30 (9.7%)
Most recorded PTs
Drug abuse/drug abuser/substance abuse 228/3/6
Intentional product misuse/Intentional product use issue 77/3
Drug dependence 1
Reported death code
Intentional overdose 1
Overdose 4
Completed suicide/suicide 7
Drug toxicity/drug abuse 197
Toxicity to various agents 48
Intentional product misuse 41
Respiratory depression 5
Pneumonia 1
Cardiac arrest 10
Drug dependence 1
Most reported concomitant drugs
Opioids 356
Methadone 103
Dihydrocodeine 1
Codeine 32
Fentanyl 44
Oxycodone 63
Morphine 55
Hydrocodone 33
Hydromorphone 3
Tramadol 22
Antidepressants 221
Duloxetine 1
Escitalopram 1
Sertraline 16
Paroxetine 34
Trazodone 15
Mirtazapine 33
Fluoxetine 24
Venlafaxine 9
Bupropion 1
Amitriptyline 35
Nortriptyline 6
Clomipramine 5
Citalopram 41
Benzodiazepines 141
Lorazepam 3
Temazepam 6
Clonazepam 21
Diazepam 60
Flunitrazepam 1
Brotizolam 1
Alprazolam 42
Midazolam 4
Oxazepam 3
Mood stabilisers 11
Gabapentin 3
Topiramate 8
Antipsychotics 24
Olanzapine 1
Quetiapine 20
Haloperidol 1
Amisulpride 1
Levomepromazine 1
Z-drugs 39
Zolpidem 37
Zopiclone 2
Illicit drugs
Amphetamine 15
Cocaine 40
Heroin 52
Alcohol 26
PTs: preferred terms.
Discussion
Non-medical prescription drug use is a globally recognised problem, with severe adverse consequences. The current study provides a large amount of descriptive data highlighting that promethazine can be taken at high dosages, through non-approved administration routes, and in a setting of polydrug use (Hughes et al., 2016; Novak et al., 2016).
Promethazine misuse has been increasingly recorded since the early 2000s, consistently with data from US poison centres reporting antihistamine exposures rising in the period 2007–2013 (Jensen et al., 2017). This is not surprising, since the pharmacodynamic properties of promethazine underpins its sought-after central effects. In 2014, e.g. the highest peak here, the increase in promethazine misuse reporting was solely driven by the USA (245/245 cases; 100%). This may have been associated with intense media attention to the subject in that year (TMZ, 2014). The increments reported in 2010, 2014 and 2017 were then followed by decrements, which may have been related to not only reporting variabilities, but also to differences in sales of antihistamines following local/national drug abuse prevention campaigns (Klein-Schwartz, 2017). Overall, the USA appeared here to be the country most involved in reporting of promethazine ADRs. Several reasons may help in explaining this, including healthcare professionals’ awareness of prescription/OTC drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Lynch et al., 2015; Manchikanti et al., 2006; NIDA, 2014; Tsay et al., 2015) which, in turn, may have facilitated pharmacovigilance reporting. According to an 11-year period of the US National Poison Centers’ database, the annual rate of promethazine abuse/misuse per 100,000 US population doubled over time (Tsay et al., 2015). In the USA, promethazine abuse/misuse has been described in teenagers and young adults (Peters et al., 2003), methadone maintenance patients, heroin users and opioid-prescribed chronic pain patients (Lynch et al., 2015; Shapiro et al., 2013).
Consistent with previous observations (Agnich et al., 2013; Burns and Boyer, 2013; Carr, 2006; Elwood, 2001; Höjer and Tellerup, 2018; NIDA, 2014; Page et al., 2009; Parker et al., 2013; Peters et al., 2007), most recorded ADRs related here to either ‘drug abuse’ and ‘intentional product misuse’, involving young adult (19–25 years) males. Although considered a vulnerable category with respect to prescription drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014; Peters et al., 2007), adolescents (10–18 years) were here reported in only a minority (23/1543:1.5%) of cases.
Several drugs were here associated with promethazine, although opiates/opioids were the most represented molecules in related fatalities. This combination might intensify effects such as sedation and analgesia (Burns and Boyer, 2013; Lynch et al., 2015; Shapiro et al., 2013), and in the 1950s the association was medically used to reduce the dosage of opiates/opioids (McGee and Weiss, 1956). However, due to a range of adverse effects (Lynch et al., 2015) including lack of data supporting clinical efficacy (Richter and Burk, 1992) and an enhanced addiction potential of opioids (Lynch et al., 2015; Peters et al., 2007; Shapiro et al., 2013), the combination of promethazine/opioids has declined in popularity.
So far, the recreational intake of promethazine with opioids has been typically reported in cough mixtures containing codeine (Casati et al., 2012; Clatts et al., 2010; Elwood, 2001; Foley et al., 2015; Peters et al., 2007). However, current EMA data suggest that, apart from methadone, oxycodone and fentanyl were the most typical opiates/opiates identified in association with promethazine, possibly due to their recent popularity, especially in the USA (Manchikanti et al., 2018; Rose, 2018). In the promethazine fatalities (e.g. 310 cases) dataset analysed, codeine, fentanyl and oxycodone were respectively reported in 32, 44 and 63 cases. Consistent with current data, a concomitant use of opioids and promethazine has been described in various subpopulations, such as methadone maintenance patients, injecting drug users and chronic pain patients (Banta-Green et al., 2005; Lynch et al., 2015; Shapiro et al., 2013; Shields et al., 2007; Van Hout and Norman, 2016). Overall, there is now a high level of awareness of the abuse potential of antihistamine/opioid-containing products (Hou et al., 2011; Hughes et al., 1999; Wazaify et al., 2005). Hence, some countries are limiting both the medication pack size levels and the quantities of drugs sold in a single transaction, whilst also promoting non-injectable and non-inhaling formulations and changing some formulations’ OTC status (Cooper, 2013; Foley et al., 2015; Van Hout and Norman, 2016).
Benzodiazepines (e.g. diazepam, alprazolam and lorazepam) were here also frequently recorded, suggesting sedative synergistic effects in combination with promethazine (Lynch et al., 2015), and hence an increased risk of untoward clinical issues (McLellan and Turner, 2010). Other prescription drug categories recorded included antidepressants (most typically: citalopram and amitriptyline, respectively in 149/557 and 95/557 cases), which is consistent with the most typically recorded diagnoses, e.g. depressive (68 cases); bipolar (14 cases); and anxiety (23 cases) disorders. It is also possible that antidepressants were here ingested in combination with promethazine for sleep induction purposes. It is a reason for concern that promethazine ADRs, either alone or in combination, resulted in either fatal (50.6%) or ‘recovered/resolved’ outcomes (22.2%). This is consistent with previous promethazine misuse/abuse data, reporting both adverse clinical outcomes and high frequency of healthcare facility treatment (Bergman and Wallman, 1998; Ichikura et al., 2016; McLellan and Turner, 2010; Tsay et al., 2015). A list of possibly misused substances which might reinforce promethazine psychoactive effects and possibly increase its toxicity is included in Table 3.
Table 3. List of substances recorded in the literature as used in association with promethazine in order to increase its effects; prescription drugs are recorded according to the Neuroscience-based Nomenclature description (Nutt and Blier, 2016).
Psychoactive substances
Description Mode of action Examples Effects
Alcohol (Burns and Boyer, 2013; Jensen et al., 2017) CNS depressant effects ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, relaxation, ‘slight giddiness and disorienting’ and ‘nice hallucination’.
It may increase, prolong or intensify promethazine sedative effect. It should be avoided in patients receiving promethazine.
Heroin and other illicit opioids (Dahlman et al., 2016; Tsay et al., 2015) Opioid depressant effects It may increase, prolong, or intensify promethazine sedative effect.
Prescription drugs
Categories Mode of action Examples Effects
Drugs for insomnia (Burns and Boyer, 2013) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Z-drugs: zaleplon, zolpidem, zopiclone, eszopiclone They may increase, prolong or intensify promethazine sedative effect.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Drugs for anxiety (Burns and Boyer, 2013; Lynch et al., 2015) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, lorazepam, oxazepam They may increase, prolong or intensify promethazine sedative action.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Dextrometorphan (Tsay et al., 2015) At high doses, acting as NMDA-receptor antagonist; dextrometorphan and its potent metabolite dextrorphan inhibit the excitatory amino acid and neurotransmitter glutamate in the brain, determining hallucinogenic and dissociative activities, which are recreationally searched It might be combined with promethazine in cough-suppressant formulation Dextrometorphan neurobehavioural effects are dose-related, starting from a mild to moderate stimulation with restlessness and euphoria (100–200 mg), to a dissociated state characterised by hallucinations, paranoia, perceptual distortions, delusional beliefs, ataxia and out-of-body experiences (‘robo-ing’/‘robo-copping’/‘robo-tripping’) (>1000 mg). In overdosage they might increase promethazine effects.
Drugs for depression (Burns and Boyer, 2013; Jensen et al., 2017): TCA Multimodal action: reuptake inhibitor (SERT and NET), receptor antagonist (5-HT2) Amitriptyline Promethazine may increase, prolong or intensify their sedative effect. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Anticholinergic drugs Antagonist at cholinergic receptors Hyoscine butyl bromide/scopolamine (Burns and Boyer, 2013) Together with promethazine an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility may be seen. A typical mental status alteration with a dose-dependent agitated delirium characterised by abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia, has been described. These molecules should be avoided or administered in reduced dosage to patients receiving promethazine.
Prescription opioids
Codeine (Burns and Boyer, 2013; Jouanjus et al., 2018; Lynch et al., 2015; O Reilly et al., 2015; Shapiro et al., 2013) ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, elation, analgesia and ‘liking’, with increased potential of addiction. Overdosage of codeine might determine respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne–Stokes respiration and cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Opiate overdosage, particularly by the intravenous route, may be associated with apnoea, circulatory collapse, cardiac arrest and death. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Other opioid analgesics (Burns and Boyer, 2013; Dahlman et al., 2016; Lynch et al., 2015; Shapiro et al., 2013) Methadone They may increase, prolong or intensify promethazine sedative effects. Opioids should be avoided or administered in reduced dosage to patients receiving promethazine.
The addiction potential of opioids might be enhanced. Also, increasing life-threatening events, such as respiratory depression, overdose and prolongation of the QT interval, might be responsible for drug-related fatalities.
5-HT2: serotonin-2 receptor; CNS: central nervous system; D2: dopamine 2 receptor; GABA: gamma-amino-butyric acid; H1: histamine 1 receptor; NE: norepinephrine; NET: norepinephrine transporter; NMDA: N-methyl-D-aspartate; SERT: serotonin transporter; SSRI: selective-serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
Finally, among abuse-related cases, neonates, infants and children were here reported as well. This is consistent with cases of unexpected infant deaths associated with use of cold medications, poor socioeconomic conditions (Rimsza and Newberry, 2008) and/or accidental ingestion (McLellan and Turner, 2010).
Limitations
One of the limitations was given here by the descriptive nature of the study. Indeed, a comparator molecule, for a disproportionality analysis (Chiappini and Schifano, 2016; Schifano and Chiappini, 2018b) to be carried out, was not available due to data access limitations (EMA, 2017; Postigo et al., 2018). Furthermore, current data did not appear to show an increasing trend of abuse or misuse across the years. Since proper denominator figures (e.g. data on worldwide promethazine prescriptions) are not available, it was unclear if what observed was a substantial number of cases, indicative of clinically meaningful abuse potential, or a passing trend for promethazine misuse by a very small number of individuals. However, consistent with previous suggestions (Montastruc et al, 2011), the value of the current study was that its rationale was driven by a proper, detailed, pharmacodynamic hypothesis established on the basic properties of promethazine. Similar to remaining pharmacovigilance datasets (EMA, 2010; Evoy et al., 2019; Schifano and Chiappini, 2018a; Schifano et al., 2019a, 2019b; Schwan et al., 2010), focussing on the analysis of voluntary adverse events, a further limitation was given here by reliance on self-reporting and the likelihood of missing data occurrence. Moreover, although healthcare professionals have a main role in detection, assessment and spontaneous reporting of ADRs (Belton, 1997; Khalili et al., 2012), specific abuse/misuse/dependence issues relating to promethazine may have been underestimated, with only the most serious cases having been reported, hence the high rates of promethazine fatalities here recorded. Furthermore, although patients and their carers are allowed indeed to flag up an ADR, it is unlikely that they have spontaneously reported misusing events. Other factors, such as increased knowledge of promethazine misuse/abuse, may have resulted here in outcome reporting bias. There was also a potential for duplicate reports, with the same report submitted by the consumer, the healthcare professional and by the manufacturer as well, causing skewed study results. This may occur when a healthcare professional reported the same suspected ADR to both the national Regulatory Authority and the Marketing Authorisation Holder and they both reported subsequently to EV. However, the EV local report number which was here considered unequivocally identified an individual case. In addition, whilst this study represents one of the largest sample of promethazine abuse events published to date, the overall number of events is still relatively small, potentially limiting external validity. Case reports of suspected ADRs alone are not always sufficient to prove that a certain suspected reaction has indeed been caused by a specific medicine. This could be a symptom of another illness, or it could be associated with another medicinal product taken by the patient at the same time. The suspected ADRs were here presented using the PTs of the MedDRA Dictionary (Postigo et al., 2018). Thus, any case report should be considered together with all available data including case reports worldwide, clinical trials, epidemiological studies and toxicological investigations, in order to allow for robust conclusions. Finally, case reports reflect the information as provided to EV by the reporter, and not all data fields were completed for all reports.
Conclusion
To the best of our understanding, the current study described in detail the largest sample ever of abuse, misuse and dependence issues related to promethazine, whilst focussing on a large multinational dataset, such as the EV. The substantial number of promethazine-related events identified over the years represents a pharmacovigilance signal which needs to be better investigated (Montastruc et al., 2011). Although the observed trend of promethazine abuse and misuse, especially in young adults, is not a new phenomenon, further details of the issue have been here provided and future studies will optimally identify the related risk factors, with these measures enabling policymakers and regulators to take action to detect and prevent such misusing practices (Jouanjus et al., 2019). A multicomponent approach is recommended, including monitoring drug utilisation, tracking users’ posts on social media, and exploring healthcare databases; this will enable performing proactive and effective post-marketing surveillance and pharmacovigilance approaches. This has proved to be a relevant, efficient and accurate strategy, for example with gabapentinoids, which have recently been rescheduled in the UK (Borg et al., 2011; Eickhoff et al., 2012; Jouanjus et al., 2019; Novak et al., 2016; Parker et al., 2013; Schifano and Chiappini, 2019; Throckmorton et al., 2018). In this context, the role of the Web is rapidly spreading, playing a significant role in the marketing, sale and distribution of drugs, hence facilitating continuous changes in drug scenarios (Orsolini et al., 2017). Indeed, over the last 10 years access to online pharmacies to purchase medicinal compounds has increased (Desai, 2016; Monteith and Glenn, 2018). On the other hand, professionals access the Web to gather data on emerging trends of drug abuse (Deluca et al., 2002; Orsolini et al., 2015; Schifano, 2020; Schifano et al., 2003).
OTC and prescription drug misuse is perceived to be a significantly under-recognised issue affecting a range of vulnerable individuals (Coombes and Cooper, 2019). However, controlling the problem of OTC misuse and abuse might be challenging, due to the need for achieving high levels of consumer safety whilst not restricting access to OTC products for those who continue to use them safely.
Staff training should be evaluated, in order for pharmacists to self-monitor care and use of medicines, to educate patients and intervene/support those experiencing problematic drug use (Elwood, 2001; GPC, 2019; Tobin et al., 2013; Wells et al., 2018). Record-keeping (Hou et al., 2011) and real time monitoring (Cairns et al., 2016) could be a method of restricting access to some OTC drugs and prevent ‘shopping’ from one pharmacy to another, and where these measures would result to be ineffective, regulatory interventions, e.g. drug re-scheduling, might be useful (Marsden et al., 2019; McDonough, 2016; Peacock et al., 2019). Also, prevention and early education on substance abuse in young teenagers are critical (Levine, 2007; Marsden et al., 2019). Finally, appropriate and specific clinical guidelines for the treatment of misuse, abuse and dependence on prescription or OTC drugs should be implemented (Fingleton et al., 2019).
The review and study design were developed by SC, FS, JMC and AG. SC drafted the first version of the manuscript with input from all authors. All authors contributed to the interpretation of the data analysis and the further drafting of the manuscript and approved the final version.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FS was a member of the UK Advisory Council on the Misuse Drugs (ACMD) from 2011–2019; and is currently an EMA Advisory board (psychiatry) member. JMC is a member of the ACMD’s Novel Psychoactive Substances and Technical Committees. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
ORCID iDs: Stefania Chiappini https://orcid.org/0000-0002-6810-1540
John Martin Corkery https://orcid.org/0000-0002-3849-817X | Fatal | ReactionOutcome | CC BY | 33427017 | 18,928,797 | 2021-06 |
What was the outcome of reaction 'Intentional product misuse'? | Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.
Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents.
We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database.
After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234).
The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used.
Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.
Introduction
Pharmacological properties of promethazine
Promethazine is a phenothiazine derivative and a histamine (H1) receptor antagonist that is commonly used for symptomatic relief of nausea and vomiting, for allergic conditions, motion sickness and common cold, and for short-term use treatment of insomnia in adults or as a paediatric sedative (EMC, 2019). It also acts as a direct antagonist at muscarinic (M1) and dopamine (D2) receptors (Cookson, 2018; Page et al., 2009; Sharma and Hamelin, 2003). Promethazine hydrochloride is well absorbed from the gastrointestinal tract, with an average of 88% of the dose absorbed after oral administration, and clinical effects appearing within 20 min after intake whilst lasting 4–6 h. The plasma half-life is approximately 7–14 h (Burns and Boyer, 2013). It is classified as a first-generation antihistamine molecule which, compared with second-generation antihistamines, easily penetrates the blood-brain barrier and is associated with adverse effects such as moderate/intense sedation (Jensen et al., 2017). Thus, promethazine might be used in rapid (acute) tranquilization due to its blocking action at H1 and M receptors (Cookson, 2018). Toxicity might result in severe impairment of cognitive and psychomotor functions due to central nervous system (CNS) depression/reduced levels of consciousness, and may cause fatalities (Jensen et al., 2017).
Availability of promethazine
Promethazine is a medicinal product available on its own or in combination with other ingredients, including dextromethorphan, paracetamol and/or expectorants. With regards to promethazine availability, there are wide variations across countries. In fact, in some European countries such as France, Italy and the UK, but also outside Europe, some medicinal products containing promethazine can be purchased over-the-counter (OTC). Promethazine was restricted from an OTC status to prescription only in Denmark as of December 2014. This restriction was partly based on increasing enquiries regarding promethazine exposures to the Danish Poison and Information Centre (DPIC), highlighting its abuse potential and subsequent observations of side-effects after ingestion of standard doses. In Australia, promethazine is available as an OTC medication either alone as a tablet or as a liquid preparation or in combination with paracetamol and codeine phosphate as a syrup (Sharma and Hamelin, 2003). In the USA, some cough preparations containing no more than 200 mg of codeine per 100 mL are considered Schedule V controlled substances (Drug Enforcement Administration (DEA), 2020), purportedly possessing the lowest potential for both misuse and development of a Substance Use Disorder (SUD).
Pharming
Recently, the potential for misuse of medications that are not already controlled has been reported worldwide (Reeves et al., 2015). ‘Pharming’ is a phenomenon involving the non-medical use of prescription (pain relievers, tranquilisers, stimulants, sedatives) and OTC drugs, including cough and cold preparations, particularly those containing dextromethorphan and promethazine (Burns and Boyer, 2013; Jouanjus et al., 2018; Levine, 2007; McCarthy, 2007; National Institute on Drug Abuse (NIDA), 2014). The abuse of these compounds may be facilitated by their easy accessibility, low cost, decreased perception of potential for harm and growing social acceptance (Burns and Boyer, 2013; Levine, 2007; McCarthy, 2007; Substance Abuse Mental Health Services Administration (SAMHSA), 2008). In the current drug abuse scenario, young people/youths have been described abusing with a range of prescription or OTC medicines (Soussan et al., 2018), with these molecules possibly being ingested at high/super-high dosages (Orsolini et al., 2015; Schifano, 2020) and at times in combination with alcohol/remaining recreational substances (Levine, 2007)
Recreational use of promethazine
Centrally acting antihistamines have long been known to induce physical and psychological dependence (Clatts et al., 2010; Gracious et al., 2010; Page et al., 2009; Saatcioglu and Evren, 2005; Thomas et al., 2008). During the past 15 years the abuse of promethazine, especially from OTC and prescription cough and cold medicines and at higher-than-recommended dosages, has been reported (NIDA, 2014). Consistent with this, during the last decade the yearly number of promethazine-related overdose cases in Sweden has increased from 100 to nearly 700 and its sales have increased threefold (Höjer and Tellerup, 2018). Also, according to the 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), antihistamines accounted for the seventh most frequently involved substance in human exposures, resulting in the third type of substance category for rate of exposure increase (Gummin et al., 2019). In Denmark, the number of registered antihistamine exposures increased during 2007–2013, with first-generation antihistamines, specifically promethazine, having been responsible for most exposures and related fatalities (Jensen et al., 2017). Also, in New Zealand a number of promethazine poisoning cases (57/199 patients) were identified from a database of poisoning admissions to a regional toxicology service (Bergman and Wallman, 1998).
Effects
Promethazine reported effects mostly include a range of CNS side effects, such as: confusion; disorientation; drowsiness; cardiovascular symptoms; and respiratory depression (Burns and Boyer, 2013; Höjer and Tellerup, 2018; Page et al., 2009; Tsay et al., 2015). A clear abuse potential has been observed and reported for first-generation antihistamines such as promethazine and cyclizine, due to: calming and sedating effects (Cookson, 2018; Jensen et al., 2017) and enhancement of other co-ingested substances, and especially those interacting with gamma-amino-butyric acid (GABA), opiate and muscarinic acetylcholine receptors (Speeg et al., 1981), leading to hallucinogenic experiences (Clatts et al., 2010; Jensen et al., 2017; Lynch et al., 2015). Indeed, an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility has been described (Burns and Boyer, 2013). In these cases, the mental state alteration is characterised by agitated delirium, with abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia (Agnich et al., 2013; Cowen, 1979; Dollberg et al., 1989; Höjer and Tellerup, 2018; Leak and Carroll, 1967; Page et al., 2009; Scott et al., 2007; Timnak et al., 2004). With the promethazine-codeine cough syrup, ‘euphoric feelings’, ‘relaxation’, ‘slight giddiness and disorienting’, and ‘nice hallucinations’ have been described as well (Bluelight.org [2020]; Erowid.org [2020]). Reported side-effects include drowsiness, fatigue, loss of coordination, constipation and urinary retention (Elwood, 2001).
Vulnerable categories
An increasing trend in abuse of promethazine in co-formulation with some components of OTC cough medications has been reported in young adult populations (Carney et al., 2018; Carr, 2006; Höjer and Tellerup, 2018) since the late 1990s, particularly in the southern USA (Carr, 2006; Elwood, 2001). Codeine and promethazine were recorded as the most requested psychoactive drugs by adolescents/young adults in community pharmacies (Delcourt et al., 2017).
Known by the street names ‘lean’, ‘drank’, ‘barre’, ‘purple stuff’, ‘syrup’ and ‘sizzurp’ (Agnich et al., 2013; NIDA, 2014; Peters et al., 2007), the abuse of promethazine mixed with opioids and other sedatives (e.g. alcohol) in a purple colour drink (‘purple drank’) (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014) has become widely popular (Agnich et al., 2013) after a rap artist/producer created a genre of music, called ‘screw music', inspired by intoxication on codeine and promethazine (Peters et al., 2007). Social media data, e.g. public posts and related hashtags on Instagram, provided additional insights into codeine abuse, depicting its common misuse combined with promethazine and soda/carbonated drinks (Cherian et al., 2018). ‘Purple drank’ has been noted for its euphoric effects and its easy accessibility (Elwood, 2001; Peters et al., 2007). ‘Lean’ creates a distinct (Jakubowski et al., 2018) feeling of euphoria and extreme relaxation (Cookson, 2018), dream-like feelings and a vivid sensation of floating away from the physical body (Peters et al., 2007).
Although at times preferred to other substances, such as benzodiazepines, to treat anxiety and sleep disorders in substance-dependent patients, promethazine has been reported to be misused among people with either opioid dependence (Agnich et al., 2013; Dahlman et al., 2016; Elwood, 2001; Lynch et al., 2015; Shapiro et al., 2013) or a substance abuse condition (Shapiro et al., 2013; Tang et al., 2012). A Hong Kong study reported a total of 63 patients with a diagnosis of cough mixture abuse; 89% were adult males with a mean age of onset of the abuse itself of 20 (±5) years. These subjects had received a diagnosis of substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%) and dysthymia (10%), with most cases having presented with a polysubstance misuse (Tang et al., 2012). Due to the opioid-coformulation, the promethazine-codeine cough mixture might lead to addiction (NIDA, 2014). The mixture may present a high risk of occurrence of near misses due to its central effect of respiratory depression, which is greatly increased by association with alcohol or other CNS depressants, such as sedatives/hypnotics, narcotic analgesics, general anaesthetics and tricyclic antidepressants (Burns and Boyer, 2013; Elwood, 2001; NIDA, 2014; Shapiro et al., 2013; Tsay et al., 2015). The concomitant use of promethazine and other depressant drugs should not be underestimated, as they might together contribute to and/or cause fatalities (Corkery et al., 2020).
Aim of the study
We were interested here in studying how promethazine abuse was reported to the European Medicines Agency (EMA) adverse drug reactions (ADRs) database. We aimed to analyse promethazine misuse/abuse/dependence/withdrawal data. Where possible, in order to have a better understanding, information/data related to diagnosis, concomitant drugs, administration and dosages were also examined.
Methods
Source of data
The EMA through EudraVigilance (EV) manages and analyses information on suspected ADRs to medicines authorised in the European Economic Area (EEA), according to Directive 2001/83/EC and Regulation (EC) No 726/2004 (EMA, 2017). Since November 2017, EV launched extensive Web access to data on suspected ADRs and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research (Postigo et al., 2018). Thus, access to data regarding cases of promethazine abuse, misuse, dependence and withdrawal was obtained by application to the voluntary reporting system of ADRs of the EMA. After 3 months all data comprised all of the ADRs reported during the years from 2003 up to June 2019, presented as large Excel files divided into information sections reporting in a standardised format according to the Medical Dictionary for Regulatory Activities (MedDRA), were sent through a hyperlink (MedDra, 2018). Such listings showed all information related to the ADR, the patient, the drug, the reporter and the diagnosis. An ADR was considered a voluntary and unsolicited communication reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorisation Holders for those ADRs occurring outside the EEA (EMA, 2010). Only ‘suspect’ ADRs were selected, meaning promethazine was considered as ‘suspected’ for the reaction reported. Regarding the content of the ADR, according to the standardised MedDRA Query (SMQ) (MedDRA, 2018), the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, intentional product use issue, substance abuse, substance abuser, substance use and withdrawal syndrome were selected. Those ADRs were defined in accordance with MedDRA in line with previous studies on the EV dataset (Chiappini et al., 2020; MedDRA, 2018; Schifano and Chiappini, 2018a, 2018b; Schifano et al., 2019a, 2019b). Specifically, abuse was here defined as the intentional, non-therapeutic use by a patient or consumer of a product, OTC or prescription, for a perceived reward or desired non-therapeutic effect including, but not limited to, getting high (euphoria) (MedDRA, 2018). Misuse was meant as the intentional use for a therapeutic purpose by a patient or consumer of a product, OTC or prescription, other than as prescribed or not in accordance with the authorised product information (MedDRA, 2018). Finally, non-medical use referred here to the use of a prescription drug, whether obtained by prescription or otherwise, other than in the manner or for the time period prescribed, or by a person for whom the drug was not prescribed (United Nations Office on Drugs and Crime (UNODC), 2013).
Analysis of data
We retrospectively analysed all reported ADRs which were available in the EV database. ADR reports were analysed with respect to age and gender of patient/consumer, source/reporter country (EEA or non-EEA) and reporter qualification (i.e. pharmacist, physician); type of ADR; seriousness (fatal, recovered, resolved outcomes); promethazine dosage; possible concomitant drug(s); and diagnosis/reporter’s comments, if recorded. The descriptive analysis included cases of overdoses, suicides, and fatalities. In the dataset, each case report may refer to one or more reporter; one or more ADR(s); as well as to one or more medicinal product(s). Therefore, a case may be represented by more than one row in the other line listings. The received data files were searched for duplicates by report ID through the ‘EV Local Report Number’, which unequivocally identified an individual case. Thus, the number of suspected ADRs appeared to be different from the number of case reports as one case report might refer to several suspected ADRs. Moreover, the number of patients was different from the number of case reports as a patient might have been described in more than one case. Finally, numbers of ADRs differed from those referring to case reports/single patients since different reporters/senders could have independently flagged the same ADR to the EMA. The descriptive analysis included here a study of the dataset (EMA, 2017) performed through IBM SPSS Statistics software (version 26).
Ethical issues
In compliance with applicable Personal Data Protection legislation (Regulation (EC) No 45/2001 and Regulation (EC) No 1049/2001, the protection of privacy and integrity of individuals was guaranteed, and in order to safeguard the identity of individuals certain data elements, including names/identifiers or country-specific information were not disclosed by the EMA (EMA, 2013, 2017). The study was ethically approved in March 2018 by the University of Hertfordshire Ethics’ Committee, with reference number LMS/PGR/UH/03234.
Results
The dataset obtained reported a total of 11,796 ADRs, correspond-ing to 1,543 single cases recorded during years 2003–2019 (Table 1). Safety reports were all voluntarily submitted, mostly from pharmaceutical companies (1,136/1,543: 73.6%) and regulatory authorities (398/1,543: 25.8%). Reports were irregularly reported over time, with spikes in 2010, 2014 and 2017 (Figure 1). Countries which reported most promethazine-related abuse/misuse/dependence cases included: the USA (805/1,543: 52.10%); Germany (299/1,543: 19.4%); Japan (162/1,543: 10.5%), Sweden (67/1,543: 4.3%), France (43/1,543: 2.8%) and Australia (42/1,543: 2.7%). Out of a total of 1543 cases, ‘suspect’ abuse/misuse/dependence-related cases were 557 (36.1%) and, among them, according to the preferred terms (PTs), most recorded reactions were abuse/misuse-related ADRs (458/557: 82.2%), specifically ‘drug abuse’ (300/557: 53.8%) and ‘intentional product misuse’ (117/557: 21.0%) (Table 1). ‘Suspect’ selected cases and related fatalities annually showed the same trend overall (Figure 1). Most typically, subjects reported were adult (19–64 years) and specifically of the youngest group (19–25 years); males were slightly more frequently recorded than females (M/F: 235/461: 0.51) (Table 1). Where all information was recorded, promethazine was reported as ingested alone in 74 cases, with supratherapeutic dosages, up to 2500 mg, in four cases. In combination with other drugs, most cases were associated with a 100–500 mg promethazine dose, with the maximum dosage recorded having been 8000 mg (Figure 2). The most common administration route was oral (n = 292), although the intramuscular (n = 8) and the parenteral (n = 19) ones were reported as well, see Table 1).
Table 1. Analysis of promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV) during years 2003–2019.
Individual cases (% of total within parentheses)
Total abuse/misuse/dependence cases 1543 Single cases; number of ADRs :11,796
Age range Adult (19–64 years): 648 (648/1,543: 42.0%) - mean age: 31.8 years (SD 26.55–37.05)
Adolescent (10–18 years): 23 (23/1,543: 1.5%) – mean age: 15.9 years (SD 14.3–17.77)
Elderly (>65 years): 25 (25/1,543: 1.6%) – mean age: 72.3 years (SD 70.85–73.7)
Neonatal (hours–days) 14 (14/1,543: 0.9%) – mean age: 24 h (SD 16.6–27.4)
Infant (months–1 year): 7 (7/1,543: 0.45%) – mean age: 10 months (SD 7–13)
Child (<10 years): 4 (4: 1,543: 0.35%) – mean age: 5 years (SD 3.6–6.3)
Unknown: 822 (822/1,543: 53.2%)
Male/female 235/461: 0.51
Most represented abuse/misuse/dependence-related ADRs according to the PTs: 557 (557/1,543: 36.1%)
Abuse-related ADRs 458 (458/557: 82.2%)
Drug abuse 300
Drug abuser 15
Drug diversion 1
Intentional product misuse 117
Intentional product use issue 9
Substance abuse 11
Substance abuser 3
Substance use 2
Dependence-related ADRs 44 (44/557: 7.9%)
Dependence 4
Drug dependence 39
Substance dependence 1
Withdrawal-related ADRs 55 (55/557: 9.8%)
Withdrawal syndrome 19
Drug withdrawal convulsions 1
Drug withdrawal neonatal syndrome 18
Drug withdrawal syndrome 17
Outcome Fatal 310 (310/557: 55.6%)
Unknown 161 (161/557: 28.9%)
Recovered/resolved 55 (55/557: 9.9%)
Recovering/resolving 18 (18/557: 3.3%)
Not recovered/not resolved 13 (13/557: 2.3%)
Promethazine-cases alone 74 (with maximum dosage 2500 mg)
Promethazine-cases with other drugs Most cases (122) were over 100 mg (with maximum dosage 8000 mg)
Most common psychoactive substances used Alcohol: 114
Cocaine: 68
Cannabis: 16
Ketamine: 4
Amphetamine: 1
Most common prescription drugs used Opioids: 1187
Benzodiazepines: 914
Antidepressants: 871
Antipsychotics: 437
Z-drugs: 222
Mood stabilisers: 197
ADR: adverse drug reaction; PTs: preferred terms; SD: standard deviation.
Figure 1. Number of promethazine abuse/misuse/dependence/withdrawal cases reported by year in the EudraVigilance (EV) dataset.
Figure 2. Most represented dosages reported among all promethazine abuse/misuse/dependence/withdrawal cases recorded by the EudraVigilance (EV) dataset.
Concomitantly used drugs recorded were opioids (e.g. oxycodone and fentanyl), benzodiazepines (e.g. diazepam, alprazolam and lorazepam) and antidepressants (e.g. citalopram, venlafaxine and amitriptyline), whilst recreational drugs most represented were alcohol and cocaine (Table 1). Most reported diagnoses, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V; American Psychiatric Association (APA), 2013) related to: mood disorders, e.g. depression/depressed mood/major depression (68 cases) and bipolar disorder (14 cases); anxiety/anxiety disorders (23 cases); alcohol abuse/alcoholic/alcoholism (26 cases); and schizophrenia (14 cases). The outcome of the reactions reported included: ‘fatal’ (n=310/557; 55.6%) and secondarily ‘recovered/resolved’ (n=73; 15.2%) (Table 1). Some 27 cases were related to suicidal or self-harm behaviour, being recorded as ‘suicidal attempt/suicidal ideation’ (n=24), ‘self-injurious ideation’ (n=1), and ‘suicide attempt’ (n=2). Fatalities mostly involved adult females; in these cases, most typical ADRs recorded were ‘drug abuse’ (n=228) and ‘intentional product misuse’ (n=77) (Table 2). Opiates/opioids were the most recorded concomitant drugs (n=356), with methadone being the most represented (n=103), followed by antidepressants (n=221) and benzodiazepines (n=141). Among illicit drugs, heroin appeared to be the most represented (Table 2).
Table 2. Analysis of fatal promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV), 2003–2019.
Fatal cases on abuse/misuse/dependence/withdrawal reactions 310 (310/557 = 55.6%)
Age-range
Adult 303 (97.7%)
Adolescent 7 (2.3%)
Elderly (>65 years) –
Neonatal –
Infant –
Child –
Gender M 103 (33.2%)
F 177 (57.1%)
Unknown 30 (9.7%)
Most recorded PTs
Drug abuse/drug abuser/substance abuse 228/3/6
Intentional product misuse/Intentional product use issue 77/3
Drug dependence 1
Reported death code
Intentional overdose 1
Overdose 4
Completed suicide/suicide 7
Drug toxicity/drug abuse 197
Toxicity to various agents 48
Intentional product misuse 41
Respiratory depression 5
Pneumonia 1
Cardiac arrest 10
Drug dependence 1
Most reported concomitant drugs
Opioids 356
Methadone 103
Dihydrocodeine 1
Codeine 32
Fentanyl 44
Oxycodone 63
Morphine 55
Hydrocodone 33
Hydromorphone 3
Tramadol 22
Antidepressants 221
Duloxetine 1
Escitalopram 1
Sertraline 16
Paroxetine 34
Trazodone 15
Mirtazapine 33
Fluoxetine 24
Venlafaxine 9
Bupropion 1
Amitriptyline 35
Nortriptyline 6
Clomipramine 5
Citalopram 41
Benzodiazepines 141
Lorazepam 3
Temazepam 6
Clonazepam 21
Diazepam 60
Flunitrazepam 1
Brotizolam 1
Alprazolam 42
Midazolam 4
Oxazepam 3
Mood stabilisers 11
Gabapentin 3
Topiramate 8
Antipsychotics 24
Olanzapine 1
Quetiapine 20
Haloperidol 1
Amisulpride 1
Levomepromazine 1
Z-drugs 39
Zolpidem 37
Zopiclone 2
Illicit drugs
Amphetamine 15
Cocaine 40
Heroin 52
Alcohol 26
PTs: preferred terms.
Discussion
Non-medical prescription drug use is a globally recognised problem, with severe adverse consequences. The current study provides a large amount of descriptive data highlighting that promethazine can be taken at high dosages, through non-approved administration routes, and in a setting of polydrug use (Hughes et al., 2016; Novak et al., 2016).
Promethazine misuse has been increasingly recorded since the early 2000s, consistently with data from US poison centres reporting antihistamine exposures rising in the period 2007–2013 (Jensen et al., 2017). This is not surprising, since the pharmacodynamic properties of promethazine underpins its sought-after central effects. In 2014, e.g. the highest peak here, the increase in promethazine misuse reporting was solely driven by the USA (245/245 cases; 100%). This may have been associated with intense media attention to the subject in that year (TMZ, 2014). The increments reported in 2010, 2014 and 2017 were then followed by decrements, which may have been related to not only reporting variabilities, but also to differences in sales of antihistamines following local/national drug abuse prevention campaigns (Klein-Schwartz, 2017). Overall, the USA appeared here to be the country most involved in reporting of promethazine ADRs. Several reasons may help in explaining this, including healthcare professionals’ awareness of prescription/OTC drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Lynch et al., 2015; Manchikanti et al., 2006; NIDA, 2014; Tsay et al., 2015) which, in turn, may have facilitated pharmacovigilance reporting. According to an 11-year period of the US National Poison Centers’ database, the annual rate of promethazine abuse/misuse per 100,000 US population doubled over time (Tsay et al., 2015). In the USA, promethazine abuse/misuse has been described in teenagers and young adults (Peters et al., 2003), methadone maintenance patients, heroin users and opioid-prescribed chronic pain patients (Lynch et al., 2015; Shapiro et al., 2013).
Consistent with previous observations (Agnich et al., 2013; Burns and Boyer, 2013; Carr, 2006; Elwood, 2001; Höjer and Tellerup, 2018; NIDA, 2014; Page et al., 2009; Parker et al., 2013; Peters et al., 2007), most recorded ADRs related here to either ‘drug abuse’ and ‘intentional product misuse’, involving young adult (19–25 years) males. Although considered a vulnerable category with respect to prescription drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014; Peters et al., 2007), adolescents (10–18 years) were here reported in only a minority (23/1543:1.5%) of cases.
Several drugs were here associated with promethazine, although opiates/opioids were the most represented molecules in related fatalities. This combination might intensify effects such as sedation and analgesia (Burns and Boyer, 2013; Lynch et al., 2015; Shapiro et al., 2013), and in the 1950s the association was medically used to reduce the dosage of opiates/opioids (McGee and Weiss, 1956). However, due to a range of adverse effects (Lynch et al., 2015) including lack of data supporting clinical efficacy (Richter and Burk, 1992) and an enhanced addiction potential of opioids (Lynch et al., 2015; Peters et al., 2007; Shapiro et al., 2013), the combination of promethazine/opioids has declined in popularity.
So far, the recreational intake of promethazine with opioids has been typically reported in cough mixtures containing codeine (Casati et al., 2012; Clatts et al., 2010; Elwood, 2001; Foley et al., 2015; Peters et al., 2007). However, current EMA data suggest that, apart from methadone, oxycodone and fentanyl were the most typical opiates/opiates identified in association with promethazine, possibly due to their recent popularity, especially in the USA (Manchikanti et al., 2018; Rose, 2018). In the promethazine fatalities (e.g. 310 cases) dataset analysed, codeine, fentanyl and oxycodone were respectively reported in 32, 44 and 63 cases. Consistent with current data, a concomitant use of opioids and promethazine has been described in various subpopulations, such as methadone maintenance patients, injecting drug users and chronic pain patients (Banta-Green et al., 2005; Lynch et al., 2015; Shapiro et al., 2013; Shields et al., 2007; Van Hout and Norman, 2016). Overall, there is now a high level of awareness of the abuse potential of antihistamine/opioid-containing products (Hou et al., 2011; Hughes et al., 1999; Wazaify et al., 2005). Hence, some countries are limiting both the medication pack size levels and the quantities of drugs sold in a single transaction, whilst also promoting non-injectable and non-inhaling formulations and changing some formulations’ OTC status (Cooper, 2013; Foley et al., 2015; Van Hout and Norman, 2016).
Benzodiazepines (e.g. diazepam, alprazolam and lorazepam) were here also frequently recorded, suggesting sedative synergistic effects in combination with promethazine (Lynch et al., 2015), and hence an increased risk of untoward clinical issues (McLellan and Turner, 2010). Other prescription drug categories recorded included antidepressants (most typically: citalopram and amitriptyline, respectively in 149/557 and 95/557 cases), which is consistent with the most typically recorded diagnoses, e.g. depressive (68 cases); bipolar (14 cases); and anxiety (23 cases) disorders. It is also possible that antidepressants were here ingested in combination with promethazine for sleep induction purposes. It is a reason for concern that promethazine ADRs, either alone or in combination, resulted in either fatal (50.6%) or ‘recovered/resolved’ outcomes (22.2%). This is consistent with previous promethazine misuse/abuse data, reporting both adverse clinical outcomes and high frequency of healthcare facility treatment (Bergman and Wallman, 1998; Ichikura et al., 2016; McLellan and Turner, 2010; Tsay et al., 2015). A list of possibly misused substances which might reinforce promethazine psychoactive effects and possibly increase its toxicity is included in Table 3.
Table 3. List of substances recorded in the literature as used in association with promethazine in order to increase its effects; prescription drugs are recorded according to the Neuroscience-based Nomenclature description (Nutt and Blier, 2016).
Psychoactive substances
Description Mode of action Examples Effects
Alcohol (Burns and Boyer, 2013; Jensen et al., 2017) CNS depressant effects ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, relaxation, ‘slight giddiness and disorienting’ and ‘nice hallucination’.
It may increase, prolong or intensify promethazine sedative effect. It should be avoided in patients receiving promethazine.
Heroin and other illicit opioids (Dahlman et al., 2016; Tsay et al., 2015) Opioid depressant effects It may increase, prolong, or intensify promethazine sedative effect.
Prescription drugs
Categories Mode of action Examples Effects
Drugs for insomnia (Burns and Boyer, 2013) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Z-drugs: zaleplon, zolpidem, zopiclone, eszopiclone They may increase, prolong or intensify promethazine sedative effect.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Drugs for anxiety (Burns and Boyer, 2013; Lynch et al., 2015) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, lorazepam, oxazepam They may increase, prolong or intensify promethazine sedative action.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Dextrometorphan (Tsay et al., 2015) At high doses, acting as NMDA-receptor antagonist; dextrometorphan and its potent metabolite dextrorphan inhibit the excitatory amino acid and neurotransmitter glutamate in the brain, determining hallucinogenic and dissociative activities, which are recreationally searched It might be combined with promethazine in cough-suppressant formulation Dextrometorphan neurobehavioural effects are dose-related, starting from a mild to moderate stimulation with restlessness and euphoria (100–200 mg), to a dissociated state characterised by hallucinations, paranoia, perceptual distortions, delusional beliefs, ataxia and out-of-body experiences (‘robo-ing’/‘robo-copping’/‘robo-tripping’) (>1000 mg). In overdosage they might increase promethazine effects.
Drugs for depression (Burns and Boyer, 2013; Jensen et al., 2017): TCA Multimodal action: reuptake inhibitor (SERT and NET), receptor antagonist (5-HT2) Amitriptyline Promethazine may increase, prolong or intensify their sedative effect. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Anticholinergic drugs Antagonist at cholinergic receptors Hyoscine butyl bromide/scopolamine (Burns and Boyer, 2013) Together with promethazine an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility may be seen. A typical mental status alteration with a dose-dependent agitated delirium characterised by abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia, has been described. These molecules should be avoided or administered in reduced dosage to patients receiving promethazine.
Prescription opioids
Codeine (Burns and Boyer, 2013; Jouanjus et al., 2018; Lynch et al., 2015; O Reilly et al., 2015; Shapiro et al., 2013) ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, elation, analgesia and ‘liking’, with increased potential of addiction. Overdosage of codeine might determine respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne–Stokes respiration and cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Opiate overdosage, particularly by the intravenous route, may be associated with apnoea, circulatory collapse, cardiac arrest and death. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Other opioid analgesics (Burns and Boyer, 2013; Dahlman et al., 2016; Lynch et al., 2015; Shapiro et al., 2013) Methadone They may increase, prolong or intensify promethazine sedative effects. Opioids should be avoided or administered in reduced dosage to patients receiving promethazine.
The addiction potential of opioids might be enhanced. Also, increasing life-threatening events, such as respiratory depression, overdose and prolongation of the QT interval, might be responsible for drug-related fatalities.
5-HT2: serotonin-2 receptor; CNS: central nervous system; D2: dopamine 2 receptor; GABA: gamma-amino-butyric acid; H1: histamine 1 receptor; NE: norepinephrine; NET: norepinephrine transporter; NMDA: N-methyl-D-aspartate; SERT: serotonin transporter; SSRI: selective-serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
Finally, among abuse-related cases, neonates, infants and children were here reported as well. This is consistent with cases of unexpected infant deaths associated with use of cold medications, poor socioeconomic conditions (Rimsza and Newberry, 2008) and/or accidental ingestion (McLellan and Turner, 2010).
Limitations
One of the limitations was given here by the descriptive nature of the study. Indeed, a comparator molecule, for a disproportionality analysis (Chiappini and Schifano, 2016; Schifano and Chiappini, 2018b) to be carried out, was not available due to data access limitations (EMA, 2017; Postigo et al., 2018). Furthermore, current data did not appear to show an increasing trend of abuse or misuse across the years. Since proper denominator figures (e.g. data on worldwide promethazine prescriptions) are not available, it was unclear if what observed was a substantial number of cases, indicative of clinically meaningful abuse potential, or a passing trend for promethazine misuse by a very small number of individuals. However, consistent with previous suggestions (Montastruc et al, 2011), the value of the current study was that its rationale was driven by a proper, detailed, pharmacodynamic hypothesis established on the basic properties of promethazine. Similar to remaining pharmacovigilance datasets (EMA, 2010; Evoy et al., 2019; Schifano and Chiappini, 2018a; Schifano et al., 2019a, 2019b; Schwan et al., 2010), focussing on the analysis of voluntary adverse events, a further limitation was given here by reliance on self-reporting and the likelihood of missing data occurrence. Moreover, although healthcare professionals have a main role in detection, assessment and spontaneous reporting of ADRs (Belton, 1997; Khalili et al., 2012), specific abuse/misuse/dependence issues relating to promethazine may have been underestimated, with only the most serious cases having been reported, hence the high rates of promethazine fatalities here recorded. Furthermore, although patients and their carers are allowed indeed to flag up an ADR, it is unlikely that they have spontaneously reported misusing events. Other factors, such as increased knowledge of promethazine misuse/abuse, may have resulted here in outcome reporting bias. There was also a potential for duplicate reports, with the same report submitted by the consumer, the healthcare professional and by the manufacturer as well, causing skewed study results. This may occur when a healthcare professional reported the same suspected ADR to both the national Regulatory Authority and the Marketing Authorisation Holder and they both reported subsequently to EV. However, the EV local report number which was here considered unequivocally identified an individual case. In addition, whilst this study represents one of the largest sample of promethazine abuse events published to date, the overall number of events is still relatively small, potentially limiting external validity. Case reports of suspected ADRs alone are not always sufficient to prove that a certain suspected reaction has indeed been caused by a specific medicine. This could be a symptom of another illness, or it could be associated with another medicinal product taken by the patient at the same time. The suspected ADRs were here presented using the PTs of the MedDRA Dictionary (Postigo et al., 2018). Thus, any case report should be considered together with all available data including case reports worldwide, clinical trials, epidemiological studies and toxicological investigations, in order to allow for robust conclusions. Finally, case reports reflect the information as provided to EV by the reporter, and not all data fields were completed for all reports.
Conclusion
To the best of our understanding, the current study described in detail the largest sample ever of abuse, misuse and dependence issues related to promethazine, whilst focussing on a large multinational dataset, such as the EV. The substantial number of promethazine-related events identified over the years represents a pharmacovigilance signal which needs to be better investigated (Montastruc et al., 2011). Although the observed trend of promethazine abuse and misuse, especially in young adults, is not a new phenomenon, further details of the issue have been here provided and future studies will optimally identify the related risk factors, with these measures enabling policymakers and regulators to take action to detect and prevent such misusing practices (Jouanjus et al., 2019). A multicomponent approach is recommended, including monitoring drug utilisation, tracking users’ posts on social media, and exploring healthcare databases; this will enable performing proactive and effective post-marketing surveillance and pharmacovigilance approaches. This has proved to be a relevant, efficient and accurate strategy, for example with gabapentinoids, which have recently been rescheduled in the UK (Borg et al., 2011; Eickhoff et al., 2012; Jouanjus et al., 2019; Novak et al., 2016; Parker et al., 2013; Schifano and Chiappini, 2019; Throckmorton et al., 2018). In this context, the role of the Web is rapidly spreading, playing a significant role in the marketing, sale and distribution of drugs, hence facilitating continuous changes in drug scenarios (Orsolini et al., 2017). Indeed, over the last 10 years access to online pharmacies to purchase medicinal compounds has increased (Desai, 2016; Monteith and Glenn, 2018). On the other hand, professionals access the Web to gather data on emerging trends of drug abuse (Deluca et al., 2002; Orsolini et al., 2015; Schifano, 2020; Schifano et al., 2003).
OTC and prescription drug misuse is perceived to be a significantly under-recognised issue affecting a range of vulnerable individuals (Coombes and Cooper, 2019). However, controlling the problem of OTC misuse and abuse might be challenging, due to the need for achieving high levels of consumer safety whilst not restricting access to OTC products for those who continue to use them safely.
Staff training should be evaluated, in order for pharmacists to self-monitor care and use of medicines, to educate patients and intervene/support those experiencing problematic drug use (Elwood, 2001; GPC, 2019; Tobin et al., 2013; Wells et al., 2018). Record-keeping (Hou et al., 2011) and real time monitoring (Cairns et al., 2016) could be a method of restricting access to some OTC drugs and prevent ‘shopping’ from one pharmacy to another, and where these measures would result to be ineffective, regulatory interventions, e.g. drug re-scheduling, might be useful (Marsden et al., 2019; McDonough, 2016; Peacock et al., 2019). Also, prevention and early education on substance abuse in young teenagers are critical (Levine, 2007; Marsden et al., 2019). Finally, appropriate and specific clinical guidelines for the treatment of misuse, abuse and dependence on prescription or OTC drugs should be implemented (Fingleton et al., 2019).
The review and study design were developed by SC, FS, JMC and AG. SC drafted the first version of the manuscript with input from all authors. All authors contributed to the interpretation of the data analysis and the further drafting of the manuscript and approved the final version.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FS was a member of the UK Advisory Council on the Misuse Drugs (ACMD) from 2011–2019; and is currently an EMA Advisory board (psychiatry) member. JMC is a member of the ACMD’s Novel Psychoactive Substances and Technical Committees. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
ORCID iDs: Stefania Chiappini https://orcid.org/0000-0002-6810-1540
John Martin Corkery https://orcid.org/0000-0002-3849-817X | Fatal | ReactionOutcome | CC BY | 33427017 | 18,928,797 | 2021-06 |
What was the outcome of reaction 'Overdose'? | Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.
Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents.
We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database.
After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234).
The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used.
Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.
Introduction
Pharmacological properties of promethazine
Promethazine is a phenothiazine derivative and a histamine (H1) receptor antagonist that is commonly used for symptomatic relief of nausea and vomiting, for allergic conditions, motion sickness and common cold, and for short-term use treatment of insomnia in adults or as a paediatric sedative (EMC, 2019). It also acts as a direct antagonist at muscarinic (M1) and dopamine (D2) receptors (Cookson, 2018; Page et al., 2009; Sharma and Hamelin, 2003). Promethazine hydrochloride is well absorbed from the gastrointestinal tract, with an average of 88% of the dose absorbed after oral administration, and clinical effects appearing within 20 min after intake whilst lasting 4–6 h. The plasma half-life is approximately 7–14 h (Burns and Boyer, 2013). It is classified as a first-generation antihistamine molecule which, compared with second-generation antihistamines, easily penetrates the blood-brain barrier and is associated with adverse effects such as moderate/intense sedation (Jensen et al., 2017). Thus, promethazine might be used in rapid (acute) tranquilization due to its blocking action at H1 and M receptors (Cookson, 2018). Toxicity might result in severe impairment of cognitive and psychomotor functions due to central nervous system (CNS) depression/reduced levels of consciousness, and may cause fatalities (Jensen et al., 2017).
Availability of promethazine
Promethazine is a medicinal product available on its own or in combination with other ingredients, including dextromethorphan, paracetamol and/or expectorants. With regards to promethazine availability, there are wide variations across countries. In fact, in some European countries such as France, Italy and the UK, but also outside Europe, some medicinal products containing promethazine can be purchased over-the-counter (OTC). Promethazine was restricted from an OTC status to prescription only in Denmark as of December 2014. This restriction was partly based on increasing enquiries regarding promethazine exposures to the Danish Poison and Information Centre (DPIC), highlighting its abuse potential and subsequent observations of side-effects after ingestion of standard doses. In Australia, promethazine is available as an OTC medication either alone as a tablet or as a liquid preparation or in combination with paracetamol and codeine phosphate as a syrup (Sharma and Hamelin, 2003). In the USA, some cough preparations containing no more than 200 mg of codeine per 100 mL are considered Schedule V controlled substances (Drug Enforcement Administration (DEA), 2020), purportedly possessing the lowest potential for both misuse and development of a Substance Use Disorder (SUD).
Pharming
Recently, the potential for misuse of medications that are not already controlled has been reported worldwide (Reeves et al., 2015). ‘Pharming’ is a phenomenon involving the non-medical use of prescription (pain relievers, tranquilisers, stimulants, sedatives) and OTC drugs, including cough and cold preparations, particularly those containing dextromethorphan and promethazine (Burns and Boyer, 2013; Jouanjus et al., 2018; Levine, 2007; McCarthy, 2007; National Institute on Drug Abuse (NIDA), 2014). The abuse of these compounds may be facilitated by their easy accessibility, low cost, decreased perception of potential for harm and growing social acceptance (Burns and Boyer, 2013; Levine, 2007; McCarthy, 2007; Substance Abuse Mental Health Services Administration (SAMHSA), 2008). In the current drug abuse scenario, young people/youths have been described abusing with a range of prescription or OTC medicines (Soussan et al., 2018), with these molecules possibly being ingested at high/super-high dosages (Orsolini et al., 2015; Schifano, 2020) and at times in combination with alcohol/remaining recreational substances (Levine, 2007)
Recreational use of promethazine
Centrally acting antihistamines have long been known to induce physical and psychological dependence (Clatts et al., 2010; Gracious et al., 2010; Page et al., 2009; Saatcioglu and Evren, 2005; Thomas et al., 2008). During the past 15 years the abuse of promethazine, especially from OTC and prescription cough and cold medicines and at higher-than-recommended dosages, has been reported (NIDA, 2014). Consistent with this, during the last decade the yearly number of promethazine-related overdose cases in Sweden has increased from 100 to nearly 700 and its sales have increased threefold (Höjer and Tellerup, 2018). Also, according to the 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), antihistamines accounted for the seventh most frequently involved substance in human exposures, resulting in the third type of substance category for rate of exposure increase (Gummin et al., 2019). In Denmark, the number of registered antihistamine exposures increased during 2007–2013, with first-generation antihistamines, specifically promethazine, having been responsible for most exposures and related fatalities (Jensen et al., 2017). Also, in New Zealand a number of promethazine poisoning cases (57/199 patients) were identified from a database of poisoning admissions to a regional toxicology service (Bergman and Wallman, 1998).
Effects
Promethazine reported effects mostly include a range of CNS side effects, such as: confusion; disorientation; drowsiness; cardiovascular symptoms; and respiratory depression (Burns and Boyer, 2013; Höjer and Tellerup, 2018; Page et al., 2009; Tsay et al., 2015). A clear abuse potential has been observed and reported for first-generation antihistamines such as promethazine and cyclizine, due to: calming and sedating effects (Cookson, 2018; Jensen et al., 2017) and enhancement of other co-ingested substances, and especially those interacting with gamma-amino-butyric acid (GABA), opiate and muscarinic acetylcholine receptors (Speeg et al., 1981), leading to hallucinogenic experiences (Clatts et al., 2010; Jensen et al., 2017; Lynch et al., 2015). Indeed, an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility has been described (Burns and Boyer, 2013). In these cases, the mental state alteration is characterised by agitated delirium, with abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia (Agnich et al., 2013; Cowen, 1979; Dollberg et al., 1989; Höjer and Tellerup, 2018; Leak and Carroll, 1967; Page et al., 2009; Scott et al., 2007; Timnak et al., 2004). With the promethazine-codeine cough syrup, ‘euphoric feelings’, ‘relaxation’, ‘slight giddiness and disorienting’, and ‘nice hallucinations’ have been described as well (Bluelight.org [2020]; Erowid.org [2020]). Reported side-effects include drowsiness, fatigue, loss of coordination, constipation and urinary retention (Elwood, 2001).
Vulnerable categories
An increasing trend in abuse of promethazine in co-formulation with some components of OTC cough medications has been reported in young adult populations (Carney et al., 2018; Carr, 2006; Höjer and Tellerup, 2018) since the late 1990s, particularly in the southern USA (Carr, 2006; Elwood, 2001). Codeine and promethazine were recorded as the most requested psychoactive drugs by adolescents/young adults in community pharmacies (Delcourt et al., 2017).
Known by the street names ‘lean’, ‘drank’, ‘barre’, ‘purple stuff’, ‘syrup’ and ‘sizzurp’ (Agnich et al., 2013; NIDA, 2014; Peters et al., 2007), the abuse of promethazine mixed with opioids and other sedatives (e.g. alcohol) in a purple colour drink (‘purple drank’) (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014) has become widely popular (Agnich et al., 2013) after a rap artist/producer created a genre of music, called ‘screw music', inspired by intoxication on codeine and promethazine (Peters et al., 2007). Social media data, e.g. public posts and related hashtags on Instagram, provided additional insights into codeine abuse, depicting its common misuse combined with promethazine and soda/carbonated drinks (Cherian et al., 2018). ‘Purple drank’ has been noted for its euphoric effects and its easy accessibility (Elwood, 2001; Peters et al., 2007). ‘Lean’ creates a distinct (Jakubowski et al., 2018) feeling of euphoria and extreme relaxation (Cookson, 2018), dream-like feelings and a vivid sensation of floating away from the physical body (Peters et al., 2007).
Although at times preferred to other substances, such as benzodiazepines, to treat anxiety and sleep disorders in substance-dependent patients, promethazine has been reported to be misused among people with either opioid dependence (Agnich et al., 2013; Dahlman et al., 2016; Elwood, 2001; Lynch et al., 2015; Shapiro et al., 2013) or a substance abuse condition (Shapiro et al., 2013; Tang et al., 2012). A Hong Kong study reported a total of 63 patients with a diagnosis of cough mixture abuse; 89% were adult males with a mean age of onset of the abuse itself of 20 (±5) years. These subjects had received a diagnosis of substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%) and dysthymia (10%), with most cases having presented with a polysubstance misuse (Tang et al., 2012). Due to the opioid-coformulation, the promethazine-codeine cough mixture might lead to addiction (NIDA, 2014). The mixture may present a high risk of occurrence of near misses due to its central effect of respiratory depression, which is greatly increased by association with alcohol or other CNS depressants, such as sedatives/hypnotics, narcotic analgesics, general anaesthetics and tricyclic antidepressants (Burns and Boyer, 2013; Elwood, 2001; NIDA, 2014; Shapiro et al., 2013; Tsay et al., 2015). The concomitant use of promethazine and other depressant drugs should not be underestimated, as they might together contribute to and/or cause fatalities (Corkery et al., 2020).
Aim of the study
We were interested here in studying how promethazine abuse was reported to the European Medicines Agency (EMA) adverse drug reactions (ADRs) database. We aimed to analyse promethazine misuse/abuse/dependence/withdrawal data. Where possible, in order to have a better understanding, information/data related to diagnosis, concomitant drugs, administration and dosages were also examined.
Methods
Source of data
The EMA through EudraVigilance (EV) manages and analyses information on suspected ADRs to medicines authorised in the European Economic Area (EEA), according to Directive 2001/83/EC and Regulation (EC) No 726/2004 (EMA, 2017). Since November 2017, EV launched extensive Web access to data on suspected ADRs and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research (Postigo et al., 2018). Thus, access to data regarding cases of promethazine abuse, misuse, dependence and withdrawal was obtained by application to the voluntary reporting system of ADRs of the EMA. After 3 months all data comprised all of the ADRs reported during the years from 2003 up to June 2019, presented as large Excel files divided into information sections reporting in a standardised format according to the Medical Dictionary for Regulatory Activities (MedDRA), were sent through a hyperlink (MedDra, 2018). Such listings showed all information related to the ADR, the patient, the drug, the reporter and the diagnosis. An ADR was considered a voluntary and unsolicited communication reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorisation Holders for those ADRs occurring outside the EEA (EMA, 2010). Only ‘suspect’ ADRs were selected, meaning promethazine was considered as ‘suspected’ for the reaction reported. Regarding the content of the ADR, according to the standardised MedDRA Query (SMQ) (MedDRA, 2018), the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, intentional product use issue, substance abuse, substance abuser, substance use and withdrawal syndrome were selected. Those ADRs were defined in accordance with MedDRA in line with previous studies on the EV dataset (Chiappini et al., 2020; MedDRA, 2018; Schifano and Chiappini, 2018a, 2018b; Schifano et al., 2019a, 2019b). Specifically, abuse was here defined as the intentional, non-therapeutic use by a patient or consumer of a product, OTC or prescription, for a perceived reward or desired non-therapeutic effect including, but not limited to, getting high (euphoria) (MedDRA, 2018). Misuse was meant as the intentional use for a therapeutic purpose by a patient or consumer of a product, OTC or prescription, other than as prescribed or not in accordance with the authorised product information (MedDRA, 2018). Finally, non-medical use referred here to the use of a prescription drug, whether obtained by prescription or otherwise, other than in the manner or for the time period prescribed, or by a person for whom the drug was not prescribed (United Nations Office on Drugs and Crime (UNODC), 2013).
Analysis of data
We retrospectively analysed all reported ADRs which were available in the EV database. ADR reports were analysed with respect to age and gender of patient/consumer, source/reporter country (EEA or non-EEA) and reporter qualification (i.e. pharmacist, physician); type of ADR; seriousness (fatal, recovered, resolved outcomes); promethazine dosage; possible concomitant drug(s); and diagnosis/reporter’s comments, if recorded. The descriptive analysis included cases of overdoses, suicides, and fatalities. In the dataset, each case report may refer to one or more reporter; one or more ADR(s); as well as to one or more medicinal product(s). Therefore, a case may be represented by more than one row in the other line listings. The received data files were searched for duplicates by report ID through the ‘EV Local Report Number’, which unequivocally identified an individual case. Thus, the number of suspected ADRs appeared to be different from the number of case reports as one case report might refer to several suspected ADRs. Moreover, the number of patients was different from the number of case reports as a patient might have been described in more than one case. Finally, numbers of ADRs differed from those referring to case reports/single patients since different reporters/senders could have independently flagged the same ADR to the EMA. The descriptive analysis included here a study of the dataset (EMA, 2017) performed through IBM SPSS Statistics software (version 26).
Ethical issues
In compliance with applicable Personal Data Protection legislation (Regulation (EC) No 45/2001 and Regulation (EC) No 1049/2001, the protection of privacy and integrity of individuals was guaranteed, and in order to safeguard the identity of individuals certain data elements, including names/identifiers or country-specific information were not disclosed by the EMA (EMA, 2013, 2017). The study was ethically approved in March 2018 by the University of Hertfordshire Ethics’ Committee, with reference number LMS/PGR/UH/03234.
Results
The dataset obtained reported a total of 11,796 ADRs, correspond-ing to 1,543 single cases recorded during years 2003–2019 (Table 1). Safety reports were all voluntarily submitted, mostly from pharmaceutical companies (1,136/1,543: 73.6%) and regulatory authorities (398/1,543: 25.8%). Reports were irregularly reported over time, with spikes in 2010, 2014 and 2017 (Figure 1). Countries which reported most promethazine-related abuse/misuse/dependence cases included: the USA (805/1,543: 52.10%); Germany (299/1,543: 19.4%); Japan (162/1,543: 10.5%), Sweden (67/1,543: 4.3%), France (43/1,543: 2.8%) and Australia (42/1,543: 2.7%). Out of a total of 1543 cases, ‘suspect’ abuse/misuse/dependence-related cases were 557 (36.1%) and, among them, according to the preferred terms (PTs), most recorded reactions were abuse/misuse-related ADRs (458/557: 82.2%), specifically ‘drug abuse’ (300/557: 53.8%) and ‘intentional product misuse’ (117/557: 21.0%) (Table 1). ‘Suspect’ selected cases and related fatalities annually showed the same trend overall (Figure 1). Most typically, subjects reported were adult (19–64 years) and specifically of the youngest group (19–25 years); males were slightly more frequently recorded than females (M/F: 235/461: 0.51) (Table 1). Where all information was recorded, promethazine was reported as ingested alone in 74 cases, with supratherapeutic dosages, up to 2500 mg, in four cases. In combination with other drugs, most cases were associated with a 100–500 mg promethazine dose, with the maximum dosage recorded having been 8000 mg (Figure 2). The most common administration route was oral (n = 292), although the intramuscular (n = 8) and the parenteral (n = 19) ones were reported as well, see Table 1).
Table 1. Analysis of promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV) during years 2003–2019.
Individual cases (% of total within parentheses)
Total abuse/misuse/dependence cases 1543 Single cases; number of ADRs :11,796
Age range Adult (19–64 years): 648 (648/1,543: 42.0%) - mean age: 31.8 years (SD 26.55–37.05)
Adolescent (10–18 years): 23 (23/1,543: 1.5%) – mean age: 15.9 years (SD 14.3–17.77)
Elderly (>65 years): 25 (25/1,543: 1.6%) – mean age: 72.3 years (SD 70.85–73.7)
Neonatal (hours–days) 14 (14/1,543: 0.9%) – mean age: 24 h (SD 16.6–27.4)
Infant (months–1 year): 7 (7/1,543: 0.45%) – mean age: 10 months (SD 7–13)
Child (<10 years): 4 (4: 1,543: 0.35%) – mean age: 5 years (SD 3.6–6.3)
Unknown: 822 (822/1,543: 53.2%)
Male/female 235/461: 0.51
Most represented abuse/misuse/dependence-related ADRs according to the PTs: 557 (557/1,543: 36.1%)
Abuse-related ADRs 458 (458/557: 82.2%)
Drug abuse 300
Drug abuser 15
Drug diversion 1
Intentional product misuse 117
Intentional product use issue 9
Substance abuse 11
Substance abuser 3
Substance use 2
Dependence-related ADRs 44 (44/557: 7.9%)
Dependence 4
Drug dependence 39
Substance dependence 1
Withdrawal-related ADRs 55 (55/557: 9.8%)
Withdrawal syndrome 19
Drug withdrawal convulsions 1
Drug withdrawal neonatal syndrome 18
Drug withdrawal syndrome 17
Outcome Fatal 310 (310/557: 55.6%)
Unknown 161 (161/557: 28.9%)
Recovered/resolved 55 (55/557: 9.9%)
Recovering/resolving 18 (18/557: 3.3%)
Not recovered/not resolved 13 (13/557: 2.3%)
Promethazine-cases alone 74 (with maximum dosage 2500 mg)
Promethazine-cases with other drugs Most cases (122) were over 100 mg (with maximum dosage 8000 mg)
Most common psychoactive substances used Alcohol: 114
Cocaine: 68
Cannabis: 16
Ketamine: 4
Amphetamine: 1
Most common prescription drugs used Opioids: 1187
Benzodiazepines: 914
Antidepressants: 871
Antipsychotics: 437
Z-drugs: 222
Mood stabilisers: 197
ADR: adverse drug reaction; PTs: preferred terms; SD: standard deviation.
Figure 1. Number of promethazine abuse/misuse/dependence/withdrawal cases reported by year in the EudraVigilance (EV) dataset.
Figure 2. Most represented dosages reported among all promethazine abuse/misuse/dependence/withdrawal cases recorded by the EudraVigilance (EV) dataset.
Concomitantly used drugs recorded were opioids (e.g. oxycodone and fentanyl), benzodiazepines (e.g. diazepam, alprazolam and lorazepam) and antidepressants (e.g. citalopram, venlafaxine and amitriptyline), whilst recreational drugs most represented were alcohol and cocaine (Table 1). Most reported diagnoses, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V; American Psychiatric Association (APA), 2013) related to: mood disorders, e.g. depression/depressed mood/major depression (68 cases) and bipolar disorder (14 cases); anxiety/anxiety disorders (23 cases); alcohol abuse/alcoholic/alcoholism (26 cases); and schizophrenia (14 cases). The outcome of the reactions reported included: ‘fatal’ (n=310/557; 55.6%) and secondarily ‘recovered/resolved’ (n=73; 15.2%) (Table 1). Some 27 cases were related to suicidal or self-harm behaviour, being recorded as ‘suicidal attempt/suicidal ideation’ (n=24), ‘self-injurious ideation’ (n=1), and ‘suicide attempt’ (n=2). Fatalities mostly involved adult females; in these cases, most typical ADRs recorded were ‘drug abuse’ (n=228) and ‘intentional product misuse’ (n=77) (Table 2). Opiates/opioids were the most recorded concomitant drugs (n=356), with methadone being the most represented (n=103), followed by antidepressants (n=221) and benzodiazepines (n=141). Among illicit drugs, heroin appeared to be the most represented (Table 2).
Table 2. Analysis of fatal promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV), 2003–2019.
Fatal cases on abuse/misuse/dependence/withdrawal reactions 310 (310/557 = 55.6%)
Age-range
Adult 303 (97.7%)
Adolescent 7 (2.3%)
Elderly (>65 years) –
Neonatal –
Infant –
Child –
Gender M 103 (33.2%)
F 177 (57.1%)
Unknown 30 (9.7%)
Most recorded PTs
Drug abuse/drug abuser/substance abuse 228/3/6
Intentional product misuse/Intentional product use issue 77/3
Drug dependence 1
Reported death code
Intentional overdose 1
Overdose 4
Completed suicide/suicide 7
Drug toxicity/drug abuse 197
Toxicity to various agents 48
Intentional product misuse 41
Respiratory depression 5
Pneumonia 1
Cardiac arrest 10
Drug dependence 1
Most reported concomitant drugs
Opioids 356
Methadone 103
Dihydrocodeine 1
Codeine 32
Fentanyl 44
Oxycodone 63
Morphine 55
Hydrocodone 33
Hydromorphone 3
Tramadol 22
Antidepressants 221
Duloxetine 1
Escitalopram 1
Sertraline 16
Paroxetine 34
Trazodone 15
Mirtazapine 33
Fluoxetine 24
Venlafaxine 9
Bupropion 1
Amitriptyline 35
Nortriptyline 6
Clomipramine 5
Citalopram 41
Benzodiazepines 141
Lorazepam 3
Temazepam 6
Clonazepam 21
Diazepam 60
Flunitrazepam 1
Brotizolam 1
Alprazolam 42
Midazolam 4
Oxazepam 3
Mood stabilisers 11
Gabapentin 3
Topiramate 8
Antipsychotics 24
Olanzapine 1
Quetiapine 20
Haloperidol 1
Amisulpride 1
Levomepromazine 1
Z-drugs 39
Zolpidem 37
Zopiclone 2
Illicit drugs
Amphetamine 15
Cocaine 40
Heroin 52
Alcohol 26
PTs: preferred terms.
Discussion
Non-medical prescription drug use is a globally recognised problem, with severe adverse consequences. The current study provides a large amount of descriptive data highlighting that promethazine can be taken at high dosages, through non-approved administration routes, and in a setting of polydrug use (Hughes et al., 2016; Novak et al., 2016).
Promethazine misuse has been increasingly recorded since the early 2000s, consistently with data from US poison centres reporting antihistamine exposures rising in the period 2007–2013 (Jensen et al., 2017). This is not surprising, since the pharmacodynamic properties of promethazine underpins its sought-after central effects. In 2014, e.g. the highest peak here, the increase in promethazine misuse reporting was solely driven by the USA (245/245 cases; 100%). This may have been associated with intense media attention to the subject in that year (TMZ, 2014). The increments reported in 2010, 2014 and 2017 were then followed by decrements, which may have been related to not only reporting variabilities, but also to differences in sales of antihistamines following local/national drug abuse prevention campaigns (Klein-Schwartz, 2017). Overall, the USA appeared here to be the country most involved in reporting of promethazine ADRs. Several reasons may help in explaining this, including healthcare professionals’ awareness of prescription/OTC drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Lynch et al., 2015; Manchikanti et al., 2006; NIDA, 2014; Tsay et al., 2015) which, in turn, may have facilitated pharmacovigilance reporting. According to an 11-year period of the US National Poison Centers’ database, the annual rate of promethazine abuse/misuse per 100,000 US population doubled over time (Tsay et al., 2015). In the USA, promethazine abuse/misuse has been described in teenagers and young adults (Peters et al., 2003), methadone maintenance patients, heroin users and opioid-prescribed chronic pain patients (Lynch et al., 2015; Shapiro et al., 2013).
Consistent with previous observations (Agnich et al., 2013; Burns and Boyer, 2013; Carr, 2006; Elwood, 2001; Höjer and Tellerup, 2018; NIDA, 2014; Page et al., 2009; Parker et al., 2013; Peters et al., 2007), most recorded ADRs related here to either ‘drug abuse’ and ‘intentional product misuse’, involving young adult (19–25 years) males. Although considered a vulnerable category with respect to prescription drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014; Peters et al., 2007), adolescents (10–18 years) were here reported in only a minority (23/1543:1.5%) of cases.
Several drugs were here associated with promethazine, although opiates/opioids were the most represented molecules in related fatalities. This combination might intensify effects such as sedation and analgesia (Burns and Boyer, 2013; Lynch et al., 2015; Shapiro et al., 2013), and in the 1950s the association was medically used to reduce the dosage of opiates/opioids (McGee and Weiss, 1956). However, due to a range of adverse effects (Lynch et al., 2015) including lack of data supporting clinical efficacy (Richter and Burk, 1992) and an enhanced addiction potential of opioids (Lynch et al., 2015; Peters et al., 2007; Shapiro et al., 2013), the combination of promethazine/opioids has declined in popularity.
So far, the recreational intake of promethazine with opioids has been typically reported in cough mixtures containing codeine (Casati et al., 2012; Clatts et al., 2010; Elwood, 2001; Foley et al., 2015; Peters et al., 2007). However, current EMA data suggest that, apart from methadone, oxycodone and fentanyl were the most typical opiates/opiates identified in association with promethazine, possibly due to their recent popularity, especially in the USA (Manchikanti et al., 2018; Rose, 2018). In the promethazine fatalities (e.g. 310 cases) dataset analysed, codeine, fentanyl and oxycodone were respectively reported in 32, 44 and 63 cases. Consistent with current data, a concomitant use of opioids and promethazine has been described in various subpopulations, such as methadone maintenance patients, injecting drug users and chronic pain patients (Banta-Green et al., 2005; Lynch et al., 2015; Shapiro et al., 2013; Shields et al., 2007; Van Hout and Norman, 2016). Overall, there is now a high level of awareness of the abuse potential of antihistamine/opioid-containing products (Hou et al., 2011; Hughes et al., 1999; Wazaify et al., 2005). Hence, some countries are limiting both the medication pack size levels and the quantities of drugs sold in a single transaction, whilst also promoting non-injectable and non-inhaling formulations and changing some formulations’ OTC status (Cooper, 2013; Foley et al., 2015; Van Hout and Norman, 2016).
Benzodiazepines (e.g. diazepam, alprazolam and lorazepam) were here also frequently recorded, suggesting sedative synergistic effects in combination with promethazine (Lynch et al., 2015), and hence an increased risk of untoward clinical issues (McLellan and Turner, 2010). Other prescription drug categories recorded included antidepressants (most typically: citalopram and amitriptyline, respectively in 149/557 and 95/557 cases), which is consistent with the most typically recorded diagnoses, e.g. depressive (68 cases); bipolar (14 cases); and anxiety (23 cases) disorders. It is also possible that antidepressants were here ingested in combination with promethazine for sleep induction purposes. It is a reason for concern that promethazine ADRs, either alone or in combination, resulted in either fatal (50.6%) or ‘recovered/resolved’ outcomes (22.2%). This is consistent with previous promethazine misuse/abuse data, reporting both adverse clinical outcomes and high frequency of healthcare facility treatment (Bergman and Wallman, 1998; Ichikura et al., 2016; McLellan and Turner, 2010; Tsay et al., 2015). A list of possibly misused substances which might reinforce promethazine psychoactive effects and possibly increase its toxicity is included in Table 3.
Table 3. List of substances recorded in the literature as used in association with promethazine in order to increase its effects; prescription drugs are recorded according to the Neuroscience-based Nomenclature description (Nutt and Blier, 2016).
Psychoactive substances
Description Mode of action Examples Effects
Alcohol (Burns and Boyer, 2013; Jensen et al., 2017) CNS depressant effects ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, relaxation, ‘slight giddiness and disorienting’ and ‘nice hallucination’.
It may increase, prolong or intensify promethazine sedative effect. It should be avoided in patients receiving promethazine.
Heroin and other illicit opioids (Dahlman et al., 2016; Tsay et al., 2015) Opioid depressant effects It may increase, prolong, or intensify promethazine sedative effect.
Prescription drugs
Categories Mode of action Examples Effects
Drugs for insomnia (Burns and Boyer, 2013) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Z-drugs: zaleplon, zolpidem, zopiclone, eszopiclone They may increase, prolong or intensify promethazine sedative effect.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Drugs for anxiety (Burns and Boyer, 2013; Lynch et al., 2015) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, lorazepam, oxazepam They may increase, prolong or intensify promethazine sedative action.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Dextrometorphan (Tsay et al., 2015) At high doses, acting as NMDA-receptor antagonist; dextrometorphan and its potent metabolite dextrorphan inhibit the excitatory amino acid and neurotransmitter glutamate in the brain, determining hallucinogenic and dissociative activities, which are recreationally searched It might be combined with promethazine in cough-suppressant formulation Dextrometorphan neurobehavioural effects are dose-related, starting from a mild to moderate stimulation with restlessness and euphoria (100–200 mg), to a dissociated state characterised by hallucinations, paranoia, perceptual distortions, delusional beliefs, ataxia and out-of-body experiences (‘robo-ing’/‘robo-copping’/‘robo-tripping’) (>1000 mg). In overdosage they might increase promethazine effects.
Drugs for depression (Burns and Boyer, 2013; Jensen et al., 2017): TCA Multimodal action: reuptake inhibitor (SERT and NET), receptor antagonist (5-HT2) Amitriptyline Promethazine may increase, prolong or intensify their sedative effect. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Anticholinergic drugs Antagonist at cholinergic receptors Hyoscine butyl bromide/scopolamine (Burns and Boyer, 2013) Together with promethazine an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility may be seen. A typical mental status alteration with a dose-dependent agitated delirium characterised by abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia, has been described. These molecules should be avoided or administered in reduced dosage to patients receiving promethazine.
Prescription opioids
Codeine (Burns and Boyer, 2013; Jouanjus et al., 2018; Lynch et al., 2015; O Reilly et al., 2015; Shapiro et al., 2013) ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, elation, analgesia and ‘liking’, with increased potential of addiction. Overdosage of codeine might determine respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne–Stokes respiration and cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Opiate overdosage, particularly by the intravenous route, may be associated with apnoea, circulatory collapse, cardiac arrest and death. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Other opioid analgesics (Burns and Boyer, 2013; Dahlman et al., 2016; Lynch et al., 2015; Shapiro et al., 2013) Methadone They may increase, prolong or intensify promethazine sedative effects. Opioids should be avoided or administered in reduced dosage to patients receiving promethazine.
The addiction potential of opioids might be enhanced. Also, increasing life-threatening events, such as respiratory depression, overdose and prolongation of the QT interval, might be responsible for drug-related fatalities.
5-HT2: serotonin-2 receptor; CNS: central nervous system; D2: dopamine 2 receptor; GABA: gamma-amino-butyric acid; H1: histamine 1 receptor; NE: norepinephrine; NET: norepinephrine transporter; NMDA: N-methyl-D-aspartate; SERT: serotonin transporter; SSRI: selective-serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
Finally, among abuse-related cases, neonates, infants and children were here reported as well. This is consistent with cases of unexpected infant deaths associated with use of cold medications, poor socioeconomic conditions (Rimsza and Newberry, 2008) and/or accidental ingestion (McLellan and Turner, 2010).
Limitations
One of the limitations was given here by the descriptive nature of the study. Indeed, a comparator molecule, for a disproportionality analysis (Chiappini and Schifano, 2016; Schifano and Chiappini, 2018b) to be carried out, was not available due to data access limitations (EMA, 2017; Postigo et al., 2018). Furthermore, current data did not appear to show an increasing trend of abuse or misuse across the years. Since proper denominator figures (e.g. data on worldwide promethazine prescriptions) are not available, it was unclear if what observed was a substantial number of cases, indicative of clinically meaningful abuse potential, or a passing trend for promethazine misuse by a very small number of individuals. However, consistent with previous suggestions (Montastruc et al, 2011), the value of the current study was that its rationale was driven by a proper, detailed, pharmacodynamic hypothesis established on the basic properties of promethazine. Similar to remaining pharmacovigilance datasets (EMA, 2010; Evoy et al., 2019; Schifano and Chiappini, 2018a; Schifano et al., 2019a, 2019b; Schwan et al., 2010), focussing on the analysis of voluntary adverse events, a further limitation was given here by reliance on self-reporting and the likelihood of missing data occurrence. Moreover, although healthcare professionals have a main role in detection, assessment and spontaneous reporting of ADRs (Belton, 1997; Khalili et al., 2012), specific abuse/misuse/dependence issues relating to promethazine may have been underestimated, with only the most serious cases having been reported, hence the high rates of promethazine fatalities here recorded. Furthermore, although patients and their carers are allowed indeed to flag up an ADR, it is unlikely that they have spontaneously reported misusing events. Other factors, such as increased knowledge of promethazine misuse/abuse, may have resulted here in outcome reporting bias. There was also a potential for duplicate reports, with the same report submitted by the consumer, the healthcare professional and by the manufacturer as well, causing skewed study results. This may occur when a healthcare professional reported the same suspected ADR to both the national Regulatory Authority and the Marketing Authorisation Holder and they both reported subsequently to EV. However, the EV local report number which was here considered unequivocally identified an individual case. In addition, whilst this study represents one of the largest sample of promethazine abuse events published to date, the overall number of events is still relatively small, potentially limiting external validity. Case reports of suspected ADRs alone are not always sufficient to prove that a certain suspected reaction has indeed been caused by a specific medicine. This could be a symptom of another illness, or it could be associated with another medicinal product taken by the patient at the same time. The suspected ADRs were here presented using the PTs of the MedDRA Dictionary (Postigo et al., 2018). Thus, any case report should be considered together with all available data including case reports worldwide, clinical trials, epidemiological studies and toxicological investigations, in order to allow for robust conclusions. Finally, case reports reflect the information as provided to EV by the reporter, and not all data fields were completed for all reports.
Conclusion
To the best of our understanding, the current study described in detail the largest sample ever of abuse, misuse and dependence issues related to promethazine, whilst focussing on a large multinational dataset, such as the EV. The substantial number of promethazine-related events identified over the years represents a pharmacovigilance signal which needs to be better investigated (Montastruc et al., 2011). Although the observed trend of promethazine abuse and misuse, especially in young adults, is not a new phenomenon, further details of the issue have been here provided and future studies will optimally identify the related risk factors, with these measures enabling policymakers and regulators to take action to detect and prevent such misusing practices (Jouanjus et al., 2019). A multicomponent approach is recommended, including monitoring drug utilisation, tracking users’ posts on social media, and exploring healthcare databases; this will enable performing proactive and effective post-marketing surveillance and pharmacovigilance approaches. This has proved to be a relevant, efficient and accurate strategy, for example with gabapentinoids, which have recently been rescheduled in the UK (Borg et al., 2011; Eickhoff et al., 2012; Jouanjus et al., 2019; Novak et al., 2016; Parker et al., 2013; Schifano and Chiappini, 2019; Throckmorton et al., 2018). In this context, the role of the Web is rapidly spreading, playing a significant role in the marketing, sale and distribution of drugs, hence facilitating continuous changes in drug scenarios (Orsolini et al., 2017). Indeed, over the last 10 years access to online pharmacies to purchase medicinal compounds has increased (Desai, 2016; Monteith and Glenn, 2018). On the other hand, professionals access the Web to gather data on emerging trends of drug abuse (Deluca et al., 2002; Orsolini et al., 2015; Schifano, 2020; Schifano et al., 2003).
OTC and prescription drug misuse is perceived to be a significantly under-recognised issue affecting a range of vulnerable individuals (Coombes and Cooper, 2019). However, controlling the problem of OTC misuse and abuse might be challenging, due to the need for achieving high levels of consumer safety whilst not restricting access to OTC products for those who continue to use them safely.
Staff training should be evaluated, in order for pharmacists to self-monitor care and use of medicines, to educate patients and intervene/support those experiencing problematic drug use (Elwood, 2001; GPC, 2019; Tobin et al., 2013; Wells et al., 2018). Record-keeping (Hou et al., 2011) and real time monitoring (Cairns et al., 2016) could be a method of restricting access to some OTC drugs and prevent ‘shopping’ from one pharmacy to another, and where these measures would result to be ineffective, regulatory interventions, e.g. drug re-scheduling, might be useful (Marsden et al., 2019; McDonough, 2016; Peacock et al., 2019). Also, prevention and early education on substance abuse in young teenagers are critical (Levine, 2007; Marsden et al., 2019). Finally, appropriate and specific clinical guidelines for the treatment of misuse, abuse and dependence on prescription or OTC drugs should be implemented (Fingleton et al., 2019).
The review and study design were developed by SC, FS, JMC and AG. SC drafted the first version of the manuscript with input from all authors. All authors contributed to the interpretation of the data analysis and the further drafting of the manuscript and approved the final version.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FS was a member of the UK Advisory Council on the Misuse Drugs (ACMD) from 2011–2019; and is currently an EMA Advisory board (psychiatry) member. JMC is a member of the ACMD’s Novel Psychoactive Substances and Technical Committees. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
ORCID iDs: Stefania Chiappini https://orcid.org/0000-0002-6810-1540
John Martin Corkery https://orcid.org/0000-0002-3849-817X | Fatal | ReactionOutcome | CC BY | 33427017 | 18,928,797 | 2021-06 |
What was the outcome of reaction 'Pneumonia'? | Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.
Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents.
We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database.
After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234).
The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used.
Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.
Introduction
Pharmacological properties of promethazine
Promethazine is a phenothiazine derivative and a histamine (H1) receptor antagonist that is commonly used for symptomatic relief of nausea and vomiting, for allergic conditions, motion sickness and common cold, and for short-term use treatment of insomnia in adults or as a paediatric sedative (EMC, 2019). It also acts as a direct antagonist at muscarinic (M1) and dopamine (D2) receptors (Cookson, 2018; Page et al., 2009; Sharma and Hamelin, 2003). Promethazine hydrochloride is well absorbed from the gastrointestinal tract, with an average of 88% of the dose absorbed after oral administration, and clinical effects appearing within 20 min after intake whilst lasting 4–6 h. The plasma half-life is approximately 7–14 h (Burns and Boyer, 2013). It is classified as a first-generation antihistamine molecule which, compared with second-generation antihistamines, easily penetrates the blood-brain barrier and is associated with adverse effects such as moderate/intense sedation (Jensen et al., 2017). Thus, promethazine might be used in rapid (acute) tranquilization due to its blocking action at H1 and M receptors (Cookson, 2018). Toxicity might result in severe impairment of cognitive and psychomotor functions due to central nervous system (CNS) depression/reduced levels of consciousness, and may cause fatalities (Jensen et al., 2017).
Availability of promethazine
Promethazine is a medicinal product available on its own or in combination with other ingredients, including dextromethorphan, paracetamol and/or expectorants. With regards to promethazine availability, there are wide variations across countries. In fact, in some European countries such as France, Italy and the UK, but also outside Europe, some medicinal products containing promethazine can be purchased over-the-counter (OTC). Promethazine was restricted from an OTC status to prescription only in Denmark as of December 2014. This restriction was partly based on increasing enquiries regarding promethazine exposures to the Danish Poison and Information Centre (DPIC), highlighting its abuse potential and subsequent observations of side-effects after ingestion of standard doses. In Australia, promethazine is available as an OTC medication either alone as a tablet or as a liquid preparation or in combination with paracetamol and codeine phosphate as a syrup (Sharma and Hamelin, 2003). In the USA, some cough preparations containing no more than 200 mg of codeine per 100 mL are considered Schedule V controlled substances (Drug Enforcement Administration (DEA), 2020), purportedly possessing the lowest potential for both misuse and development of a Substance Use Disorder (SUD).
Pharming
Recently, the potential for misuse of medications that are not already controlled has been reported worldwide (Reeves et al., 2015). ‘Pharming’ is a phenomenon involving the non-medical use of prescription (pain relievers, tranquilisers, stimulants, sedatives) and OTC drugs, including cough and cold preparations, particularly those containing dextromethorphan and promethazine (Burns and Boyer, 2013; Jouanjus et al., 2018; Levine, 2007; McCarthy, 2007; National Institute on Drug Abuse (NIDA), 2014). The abuse of these compounds may be facilitated by their easy accessibility, low cost, decreased perception of potential for harm and growing social acceptance (Burns and Boyer, 2013; Levine, 2007; McCarthy, 2007; Substance Abuse Mental Health Services Administration (SAMHSA), 2008). In the current drug abuse scenario, young people/youths have been described abusing with a range of prescription or OTC medicines (Soussan et al., 2018), with these molecules possibly being ingested at high/super-high dosages (Orsolini et al., 2015; Schifano, 2020) and at times in combination with alcohol/remaining recreational substances (Levine, 2007)
Recreational use of promethazine
Centrally acting antihistamines have long been known to induce physical and psychological dependence (Clatts et al., 2010; Gracious et al., 2010; Page et al., 2009; Saatcioglu and Evren, 2005; Thomas et al., 2008). During the past 15 years the abuse of promethazine, especially from OTC and prescription cough and cold medicines and at higher-than-recommended dosages, has been reported (NIDA, 2014). Consistent with this, during the last decade the yearly number of promethazine-related overdose cases in Sweden has increased from 100 to nearly 700 and its sales have increased threefold (Höjer and Tellerup, 2018). Also, according to the 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), antihistamines accounted for the seventh most frequently involved substance in human exposures, resulting in the third type of substance category for rate of exposure increase (Gummin et al., 2019). In Denmark, the number of registered antihistamine exposures increased during 2007–2013, with first-generation antihistamines, specifically promethazine, having been responsible for most exposures and related fatalities (Jensen et al., 2017). Also, in New Zealand a number of promethazine poisoning cases (57/199 patients) were identified from a database of poisoning admissions to a regional toxicology service (Bergman and Wallman, 1998).
Effects
Promethazine reported effects mostly include a range of CNS side effects, such as: confusion; disorientation; drowsiness; cardiovascular symptoms; and respiratory depression (Burns and Boyer, 2013; Höjer and Tellerup, 2018; Page et al., 2009; Tsay et al., 2015). A clear abuse potential has been observed and reported for first-generation antihistamines such as promethazine and cyclizine, due to: calming and sedating effects (Cookson, 2018; Jensen et al., 2017) and enhancement of other co-ingested substances, and especially those interacting with gamma-amino-butyric acid (GABA), opiate and muscarinic acetylcholine receptors (Speeg et al., 1981), leading to hallucinogenic experiences (Clatts et al., 2010; Jensen et al., 2017; Lynch et al., 2015). Indeed, an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility has been described (Burns and Boyer, 2013). In these cases, the mental state alteration is characterised by agitated delirium, with abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia (Agnich et al., 2013; Cowen, 1979; Dollberg et al., 1989; Höjer and Tellerup, 2018; Leak and Carroll, 1967; Page et al., 2009; Scott et al., 2007; Timnak et al., 2004). With the promethazine-codeine cough syrup, ‘euphoric feelings’, ‘relaxation’, ‘slight giddiness and disorienting’, and ‘nice hallucinations’ have been described as well (Bluelight.org [2020]; Erowid.org [2020]). Reported side-effects include drowsiness, fatigue, loss of coordination, constipation and urinary retention (Elwood, 2001).
Vulnerable categories
An increasing trend in abuse of promethazine in co-formulation with some components of OTC cough medications has been reported in young adult populations (Carney et al., 2018; Carr, 2006; Höjer and Tellerup, 2018) since the late 1990s, particularly in the southern USA (Carr, 2006; Elwood, 2001). Codeine and promethazine were recorded as the most requested psychoactive drugs by adolescents/young adults in community pharmacies (Delcourt et al., 2017).
Known by the street names ‘lean’, ‘drank’, ‘barre’, ‘purple stuff’, ‘syrup’ and ‘sizzurp’ (Agnich et al., 2013; NIDA, 2014; Peters et al., 2007), the abuse of promethazine mixed with opioids and other sedatives (e.g. alcohol) in a purple colour drink (‘purple drank’) (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014) has become widely popular (Agnich et al., 2013) after a rap artist/producer created a genre of music, called ‘screw music', inspired by intoxication on codeine and promethazine (Peters et al., 2007). Social media data, e.g. public posts and related hashtags on Instagram, provided additional insights into codeine abuse, depicting its common misuse combined with promethazine and soda/carbonated drinks (Cherian et al., 2018). ‘Purple drank’ has been noted for its euphoric effects and its easy accessibility (Elwood, 2001; Peters et al., 2007). ‘Lean’ creates a distinct (Jakubowski et al., 2018) feeling of euphoria and extreme relaxation (Cookson, 2018), dream-like feelings and a vivid sensation of floating away from the physical body (Peters et al., 2007).
Although at times preferred to other substances, such as benzodiazepines, to treat anxiety and sleep disorders in substance-dependent patients, promethazine has been reported to be misused among people with either opioid dependence (Agnich et al., 2013; Dahlman et al., 2016; Elwood, 2001; Lynch et al., 2015; Shapiro et al., 2013) or a substance abuse condition (Shapiro et al., 2013; Tang et al., 2012). A Hong Kong study reported a total of 63 patients with a diagnosis of cough mixture abuse; 89% were adult males with a mean age of onset of the abuse itself of 20 (±5) years. These subjects had received a diagnosis of substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%) and dysthymia (10%), with most cases having presented with a polysubstance misuse (Tang et al., 2012). Due to the opioid-coformulation, the promethazine-codeine cough mixture might lead to addiction (NIDA, 2014). The mixture may present a high risk of occurrence of near misses due to its central effect of respiratory depression, which is greatly increased by association with alcohol or other CNS depressants, such as sedatives/hypnotics, narcotic analgesics, general anaesthetics and tricyclic antidepressants (Burns and Boyer, 2013; Elwood, 2001; NIDA, 2014; Shapiro et al., 2013; Tsay et al., 2015). The concomitant use of promethazine and other depressant drugs should not be underestimated, as they might together contribute to and/or cause fatalities (Corkery et al., 2020).
Aim of the study
We were interested here in studying how promethazine abuse was reported to the European Medicines Agency (EMA) adverse drug reactions (ADRs) database. We aimed to analyse promethazine misuse/abuse/dependence/withdrawal data. Where possible, in order to have a better understanding, information/data related to diagnosis, concomitant drugs, administration and dosages were also examined.
Methods
Source of data
The EMA through EudraVigilance (EV) manages and analyses information on suspected ADRs to medicines authorised in the European Economic Area (EEA), according to Directive 2001/83/EC and Regulation (EC) No 726/2004 (EMA, 2017). Since November 2017, EV launched extensive Web access to data on suspected ADRs and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research (Postigo et al., 2018). Thus, access to data regarding cases of promethazine abuse, misuse, dependence and withdrawal was obtained by application to the voluntary reporting system of ADRs of the EMA. After 3 months all data comprised all of the ADRs reported during the years from 2003 up to June 2019, presented as large Excel files divided into information sections reporting in a standardised format according to the Medical Dictionary for Regulatory Activities (MedDRA), were sent through a hyperlink (MedDra, 2018). Such listings showed all information related to the ADR, the patient, the drug, the reporter and the diagnosis. An ADR was considered a voluntary and unsolicited communication reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorisation Holders for those ADRs occurring outside the EEA (EMA, 2010). Only ‘suspect’ ADRs were selected, meaning promethazine was considered as ‘suspected’ for the reaction reported. Regarding the content of the ADR, according to the standardised MedDRA Query (SMQ) (MedDRA, 2018), the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, intentional product use issue, substance abuse, substance abuser, substance use and withdrawal syndrome were selected. Those ADRs were defined in accordance with MedDRA in line with previous studies on the EV dataset (Chiappini et al., 2020; MedDRA, 2018; Schifano and Chiappini, 2018a, 2018b; Schifano et al., 2019a, 2019b). Specifically, abuse was here defined as the intentional, non-therapeutic use by a patient or consumer of a product, OTC or prescription, for a perceived reward or desired non-therapeutic effect including, but not limited to, getting high (euphoria) (MedDRA, 2018). Misuse was meant as the intentional use for a therapeutic purpose by a patient or consumer of a product, OTC or prescription, other than as prescribed or not in accordance with the authorised product information (MedDRA, 2018). Finally, non-medical use referred here to the use of a prescription drug, whether obtained by prescription or otherwise, other than in the manner or for the time period prescribed, or by a person for whom the drug was not prescribed (United Nations Office on Drugs and Crime (UNODC), 2013).
Analysis of data
We retrospectively analysed all reported ADRs which were available in the EV database. ADR reports were analysed with respect to age and gender of patient/consumer, source/reporter country (EEA or non-EEA) and reporter qualification (i.e. pharmacist, physician); type of ADR; seriousness (fatal, recovered, resolved outcomes); promethazine dosage; possible concomitant drug(s); and diagnosis/reporter’s comments, if recorded. The descriptive analysis included cases of overdoses, suicides, and fatalities. In the dataset, each case report may refer to one or more reporter; one or more ADR(s); as well as to one or more medicinal product(s). Therefore, a case may be represented by more than one row in the other line listings. The received data files were searched for duplicates by report ID through the ‘EV Local Report Number’, which unequivocally identified an individual case. Thus, the number of suspected ADRs appeared to be different from the number of case reports as one case report might refer to several suspected ADRs. Moreover, the number of patients was different from the number of case reports as a patient might have been described in more than one case. Finally, numbers of ADRs differed from those referring to case reports/single patients since different reporters/senders could have independently flagged the same ADR to the EMA. The descriptive analysis included here a study of the dataset (EMA, 2017) performed through IBM SPSS Statistics software (version 26).
Ethical issues
In compliance with applicable Personal Data Protection legislation (Regulation (EC) No 45/2001 and Regulation (EC) No 1049/2001, the protection of privacy and integrity of individuals was guaranteed, and in order to safeguard the identity of individuals certain data elements, including names/identifiers or country-specific information were not disclosed by the EMA (EMA, 2013, 2017). The study was ethically approved in March 2018 by the University of Hertfordshire Ethics’ Committee, with reference number LMS/PGR/UH/03234.
Results
The dataset obtained reported a total of 11,796 ADRs, correspond-ing to 1,543 single cases recorded during years 2003–2019 (Table 1). Safety reports were all voluntarily submitted, mostly from pharmaceutical companies (1,136/1,543: 73.6%) and regulatory authorities (398/1,543: 25.8%). Reports were irregularly reported over time, with spikes in 2010, 2014 and 2017 (Figure 1). Countries which reported most promethazine-related abuse/misuse/dependence cases included: the USA (805/1,543: 52.10%); Germany (299/1,543: 19.4%); Japan (162/1,543: 10.5%), Sweden (67/1,543: 4.3%), France (43/1,543: 2.8%) and Australia (42/1,543: 2.7%). Out of a total of 1543 cases, ‘suspect’ abuse/misuse/dependence-related cases were 557 (36.1%) and, among them, according to the preferred terms (PTs), most recorded reactions were abuse/misuse-related ADRs (458/557: 82.2%), specifically ‘drug abuse’ (300/557: 53.8%) and ‘intentional product misuse’ (117/557: 21.0%) (Table 1). ‘Suspect’ selected cases and related fatalities annually showed the same trend overall (Figure 1). Most typically, subjects reported were adult (19–64 years) and specifically of the youngest group (19–25 years); males were slightly more frequently recorded than females (M/F: 235/461: 0.51) (Table 1). Where all information was recorded, promethazine was reported as ingested alone in 74 cases, with supratherapeutic dosages, up to 2500 mg, in four cases. In combination with other drugs, most cases were associated with a 100–500 mg promethazine dose, with the maximum dosage recorded having been 8000 mg (Figure 2). The most common administration route was oral (n = 292), although the intramuscular (n = 8) and the parenteral (n = 19) ones were reported as well, see Table 1).
Table 1. Analysis of promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV) during years 2003–2019.
Individual cases (% of total within parentheses)
Total abuse/misuse/dependence cases 1543 Single cases; number of ADRs :11,796
Age range Adult (19–64 years): 648 (648/1,543: 42.0%) - mean age: 31.8 years (SD 26.55–37.05)
Adolescent (10–18 years): 23 (23/1,543: 1.5%) – mean age: 15.9 years (SD 14.3–17.77)
Elderly (>65 years): 25 (25/1,543: 1.6%) – mean age: 72.3 years (SD 70.85–73.7)
Neonatal (hours–days) 14 (14/1,543: 0.9%) – mean age: 24 h (SD 16.6–27.4)
Infant (months–1 year): 7 (7/1,543: 0.45%) – mean age: 10 months (SD 7–13)
Child (<10 years): 4 (4: 1,543: 0.35%) – mean age: 5 years (SD 3.6–6.3)
Unknown: 822 (822/1,543: 53.2%)
Male/female 235/461: 0.51
Most represented abuse/misuse/dependence-related ADRs according to the PTs: 557 (557/1,543: 36.1%)
Abuse-related ADRs 458 (458/557: 82.2%)
Drug abuse 300
Drug abuser 15
Drug diversion 1
Intentional product misuse 117
Intentional product use issue 9
Substance abuse 11
Substance abuser 3
Substance use 2
Dependence-related ADRs 44 (44/557: 7.9%)
Dependence 4
Drug dependence 39
Substance dependence 1
Withdrawal-related ADRs 55 (55/557: 9.8%)
Withdrawal syndrome 19
Drug withdrawal convulsions 1
Drug withdrawal neonatal syndrome 18
Drug withdrawal syndrome 17
Outcome Fatal 310 (310/557: 55.6%)
Unknown 161 (161/557: 28.9%)
Recovered/resolved 55 (55/557: 9.9%)
Recovering/resolving 18 (18/557: 3.3%)
Not recovered/not resolved 13 (13/557: 2.3%)
Promethazine-cases alone 74 (with maximum dosage 2500 mg)
Promethazine-cases with other drugs Most cases (122) were over 100 mg (with maximum dosage 8000 mg)
Most common psychoactive substances used Alcohol: 114
Cocaine: 68
Cannabis: 16
Ketamine: 4
Amphetamine: 1
Most common prescription drugs used Opioids: 1187
Benzodiazepines: 914
Antidepressants: 871
Antipsychotics: 437
Z-drugs: 222
Mood stabilisers: 197
ADR: adverse drug reaction; PTs: preferred terms; SD: standard deviation.
Figure 1. Number of promethazine abuse/misuse/dependence/withdrawal cases reported by year in the EudraVigilance (EV) dataset.
Figure 2. Most represented dosages reported among all promethazine abuse/misuse/dependence/withdrawal cases recorded by the EudraVigilance (EV) dataset.
Concomitantly used drugs recorded were opioids (e.g. oxycodone and fentanyl), benzodiazepines (e.g. diazepam, alprazolam and lorazepam) and antidepressants (e.g. citalopram, venlafaxine and amitriptyline), whilst recreational drugs most represented were alcohol and cocaine (Table 1). Most reported diagnoses, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V; American Psychiatric Association (APA), 2013) related to: mood disorders, e.g. depression/depressed mood/major depression (68 cases) and bipolar disorder (14 cases); anxiety/anxiety disorders (23 cases); alcohol abuse/alcoholic/alcoholism (26 cases); and schizophrenia (14 cases). The outcome of the reactions reported included: ‘fatal’ (n=310/557; 55.6%) and secondarily ‘recovered/resolved’ (n=73; 15.2%) (Table 1). Some 27 cases were related to suicidal or self-harm behaviour, being recorded as ‘suicidal attempt/suicidal ideation’ (n=24), ‘self-injurious ideation’ (n=1), and ‘suicide attempt’ (n=2). Fatalities mostly involved adult females; in these cases, most typical ADRs recorded were ‘drug abuse’ (n=228) and ‘intentional product misuse’ (n=77) (Table 2). Opiates/opioids were the most recorded concomitant drugs (n=356), with methadone being the most represented (n=103), followed by antidepressants (n=221) and benzodiazepines (n=141). Among illicit drugs, heroin appeared to be the most represented (Table 2).
Table 2. Analysis of fatal promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV), 2003–2019.
Fatal cases on abuse/misuse/dependence/withdrawal reactions 310 (310/557 = 55.6%)
Age-range
Adult 303 (97.7%)
Adolescent 7 (2.3%)
Elderly (>65 years) –
Neonatal –
Infant –
Child –
Gender M 103 (33.2%)
F 177 (57.1%)
Unknown 30 (9.7%)
Most recorded PTs
Drug abuse/drug abuser/substance abuse 228/3/6
Intentional product misuse/Intentional product use issue 77/3
Drug dependence 1
Reported death code
Intentional overdose 1
Overdose 4
Completed suicide/suicide 7
Drug toxicity/drug abuse 197
Toxicity to various agents 48
Intentional product misuse 41
Respiratory depression 5
Pneumonia 1
Cardiac arrest 10
Drug dependence 1
Most reported concomitant drugs
Opioids 356
Methadone 103
Dihydrocodeine 1
Codeine 32
Fentanyl 44
Oxycodone 63
Morphine 55
Hydrocodone 33
Hydromorphone 3
Tramadol 22
Antidepressants 221
Duloxetine 1
Escitalopram 1
Sertraline 16
Paroxetine 34
Trazodone 15
Mirtazapine 33
Fluoxetine 24
Venlafaxine 9
Bupropion 1
Amitriptyline 35
Nortriptyline 6
Clomipramine 5
Citalopram 41
Benzodiazepines 141
Lorazepam 3
Temazepam 6
Clonazepam 21
Diazepam 60
Flunitrazepam 1
Brotizolam 1
Alprazolam 42
Midazolam 4
Oxazepam 3
Mood stabilisers 11
Gabapentin 3
Topiramate 8
Antipsychotics 24
Olanzapine 1
Quetiapine 20
Haloperidol 1
Amisulpride 1
Levomepromazine 1
Z-drugs 39
Zolpidem 37
Zopiclone 2
Illicit drugs
Amphetamine 15
Cocaine 40
Heroin 52
Alcohol 26
PTs: preferred terms.
Discussion
Non-medical prescription drug use is a globally recognised problem, with severe adverse consequences. The current study provides a large amount of descriptive data highlighting that promethazine can be taken at high dosages, through non-approved administration routes, and in a setting of polydrug use (Hughes et al., 2016; Novak et al., 2016).
Promethazine misuse has been increasingly recorded since the early 2000s, consistently with data from US poison centres reporting antihistamine exposures rising in the period 2007–2013 (Jensen et al., 2017). This is not surprising, since the pharmacodynamic properties of promethazine underpins its sought-after central effects. In 2014, e.g. the highest peak here, the increase in promethazine misuse reporting was solely driven by the USA (245/245 cases; 100%). This may have been associated with intense media attention to the subject in that year (TMZ, 2014). The increments reported in 2010, 2014 and 2017 were then followed by decrements, which may have been related to not only reporting variabilities, but also to differences in sales of antihistamines following local/national drug abuse prevention campaigns (Klein-Schwartz, 2017). Overall, the USA appeared here to be the country most involved in reporting of promethazine ADRs. Several reasons may help in explaining this, including healthcare professionals’ awareness of prescription/OTC drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Lynch et al., 2015; Manchikanti et al., 2006; NIDA, 2014; Tsay et al., 2015) which, in turn, may have facilitated pharmacovigilance reporting. According to an 11-year period of the US National Poison Centers’ database, the annual rate of promethazine abuse/misuse per 100,000 US population doubled over time (Tsay et al., 2015). In the USA, promethazine abuse/misuse has been described in teenagers and young adults (Peters et al., 2003), methadone maintenance patients, heroin users and opioid-prescribed chronic pain patients (Lynch et al., 2015; Shapiro et al., 2013).
Consistent with previous observations (Agnich et al., 2013; Burns and Boyer, 2013; Carr, 2006; Elwood, 2001; Höjer and Tellerup, 2018; NIDA, 2014; Page et al., 2009; Parker et al., 2013; Peters et al., 2007), most recorded ADRs related here to either ‘drug abuse’ and ‘intentional product misuse’, involving young adult (19–25 years) males. Although considered a vulnerable category with respect to prescription drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014; Peters et al., 2007), adolescents (10–18 years) were here reported in only a minority (23/1543:1.5%) of cases.
Several drugs were here associated with promethazine, although opiates/opioids were the most represented molecules in related fatalities. This combination might intensify effects such as sedation and analgesia (Burns and Boyer, 2013; Lynch et al., 2015; Shapiro et al., 2013), and in the 1950s the association was medically used to reduce the dosage of opiates/opioids (McGee and Weiss, 1956). However, due to a range of adverse effects (Lynch et al., 2015) including lack of data supporting clinical efficacy (Richter and Burk, 1992) and an enhanced addiction potential of opioids (Lynch et al., 2015; Peters et al., 2007; Shapiro et al., 2013), the combination of promethazine/opioids has declined in popularity.
So far, the recreational intake of promethazine with opioids has been typically reported in cough mixtures containing codeine (Casati et al., 2012; Clatts et al., 2010; Elwood, 2001; Foley et al., 2015; Peters et al., 2007). However, current EMA data suggest that, apart from methadone, oxycodone and fentanyl were the most typical opiates/opiates identified in association with promethazine, possibly due to their recent popularity, especially in the USA (Manchikanti et al., 2018; Rose, 2018). In the promethazine fatalities (e.g. 310 cases) dataset analysed, codeine, fentanyl and oxycodone were respectively reported in 32, 44 and 63 cases. Consistent with current data, a concomitant use of opioids and promethazine has been described in various subpopulations, such as methadone maintenance patients, injecting drug users and chronic pain patients (Banta-Green et al., 2005; Lynch et al., 2015; Shapiro et al., 2013; Shields et al., 2007; Van Hout and Norman, 2016). Overall, there is now a high level of awareness of the abuse potential of antihistamine/opioid-containing products (Hou et al., 2011; Hughes et al., 1999; Wazaify et al., 2005). Hence, some countries are limiting both the medication pack size levels and the quantities of drugs sold in a single transaction, whilst also promoting non-injectable and non-inhaling formulations and changing some formulations’ OTC status (Cooper, 2013; Foley et al., 2015; Van Hout and Norman, 2016).
Benzodiazepines (e.g. diazepam, alprazolam and lorazepam) were here also frequently recorded, suggesting sedative synergistic effects in combination with promethazine (Lynch et al., 2015), and hence an increased risk of untoward clinical issues (McLellan and Turner, 2010). Other prescription drug categories recorded included antidepressants (most typically: citalopram and amitriptyline, respectively in 149/557 and 95/557 cases), which is consistent with the most typically recorded diagnoses, e.g. depressive (68 cases); bipolar (14 cases); and anxiety (23 cases) disorders. It is also possible that antidepressants were here ingested in combination with promethazine for sleep induction purposes. It is a reason for concern that promethazine ADRs, either alone or in combination, resulted in either fatal (50.6%) or ‘recovered/resolved’ outcomes (22.2%). This is consistent with previous promethazine misuse/abuse data, reporting both adverse clinical outcomes and high frequency of healthcare facility treatment (Bergman and Wallman, 1998; Ichikura et al., 2016; McLellan and Turner, 2010; Tsay et al., 2015). A list of possibly misused substances which might reinforce promethazine psychoactive effects and possibly increase its toxicity is included in Table 3.
Table 3. List of substances recorded in the literature as used in association with promethazine in order to increase its effects; prescription drugs are recorded according to the Neuroscience-based Nomenclature description (Nutt and Blier, 2016).
Psychoactive substances
Description Mode of action Examples Effects
Alcohol (Burns and Boyer, 2013; Jensen et al., 2017) CNS depressant effects ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, relaxation, ‘slight giddiness and disorienting’ and ‘nice hallucination’.
It may increase, prolong or intensify promethazine sedative effect. It should be avoided in patients receiving promethazine.
Heroin and other illicit opioids (Dahlman et al., 2016; Tsay et al., 2015) Opioid depressant effects It may increase, prolong, or intensify promethazine sedative effect.
Prescription drugs
Categories Mode of action Examples Effects
Drugs for insomnia (Burns and Boyer, 2013) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Z-drugs: zaleplon, zolpidem, zopiclone, eszopiclone They may increase, prolong or intensify promethazine sedative effect.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Drugs for anxiety (Burns and Boyer, 2013; Lynch et al., 2015) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, lorazepam, oxazepam They may increase, prolong or intensify promethazine sedative action.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Dextrometorphan (Tsay et al., 2015) At high doses, acting as NMDA-receptor antagonist; dextrometorphan and its potent metabolite dextrorphan inhibit the excitatory amino acid and neurotransmitter glutamate in the brain, determining hallucinogenic and dissociative activities, which are recreationally searched It might be combined with promethazine in cough-suppressant formulation Dextrometorphan neurobehavioural effects are dose-related, starting from a mild to moderate stimulation with restlessness and euphoria (100–200 mg), to a dissociated state characterised by hallucinations, paranoia, perceptual distortions, delusional beliefs, ataxia and out-of-body experiences (‘robo-ing’/‘robo-copping’/‘robo-tripping’) (>1000 mg). In overdosage they might increase promethazine effects.
Drugs for depression (Burns and Boyer, 2013; Jensen et al., 2017): TCA Multimodal action: reuptake inhibitor (SERT and NET), receptor antagonist (5-HT2) Amitriptyline Promethazine may increase, prolong or intensify their sedative effect. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Anticholinergic drugs Antagonist at cholinergic receptors Hyoscine butyl bromide/scopolamine (Burns and Boyer, 2013) Together with promethazine an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility may be seen. A typical mental status alteration with a dose-dependent agitated delirium characterised by abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia, has been described. These molecules should be avoided or administered in reduced dosage to patients receiving promethazine.
Prescription opioids
Codeine (Burns and Boyer, 2013; Jouanjus et al., 2018; Lynch et al., 2015; O Reilly et al., 2015; Shapiro et al., 2013) ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, elation, analgesia and ‘liking’, with increased potential of addiction. Overdosage of codeine might determine respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne–Stokes respiration and cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Opiate overdosage, particularly by the intravenous route, may be associated with apnoea, circulatory collapse, cardiac arrest and death. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Other opioid analgesics (Burns and Boyer, 2013; Dahlman et al., 2016; Lynch et al., 2015; Shapiro et al., 2013) Methadone They may increase, prolong or intensify promethazine sedative effects. Opioids should be avoided or administered in reduced dosage to patients receiving promethazine.
The addiction potential of opioids might be enhanced. Also, increasing life-threatening events, such as respiratory depression, overdose and prolongation of the QT interval, might be responsible for drug-related fatalities.
5-HT2: serotonin-2 receptor; CNS: central nervous system; D2: dopamine 2 receptor; GABA: gamma-amino-butyric acid; H1: histamine 1 receptor; NE: norepinephrine; NET: norepinephrine transporter; NMDA: N-methyl-D-aspartate; SERT: serotonin transporter; SSRI: selective-serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
Finally, among abuse-related cases, neonates, infants and children were here reported as well. This is consistent with cases of unexpected infant deaths associated with use of cold medications, poor socioeconomic conditions (Rimsza and Newberry, 2008) and/or accidental ingestion (McLellan and Turner, 2010).
Limitations
One of the limitations was given here by the descriptive nature of the study. Indeed, a comparator molecule, for a disproportionality analysis (Chiappini and Schifano, 2016; Schifano and Chiappini, 2018b) to be carried out, was not available due to data access limitations (EMA, 2017; Postigo et al., 2018). Furthermore, current data did not appear to show an increasing trend of abuse or misuse across the years. Since proper denominator figures (e.g. data on worldwide promethazine prescriptions) are not available, it was unclear if what observed was a substantial number of cases, indicative of clinically meaningful abuse potential, or a passing trend for promethazine misuse by a very small number of individuals. However, consistent with previous suggestions (Montastruc et al, 2011), the value of the current study was that its rationale was driven by a proper, detailed, pharmacodynamic hypothesis established on the basic properties of promethazine. Similar to remaining pharmacovigilance datasets (EMA, 2010; Evoy et al., 2019; Schifano and Chiappini, 2018a; Schifano et al., 2019a, 2019b; Schwan et al., 2010), focussing on the analysis of voluntary adverse events, a further limitation was given here by reliance on self-reporting and the likelihood of missing data occurrence. Moreover, although healthcare professionals have a main role in detection, assessment and spontaneous reporting of ADRs (Belton, 1997; Khalili et al., 2012), specific abuse/misuse/dependence issues relating to promethazine may have been underestimated, with only the most serious cases having been reported, hence the high rates of promethazine fatalities here recorded. Furthermore, although patients and their carers are allowed indeed to flag up an ADR, it is unlikely that they have spontaneously reported misusing events. Other factors, such as increased knowledge of promethazine misuse/abuse, may have resulted here in outcome reporting bias. There was also a potential for duplicate reports, with the same report submitted by the consumer, the healthcare professional and by the manufacturer as well, causing skewed study results. This may occur when a healthcare professional reported the same suspected ADR to both the national Regulatory Authority and the Marketing Authorisation Holder and they both reported subsequently to EV. However, the EV local report number which was here considered unequivocally identified an individual case. In addition, whilst this study represents one of the largest sample of promethazine abuse events published to date, the overall number of events is still relatively small, potentially limiting external validity. Case reports of suspected ADRs alone are not always sufficient to prove that a certain suspected reaction has indeed been caused by a specific medicine. This could be a symptom of another illness, or it could be associated with another medicinal product taken by the patient at the same time. The suspected ADRs were here presented using the PTs of the MedDRA Dictionary (Postigo et al., 2018). Thus, any case report should be considered together with all available data including case reports worldwide, clinical trials, epidemiological studies and toxicological investigations, in order to allow for robust conclusions. Finally, case reports reflect the information as provided to EV by the reporter, and not all data fields were completed for all reports.
Conclusion
To the best of our understanding, the current study described in detail the largest sample ever of abuse, misuse and dependence issues related to promethazine, whilst focussing on a large multinational dataset, such as the EV. The substantial number of promethazine-related events identified over the years represents a pharmacovigilance signal which needs to be better investigated (Montastruc et al., 2011). Although the observed trend of promethazine abuse and misuse, especially in young adults, is not a new phenomenon, further details of the issue have been here provided and future studies will optimally identify the related risk factors, with these measures enabling policymakers and regulators to take action to detect and prevent such misusing practices (Jouanjus et al., 2019). A multicomponent approach is recommended, including monitoring drug utilisation, tracking users’ posts on social media, and exploring healthcare databases; this will enable performing proactive and effective post-marketing surveillance and pharmacovigilance approaches. This has proved to be a relevant, efficient and accurate strategy, for example with gabapentinoids, which have recently been rescheduled in the UK (Borg et al., 2011; Eickhoff et al., 2012; Jouanjus et al., 2019; Novak et al., 2016; Parker et al., 2013; Schifano and Chiappini, 2019; Throckmorton et al., 2018). In this context, the role of the Web is rapidly spreading, playing a significant role in the marketing, sale and distribution of drugs, hence facilitating continuous changes in drug scenarios (Orsolini et al., 2017). Indeed, over the last 10 years access to online pharmacies to purchase medicinal compounds has increased (Desai, 2016; Monteith and Glenn, 2018). On the other hand, professionals access the Web to gather data on emerging trends of drug abuse (Deluca et al., 2002; Orsolini et al., 2015; Schifano, 2020; Schifano et al., 2003).
OTC and prescription drug misuse is perceived to be a significantly under-recognised issue affecting a range of vulnerable individuals (Coombes and Cooper, 2019). However, controlling the problem of OTC misuse and abuse might be challenging, due to the need for achieving high levels of consumer safety whilst not restricting access to OTC products for those who continue to use them safely.
Staff training should be evaluated, in order for pharmacists to self-monitor care and use of medicines, to educate patients and intervene/support those experiencing problematic drug use (Elwood, 2001; GPC, 2019; Tobin et al., 2013; Wells et al., 2018). Record-keeping (Hou et al., 2011) and real time monitoring (Cairns et al., 2016) could be a method of restricting access to some OTC drugs and prevent ‘shopping’ from one pharmacy to another, and where these measures would result to be ineffective, regulatory interventions, e.g. drug re-scheduling, might be useful (Marsden et al., 2019; McDonough, 2016; Peacock et al., 2019). Also, prevention and early education on substance abuse in young teenagers are critical (Levine, 2007; Marsden et al., 2019). Finally, appropriate and specific clinical guidelines for the treatment of misuse, abuse and dependence on prescription or OTC drugs should be implemented (Fingleton et al., 2019).
The review and study design were developed by SC, FS, JMC and AG. SC drafted the first version of the manuscript with input from all authors. All authors contributed to the interpretation of the data analysis and the further drafting of the manuscript and approved the final version.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FS was a member of the UK Advisory Council on the Misuse Drugs (ACMD) from 2011–2019; and is currently an EMA Advisory board (psychiatry) member. JMC is a member of the ACMD’s Novel Psychoactive Substances and Technical Committees. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
ORCID iDs: Stefania Chiappini https://orcid.org/0000-0002-6810-1540
John Martin Corkery https://orcid.org/0000-0002-3849-817X | Fatal | ReactionOutcome | CC BY | 33427017 | 18,928,797 | 2021-06 |
What was the outcome of reaction 'Respiratory depression'? | Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.
Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents.
We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database.
After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234).
The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used.
Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.
Introduction
Pharmacological properties of promethazine
Promethazine is a phenothiazine derivative and a histamine (H1) receptor antagonist that is commonly used for symptomatic relief of nausea and vomiting, for allergic conditions, motion sickness and common cold, and for short-term use treatment of insomnia in adults or as a paediatric sedative (EMC, 2019). It also acts as a direct antagonist at muscarinic (M1) and dopamine (D2) receptors (Cookson, 2018; Page et al., 2009; Sharma and Hamelin, 2003). Promethazine hydrochloride is well absorbed from the gastrointestinal tract, with an average of 88% of the dose absorbed after oral administration, and clinical effects appearing within 20 min after intake whilst lasting 4–6 h. The plasma half-life is approximately 7–14 h (Burns and Boyer, 2013). It is classified as a first-generation antihistamine molecule which, compared with second-generation antihistamines, easily penetrates the blood-brain barrier and is associated with adverse effects such as moderate/intense sedation (Jensen et al., 2017). Thus, promethazine might be used in rapid (acute) tranquilization due to its blocking action at H1 and M receptors (Cookson, 2018). Toxicity might result in severe impairment of cognitive and psychomotor functions due to central nervous system (CNS) depression/reduced levels of consciousness, and may cause fatalities (Jensen et al., 2017).
Availability of promethazine
Promethazine is a medicinal product available on its own or in combination with other ingredients, including dextromethorphan, paracetamol and/or expectorants. With regards to promethazine availability, there are wide variations across countries. In fact, in some European countries such as France, Italy and the UK, but also outside Europe, some medicinal products containing promethazine can be purchased over-the-counter (OTC). Promethazine was restricted from an OTC status to prescription only in Denmark as of December 2014. This restriction was partly based on increasing enquiries regarding promethazine exposures to the Danish Poison and Information Centre (DPIC), highlighting its abuse potential and subsequent observations of side-effects after ingestion of standard doses. In Australia, promethazine is available as an OTC medication either alone as a tablet or as a liquid preparation or in combination with paracetamol and codeine phosphate as a syrup (Sharma and Hamelin, 2003). In the USA, some cough preparations containing no more than 200 mg of codeine per 100 mL are considered Schedule V controlled substances (Drug Enforcement Administration (DEA), 2020), purportedly possessing the lowest potential for both misuse and development of a Substance Use Disorder (SUD).
Pharming
Recently, the potential for misuse of medications that are not already controlled has been reported worldwide (Reeves et al., 2015). ‘Pharming’ is a phenomenon involving the non-medical use of prescription (pain relievers, tranquilisers, stimulants, sedatives) and OTC drugs, including cough and cold preparations, particularly those containing dextromethorphan and promethazine (Burns and Boyer, 2013; Jouanjus et al., 2018; Levine, 2007; McCarthy, 2007; National Institute on Drug Abuse (NIDA), 2014). The abuse of these compounds may be facilitated by their easy accessibility, low cost, decreased perception of potential for harm and growing social acceptance (Burns and Boyer, 2013; Levine, 2007; McCarthy, 2007; Substance Abuse Mental Health Services Administration (SAMHSA), 2008). In the current drug abuse scenario, young people/youths have been described abusing with a range of prescription or OTC medicines (Soussan et al., 2018), with these molecules possibly being ingested at high/super-high dosages (Orsolini et al., 2015; Schifano, 2020) and at times in combination with alcohol/remaining recreational substances (Levine, 2007)
Recreational use of promethazine
Centrally acting antihistamines have long been known to induce physical and psychological dependence (Clatts et al., 2010; Gracious et al., 2010; Page et al., 2009; Saatcioglu and Evren, 2005; Thomas et al., 2008). During the past 15 years the abuse of promethazine, especially from OTC and prescription cough and cold medicines and at higher-than-recommended dosages, has been reported (NIDA, 2014). Consistent with this, during the last decade the yearly number of promethazine-related overdose cases in Sweden has increased from 100 to nearly 700 and its sales have increased threefold (Höjer and Tellerup, 2018). Also, according to the 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), antihistamines accounted for the seventh most frequently involved substance in human exposures, resulting in the third type of substance category for rate of exposure increase (Gummin et al., 2019). In Denmark, the number of registered antihistamine exposures increased during 2007–2013, with first-generation antihistamines, specifically promethazine, having been responsible for most exposures and related fatalities (Jensen et al., 2017). Also, in New Zealand a number of promethazine poisoning cases (57/199 patients) were identified from a database of poisoning admissions to a regional toxicology service (Bergman and Wallman, 1998).
Effects
Promethazine reported effects mostly include a range of CNS side effects, such as: confusion; disorientation; drowsiness; cardiovascular symptoms; and respiratory depression (Burns and Boyer, 2013; Höjer and Tellerup, 2018; Page et al., 2009; Tsay et al., 2015). A clear abuse potential has been observed and reported for first-generation antihistamines such as promethazine and cyclizine, due to: calming and sedating effects (Cookson, 2018; Jensen et al., 2017) and enhancement of other co-ingested substances, and especially those interacting with gamma-amino-butyric acid (GABA), opiate and muscarinic acetylcholine receptors (Speeg et al., 1981), leading to hallucinogenic experiences (Clatts et al., 2010; Jensen et al., 2017; Lynch et al., 2015). Indeed, an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility has been described (Burns and Boyer, 2013). In these cases, the mental state alteration is characterised by agitated delirium, with abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia (Agnich et al., 2013; Cowen, 1979; Dollberg et al., 1989; Höjer and Tellerup, 2018; Leak and Carroll, 1967; Page et al., 2009; Scott et al., 2007; Timnak et al., 2004). With the promethazine-codeine cough syrup, ‘euphoric feelings’, ‘relaxation’, ‘slight giddiness and disorienting’, and ‘nice hallucinations’ have been described as well (Bluelight.org [2020]; Erowid.org [2020]). Reported side-effects include drowsiness, fatigue, loss of coordination, constipation and urinary retention (Elwood, 2001).
Vulnerable categories
An increasing trend in abuse of promethazine in co-formulation with some components of OTC cough medications has been reported in young adult populations (Carney et al., 2018; Carr, 2006; Höjer and Tellerup, 2018) since the late 1990s, particularly in the southern USA (Carr, 2006; Elwood, 2001). Codeine and promethazine were recorded as the most requested psychoactive drugs by adolescents/young adults in community pharmacies (Delcourt et al., 2017).
Known by the street names ‘lean’, ‘drank’, ‘barre’, ‘purple stuff’, ‘syrup’ and ‘sizzurp’ (Agnich et al., 2013; NIDA, 2014; Peters et al., 2007), the abuse of promethazine mixed with opioids and other sedatives (e.g. alcohol) in a purple colour drink (‘purple drank’) (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014) has become widely popular (Agnich et al., 2013) after a rap artist/producer created a genre of music, called ‘screw music', inspired by intoxication on codeine and promethazine (Peters et al., 2007). Social media data, e.g. public posts and related hashtags on Instagram, provided additional insights into codeine abuse, depicting its common misuse combined with promethazine and soda/carbonated drinks (Cherian et al., 2018). ‘Purple drank’ has been noted for its euphoric effects and its easy accessibility (Elwood, 2001; Peters et al., 2007). ‘Lean’ creates a distinct (Jakubowski et al., 2018) feeling of euphoria and extreme relaxation (Cookson, 2018), dream-like feelings and a vivid sensation of floating away from the physical body (Peters et al., 2007).
Although at times preferred to other substances, such as benzodiazepines, to treat anxiety and sleep disorders in substance-dependent patients, promethazine has been reported to be misused among people with either opioid dependence (Agnich et al., 2013; Dahlman et al., 2016; Elwood, 2001; Lynch et al., 2015; Shapiro et al., 2013) or a substance abuse condition (Shapiro et al., 2013; Tang et al., 2012). A Hong Kong study reported a total of 63 patients with a diagnosis of cough mixture abuse; 89% were adult males with a mean age of onset of the abuse itself of 20 (±5) years. These subjects had received a diagnosis of substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%) and dysthymia (10%), with most cases having presented with a polysubstance misuse (Tang et al., 2012). Due to the opioid-coformulation, the promethazine-codeine cough mixture might lead to addiction (NIDA, 2014). The mixture may present a high risk of occurrence of near misses due to its central effect of respiratory depression, which is greatly increased by association with alcohol or other CNS depressants, such as sedatives/hypnotics, narcotic analgesics, general anaesthetics and tricyclic antidepressants (Burns and Boyer, 2013; Elwood, 2001; NIDA, 2014; Shapiro et al., 2013; Tsay et al., 2015). The concomitant use of promethazine and other depressant drugs should not be underestimated, as they might together contribute to and/or cause fatalities (Corkery et al., 2020).
Aim of the study
We were interested here in studying how promethazine abuse was reported to the European Medicines Agency (EMA) adverse drug reactions (ADRs) database. We aimed to analyse promethazine misuse/abuse/dependence/withdrawal data. Where possible, in order to have a better understanding, information/data related to diagnosis, concomitant drugs, administration and dosages were also examined.
Methods
Source of data
The EMA through EudraVigilance (EV) manages and analyses information on suspected ADRs to medicines authorised in the European Economic Area (EEA), according to Directive 2001/83/EC and Regulation (EC) No 726/2004 (EMA, 2017). Since November 2017, EV launched extensive Web access to data on suspected ADRs and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research (Postigo et al., 2018). Thus, access to data regarding cases of promethazine abuse, misuse, dependence and withdrawal was obtained by application to the voluntary reporting system of ADRs of the EMA. After 3 months all data comprised all of the ADRs reported during the years from 2003 up to June 2019, presented as large Excel files divided into information sections reporting in a standardised format according to the Medical Dictionary for Regulatory Activities (MedDRA), were sent through a hyperlink (MedDra, 2018). Such listings showed all information related to the ADR, the patient, the drug, the reporter and the diagnosis. An ADR was considered a voluntary and unsolicited communication reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorisation Holders for those ADRs occurring outside the EEA (EMA, 2010). Only ‘suspect’ ADRs were selected, meaning promethazine was considered as ‘suspected’ for the reaction reported. Regarding the content of the ADR, according to the standardised MedDRA Query (SMQ) (MedDRA, 2018), the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, intentional product use issue, substance abuse, substance abuser, substance use and withdrawal syndrome were selected. Those ADRs were defined in accordance with MedDRA in line with previous studies on the EV dataset (Chiappini et al., 2020; MedDRA, 2018; Schifano and Chiappini, 2018a, 2018b; Schifano et al., 2019a, 2019b). Specifically, abuse was here defined as the intentional, non-therapeutic use by a patient or consumer of a product, OTC or prescription, for a perceived reward or desired non-therapeutic effect including, but not limited to, getting high (euphoria) (MedDRA, 2018). Misuse was meant as the intentional use for a therapeutic purpose by a patient or consumer of a product, OTC or prescription, other than as prescribed or not in accordance with the authorised product information (MedDRA, 2018). Finally, non-medical use referred here to the use of a prescription drug, whether obtained by prescription or otherwise, other than in the manner or for the time period prescribed, or by a person for whom the drug was not prescribed (United Nations Office on Drugs and Crime (UNODC), 2013).
Analysis of data
We retrospectively analysed all reported ADRs which were available in the EV database. ADR reports were analysed with respect to age and gender of patient/consumer, source/reporter country (EEA or non-EEA) and reporter qualification (i.e. pharmacist, physician); type of ADR; seriousness (fatal, recovered, resolved outcomes); promethazine dosage; possible concomitant drug(s); and diagnosis/reporter’s comments, if recorded. The descriptive analysis included cases of overdoses, suicides, and fatalities. In the dataset, each case report may refer to one or more reporter; one or more ADR(s); as well as to one or more medicinal product(s). Therefore, a case may be represented by more than one row in the other line listings. The received data files were searched for duplicates by report ID through the ‘EV Local Report Number’, which unequivocally identified an individual case. Thus, the number of suspected ADRs appeared to be different from the number of case reports as one case report might refer to several suspected ADRs. Moreover, the number of patients was different from the number of case reports as a patient might have been described in more than one case. Finally, numbers of ADRs differed from those referring to case reports/single patients since different reporters/senders could have independently flagged the same ADR to the EMA. The descriptive analysis included here a study of the dataset (EMA, 2017) performed through IBM SPSS Statistics software (version 26).
Ethical issues
In compliance with applicable Personal Data Protection legislation (Regulation (EC) No 45/2001 and Regulation (EC) No 1049/2001, the protection of privacy and integrity of individuals was guaranteed, and in order to safeguard the identity of individuals certain data elements, including names/identifiers or country-specific information were not disclosed by the EMA (EMA, 2013, 2017). The study was ethically approved in March 2018 by the University of Hertfordshire Ethics’ Committee, with reference number LMS/PGR/UH/03234.
Results
The dataset obtained reported a total of 11,796 ADRs, correspond-ing to 1,543 single cases recorded during years 2003–2019 (Table 1). Safety reports were all voluntarily submitted, mostly from pharmaceutical companies (1,136/1,543: 73.6%) and regulatory authorities (398/1,543: 25.8%). Reports were irregularly reported over time, with spikes in 2010, 2014 and 2017 (Figure 1). Countries which reported most promethazine-related abuse/misuse/dependence cases included: the USA (805/1,543: 52.10%); Germany (299/1,543: 19.4%); Japan (162/1,543: 10.5%), Sweden (67/1,543: 4.3%), France (43/1,543: 2.8%) and Australia (42/1,543: 2.7%). Out of a total of 1543 cases, ‘suspect’ abuse/misuse/dependence-related cases were 557 (36.1%) and, among them, according to the preferred terms (PTs), most recorded reactions were abuse/misuse-related ADRs (458/557: 82.2%), specifically ‘drug abuse’ (300/557: 53.8%) and ‘intentional product misuse’ (117/557: 21.0%) (Table 1). ‘Suspect’ selected cases and related fatalities annually showed the same trend overall (Figure 1). Most typically, subjects reported were adult (19–64 years) and specifically of the youngest group (19–25 years); males were slightly more frequently recorded than females (M/F: 235/461: 0.51) (Table 1). Where all information was recorded, promethazine was reported as ingested alone in 74 cases, with supratherapeutic dosages, up to 2500 mg, in four cases. In combination with other drugs, most cases were associated with a 100–500 mg promethazine dose, with the maximum dosage recorded having been 8000 mg (Figure 2). The most common administration route was oral (n = 292), although the intramuscular (n = 8) and the parenteral (n = 19) ones were reported as well, see Table 1).
Table 1. Analysis of promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV) during years 2003–2019.
Individual cases (% of total within parentheses)
Total abuse/misuse/dependence cases 1543 Single cases; number of ADRs :11,796
Age range Adult (19–64 years): 648 (648/1,543: 42.0%) - mean age: 31.8 years (SD 26.55–37.05)
Adolescent (10–18 years): 23 (23/1,543: 1.5%) – mean age: 15.9 years (SD 14.3–17.77)
Elderly (>65 years): 25 (25/1,543: 1.6%) – mean age: 72.3 years (SD 70.85–73.7)
Neonatal (hours–days) 14 (14/1,543: 0.9%) – mean age: 24 h (SD 16.6–27.4)
Infant (months–1 year): 7 (7/1,543: 0.45%) – mean age: 10 months (SD 7–13)
Child (<10 years): 4 (4: 1,543: 0.35%) – mean age: 5 years (SD 3.6–6.3)
Unknown: 822 (822/1,543: 53.2%)
Male/female 235/461: 0.51
Most represented abuse/misuse/dependence-related ADRs according to the PTs: 557 (557/1,543: 36.1%)
Abuse-related ADRs 458 (458/557: 82.2%)
Drug abuse 300
Drug abuser 15
Drug diversion 1
Intentional product misuse 117
Intentional product use issue 9
Substance abuse 11
Substance abuser 3
Substance use 2
Dependence-related ADRs 44 (44/557: 7.9%)
Dependence 4
Drug dependence 39
Substance dependence 1
Withdrawal-related ADRs 55 (55/557: 9.8%)
Withdrawal syndrome 19
Drug withdrawal convulsions 1
Drug withdrawal neonatal syndrome 18
Drug withdrawal syndrome 17
Outcome Fatal 310 (310/557: 55.6%)
Unknown 161 (161/557: 28.9%)
Recovered/resolved 55 (55/557: 9.9%)
Recovering/resolving 18 (18/557: 3.3%)
Not recovered/not resolved 13 (13/557: 2.3%)
Promethazine-cases alone 74 (with maximum dosage 2500 mg)
Promethazine-cases with other drugs Most cases (122) were over 100 mg (with maximum dosage 8000 mg)
Most common psychoactive substances used Alcohol: 114
Cocaine: 68
Cannabis: 16
Ketamine: 4
Amphetamine: 1
Most common prescription drugs used Opioids: 1187
Benzodiazepines: 914
Antidepressants: 871
Antipsychotics: 437
Z-drugs: 222
Mood stabilisers: 197
ADR: adverse drug reaction; PTs: preferred terms; SD: standard deviation.
Figure 1. Number of promethazine abuse/misuse/dependence/withdrawal cases reported by year in the EudraVigilance (EV) dataset.
Figure 2. Most represented dosages reported among all promethazine abuse/misuse/dependence/withdrawal cases recorded by the EudraVigilance (EV) dataset.
Concomitantly used drugs recorded were opioids (e.g. oxycodone and fentanyl), benzodiazepines (e.g. diazepam, alprazolam and lorazepam) and antidepressants (e.g. citalopram, venlafaxine and amitriptyline), whilst recreational drugs most represented were alcohol and cocaine (Table 1). Most reported diagnoses, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V; American Psychiatric Association (APA), 2013) related to: mood disorders, e.g. depression/depressed mood/major depression (68 cases) and bipolar disorder (14 cases); anxiety/anxiety disorders (23 cases); alcohol abuse/alcoholic/alcoholism (26 cases); and schizophrenia (14 cases). The outcome of the reactions reported included: ‘fatal’ (n=310/557; 55.6%) and secondarily ‘recovered/resolved’ (n=73; 15.2%) (Table 1). Some 27 cases were related to suicidal or self-harm behaviour, being recorded as ‘suicidal attempt/suicidal ideation’ (n=24), ‘self-injurious ideation’ (n=1), and ‘suicide attempt’ (n=2). Fatalities mostly involved adult females; in these cases, most typical ADRs recorded were ‘drug abuse’ (n=228) and ‘intentional product misuse’ (n=77) (Table 2). Opiates/opioids were the most recorded concomitant drugs (n=356), with methadone being the most represented (n=103), followed by antidepressants (n=221) and benzodiazepines (n=141). Among illicit drugs, heroin appeared to be the most represented (Table 2).
Table 2. Analysis of fatal promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV), 2003–2019.
Fatal cases on abuse/misuse/dependence/withdrawal reactions 310 (310/557 = 55.6%)
Age-range
Adult 303 (97.7%)
Adolescent 7 (2.3%)
Elderly (>65 years) –
Neonatal –
Infant –
Child –
Gender M 103 (33.2%)
F 177 (57.1%)
Unknown 30 (9.7%)
Most recorded PTs
Drug abuse/drug abuser/substance abuse 228/3/6
Intentional product misuse/Intentional product use issue 77/3
Drug dependence 1
Reported death code
Intentional overdose 1
Overdose 4
Completed suicide/suicide 7
Drug toxicity/drug abuse 197
Toxicity to various agents 48
Intentional product misuse 41
Respiratory depression 5
Pneumonia 1
Cardiac arrest 10
Drug dependence 1
Most reported concomitant drugs
Opioids 356
Methadone 103
Dihydrocodeine 1
Codeine 32
Fentanyl 44
Oxycodone 63
Morphine 55
Hydrocodone 33
Hydromorphone 3
Tramadol 22
Antidepressants 221
Duloxetine 1
Escitalopram 1
Sertraline 16
Paroxetine 34
Trazodone 15
Mirtazapine 33
Fluoxetine 24
Venlafaxine 9
Bupropion 1
Amitriptyline 35
Nortriptyline 6
Clomipramine 5
Citalopram 41
Benzodiazepines 141
Lorazepam 3
Temazepam 6
Clonazepam 21
Diazepam 60
Flunitrazepam 1
Brotizolam 1
Alprazolam 42
Midazolam 4
Oxazepam 3
Mood stabilisers 11
Gabapentin 3
Topiramate 8
Antipsychotics 24
Olanzapine 1
Quetiapine 20
Haloperidol 1
Amisulpride 1
Levomepromazine 1
Z-drugs 39
Zolpidem 37
Zopiclone 2
Illicit drugs
Amphetamine 15
Cocaine 40
Heroin 52
Alcohol 26
PTs: preferred terms.
Discussion
Non-medical prescription drug use is a globally recognised problem, with severe adverse consequences. The current study provides a large amount of descriptive data highlighting that promethazine can be taken at high dosages, through non-approved administration routes, and in a setting of polydrug use (Hughes et al., 2016; Novak et al., 2016).
Promethazine misuse has been increasingly recorded since the early 2000s, consistently with data from US poison centres reporting antihistamine exposures rising in the period 2007–2013 (Jensen et al., 2017). This is not surprising, since the pharmacodynamic properties of promethazine underpins its sought-after central effects. In 2014, e.g. the highest peak here, the increase in promethazine misuse reporting was solely driven by the USA (245/245 cases; 100%). This may have been associated with intense media attention to the subject in that year (TMZ, 2014). The increments reported in 2010, 2014 and 2017 were then followed by decrements, which may have been related to not only reporting variabilities, but also to differences in sales of antihistamines following local/national drug abuse prevention campaigns (Klein-Schwartz, 2017). Overall, the USA appeared here to be the country most involved in reporting of promethazine ADRs. Several reasons may help in explaining this, including healthcare professionals’ awareness of prescription/OTC drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Lynch et al., 2015; Manchikanti et al., 2006; NIDA, 2014; Tsay et al., 2015) which, in turn, may have facilitated pharmacovigilance reporting. According to an 11-year period of the US National Poison Centers’ database, the annual rate of promethazine abuse/misuse per 100,000 US population doubled over time (Tsay et al., 2015). In the USA, promethazine abuse/misuse has been described in teenagers and young adults (Peters et al., 2003), methadone maintenance patients, heroin users and opioid-prescribed chronic pain patients (Lynch et al., 2015; Shapiro et al., 2013).
Consistent with previous observations (Agnich et al., 2013; Burns and Boyer, 2013; Carr, 2006; Elwood, 2001; Höjer and Tellerup, 2018; NIDA, 2014; Page et al., 2009; Parker et al., 2013; Peters et al., 2007), most recorded ADRs related here to either ‘drug abuse’ and ‘intentional product misuse’, involving young adult (19–25 years) males. Although considered a vulnerable category with respect to prescription drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014; Peters et al., 2007), adolescents (10–18 years) were here reported in only a minority (23/1543:1.5%) of cases.
Several drugs were here associated with promethazine, although opiates/opioids were the most represented molecules in related fatalities. This combination might intensify effects such as sedation and analgesia (Burns and Boyer, 2013; Lynch et al., 2015; Shapiro et al., 2013), and in the 1950s the association was medically used to reduce the dosage of opiates/opioids (McGee and Weiss, 1956). However, due to a range of adverse effects (Lynch et al., 2015) including lack of data supporting clinical efficacy (Richter and Burk, 1992) and an enhanced addiction potential of opioids (Lynch et al., 2015; Peters et al., 2007; Shapiro et al., 2013), the combination of promethazine/opioids has declined in popularity.
So far, the recreational intake of promethazine with opioids has been typically reported in cough mixtures containing codeine (Casati et al., 2012; Clatts et al., 2010; Elwood, 2001; Foley et al., 2015; Peters et al., 2007). However, current EMA data suggest that, apart from methadone, oxycodone and fentanyl were the most typical opiates/opiates identified in association with promethazine, possibly due to their recent popularity, especially in the USA (Manchikanti et al., 2018; Rose, 2018). In the promethazine fatalities (e.g. 310 cases) dataset analysed, codeine, fentanyl and oxycodone were respectively reported in 32, 44 and 63 cases. Consistent with current data, a concomitant use of opioids and promethazine has been described in various subpopulations, such as methadone maintenance patients, injecting drug users and chronic pain patients (Banta-Green et al., 2005; Lynch et al., 2015; Shapiro et al., 2013; Shields et al., 2007; Van Hout and Norman, 2016). Overall, there is now a high level of awareness of the abuse potential of antihistamine/opioid-containing products (Hou et al., 2011; Hughes et al., 1999; Wazaify et al., 2005). Hence, some countries are limiting both the medication pack size levels and the quantities of drugs sold in a single transaction, whilst also promoting non-injectable and non-inhaling formulations and changing some formulations’ OTC status (Cooper, 2013; Foley et al., 2015; Van Hout and Norman, 2016).
Benzodiazepines (e.g. diazepam, alprazolam and lorazepam) were here also frequently recorded, suggesting sedative synergistic effects in combination with promethazine (Lynch et al., 2015), and hence an increased risk of untoward clinical issues (McLellan and Turner, 2010). Other prescription drug categories recorded included antidepressants (most typically: citalopram and amitriptyline, respectively in 149/557 and 95/557 cases), which is consistent with the most typically recorded diagnoses, e.g. depressive (68 cases); bipolar (14 cases); and anxiety (23 cases) disorders. It is also possible that antidepressants were here ingested in combination with promethazine for sleep induction purposes. It is a reason for concern that promethazine ADRs, either alone or in combination, resulted in either fatal (50.6%) or ‘recovered/resolved’ outcomes (22.2%). This is consistent with previous promethazine misuse/abuse data, reporting both adverse clinical outcomes and high frequency of healthcare facility treatment (Bergman and Wallman, 1998; Ichikura et al., 2016; McLellan and Turner, 2010; Tsay et al., 2015). A list of possibly misused substances which might reinforce promethazine psychoactive effects and possibly increase its toxicity is included in Table 3.
Table 3. List of substances recorded in the literature as used in association with promethazine in order to increase its effects; prescription drugs are recorded according to the Neuroscience-based Nomenclature description (Nutt and Blier, 2016).
Psychoactive substances
Description Mode of action Examples Effects
Alcohol (Burns and Boyer, 2013; Jensen et al., 2017) CNS depressant effects ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, relaxation, ‘slight giddiness and disorienting’ and ‘nice hallucination’.
It may increase, prolong or intensify promethazine sedative effect. It should be avoided in patients receiving promethazine.
Heroin and other illicit opioids (Dahlman et al., 2016; Tsay et al., 2015) Opioid depressant effects It may increase, prolong, or intensify promethazine sedative effect.
Prescription drugs
Categories Mode of action Examples Effects
Drugs for insomnia (Burns and Boyer, 2013) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Z-drugs: zaleplon, zolpidem, zopiclone, eszopiclone They may increase, prolong or intensify promethazine sedative effect.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Drugs for anxiety (Burns and Boyer, 2013; Lynch et al., 2015) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, lorazepam, oxazepam They may increase, prolong or intensify promethazine sedative action.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Dextrometorphan (Tsay et al., 2015) At high doses, acting as NMDA-receptor antagonist; dextrometorphan and its potent metabolite dextrorphan inhibit the excitatory amino acid and neurotransmitter glutamate in the brain, determining hallucinogenic and dissociative activities, which are recreationally searched It might be combined with promethazine in cough-suppressant formulation Dextrometorphan neurobehavioural effects are dose-related, starting from a mild to moderate stimulation with restlessness and euphoria (100–200 mg), to a dissociated state characterised by hallucinations, paranoia, perceptual distortions, delusional beliefs, ataxia and out-of-body experiences (‘robo-ing’/‘robo-copping’/‘robo-tripping’) (>1000 mg). In overdosage they might increase promethazine effects.
Drugs for depression (Burns and Boyer, 2013; Jensen et al., 2017): TCA Multimodal action: reuptake inhibitor (SERT and NET), receptor antagonist (5-HT2) Amitriptyline Promethazine may increase, prolong or intensify their sedative effect. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Anticholinergic drugs Antagonist at cholinergic receptors Hyoscine butyl bromide/scopolamine (Burns and Boyer, 2013) Together with promethazine an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility may be seen. A typical mental status alteration with a dose-dependent agitated delirium characterised by abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia, has been described. These molecules should be avoided or administered in reduced dosage to patients receiving promethazine.
Prescription opioids
Codeine (Burns and Boyer, 2013; Jouanjus et al., 2018; Lynch et al., 2015; O Reilly et al., 2015; Shapiro et al., 2013) ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, elation, analgesia and ‘liking’, with increased potential of addiction. Overdosage of codeine might determine respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne–Stokes respiration and cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Opiate overdosage, particularly by the intravenous route, may be associated with apnoea, circulatory collapse, cardiac arrest and death. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Other opioid analgesics (Burns and Boyer, 2013; Dahlman et al., 2016; Lynch et al., 2015; Shapiro et al., 2013) Methadone They may increase, prolong or intensify promethazine sedative effects. Opioids should be avoided or administered in reduced dosage to patients receiving promethazine.
The addiction potential of opioids might be enhanced. Also, increasing life-threatening events, such as respiratory depression, overdose and prolongation of the QT interval, might be responsible for drug-related fatalities.
5-HT2: serotonin-2 receptor; CNS: central nervous system; D2: dopamine 2 receptor; GABA: gamma-amino-butyric acid; H1: histamine 1 receptor; NE: norepinephrine; NET: norepinephrine transporter; NMDA: N-methyl-D-aspartate; SERT: serotonin transporter; SSRI: selective-serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
Finally, among abuse-related cases, neonates, infants and children were here reported as well. This is consistent with cases of unexpected infant deaths associated with use of cold medications, poor socioeconomic conditions (Rimsza and Newberry, 2008) and/or accidental ingestion (McLellan and Turner, 2010).
Limitations
One of the limitations was given here by the descriptive nature of the study. Indeed, a comparator molecule, for a disproportionality analysis (Chiappini and Schifano, 2016; Schifano and Chiappini, 2018b) to be carried out, was not available due to data access limitations (EMA, 2017; Postigo et al., 2018). Furthermore, current data did not appear to show an increasing trend of abuse or misuse across the years. Since proper denominator figures (e.g. data on worldwide promethazine prescriptions) are not available, it was unclear if what observed was a substantial number of cases, indicative of clinically meaningful abuse potential, or a passing trend for promethazine misuse by a very small number of individuals. However, consistent with previous suggestions (Montastruc et al, 2011), the value of the current study was that its rationale was driven by a proper, detailed, pharmacodynamic hypothesis established on the basic properties of promethazine. Similar to remaining pharmacovigilance datasets (EMA, 2010; Evoy et al., 2019; Schifano and Chiappini, 2018a; Schifano et al., 2019a, 2019b; Schwan et al., 2010), focussing on the analysis of voluntary adverse events, a further limitation was given here by reliance on self-reporting and the likelihood of missing data occurrence. Moreover, although healthcare professionals have a main role in detection, assessment and spontaneous reporting of ADRs (Belton, 1997; Khalili et al., 2012), specific abuse/misuse/dependence issues relating to promethazine may have been underestimated, with only the most serious cases having been reported, hence the high rates of promethazine fatalities here recorded. Furthermore, although patients and their carers are allowed indeed to flag up an ADR, it is unlikely that they have spontaneously reported misusing events. Other factors, such as increased knowledge of promethazine misuse/abuse, may have resulted here in outcome reporting bias. There was also a potential for duplicate reports, with the same report submitted by the consumer, the healthcare professional and by the manufacturer as well, causing skewed study results. This may occur when a healthcare professional reported the same suspected ADR to both the national Regulatory Authority and the Marketing Authorisation Holder and they both reported subsequently to EV. However, the EV local report number which was here considered unequivocally identified an individual case. In addition, whilst this study represents one of the largest sample of promethazine abuse events published to date, the overall number of events is still relatively small, potentially limiting external validity. Case reports of suspected ADRs alone are not always sufficient to prove that a certain suspected reaction has indeed been caused by a specific medicine. This could be a symptom of another illness, or it could be associated with another medicinal product taken by the patient at the same time. The suspected ADRs were here presented using the PTs of the MedDRA Dictionary (Postigo et al., 2018). Thus, any case report should be considered together with all available data including case reports worldwide, clinical trials, epidemiological studies and toxicological investigations, in order to allow for robust conclusions. Finally, case reports reflect the information as provided to EV by the reporter, and not all data fields were completed for all reports.
Conclusion
To the best of our understanding, the current study described in detail the largest sample ever of abuse, misuse and dependence issues related to promethazine, whilst focussing on a large multinational dataset, such as the EV. The substantial number of promethazine-related events identified over the years represents a pharmacovigilance signal which needs to be better investigated (Montastruc et al., 2011). Although the observed trend of promethazine abuse and misuse, especially in young adults, is not a new phenomenon, further details of the issue have been here provided and future studies will optimally identify the related risk factors, with these measures enabling policymakers and regulators to take action to detect and prevent such misusing practices (Jouanjus et al., 2019). A multicomponent approach is recommended, including monitoring drug utilisation, tracking users’ posts on social media, and exploring healthcare databases; this will enable performing proactive and effective post-marketing surveillance and pharmacovigilance approaches. This has proved to be a relevant, efficient and accurate strategy, for example with gabapentinoids, which have recently been rescheduled in the UK (Borg et al., 2011; Eickhoff et al., 2012; Jouanjus et al., 2019; Novak et al., 2016; Parker et al., 2013; Schifano and Chiappini, 2019; Throckmorton et al., 2018). In this context, the role of the Web is rapidly spreading, playing a significant role in the marketing, sale and distribution of drugs, hence facilitating continuous changes in drug scenarios (Orsolini et al., 2017). Indeed, over the last 10 years access to online pharmacies to purchase medicinal compounds has increased (Desai, 2016; Monteith and Glenn, 2018). On the other hand, professionals access the Web to gather data on emerging trends of drug abuse (Deluca et al., 2002; Orsolini et al., 2015; Schifano, 2020; Schifano et al., 2003).
OTC and prescription drug misuse is perceived to be a significantly under-recognised issue affecting a range of vulnerable individuals (Coombes and Cooper, 2019). However, controlling the problem of OTC misuse and abuse might be challenging, due to the need for achieving high levels of consumer safety whilst not restricting access to OTC products for those who continue to use them safely.
Staff training should be evaluated, in order for pharmacists to self-monitor care and use of medicines, to educate patients and intervene/support those experiencing problematic drug use (Elwood, 2001; GPC, 2019; Tobin et al., 2013; Wells et al., 2018). Record-keeping (Hou et al., 2011) and real time monitoring (Cairns et al., 2016) could be a method of restricting access to some OTC drugs and prevent ‘shopping’ from one pharmacy to another, and where these measures would result to be ineffective, regulatory interventions, e.g. drug re-scheduling, might be useful (Marsden et al., 2019; McDonough, 2016; Peacock et al., 2019). Also, prevention and early education on substance abuse in young teenagers are critical (Levine, 2007; Marsden et al., 2019). Finally, appropriate and specific clinical guidelines for the treatment of misuse, abuse and dependence on prescription or OTC drugs should be implemented (Fingleton et al., 2019).
The review and study design were developed by SC, FS, JMC and AG. SC drafted the first version of the manuscript with input from all authors. All authors contributed to the interpretation of the data analysis and the further drafting of the manuscript and approved the final version.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FS was a member of the UK Advisory Council on the Misuse Drugs (ACMD) from 2011–2019; and is currently an EMA Advisory board (psychiatry) member. JMC is a member of the ACMD’s Novel Psychoactive Substances and Technical Committees. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
ORCID iDs: Stefania Chiappini https://orcid.org/0000-0002-6810-1540
John Martin Corkery https://orcid.org/0000-0002-3849-817X | Fatal | ReactionOutcome | CC BY | 33427017 | 18,928,797 | 2021-06 |
What was the outcome of reaction 'Toxicity to various agents'? | Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.
Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents.
We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database.
After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234).
The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used.
Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.
Introduction
Pharmacological properties of promethazine
Promethazine is a phenothiazine derivative and a histamine (H1) receptor antagonist that is commonly used for symptomatic relief of nausea and vomiting, for allergic conditions, motion sickness and common cold, and for short-term use treatment of insomnia in adults or as a paediatric sedative (EMC, 2019). It also acts as a direct antagonist at muscarinic (M1) and dopamine (D2) receptors (Cookson, 2018; Page et al., 2009; Sharma and Hamelin, 2003). Promethazine hydrochloride is well absorbed from the gastrointestinal tract, with an average of 88% of the dose absorbed after oral administration, and clinical effects appearing within 20 min after intake whilst lasting 4–6 h. The plasma half-life is approximately 7–14 h (Burns and Boyer, 2013). It is classified as a first-generation antihistamine molecule which, compared with second-generation antihistamines, easily penetrates the blood-brain barrier and is associated with adverse effects such as moderate/intense sedation (Jensen et al., 2017). Thus, promethazine might be used in rapid (acute) tranquilization due to its blocking action at H1 and M receptors (Cookson, 2018). Toxicity might result in severe impairment of cognitive and psychomotor functions due to central nervous system (CNS) depression/reduced levels of consciousness, and may cause fatalities (Jensen et al., 2017).
Availability of promethazine
Promethazine is a medicinal product available on its own or in combination with other ingredients, including dextromethorphan, paracetamol and/or expectorants. With regards to promethazine availability, there are wide variations across countries. In fact, in some European countries such as France, Italy and the UK, but also outside Europe, some medicinal products containing promethazine can be purchased over-the-counter (OTC). Promethazine was restricted from an OTC status to prescription only in Denmark as of December 2014. This restriction was partly based on increasing enquiries regarding promethazine exposures to the Danish Poison and Information Centre (DPIC), highlighting its abuse potential and subsequent observations of side-effects after ingestion of standard doses. In Australia, promethazine is available as an OTC medication either alone as a tablet or as a liquid preparation or in combination with paracetamol and codeine phosphate as a syrup (Sharma and Hamelin, 2003). In the USA, some cough preparations containing no more than 200 mg of codeine per 100 mL are considered Schedule V controlled substances (Drug Enforcement Administration (DEA), 2020), purportedly possessing the lowest potential for both misuse and development of a Substance Use Disorder (SUD).
Pharming
Recently, the potential for misuse of medications that are not already controlled has been reported worldwide (Reeves et al., 2015). ‘Pharming’ is a phenomenon involving the non-medical use of prescription (pain relievers, tranquilisers, stimulants, sedatives) and OTC drugs, including cough and cold preparations, particularly those containing dextromethorphan and promethazine (Burns and Boyer, 2013; Jouanjus et al., 2018; Levine, 2007; McCarthy, 2007; National Institute on Drug Abuse (NIDA), 2014). The abuse of these compounds may be facilitated by their easy accessibility, low cost, decreased perception of potential for harm and growing social acceptance (Burns and Boyer, 2013; Levine, 2007; McCarthy, 2007; Substance Abuse Mental Health Services Administration (SAMHSA), 2008). In the current drug abuse scenario, young people/youths have been described abusing with a range of prescription or OTC medicines (Soussan et al., 2018), with these molecules possibly being ingested at high/super-high dosages (Orsolini et al., 2015; Schifano, 2020) and at times in combination with alcohol/remaining recreational substances (Levine, 2007)
Recreational use of promethazine
Centrally acting antihistamines have long been known to induce physical and psychological dependence (Clatts et al., 2010; Gracious et al., 2010; Page et al., 2009; Saatcioglu and Evren, 2005; Thomas et al., 2008). During the past 15 years the abuse of promethazine, especially from OTC and prescription cough and cold medicines and at higher-than-recommended dosages, has been reported (NIDA, 2014). Consistent with this, during the last decade the yearly number of promethazine-related overdose cases in Sweden has increased from 100 to nearly 700 and its sales have increased threefold (Höjer and Tellerup, 2018). Also, according to the 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS), antihistamines accounted for the seventh most frequently involved substance in human exposures, resulting in the third type of substance category for rate of exposure increase (Gummin et al., 2019). In Denmark, the number of registered antihistamine exposures increased during 2007–2013, with first-generation antihistamines, specifically promethazine, having been responsible for most exposures and related fatalities (Jensen et al., 2017). Also, in New Zealand a number of promethazine poisoning cases (57/199 patients) were identified from a database of poisoning admissions to a regional toxicology service (Bergman and Wallman, 1998).
Effects
Promethazine reported effects mostly include a range of CNS side effects, such as: confusion; disorientation; drowsiness; cardiovascular symptoms; and respiratory depression (Burns and Boyer, 2013; Höjer and Tellerup, 2018; Page et al., 2009; Tsay et al., 2015). A clear abuse potential has been observed and reported for first-generation antihistamines such as promethazine and cyclizine, due to: calming and sedating effects (Cookson, 2018; Jensen et al., 2017) and enhancement of other co-ingested substances, and especially those interacting with gamma-amino-butyric acid (GABA), opiate and muscarinic acetylcholine receptors (Speeg et al., 1981), leading to hallucinogenic experiences (Clatts et al., 2010; Jensen et al., 2017; Lynch et al., 2015). Indeed, an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility has been described (Burns and Boyer, 2013). In these cases, the mental state alteration is characterised by agitated delirium, with abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia (Agnich et al., 2013; Cowen, 1979; Dollberg et al., 1989; Höjer and Tellerup, 2018; Leak and Carroll, 1967; Page et al., 2009; Scott et al., 2007; Timnak et al., 2004). With the promethazine-codeine cough syrup, ‘euphoric feelings’, ‘relaxation’, ‘slight giddiness and disorienting’, and ‘nice hallucinations’ have been described as well (Bluelight.org [2020]; Erowid.org [2020]). Reported side-effects include drowsiness, fatigue, loss of coordination, constipation and urinary retention (Elwood, 2001).
Vulnerable categories
An increasing trend in abuse of promethazine in co-formulation with some components of OTC cough medications has been reported in young adult populations (Carney et al., 2018; Carr, 2006; Höjer and Tellerup, 2018) since the late 1990s, particularly in the southern USA (Carr, 2006; Elwood, 2001). Codeine and promethazine were recorded as the most requested psychoactive drugs by adolescents/young adults in community pharmacies (Delcourt et al., 2017).
Known by the street names ‘lean’, ‘drank’, ‘barre’, ‘purple stuff’, ‘syrup’ and ‘sizzurp’ (Agnich et al., 2013; NIDA, 2014; Peters et al., 2007), the abuse of promethazine mixed with opioids and other sedatives (e.g. alcohol) in a purple colour drink (‘purple drank’) (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014) has become widely popular (Agnich et al., 2013) after a rap artist/producer created a genre of music, called ‘screw music', inspired by intoxication on codeine and promethazine (Peters et al., 2007). Social media data, e.g. public posts and related hashtags on Instagram, provided additional insights into codeine abuse, depicting its common misuse combined with promethazine and soda/carbonated drinks (Cherian et al., 2018). ‘Purple drank’ has been noted for its euphoric effects and its easy accessibility (Elwood, 2001; Peters et al., 2007). ‘Lean’ creates a distinct (Jakubowski et al., 2018) feeling of euphoria and extreme relaxation (Cookson, 2018), dream-like feelings and a vivid sensation of floating away from the physical body (Peters et al., 2007).
Although at times preferred to other substances, such as benzodiazepines, to treat anxiety and sleep disorders in substance-dependent patients, promethazine has been reported to be misused among people with either opioid dependence (Agnich et al., 2013; Dahlman et al., 2016; Elwood, 2001; Lynch et al., 2015; Shapiro et al., 2013) or a substance abuse condition (Shapiro et al., 2013; Tang et al., 2012). A Hong Kong study reported a total of 63 patients with a diagnosis of cough mixture abuse; 89% were adult males with a mean age of onset of the abuse itself of 20 (±5) years. These subjects had received a diagnosis of substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%) and dysthymia (10%), with most cases having presented with a polysubstance misuse (Tang et al., 2012). Due to the opioid-coformulation, the promethazine-codeine cough mixture might lead to addiction (NIDA, 2014). The mixture may present a high risk of occurrence of near misses due to its central effect of respiratory depression, which is greatly increased by association with alcohol or other CNS depressants, such as sedatives/hypnotics, narcotic analgesics, general anaesthetics and tricyclic antidepressants (Burns and Boyer, 2013; Elwood, 2001; NIDA, 2014; Shapiro et al., 2013; Tsay et al., 2015). The concomitant use of promethazine and other depressant drugs should not be underestimated, as they might together contribute to and/or cause fatalities (Corkery et al., 2020).
Aim of the study
We were interested here in studying how promethazine abuse was reported to the European Medicines Agency (EMA) adverse drug reactions (ADRs) database. We aimed to analyse promethazine misuse/abuse/dependence/withdrawal data. Where possible, in order to have a better understanding, information/data related to diagnosis, concomitant drugs, administration and dosages were also examined.
Methods
Source of data
The EMA through EudraVigilance (EV) manages and analyses information on suspected ADRs to medicines authorised in the European Economic Area (EEA), according to Directive 2001/83/EC and Regulation (EC) No 726/2004 (EMA, 2017). Since November 2017, EV launched extensive Web access to data on suspected ADRs and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research (Postigo et al., 2018). Thus, access to data regarding cases of promethazine abuse, misuse, dependence and withdrawal was obtained by application to the voluntary reporting system of ADRs of the EMA. After 3 months all data comprised all of the ADRs reported during the years from 2003 up to June 2019, presented as large Excel files divided into information sections reporting in a standardised format according to the Medical Dictionary for Regulatory Activities (MedDRA), were sent through a hyperlink (MedDra, 2018). Such listings showed all information related to the ADR, the patient, the drug, the reporter and the diagnosis. An ADR was considered a voluntary and unsolicited communication reported by both Regulatory Authorities of the EU Member States where the reaction occurred and/or by the Marketing Authorisation Holders for those ADRs occurring outside the EEA (EMA, 2010). Only ‘suspect’ ADRs were selected, meaning promethazine was considered as ‘suspected’ for the reaction reported. Regarding the content of the ADR, according to the standardised MedDRA Query (SMQ) (MedDRA, 2018), the following ADRs: dependence, drug abuse, drug abuser, drug dependence, drug withdrawal convulsions, drug withdrawal syndrome, drug withdrawal neonatal syndrome, intentional product misuse, intentional product use issue, substance abuse, substance abuser, substance use and withdrawal syndrome were selected. Those ADRs were defined in accordance with MedDRA in line with previous studies on the EV dataset (Chiappini et al., 2020; MedDRA, 2018; Schifano and Chiappini, 2018a, 2018b; Schifano et al., 2019a, 2019b). Specifically, abuse was here defined as the intentional, non-therapeutic use by a patient or consumer of a product, OTC or prescription, for a perceived reward or desired non-therapeutic effect including, but not limited to, getting high (euphoria) (MedDRA, 2018). Misuse was meant as the intentional use for a therapeutic purpose by a patient or consumer of a product, OTC or prescription, other than as prescribed or not in accordance with the authorised product information (MedDRA, 2018). Finally, non-medical use referred here to the use of a prescription drug, whether obtained by prescription or otherwise, other than in the manner or for the time period prescribed, or by a person for whom the drug was not prescribed (United Nations Office on Drugs and Crime (UNODC), 2013).
Analysis of data
We retrospectively analysed all reported ADRs which were available in the EV database. ADR reports were analysed with respect to age and gender of patient/consumer, source/reporter country (EEA or non-EEA) and reporter qualification (i.e. pharmacist, physician); type of ADR; seriousness (fatal, recovered, resolved outcomes); promethazine dosage; possible concomitant drug(s); and diagnosis/reporter’s comments, if recorded. The descriptive analysis included cases of overdoses, suicides, and fatalities. In the dataset, each case report may refer to one or more reporter; one or more ADR(s); as well as to one or more medicinal product(s). Therefore, a case may be represented by more than one row in the other line listings. The received data files were searched for duplicates by report ID through the ‘EV Local Report Number’, which unequivocally identified an individual case. Thus, the number of suspected ADRs appeared to be different from the number of case reports as one case report might refer to several suspected ADRs. Moreover, the number of patients was different from the number of case reports as a patient might have been described in more than one case. Finally, numbers of ADRs differed from those referring to case reports/single patients since different reporters/senders could have independently flagged the same ADR to the EMA. The descriptive analysis included here a study of the dataset (EMA, 2017) performed through IBM SPSS Statistics software (version 26).
Ethical issues
In compliance with applicable Personal Data Protection legislation (Regulation (EC) No 45/2001 and Regulation (EC) No 1049/2001, the protection of privacy and integrity of individuals was guaranteed, and in order to safeguard the identity of individuals certain data elements, including names/identifiers or country-specific information were not disclosed by the EMA (EMA, 2013, 2017). The study was ethically approved in March 2018 by the University of Hertfordshire Ethics’ Committee, with reference number LMS/PGR/UH/03234.
Results
The dataset obtained reported a total of 11,796 ADRs, correspond-ing to 1,543 single cases recorded during years 2003–2019 (Table 1). Safety reports were all voluntarily submitted, mostly from pharmaceutical companies (1,136/1,543: 73.6%) and regulatory authorities (398/1,543: 25.8%). Reports were irregularly reported over time, with spikes in 2010, 2014 and 2017 (Figure 1). Countries which reported most promethazine-related abuse/misuse/dependence cases included: the USA (805/1,543: 52.10%); Germany (299/1,543: 19.4%); Japan (162/1,543: 10.5%), Sweden (67/1,543: 4.3%), France (43/1,543: 2.8%) and Australia (42/1,543: 2.7%). Out of a total of 1543 cases, ‘suspect’ abuse/misuse/dependence-related cases were 557 (36.1%) and, among them, according to the preferred terms (PTs), most recorded reactions were abuse/misuse-related ADRs (458/557: 82.2%), specifically ‘drug abuse’ (300/557: 53.8%) and ‘intentional product misuse’ (117/557: 21.0%) (Table 1). ‘Suspect’ selected cases and related fatalities annually showed the same trend overall (Figure 1). Most typically, subjects reported were adult (19–64 years) and specifically of the youngest group (19–25 years); males were slightly more frequently recorded than females (M/F: 235/461: 0.51) (Table 1). Where all information was recorded, promethazine was reported as ingested alone in 74 cases, with supratherapeutic dosages, up to 2500 mg, in four cases. In combination with other drugs, most cases were associated with a 100–500 mg promethazine dose, with the maximum dosage recorded having been 8000 mg (Figure 2). The most common administration route was oral (n = 292), although the intramuscular (n = 8) and the parenteral (n = 19) ones were reported as well, see Table 1).
Table 1. Analysis of promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV) during years 2003–2019.
Individual cases (% of total within parentheses)
Total abuse/misuse/dependence cases 1543 Single cases; number of ADRs :11,796
Age range Adult (19–64 years): 648 (648/1,543: 42.0%) - mean age: 31.8 years (SD 26.55–37.05)
Adolescent (10–18 years): 23 (23/1,543: 1.5%) – mean age: 15.9 years (SD 14.3–17.77)
Elderly (>65 years): 25 (25/1,543: 1.6%) – mean age: 72.3 years (SD 70.85–73.7)
Neonatal (hours–days) 14 (14/1,543: 0.9%) – mean age: 24 h (SD 16.6–27.4)
Infant (months–1 year): 7 (7/1,543: 0.45%) – mean age: 10 months (SD 7–13)
Child (<10 years): 4 (4: 1,543: 0.35%) – mean age: 5 years (SD 3.6–6.3)
Unknown: 822 (822/1,543: 53.2%)
Male/female 235/461: 0.51
Most represented abuse/misuse/dependence-related ADRs according to the PTs: 557 (557/1,543: 36.1%)
Abuse-related ADRs 458 (458/557: 82.2%)
Drug abuse 300
Drug abuser 15
Drug diversion 1
Intentional product misuse 117
Intentional product use issue 9
Substance abuse 11
Substance abuser 3
Substance use 2
Dependence-related ADRs 44 (44/557: 7.9%)
Dependence 4
Drug dependence 39
Substance dependence 1
Withdrawal-related ADRs 55 (55/557: 9.8%)
Withdrawal syndrome 19
Drug withdrawal convulsions 1
Drug withdrawal neonatal syndrome 18
Drug withdrawal syndrome 17
Outcome Fatal 310 (310/557: 55.6%)
Unknown 161 (161/557: 28.9%)
Recovered/resolved 55 (55/557: 9.9%)
Recovering/resolving 18 (18/557: 3.3%)
Not recovered/not resolved 13 (13/557: 2.3%)
Promethazine-cases alone 74 (with maximum dosage 2500 mg)
Promethazine-cases with other drugs Most cases (122) were over 100 mg (with maximum dosage 8000 mg)
Most common psychoactive substances used Alcohol: 114
Cocaine: 68
Cannabis: 16
Ketamine: 4
Amphetamine: 1
Most common prescription drugs used Opioids: 1187
Benzodiazepines: 914
Antidepressants: 871
Antipsychotics: 437
Z-drugs: 222
Mood stabilisers: 197
ADR: adverse drug reaction; PTs: preferred terms; SD: standard deviation.
Figure 1. Number of promethazine abuse/misuse/dependence/withdrawal cases reported by year in the EudraVigilance (EV) dataset.
Figure 2. Most represented dosages reported among all promethazine abuse/misuse/dependence/withdrawal cases recorded by the EudraVigilance (EV) dataset.
Concomitantly used drugs recorded were opioids (e.g. oxycodone and fentanyl), benzodiazepines (e.g. diazepam, alprazolam and lorazepam) and antidepressants (e.g. citalopram, venlafaxine and amitriptyline), whilst recreational drugs most represented were alcohol and cocaine (Table 1). Most reported diagnoses, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V; American Psychiatric Association (APA), 2013) related to: mood disorders, e.g. depression/depressed mood/major depression (68 cases) and bipolar disorder (14 cases); anxiety/anxiety disorders (23 cases); alcohol abuse/alcoholic/alcoholism (26 cases); and schizophrenia (14 cases). The outcome of the reactions reported included: ‘fatal’ (n=310/557; 55.6%) and secondarily ‘recovered/resolved’ (n=73; 15.2%) (Table 1). Some 27 cases were related to suicidal or self-harm behaviour, being recorded as ‘suicidal attempt/suicidal ideation’ (n=24), ‘self-injurious ideation’ (n=1), and ‘suicide attempt’ (n=2). Fatalities mostly involved adult females; in these cases, most typical ADRs recorded were ‘drug abuse’ (n=228) and ‘intentional product misuse’ (n=77) (Table 2). Opiates/opioids were the most recorded concomitant drugs (n=356), with methadone being the most represented (n=103), followed by antidepressants (n=221) and benzodiazepines (n=141). Among illicit drugs, heroin appeared to be the most represented (Table 2).
Table 2. Analysis of fatal promethazine abuse/misuse/dependence/withdrawal cases recorded by EudraVigilance (EV), 2003–2019.
Fatal cases on abuse/misuse/dependence/withdrawal reactions 310 (310/557 = 55.6%)
Age-range
Adult 303 (97.7%)
Adolescent 7 (2.3%)
Elderly (>65 years) –
Neonatal –
Infant –
Child –
Gender M 103 (33.2%)
F 177 (57.1%)
Unknown 30 (9.7%)
Most recorded PTs
Drug abuse/drug abuser/substance abuse 228/3/6
Intentional product misuse/Intentional product use issue 77/3
Drug dependence 1
Reported death code
Intentional overdose 1
Overdose 4
Completed suicide/suicide 7
Drug toxicity/drug abuse 197
Toxicity to various agents 48
Intentional product misuse 41
Respiratory depression 5
Pneumonia 1
Cardiac arrest 10
Drug dependence 1
Most reported concomitant drugs
Opioids 356
Methadone 103
Dihydrocodeine 1
Codeine 32
Fentanyl 44
Oxycodone 63
Morphine 55
Hydrocodone 33
Hydromorphone 3
Tramadol 22
Antidepressants 221
Duloxetine 1
Escitalopram 1
Sertraline 16
Paroxetine 34
Trazodone 15
Mirtazapine 33
Fluoxetine 24
Venlafaxine 9
Bupropion 1
Amitriptyline 35
Nortriptyline 6
Clomipramine 5
Citalopram 41
Benzodiazepines 141
Lorazepam 3
Temazepam 6
Clonazepam 21
Diazepam 60
Flunitrazepam 1
Brotizolam 1
Alprazolam 42
Midazolam 4
Oxazepam 3
Mood stabilisers 11
Gabapentin 3
Topiramate 8
Antipsychotics 24
Olanzapine 1
Quetiapine 20
Haloperidol 1
Amisulpride 1
Levomepromazine 1
Z-drugs 39
Zolpidem 37
Zopiclone 2
Illicit drugs
Amphetamine 15
Cocaine 40
Heroin 52
Alcohol 26
PTs: preferred terms.
Discussion
Non-medical prescription drug use is a globally recognised problem, with severe adverse consequences. The current study provides a large amount of descriptive data highlighting that promethazine can be taken at high dosages, through non-approved administration routes, and in a setting of polydrug use (Hughes et al., 2016; Novak et al., 2016).
Promethazine misuse has been increasingly recorded since the early 2000s, consistently with data from US poison centres reporting antihistamine exposures rising in the period 2007–2013 (Jensen et al., 2017). This is not surprising, since the pharmacodynamic properties of promethazine underpins its sought-after central effects. In 2014, e.g. the highest peak here, the increase in promethazine misuse reporting was solely driven by the USA (245/245 cases; 100%). This may have been associated with intense media attention to the subject in that year (TMZ, 2014). The increments reported in 2010, 2014 and 2017 were then followed by decrements, which may have been related to not only reporting variabilities, but also to differences in sales of antihistamines following local/national drug abuse prevention campaigns (Klein-Schwartz, 2017). Overall, the USA appeared here to be the country most involved in reporting of promethazine ADRs. Several reasons may help in explaining this, including healthcare professionals’ awareness of prescription/OTC drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Lynch et al., 2015; Manchikanti et al., 2006; NIDA, 2014; Tsay et al., 2015) which, in turn, may have facilitated pharmacovigilance reporting. According to an 11-year period of the US National Poison Centers’ database, the annual rate of promethazine abuse/misuse per 100,000 US population doubled over time (Tsay et al., 2015). In the USA, promethazine abuse/misuse has been described in teenagers and young adults (Peters et al., 2003), methadone maintenance patients, heroin users and opioid-prescribed chronic pain patients (Lynch et al., 2015; Shapiro et al., 2013).
Consistent with previous observations (Agnich et al., 2013; Burns and Boyer, 2013; Carr, 2006; Elwood, 2001; Höjer and Tellerup, 2018; NIDA, 2014; Page et al., 2009; Parker et al., 2013; Peters et al., 2007), most recorded ADRs related here to either ‘drug abuse’ and ‘intentional product misuse’, involving young adult (19–25 years) males. Although considered a vulnerable category with respect to prescription drug abuse (Agnich et al., 2013; Burns and Boyer, 2013; Cherian et al., 2018; NIDA, 2014; Peters et al., 2007), adolescents (10–18 years) were here reported in only a minority (23/1543:1.5%) of cases.
Several drugs were here associated with promethazine, although opiates/opioids were the most represented molecules in related fatalities. This combination might intensify effects such as sedation and analgesia (Burns and Boyer, 2013; Lynch et al., 2015; Shapiro et al., 2013), and in the 1950s the association was medically used to reduce the dosage of opiates/opioids (McGee and Weiss, 1956). However, due to a range of adverse effects (Lynch et al., 2015) including lack of data supporting clinical efficacy (Richter and Burk, 1992) and an enhanced addiction potential of opioids (Lynch et al., 2015; Peters et al., 2007; Shapiro et al., 2013), the combination of promethazine/opioids has declined in popularity.
So far, the recreational intake of promethazine with opioids has been typically reported in cough mixtures containing codeine (Casati et al., 2012; Clatts et al., 2010; Elwood, 2001; Foley et al., 2015; Peters et al., 2007). However, current EMA data suggest that, apart from methadone, oxycodone and fentanyl were the most typical opiates/opiates identified in association with promethazine, possibly due to their recent popularity, especially in the USA (Manchikanti et al., 2018; Rose, 2018). In the promethazine fatalities (e.g. 310 cases) dataset analysed, codeine, fentanyl and oxycodone were respectively reported in 32, 44 and 63 cases. Consistent with current data, a concomitant use of opioids and promethazine has been described in various subpopulations, such as methadone maintenance patients, injecting drug users and chronic pain patients (Banta-Green et al., 2005; Lynch et al., 2015; Shapiro et al., 2013; Shields et al., 2007; Van Hout and Norman, 2016). Overall, there is now a high level of awareness of the abuse potential of antihistamine/opioid-containing products (Hou et al., 2011; Hughes et al., 1999; Wazaify et al., 2005). Hence, some countries are limiting both the medication pack size levels and the quantities of drugs sold in a single transaction, whilst also promoting non-injectable and non-inhaling formulations and changing some formulations’ OTC status (Cooper, 2013; Foley et al., 2015; Van Hout and Norman, 2016).
Benzodiazepines (e.g. diazepam, alprazolam and lorazepam) were here also frequently recorded, suggesting sedative synergistic effects in combination with promethazine (Lynch et al., 2015), and hence an increased risk of untoward clinical issues (McLellan and Turner, 2010). Other prescription drug categories recorded included antidepressants (most typically: citalopram and amitriptyline, respectively in 149/557 and 95/557 cases), which is consistent with the most typically recorded diagnoses, e.g. depressive (68 cases); bipolar (14 cases); and anxiety (23 cases) disorders. It is also possible that antidepressants were here ingested in combination with promethazine for sleep induction purposes. It is a reason for concern that promethazine ADRs, either alone or in combination, resulted in either fatal (50.6%) or ‘recovered/resolved’ outcomes (22.2%). This is consistent with previous promethazine misuse/abuse data, reporting both adverse clinical outcomes and high frequency of healthcare facility treatment (Bergman and Wallman, 1998; Ichikura et al., 2016; McLellan and Turner, 2010; Tsay et al., 2015). A list of possibly misused substances which might reinforce promethazine psychoactive effects and possibly increase its toxicity is included in Table 3.
Table 3. List of substances recorded in the literature as used in association with promethazine in order to increase its effects; prescription drugs are recorded according to the Neuroscience-based Nomenclature description (Nutt and Blier, 2016).
Psychoactive substances
Description Mode of action Examples Effects
Alcohol (Burns and Boyer, 2013; Jensen et al., 2017) CNS depressant effects ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, relaxation, ‘slight giddiness and disorienting’ and ‘nice hallucination’.
It may increase, prolong or intensify promethazine sedative effect. It should be avoided in patients receiving promethazine.
Heroin and other illicit opioids (Dahlman et al., 2016; Tsay et al., 2015) Opioid depressant effects It may increase, prolong, or intensify promethazine sedative effect.
Prescription drugs
Categories Mode of action Examples Effects
Drugs for insomnia (Burns and Boyer, 2013) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Z-drugs: zaleplon, zolpidem, zopiclone, eszopiclone They may increase, prolong or intensify promethazine sedative effect.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Drugs for anxiety (Burns and Boyer, 2013; Lynch et al., 2015) Positive allosteric modulator (GABA-A receptor, benzodiazepine site) Benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, lorazepam, oxazepam They may increase, prolong or intensify promethazine sedative action.
They should be avoided or administered in reduced dosage to patients receiving promethazine.
Dextrometorphan (Tsay et al., 2015) At high doses, acting as NMDA-receptor antagonist; dextrometorphan and its potent metabolite dextrorphan inhibit the excitatory amino acid and neurotransmitter glutamate in the brain, determining hallucinogenic and dissociative activities, which are recreationally searched It might be combined with promethazine in cough-suppressant formulation Dextrometorphan neurobehavioural effects are dose-related, starting from a mild to moderate stimulation with restlessness and euphoria (100–200 mg), to a dissociated state characterised by hallucinations, paranoia, perceptual distortions, delusional beliefs, ataxia and out-of-body experiences (‘robo-ing’/‘robo-copping’/‘robo-tripping’) (>1000 mg). In overdosage they might increase promethazine effects.
Drugs for depression (Burns and Boyer, 2013; Jensen et al., 2017): TCA Multimodal action: reuptake inhibitor (SERT and NET), receptor antagonist (5-HT2) Amitriptyline Promethazine may increase, prolong or intensify their sedative effect. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Anticholinergic drugs Antagonist at cholinergic receptors Hyoscine butyl bromide/scopolamine (Burns and Boyer, 2013) Together with promethazine an anti-cholinergic toxidrome with hyperthermia, flushing, tachycardia, dry mucosa, mydriasis, urinary retention and gastrointestinal dysmotility may be seen. A typical mental status alteration with a dose-dependent agitated delirium characterised by abnormal thoughts, irritability, distressing visual hallucinations, disorganised behaviour and insomnia, has been described. These molecules should be avoided or administered in reduced dosage to patients receiving promethazine.
Prescription opioids
Codeine (Burns and Boyer, 2013; Jouanjus et al., 2018; Lynch et al., 2015; O Reilly et al., 2015; Shapiro et al., 2013) ‘Lean’, ‘sizzurp’, ‘purple drank’ and other street concoctions containing promethazine, codeine and alcohol, along with other potential sedatives Euphoria, elation, analgesia and ‘liking’, with increased potential of addiction. Overdosage of codeine might determine respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne–Stokes respiration and cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Opiate overdosage, particularly by the intravenous route, may be associated with apnoea, circulatory collapse, cardiac arrest and death. It should be avoided or administered in reduced dosage to patients receiving promethazine.
Other opioid analgesics (Burns and Boyer, 2013; Dahlman et al., 2016; Lynch et al., 2015; Shapiro et al., 2013) Methadone They may increase, prolong or intensify promethazine sedative effects. Opioids should be avoided or administered in reduced dosage to patients receiving promethazine.
The addiction potential of opioids might be enhanced. Also, increasing life-threatening events, such as respiratory depression, overdose and prolongation of the QT interval, might be responsible for drug-related fatalities.
5-HT2: serotonin-2 receptor; CNS: central nervous system; D2: dopamine 2 receptor; GABA: gamma-amino-butyric acid; H1: histamine 1 receptor; NE: norepinephrine; NET: norepinephrine transporter; NMDA: N-methyl-D-aspartate; SERT: serotonin transporter; SSRI: selective-serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
Finally, among abuse-related cases, neonates, infants and children were here reported as well. This is consistent with cases of unexpected infant deaths associated with use of cold medications, poor socioeconomic conditions (Rimsza and Newberry, 2008) and/or accidental ingestion (McLellan and Turner, 2010).
Limitations
One of the limitations was given here by the descriptive nature of the study. Indeed, a comparator molecule, for a disproportionality analysis (Chiappini and Schifano, 2016; Schifano and Chiappini, 2018b) to be carried out, was not available due to data access limitations (EMA, 2017; Postigo et al., 2018). Furthermore, current data did not appear to show an increasing trend of abuse or misuse across the years. Since proper denominator figures (e.g. data on worldwide promethazine prescriptions) are not available, it was unclear if what observed was a substantial number of cases, indicative of clinically meaningful abuse potential, or a passing trend for promethazine misuse by a very small number of individuals. However, consistent with previous suggestions (Montastruc et al, 2011), the value of the current study was that its rationale was driven by a proper, detailed, pharmacodynamic hypothesis established on the basic properties of promethazine. Similar to remaining pharmacovigilance datasets (EMA, 2010; Evoy et al., 2019; Schifano and Chiappini, 2018a; Schifano et al., 2019a, 2019b; Schwan et al., 2010), focussing on the analysis of voluntary adverse events, a further limitation was given here by reliance on self-reporting and the likelihood of missing data occurrence. Moreover, although healthcare professionals have a main role in detection, assessment and spontaneous reporting of ADRs (Belton, 1997; Khalili et al., 2012), specific abuse/misuse/dependence issues relating to promethazine may have been underestimated, with only the most serious cases having been reported, hence the high rates of promethazine fatalities here recorded. Furthermore, although patients and their carers are allowed indeed to flag up an ADR, it is unlikely that they have spontaneously reported misusing events. Other factors, such as increased knowledge of promethazine misuse/abuse, may have resulted here in outcome reporting bias. There was also a potential for duplicate reports, with the same report submitted by the consumer, the healthcare professional and by the manufacturer as well, causing skewed study results. This may occur when a healthcare professional reported the same suspected ADR to both the national Regulatory Authority and the Marketing Authorisation Holder and they both reported subsequently to EV. However, the EV local report number which was here considered unequivocally identified an individual case. In addition, whilst this study represents one of the largest sample of promethazine abuse events published to date, the overall number of events is still relatively small, potentially limiting external validity. Case reports of suspected ADRs alone are not always sufficient to prove that a certain suspected reaction has indeed been caused by a specific medicine. This could be a symptom of another illness, or it could be associated with another medicinal product taken by the patient at the same time. The suspected ADRs were here presented using the PTs of the MedDRA Dictionary (Postigo et al., 2018). Thus, any case report should be considered together with all available data including case reports worldwide, clinical trials, epidemiological studies and toxicological investigations, in order to allow for robust conclusions. Finally, case reports reflect the information as provided to EV by the reporter, and not all data fields were completed for all reports.
Conclusion
To the best of our understanding, the current study described in detail the largest sample ever of abuse, misuse and dependence issues related to promethazine, whilst focussing on a large multinational dataset, such as the EV. The substantial number of promethazine-related events identified over the years represents a pharmacovigilance signal which needs to be better investigated (Montastruc et al., 2011). Although the observed trend of promethazine abuse and misuse, especially in young adults, is not a new phenomenon, further details of the issue have been here provided and future studies will optimally identify the related risk factors, with these measures enabling policymakers and regulators to take action to detect and prevent such misusing practices (Jouanjus et al., 2019). A multicomponent approach is recommended, including monitoring drug utilisation, tracking users’ posts on social media, and exploring healthcare databases; this will enable performing proactive and effective post-marketing surveillance and pharmacovigilance approaches. This has proved to be a relevant, efficient and accurate strategy, for example with gabapentinoids, which have recently been rescheduled in the UK (Borg et al., 2011; Eickhoff et al., 2012; Jouanjus et al., 2019; Novak et al., 2016; Parker et al., 2013; Schifano and Chiappini, 2019; Throckmorton et al., 2018). In this context, the role of the Web is rapidly spreading, playing a significant role in the marketing, sale and distribution of drugs, hence facilitating continuous changes in drug scenarios (Orsolini et al., 2017). Indeed, over the last 10 years access to online pharmacies to purchase medicinal compounds has increased (Desai, 2016; Monteith and Glenn, 2018). On the other hand, professionals access the Web to gather data on emerging trends of drug abuse (Deluca et al., 2002; Orsolini et al., 2015; Schifano, 2020; Schifano et al., 2003).
OTC and prescription drug misuse is perceived to be a significantly under-recognised issue affecting a range of vulnerable individuals (Coombes and Cooper, 2019). However, controlling the problem of OTC misuse and abuse might be challenging, due to the need for achieving high levels of consumer safety whilst not restricting access to OTC products for those who continue to use them safely.
Staff training should be evaluated, in order for pharmacists to self-monitor care and use of medicines, to educate patients and intervene/support those experiencing problematic drug use (Elwood, 2001; GPC, 2019; Tobin et al., 2013; Wells et al., 2018). Record-keeping (Hou et al., 2011) and real time monitoring (Cairns et al., 2016) could be a method of restricting access to some OTC drugs and prevent ‘shopping’ from one pharmacy to another, and where these measures would result to be ineffective, regulatory interventions, e.g. drug re-scheduling, might be useful (Marsden et al., 2019; McDonough, 2016; Peacock et al., 2019). Also, prevention and early education on substance abuse in young teenagers are critical (Levine, 2007; Marsden et al., 2019). Finally, appropriate and specific clinical guidelines for the treatment of misuse, abuse and dependence on prescription or OTC drugs should be implemented (Fingleton et al., 2019).
The review and study design were developed by SC, FS, JMC and AG. SC drafted the first version of the manuscript with input from all authors. All authors contributed to the interpretation of the data analysis and the further drafting of the manuscript and approved the final version.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FS was a member of the UK Advisory Council on the Misuse Drugs (ACMD) from 2011–2019; and is currently an EMA Advisory board (psychiatry) member. JMC is a member of the ACMD’s Novel Psychoactive Substances and Technical Committees. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
ORCID iDs: Stefania Chiappini https://orcid.org/0000-0002-6810-1540
John Martin Corkery https://orcid.org/0000-0002-3849-817X | Fatal | ReactionOutcome | CC BY | 33427017 | 18,928,797 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anastomotic complication'. | Management of an uncommon T-Cell lymphoma revealed by an anastomotic dehiscence in Crohn's disease: A case report.
T-cell lymphoma degeneration in pancolic crohn's disease is scarce. It is mostly related to long-standing inflammatory bowel disease in patients under immunosuppressants. We reviewed the clinical, endoscopic, radiological and histologic data of the patient as well as the literature dealing with T-cell lymphoma arising from pancolic crohn's disease.
METHODS
We describe in this paper an unusual case of a female young patient who underwent emergency surgery for per endoscopic perforation of the right colon while being under azathioprine. She had a subtotal colectomy with ileostomy and sigmoidostomy. After six months, we restored the digestive continuity through an ileorectal anastomosis. She was kept in remission on azathioprine. After one year, she presented with a pelvic abscess revealing a dehiscence of the ileorectal anastomosis leading to a surgical drainage and resection of the anastomosis associated with terminal ileostomy and closure of the rectal stump. Pathology examination revealed T cell lymphoma arising from the ileorectal anastomosis.
CONCLUSIONS
Patients with long-standing IBD have an increased risk of developing colorectal cancer. The onset of a malignant lymphoma during the course of the CD is scarce. Some studies haves failed to identify crohn's disease as a risk factor of lymphoma whereas other ones have succeeded to. Immunosuppressants are reported to have carcinogenic effect. Rarely, lymphoma degeneration can be revealed by intestinal complications such as perforation like in our case.
CONCLUSIONS
Many studies reported lymphoma degeneration of crohn's disease after long-term immunosuppressant therapy. However, rapid T-cell lymphoma degeneration revealed by anastomotic dehiscence in crohn's disease made our case unique and interesting.
1 Introduction
Crohn’s disease (CD) is a chronic inflammatory bowel disease that can affect any part of the digestive tract. It mainly occurs in young people. Furthermore, CD is associated with an increased risk of degeneration after a few years of evolution.
Literature has long studied the development of colorectal adenocarcinoma in inflammatory bowel diseases (IBD). However, there are wide variations between results reporting the incidence of this complication especially in long-standing CD [1]. Developing intestinal non-Hodgkin lymphoma in patients with IBD is scarce and fewly described in literature. We report herein a case of CD degenerated into an intestinal T lymphoma revealed by a dehiscence of an old ileo-rectal anastomosis in a 31-year-old female patient.
The case report has been reported in line with the SCARE criteria [2].
2 Case report
We report the case of a 31-year-old patient with a surgical history of appendectomy 15 years ago and an acoustic neuroma surgery 5 years ago, who is followed for a pancolic CD for 12 years. After 2 years of evolution of the disease, she presented with a severe acute colitis, which evolved favorably under medical treatment. She was then put on immunosuppressive drugs using initially 5ASA then Azathioprine for 6 years. She underwent in 2016 an emergency surgery for a per endoscopic perforation of the right colon. She had a subtotal colectomy with ileostomy and sigmoidostomy by median route with favorable outcomes. Six months later, we performed a complementary colectomy and we restored the digestive tract through a lateral ileorectal manual anastomosis. The postoperative course was uneventful. The patient was kept in remission on Azathioprine for one year with good drug tolerance.
In December 2019, she presented via ambulance with an acute diffuse abdominal pain evolving for two days with impaired general condition. The patient reported recent Six-times diarrhea per day during the previous week.
On physical examination, we found a 39 °C fever. The abdominal examination showed a diffuse abdominal tenderness with a guarding of the infra-umbilical area. Digital rectal exam revealed liquid blood-free stool but the ileorectal anastomosis was unreachable and therefore not evaluable. Tachycardia (120 bpm) and low blood pressure (08 / 05 mmHg) were found on cardiovascular exam. Increased respiratory rate (22 cycle / minute) was noticed. No other abnormalities on the remainder physical examination.
Laboratory tests showed a significant biological inflammatory syndrome with a high white blood cells count (18,000/ μl) and C-reactive protein level (150 mg/L). In addition, a 7.6 g / dl was shown up by biological results.
An abdominal-pelvic computed tomography was performed as a matter of urgency. It showed a mesenteric lymph node with necrotic center and a tissular mass of the left pericolic gutter measuring 4 * 3 cm. There was also an oblong uterine collection of 18 * 2 cm communicating with the anastomotic ileal loop through a fistula (Fig. 1).Fig. 1 Abdominal-pelvic CT-scan. a: Tissular mass of the left pericolic gutter. b: Mesenteric lymph node with necrotic center.c: Uterine collection communicating with the anastomotic ileal loop.
Fig. 1
We decided then to perform a CT-scan-guided biopsy of the tissular mass. Pathology examination findings were suggestive of peritoneal tuberculosis. However, no formal diagnosis could be set on these pathological results. Moreover, CT-Scan guided drainage of the uterine collection was performed and has brought pus. Radiological treatment was associated with broad-spectrum antibiotics combined with resuscitation. Bacteriological examination of the purulent fluid collected isolated a multi-sensitive Escherichia Coli allowing adaptation of antibiotic therapy.
The patient was therefore put on anti-tuberculosis treatment, complicated on Day eight by a drug-induced hepatitis. Several attempts to reintroduce anti-tuberculosis therapy have failed.
A proctoscopy was compulsory to explore the remnant part of the rectum and the ileorectal anastomosis. It showed multiple ulcerations at the level of the anastomosis with no other abnormalities noticed during the exam.
Faced with the absence of clinical, biological and radiological improvement during three weeks of management, a university hospital assistant decided to operate the patient with the aim of performing surgical drainage of the collection with eventual resection of the fistulized ileorectal anastomosis.
Through a median incision, we found a pelvic shield made of small agglutinated handles clogging an anastomotic hemi-circumferential dehiscence that feeds a collection of 3 cm (Fig. 2). There was also a whitish 2 cm nodule at the level of the right pericolic gutter and a mesenteric lymph node of 6 cm that were resected for pathological study.Fig. 2 Anastomotic dehiscence.
Fig. 2
We therefore decided to perform a resection of the ileorectal anastomosis, with closure of the rectal stump and preparation of a right iliac terminal ileostomy. We left in place a wide drainage in the pelvis.
Histological examination of the specimen concluded that there was a morphological and immunohistochemical aspect consistent with small intestinal T lymphoma of the NOS type (CD3 +, CD30 +, ALK-) without any argument in favor of associated tuberculosis disease (Fig. 3).Fig. 3 Pathological findings of resected specimen. a: Hematoxylin Eosin x 10: intestinal mucosa site of a diffuse lymphoid proliferation. b: Hematoxylin Eosin x 40: pleomorphic lymphoid cells, sometimes large, with atypical nuclei. c: Immunohistochemistry x 40: tumor cells express CD3 intensely.
Fig. 3
The parietal nodule and the mesenteric mass removed are free from any tumor proliferation or tuberculosis involvement.
The evolution was favorable and post-operative course was uneventful.
The patient was discharged on Day 10 postoperatively, and was referred to oncology department in order to benefit from adjuvant treatment. Six months follow up showed no recurrence under anthracycline-containing chemotherapy (CHOP: cyclophosphamide, doxorubicin, vincristine and prednisone).
3 Discussion
The association of cancer and CD is well documented. Many studies confirmed that patients with long-standing IBD have an increased risk of developing colorectal cancer [3]. The results vary widely between different studies. Jess et al. [4] reported a meta-analysis of intestinal cancer risk in crohn’s disease based on population-based studies revealing an overall increased risk of both colorectal cancers and small bowel cancers among patients with CD with standardized incidence ratios (SIR) ranging from 0.9 to 2.2. These findings stress the importance of endoscopic follow-up and treatment of patients with operated or not IBD.
Although the type of lymphoma most frequently described with immunosuppressants is large cell B lymphoma, non-Hodgkin's T lymphoma has been described in individuals with IBD with a demonstrated combination of therapy or treatment with Azathioprine alone.
Digestive T cell lymphomas represent 13%–17% of all gastrointestinal lymphomas [5]. They almost all occur in the small intestine especially the jejunum but remain less frequent than B lymphomas in this location [5,6].
The onset of a malignant lymphoma during the course of the CD is a very rare finding. Almost all papers reported are case reports [7]. Crohn’s disease has long been suspected in the genesis of non-Hodgkin’s lymphoma of the digestive tract. However, most studies have failed to demonstrate this claim.
Two large-scale Swedish studies have failed to identify CD as a risk factor for lymphoma [8,9]. On the other hand, a recent American study [10] identified crohn’s disease as a risk factor for non-Hodgkin’s lymphoma but this study gathered a population of elderly patients with severe forms of the disease.
Immunosuppressive therapies used to control CD such as thiopurines have now been shown to be a risk factor for non-Hodgkin's lymphoma. This risk is increased in male patients and the elderly [11].
The risk of non-Hodgkin's lymphoma can be overlooked by the clinician in the face of the significant improvement in quality and life expectancy in young subjects whose Crohn’s disease is kept in remission thanks to maintenance therapy based on Azathopirine [12].
Maintaining such a level of immunosuppression is associated with a carcinological risk. Thus, the use of thiopurines is clearly associated with a risk of developing lymphoma [13]. In 2011, 43 cases of lymphoma were described among the 16,023 patients treated with immunosuppressants for IBD [13]. The type of lymphoma most often diagnosed was large cell B lymphoma (44%), then follicular lymphoma (14%) then Hodgkin's lymphoma (12%).
In addition, the use of azathioprine or 6-mercaptopurine increased the risk of developing lymphoma by 4–5. On the other hand, the correlation between the occurrence of lymphoma and the use of an anti TNF is more disputed due to the use, often in parallel, of anti TNF and thiopurines in most patients [14]. A meta-analysis of 26 studies had described 13 cases of non-Hodgkin's lymphoma in adults treated with anti TNF for CD. Compared to the risk in the general population of developing lymphoma (1.9 per 10,000 person-years), the risk under anti TNF therapy was 3 times higher (3.2 per 10,000 person-years). Nevertheless, among the cases, 66% were also on thiopurines at the time of the diagnosis of lymphoma.
Finally, the TREAT study [15] is the only prospective study that continues to compare the side effects of infliximab with those of other therapies in more than 6000 patients treated for CD since 1999. The last update of this study in 2014 did not report any correlation between the use of infliximab and the risk of neoplasia but confirmed that immunosuppressive treatments, alone or in combination with biotherapies, increased the carcinogenic risk with odds with respective ratios of 4.19 and 3.33.
Similarly, Herrinton et al. reported that combotherapy increased the risk of developing lymphoma by a factor of 6 compared to the risk of the general population [13].
Non-Hodgkin's lymphomas can be complicated by intestinal perforation, especially after the initiation of anti-tumor chemotherapy, but the perforations can complicate the natural history of a lymphoma. These perforations most often occur in the small intestine and generally require emergency surgery [16]. Perforation is also known as a rare acute surgical emergency complicating the natural history of the CD, occurring in 1–3% of cases [17]. However, in other cases, perforation of a cancer, endoscopic perforation or anastomotic failure may occur.
In our patient, the perforation happened at the level of the ileo-rectal anastomosis which was the seat of lymphoma complicating the CD.
Surgical resection is currently the standard treatment with a mortality of less than 4% compared to 41% of mortality observed in the past after simple sutures of the perforation [18]. We opted for a resection of the ileo-rectal anastomosis with closure of the rectal stump and preparation of an ileostomy associated with wide drainage of the pelvis given the peritoneal contamination and the immunocompromised site. The restoration of delayed digestive continuity was necessary in our view.
4 Conclusion
The appearance of lymphoma occurred in this case, in a young patient put on Thiopurines for 6 years with an evolution towards degeneration is relatively rapid compared to what is generally reported in the literature. The non-Hodgkin's lymphoma discovered fortuitously in pathology study was responsible for an anastomotic dehiscence which was blocked by the small handles carrying out a real plastron. To our knowledge, no publication has dealt with a case of dehiscence of an anastomosis at 3 years of follow-up due to degeneration in T lymphoma which makes this case all the more interesting.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
None.
Ethical approval
Not applicable.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Anis Haddad: Performed Surgery.
Ahmed Ben Mahmoud: Writing - Original draft.
Houcine Maghrebi: Supervision.
Baya Chelly: Data interpretation of the pathological findings.
Mohamed Jouini: Supervision.
Montasser Jameleddine Kacem: Supervision - Reviewing.
Registration of research studies
Not applicable.
Guarantor
Ahmed Ben Mahmoud.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgement
None. | AZATHIOPRINE, MESALAMINE | DrugsGivenReaction | CC BY-NC-ND | 33429357 | 18,817,709 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'T-cell lymphoma'. | Management of an uncommon T-Cell lymphoma revealed by an anastomotic dehiscence in Crohn's disease: A case report.
T-cell lymphoma degeneration in pancolic crohn's disease is scarce. It is mostly related to long-standing inflammatory bowel disease in patients under immunosuppressants. We reviewed the clinical, endoscopic, radiological and histologic data of the patient as well as the literature dealing with T-cell lymphoma arising from pancolic crohn's disease.
METHODS
We describe in this paper an unusual case of a female young patient who underwent emergency surgery for per endoscopic perforation of the right colon while being under azathioprine. She had a subtotal colectomy with ileostomy and sigmoidostomy. After six months, we restored the digestive continuity through an ileorectal anastomosis. She was kept in remission on azathioprine. After one year, she presented with a pelvic abscess revealing a dehiscence of the ileorectal anastomosis leading to a surgical drainage and resection of the anastomosis associated with terminal ileostomy and closure of the rectal stump. Pathology examination revealed T cell lymphoma arising from the ileorectal anastomosis.
CONCLUSIONS
Patients with long-standing IBD have an increased risk of developing colorectal cancer. The onset of a malignant lymphoma during the course of the CD is scarce. Some studies haves failed to identify crohn's disease as a risk factor of lymphoma whereas other ones have succeeded to. Immunosuppressants are reported to have carcinogenic effect. Rarely, lymphoma degeneration can be revealed by intestinal complications such as perforation like in our case.
CONCLUSIONS
Many studies reported lymphoma degeneration of crohn's disease after long-term immunosuppressant therapy. However, rapid T-cell lymphoma degeneration revealed by anastomotic dehiscence in crohn's disease made our case unique and interesting.
1 Introduction
Crohn’s disease (CD) is a chronic inflammatory bowel disease that can affect any part of the digestive tract. It mainly occurs in young people. Furthermore, CD is associated with an increased risk of degeneration after a few years of evolution.
Literature has long studied the development of colorectal adenocarcinoma in inflammatory bowel diseases (IBD). However, there are wide variations between results reporting the incidence of this complication especially in long-standing CD [1]. Developing intestinal non-Hodgkin lymphoma in patients with IBD is scarce and fewly described in literature. We report herein a case of CD degenerated into an intestinal T lymphoma revealed by a dehiscence of an old ileo-rectal anastomosis in a 31-year-old female patient.
The case report has been reported in line with the SCARE criteria [2].
2 Case report
We report the case of a 31-year-old patient with a surgical history of appendectomy 15 years ago and an acoustic neuroma surgery 5 years ago, who is followed for a pancolic CD for 12 years. After 2 years of evolution of the disease, she presented with a severe acute colitis, which evolved favorably under medical treatment. She was then put on immunosuppressive drugs using initially 5ASA then Azathioprine for 6 years. She underwent in 2016 an emergency surgery for a per endoscopic perforation of the right colon. She had a subtotal colectomy with ileostomy and sigmoidostomy by median route with favorable outcomes. Six months later, we performed a complementary colectomy and we restored the digestive tract through a lateral ileorectal manual anastomosis. The postoperative course was uneventful. The patient was kept in remission on Azathioprine for one year with good drug tolerance.
In December 2019, she presented via ambulance with an acute diffuse abdominal pain evolving for two days with impaired general condition. The patient reported recent Six-times diarrhea per day during the previous week.
On physical examination, we found a 39 °C fever. The abdominal examination showed a diffuse abdominal tenderness with a guarding of the infra-umbilical area. Digital rectal exam revealed liquid blood-free stool but the ileorectal anastomosis was unreachable and therefore not evaluable. Tachycardia (120 bpm) and low blood pressure (08 / 05 mmHg) were found on cardiovascular exam. Increased respiratory rate (22 cycle / minute) was noticed. No other abnormalities on the remainder physical examination.
Laboratory tests showed a significant biological inflammatory syndrome with a high white blood cells count (18,000/ μl) and C-reactive protein level (150 mg/L). In addition, a 7.6 g / dl was shown up by biological results.
An abdominal-pelvic computed tomography was performed as a matter of urgency. It showed a mesenteric lymph node with necrotic center and a tissular mass of the left pericolic gutter measuring 4 * 3 cm. There was also an oblong uterine collection of 18 * 2 cm communicating with the anastomotic ileal loop through a fistula (Fig. 1).Fig. 1 Abdominal-pelvic CT-scan. a: Tissular mass of the left pericolic gutter. b: Mesenteric lymph node with necrotic center.c: Uterine collection communicating with the anastomotic ileal loop.
Fig. 1
We decided then to perform a CT-scan-guided biopsy of the tissular mass. Pathology examination findings were suggestive of peritoneal tuberculosis. However, no formal diagnosis could be set on these pathological results. Moreover, CT-Scan guided drainage of the uterine collection was performed and has brought pus. Radiological treatment was associated with broad-spectrum antibiotics combined with resuscitation. Bacteriological examination of the purulent fluid collected isolated a multi-sensitive Escherichia Coli allowing adaptation of antibiotic therapy.
The patient was therefore put on anti-tuberculosis treatment, complicated on Day eight by a drug-induced hepatitis. Several attempts to reintroduce anti-tuberculosis therapy have failed.
A proctoscopy was compulsory to explore the remnant part of the rectum and the ileorectal anastomosis. It showed multiple ulcerations at the level of the anastomosis with no other abnormalities noticed during the exam.
Faced with the absence of clinical, biological and radiological improvement during three weeks of management, a university hospital assistant decided to operate the patient with the aim of performing surgical drainage of the collection with eventual resection of the fistulized ileorectal anastomosis.
Through a median incision, we found a pelvic shield made of small agglutinated handles clogging an anastomotic hemi-circumferential dehiscence that feeds a collection of 3 cm (Fig. 2). There was also a whitish 2 cm nodule at the level of the right pericolic gutter and a mesenteric lymph node of 6 cm that were resected for pathological study.Fig. 2 Anastomotic dehiscence.
Fig. 2
We therefore decided to perform a resection of the ileorectal anastomosis, with closure of the rectal stump and preparation of a right iliac terminal ileostomy. We left in place a wide drainage in the pelvis.
Histological examination of the specimen concluded that there was a morphological and immunohistochemical aspect consistent with small intestinal T lymphoma of the NOS type (CD3 +, CD30 +, ALK-) without any argument in favor of associated tuberculosis disease (Fig. 3).Fig. 3 Pathological findings of resected specimen. a: Hematoxylin Eosin x 10: intestinal mucosa site of a diffuse lymphoid proliferation. b: Hematoxylin Eosin x 40: pleomorphic lymphoid cells, sometimes large, with atypical nuclei. c: Immunohistochemistry x 40: tumor cells express CD3 intensely.
Fig. 3
The parietal nodule and the mesenteric mass removed are free from any tumor proliferation or tuberculosis involvement.
The evolution was favorable and post-operative course was uneventful.
The patient was discharged on Day 10 postoperatively, and was referred to oncology department in order to benefit from adjuvant treatment. Six months follow up showed no recurrence under anthracycline-containing chemotherapy (CHOP: cyclophosphamide, doxorubicin, vincristine and prednisone).
3 Discussion
The association of cancer and CD is well documented. Many studies confirmed that patients with long-standing IBD have an increased risk of developing colorectal cancer [3]. The results vary widely between different studies. Jess et al. [4] reported a meta-analysis of intestinal cancer risk in crohn’s disease based on population-based studies revealing an overall increased risk of both colorectal cancers and small bowel cancers among patients with CD with standardized incidence ratios (SIR) ranging from 0.9 to 2.2. These findings stress the importance of endoscopic follow-up and treatment of patients with operated or not IBD.
Although the type of lymphoma most frequently described with immunosuppressants is large cell B lymphoma, non-Hodgkin's T lymphoma has been described in individuals with IBD with a demonstrated combination of therapy or treatment with Azathioprine alone.
Digestive T cell lymphomas represent 13%–17% of all gastrointestinal lymphomas [5]. They almost all occur in the small intestine especially the jejunum but remain less frequent than B lymphomas in this location [5,6].
The onset of a malignant lymphoma during the course of the CD is a very rare finding. Almost all papers reported are case reports [7]. Crohn’s disease has long been suspected in the genesis of non-Hodgkin’s lymphoma of the digestive tract. However, most studies have failed to demonstrate this claim.
Two large-scale Swedish studies have failed to identify CD as a risk factor for lymphoma [8,9]. On the other hand, a recent American study [10] identified crohn’s disease as a risk factor for non-Hodgkin’s lymphoma but this study gathered a population of elderly patients with severe forms of the disease.
Immunosuppressive therapies used to control CD such as thiopurines have now been shown to be a risk factor for non-Hodgkin's lymphoma. This risk is increased in male patients and the elderly [11].
The risk of non-Hodgkin's lymphoma can be overlooked by the clinician in the face of the significant improvement in quality and life expectancy in young subjects whose Crohn’s disease is kept in remission thanks to maintenance therapy based on Azathopirine [12].
Maintaining such a level of immunosuppression is associated with a carcinological risk. Thus, the use of thiopurines is clearly associated with a risk of developing lymphoma [13]. In 2011, 43 cases of lymphoma were described among the 16,023 patients treated with immunosuppressants for IBD [13]. The type of lymphoma most often diagnosed was large cell B lymphoma (44%), then follicular lymphoma (14%) then Hodgkin's lymphoma (12%).
In addition, the use of azathioprine or 6-mercaptopurine increased the risk of developing lymphoma by 4–5. On the other hand, the correlation between the occurrence of lymphoma and the use of an anti TNF is more disputed due to the use, often in parallel, of anti TNF and thiopurines in most patients [14]. A meta-analysis of 26 studies had described 13 cases of non-Hodgkin's lymphoma in adults treated with anti TNF for CD. Compared to the risk in the general population of developing lymphoma (1.9 per 10,000 person-years), the risk under anti TNF therapy was 3 times higher (3.2 per 10,000 person-years). Nevertheless, among the cases, 66% were also on thiopurines at the time of the diagnosis of lymphoma.
Finally, the TREAT study [15] is the only prospective study that continues to compare the side effects of infliximab with those of other therapies in more than 6000 patients treated for CD since 1999. The last update of this study in 2014 did not report any correlation between the use of infliximab and the risk of neoplasia but confirmed that immunosuppressive treatments, alone or in combination with biotherapies, increased the carcinogenic risk with odds with respective ratios of 4.19 and 3.33.
Similarly, Herrinton et al. reported that combotherapy increased the risk of developing lymphoma by a factor of 6 compared to the risk of the general population [13].
Non-Hodgkin's lymphomas can be complicated by intestinal perforation, especially after the initiation of anti-tumor chemotherapy, but the perforations can complicate the natural history of a lymphoma. These perforations most often occur in the small intestine and generally require emergency surgery [16]. Perforation is also known as a rare acute surgical emergency complicating the natural history of the CD, occurring in 1–3% of cases [17]. However, in other cases, perforation of a cancer, endoscopic perforation or anastomotic failure may occur.
In our patient, the perforation happened at the level of the ileo-rectal anastomosis which was the seat of lymphoma complicating the CD.
Surgical resection is currently the standard treatment with a mortality of less than 4% compared to 41% of mortality observed in the past after simple sutures of the perforation [18]. We opted for a resection of the ileo-rectal anastomosis with closure of the rectal stump and preparation of an ileostomy associated with wide drainage of the pelvis given the peritoneal contamination and the immunocompromised site. The restoration of delayed digestive continuity was necessary in our view.
4 Conclusion
The appearance of lymphoma occurred in this case, in a young patient put on Thiopurines for 6 years with an evolution towards degeneration is relatively rapid compared to what is generally reported in the literature. The non-Hodgkin's lymphoma discovered fortuitously in pathology study was responsible for an anastomotic dehiscence which was blocked by the small handles carrying out a real plastron. To our knowledge, no publication has dealt with a case of dehiscence of an anastomosis at 3 years of follow-up due to degeneration in T lymphoma which makes this case all the more interesting.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
None.
Ethical approval
Not applicable.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Anis Haddad: Performed Surgery.
Ahmed Ben Mahmoud: Writing - Original draft.
Houcine Maghrebi: Supervision.
Baya Chelly: Data interpretation of the pathological findings.
Mohamed Jouini: Supervision.
Montasser Jameleddine Kacem: Supervision - Reviewing.
Registration of research studies
Not applicable.
Guarantor
Ahmed Ben Mahmoud.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgement
None. | AZATHIOPRINE, MESALAMINE | DrugsGivenReaction | CC BY-NC-ND | 33429357 | 18,817,709 | 2021-02 |
What was the outcome of reaction 'Anastomotic complication'? | Management of an uncommon T-Cell lymphoma revealed by an anastomotic dehiscence in Crohn's disease: A case report.
T-cell lymphoma degeneration in pancolic crohn's disease is scarce. It is mostly related to long-standing inflammatory bowel disease in patients under immunosuppressants. We reviewed the clinical, endoscopic, radiological and histologic data of the patient as well as the literature dealing with T-cell lymphoma arising from pancolic crohn's disease.
METHODS
We describe in this paper an unusual case of a female young patient who underwent emergency surgery for per endoscopic perforation of the right colon while being under azathioprine. She had a subtotal colectomy with ileostomy and sigmoidostomy. After six months, we restored the digestive continuity through an ileorectal anastomosis. She was kept in remission on azathioprine. After one year, she presented with a pelvic abscess revealing a dehiscence of the ileorectal anastomosis leading to a surgical drainage and resection of the anastomosis associated with terminal ileostomy and closure of the rectal stump. Pathology examination revealed T cell lymphoma arising from the ileorectal anastomosis.
CONCLUSIONS
Patients with long-standing IBD have an increased risk of developing colorectal cancer. The onset of a malignant lymphoma during the course of the CD is scarce. Some studies haves failed to identify crohn's disease as a risk factor of lymphoma whereas other ones have succeeded to. Immunosuppressants are reported to have carcinogenic effect. Rarely, lymphoma degeneration can be revealed by intestinal complications such as perforation like in our case.
CONCLUSIONS
Many studies reported lymphoma degeneration of crohn's disease after long-term immunosuppressant therapy. However, rapid T-cell lymphoma degeneration revealed by anastomotic dehiscence in crohn's disease made our case unique and interesting.
1 Introduction
Crohn’s disease (CD) is a chronic inflammatory bowel disease that can affect any part of the digestive tract. It mainly occurs in young people. Furthermore, CD is associated with an increased risk of degeneration after a few years of evolution.
Literature has long studied the development of colorectal adenocarcinoma in inflammatory bowel diseases (IBD). However, there are wide variations between results reporting the incidence of this complication especially in long-standing CD [1]. Developing intestinal non-Hodgkin lymphoma in patients with IBD is scarce and fewly described in literature. We report herein a case of CD degenerated into an intestinal T lymphoma revealed by a dehiscence of an old ileo-rectal anastomosis in a 31-year-old female patient.
The case report has been reported in line with the SCARE criteria [2].
2 Case report
We report the case of a 31-year-old patient with a surgical history of appendectomy 15 years ago and an acoustic neuroma surgery 5 years ago, who is followed for a pancolic CD for 12 years. After 2 years of evolution of the disease, she presented with a severe acute colitis, which evolved favorably under medical treatment. She was then put on immunosuppressive drugs using initially 5ASA then Azathioprine for 6 years. She underwent in 2016 an emergency surgery for a per endoscopic perforation of the right colon. She had a subtotal colectomy with ileostomy and sigmoidostomy by median route with favorable outcomes. Six months later, we performed a complementary colectomy and we restored the digestive tract through a lateral ileorectal manual anastomosis. The postoperative course was uneventful. The patient was kept in remission on Azathioprine for one year with good drug tolerance.
In December 2019, she presented via ambulance with an acute diffuse abdominal pain evolving for two days with impaired general condition. The patient reported recent Six-times diarrhea per day during the previous week.
On physical examination, we found a 39 °C fever. The abdominal examination showed a diffuse abdominal tenderness with a guarding of the infra-umbilical area. Digital rectal exam revealed liquid blood-free stool but the ileorectal anastomosis was unreachable and therefore not evaluable. Tachycardia (120 bpm) and low blood pressure (08 / 05 mmHg) were found on cardiovascular exam. Increased respiratory rate (22 cycle / minute) was noticed. No other abnormalities on the remainder physical examination.
Laboratory tests showed a significant biological inflammatory syndrome with a high white blood cells count (18,000/ μl) and C-reactive protein level (150 mg/L). In addition, a 7.6 g / dl was shown up by biological results.
An abdominal-pelvic computed tomography was performed as a matter of urgency. It showed a mesenteric lymph node with necrotic center and a tissular mass of the left pericolic gutter measuring 4 * 3 cm. There was also an oblong uterine collection of 18 * 2 cm communicating with the anastomotic ileal loop through a fistula (Fig. 1).Fig. 1 Abdominal-pelvic CT-scan. a: Tissular mass of the left pericolic gutter. b: Mesenteric lymph node with necrotic center.c: Uterine collection communicating with the anastomotic ileal loop.
Fig. 1
We decided then to perform a CT-scan-guided biopsy of the tissular mass. Pathology examination findings were suggestive of peritoneal tuberculosis. However, no formal diagnosis could be set on these pathological results. Moreover, CT-Scan guided drainage of the uterine collection was performed and has brought pus. Radiological treatment was associated with broad-spectrum antibiotics combined with resuscitation. Bacteriological examination of the purulent fluid collected isolated a multi-sensitive Escherichia Coli allowing adaptation of antibiotic therapy.
The patient was therefore put on anti-tuberculosis treatment, complicated on Day eight by a drug-induced hepatitis. Several attempts to reintroduce anti-tuberculosis therapy have failed.
A proctoscopy was compulsory to explore the remnant part of the rectum and the ileorectal anastomosis. It showed multiple ulcerations at the level of the anastomosis with no other abnormalities noticed during the exam.
Faced with the absence of clinical, biological and radiological improvement during three weeks of management, a university hospital assistant decided to operate the patient with the aim of performing surgical drainage of the collection with eventual resection of the fistulized ileorectal anastomosis.
Through a median incision, we found a pelvic shield made of small agglutinated handles clogging an anastomotic hemi-circumferential dehiscence that feeds a collection of 3 cm (Fig. 2). There was also a whitish 2 cm nodule at the level of the right pericolic gutter and a mesenteric lymph node of 6 cm that were resected for pathological study.Fig. 2 Anastomotic dehiscence.
Fig. 2
We therefore decided to perform a resection of the ileorectal anastomosis, with closure of the rectal stump and preparation of a right iliac terminal ileostomy. We left in place a wide drainage in the pelvis.
Histological examination of the specimen concluded that there was a morphological and immunohistochemical aspect consistent with small intestinal T lymphoma of the NOS type (CD3 +, CD30 +, ALK-) without any argument in favor of associated tuberculosis disease (Fig. 3).Fig. 3 Pathological findings of resected specimen. a: Hematoxylin Eosin x 10: intestinal mucosa site of a diffuse lymphoid proliferation. b: Hematoxylin Eosin x 40: pleomorphic lymphoid cells, sometimes large, with atypical nuclei. c: Immunohistochemistry x 40: tumor cells express CD3 intensely.
Fig. 3
The parietal nodule and the mesenteric mass removed are free from any tumor proliferation or tuberculosis involvement.
The evolution was favorable and post-operative course was uneventful.
The patient was discharged on Day 10 postoperatively, and was referred to oncology department in order to benefit from adjuvant treatment. Six months follow up showed no recurrence under anthracycline-containing chemotherapy (CHOP: cyclophosphamide, doxorubicin, vincristine and prednisone).
3 Discussion
The association of cancer and CD is well documented. Many studies confirmed that patients with long-standing IBD have an increased risk of developing colorectal cancer [3]. The results vary widely between different studies. Jess et al. [4] reported a meta-analysis of intestinal cancer risk in crohn’s disease based on population-based studies revealing an overall increased risk of both colorectal cancers and small bowel cancers among patients with CD with standardized incidence ratios (SIR) ranging from 0.9 to 2.2. These findings stress the importance of endoscopic follow-up and treatment of patients with operated or not IBD.
Although the type of lymphoma most frequently described with immunosuppressants is large cell B lymphoma, non-Hodgkin's T lymphoma has been described in individuals with IBD with a demonstrated combination of therapy or treatment with Azathioprine alone.
Digestive T cell lymphomas represent 13%–17% of all gastrointestinal lymphomas [5]. They almost all occur in the small intestine especially the jejunum but remain less frequent than B lymphomas in this location [5,6].
The onset of a malignant lymphoma during the course of the CD is a very rare finding. Almost all papers reported are case reports [7]. Crohn’s disease has long been suspected in the genesis of non-Hodgkin’s lymphoma of the digestive tract. However, most studies have failed to demonstrate this claim.
Two large-scale Swedish studies have failed to identify CD as a risk factor for lymphoma [8,9]. On the other hand, a recent American study [10] identified crohn’s disease as a risk factor for non-Hodgkin’s lymphoma but this study gathered a population of elderly patients with severe forms of the disease.
Immunosuppressive therapies used to control CD such as thiopurines have now been shown to be a risk factor for non-Hodgkin's lymphoma. This risk is increased in male patients and the elderly [11].
The risk of non-Hodgkin's lymphoma can be overlooked by the clinician in the face of the significant improvement in quality and life expectancy in young subjects whose Crohn’s disease is kept in remission thanks to maintenance therapy based on Azathopirine [12].
Maintaining such a level of immunosuppression is associated with a carcinological risk. Thus, the use of thiopurines is clearly associated with a risk of developing lymphoma [13]. In 2011, 43 cases of lymphoma were described among the 16,023 patients treated with immunosuppressants for IBD [13]. The type of lymphoma most often diagnosed was large cell B lymphoma (44%), then follicular lymphoma (14%) then Hodgkin's lymphoma (12%).
In addition, the use of azathioprine or 6-mercaptopurine increased the risk of developing lymphoma by 4–5. On the other hand, the correlation between the occurrence of lymphoma and the use of an anti TNF is more disputed due to the use, often in parallel, of anti TNF and thiopurines in most patients [14]. A meta-analysis of 26 studies had described 13 cases of non-Hodgkin's lymphoma in adults treated with anti TNF for CD. Compared to the risk in the general population of developing lymphoma (1.9 per 10,000 person-years), the risk under anti TNF therapy was 3 times higher (3.2 per 10,000 person-years). Nevertheless, among the cases, 66% were also on thiopurines at the time of the diagnosis of lymphoma.
Finally, the TREAT study [15] is the only prospective study that continues to compare the side effects of infliximab with those of other therapies in more than 6000 patients treated for CD since 1999. The last update of this study in 2014 did not report any correlation between the use of infliximab and the risk of neoplasia but confirmed that immunosuppressive treatments, alone or in combination with biotherapies, increased the carcinogenic risk with odds with respective ratios of 4.19 and 3.33.
Similarly, Herrinton et al. reported that combotherapy increased the risk of developing lymphoma by a factor of 6 compared to the risk of the general population [13].
Non-Hodgkin's lymphomas can be complicated by intestinal perforation, especially after the initiation of anti-tumor chemotherapy, but the perforations can complicate the natural history of a lymphoma. These perforations most often occur in the small intestine and generally require emergency surgery [16]. Perforation is also known as a rare acute surgical emergency complicating the natural history of the CD, occurring in 1–3% of cases [17]. However, in other cases, perforation of a cancer, endoscopic perforation or anastomotic failure may occur.
In our patient, the perforation happened at the level of the ileo-rectal anastomosis which was the seat of lymphoma complicating the CD.
Surgical resection is currently the standard treatment with a mortality of less than 4% compared to 41% of mortality observed in the past after simple sutures of the perforation [18]. We opted for a resection of the ileo-rectal anastomosis with closure of the rectal stump and preparation of an ileostomy associated with wide drainage of the pelvis given the peritoneal contamination and the immunocompromised site. The restoration of delayed digestive continuity was necessary in our view.
4 Conclusion
The appearance of lymphoma occurred in this case, in a young patient put on Thiopurines for 6 years with an evolution towards degeneration is relatively rapid compared to what is generally reported in the literature. The non-Hodgkin's lymphoma discovered fortuitously in pathology study was responsible for an anastomotic dehiscence which was blocked by the small handles carrying out a real plastron. To our knowledge, no publication has dealt with a case of dehiscence of an anastomosis at 3 years of follow-up due to degeneration in T lymphoma which makes this case all the more interesting.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
None.
Ethical approval
Not applicable.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Anis Haddad: Performed Surgery.
Ahmed Ben Mahmoud: Writing - Original draft.
Houcine Maghrebi: Supervision.
Baya Chelly: Data interpretation of the pathological findings.
Mohamed Jouini: Supervision.
Montasser Jameleddine Kacem: Supervision - Reviewing.
Registration of research studies
Not applicable.
Guarantor
Ahmed Ben Mahmoud.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgement
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33429357 | 18,817,709 | 2021-02 |
What was the outcome of reaction 'T-cell lymphoma'? | Management of an uncommon T-Cell lymphoma revealed by an anastomotic dehiscence in Crohn's disease: A case report.
T-cell lymphoma degeneration in pancolic crohn's disease is scarce. It is mostly related to long-standing inflammatory bowel disease in patients under immunosuppressants. We reviewed the clinical, endoscopic, radiological and histologic data of the patient as well as the literature dealing with T-cell lymphoma arising from pancolic crohn's disease.
METHODS
We describe in this paper an unusual case of a female young patient who underwent emergency surgery for per endoscopic perforation of the right colon while being under azathioprine. She had a subtotal colectomy with ileostomy and sigmoidostomy. After six months, we restored the digestive continuity through an ileorectal anastomosis. She was kept in remission on azathioprine. After one year, she presented with a pelvic abscess revealing a dehiscence of the ileorectal anastomosis leading to a surgical drainage and resection of the anastomosis associated with terminal ileostomy and closure of the rectal stump. Pathology examination revealed T cell lymphoma arising from the ileorectal anastomosis.
CONCLUSIONS
Patients with long-standing IBD have an increased risk of developing colorectal cancer. The onset of a malignant lymphoma during the course of the CD is scarce. Some studies haves failed to identify crohn's disease as a risk factor of lymphoma whereas other ones have succeeded to. Immunosuppressants are reported to have carcinogenic effect. Rarely, lymphoma degeneration can be revealed by intestinal complications such as perforation like in our case.
CONCLUSIONS
Many studies reported lymphoma degeneration of crohn's disease after long-term immunosuppressant therapy. However, rapid T-cell lymphoma degeneration revealed by anastomotic dehiscence in crohn's disease made our case unique and interesting.
1 Introduction
Crohn’s disease (CD) is a chronic inflammatory bowel disease that can affect any part of the digestive tract. It mainly occurs in young people. Furthermore, CD is associated with an increased risk of degeneration after a few years of evolution.
Literature has long studied the development of colorectal adenocarcinoma in inflammatory bowel diseases (IBD). However, there are wide variations between results reporting the incidence of this complication especially in long-standing CD [1]. Developing intestinal non-Hodgkin lymphoma in patients with IBD is scarce and fewly described in literature. We report herein a case of CD degenerated into an intestinal T lymphoma revealed by a dehiscence of an old ileo-rectal anastomosis in a 31-year-old female patient.
The case report has been reported in line with the SCARE criteria [2].
2 Case report
We report the case of a 31-year-old patient with a surgical history of appendectomy 15 years ago and an acoustic neuroma surgery 5 years ago, who is followed for a pancolic CD for 12 years. After 2 years of evolution of the disease, she presented with a severe acute colitis, which evolved favorably under medical treatment. She was then put on immunosuppressive drugs using initially 5ASA then Azathioprine for 6 years. She underwent in 2016 an emergency surgery for a per endoscopic perforation of the right colon. She had a subtotal colectomy with ileostomy and sigmoidostomy by median route with favorable outcomes. Six months later, we performed a complementary colectomy and we restored the digestive tract through a lateral ileorectal manual anastomosis. The postoperative course was uneventful. The patient was kept in remission on Azathioprine for one year with good drug tolerance.
In December 2019, she presented via ambulance with an acute diffuse abdominal pain evolving for two days with impaired general condition. The patient reported recent Six-times diarrhea per day during the previous week.
On physical examination, we found a 39 °C fever. The abdominal examination showed a diffuse abdominal tenderness with a guarding of the infra-umbilical area. Digital rectal exam revealed liquid blood-free stool but the ileorectal anastomosis was unreachable and therefore not evaluable. Tachycardia (120 bpm) and low blood pressure (08 / 05 mmHg) were found on cardiovascular exam. Increased respiratory rate (22 cycle / minute) was noticed. No other abnormalities on the remainder physical examination.
Laboratory tests showed a significant biological inflammatory syndrome with a high white blood cells count (18,000/ μl) and C-reactive protein level (150 mg/L). In addition, a 7.6 g / dl was shown up by biological results.
An abdominal-pelvic computed tomography was performed as a matter of urgency. It showed a mesenteric lymph node with necrotic center and a tissular mass of the left pericolic gutter measuring 4 * 3 cm. There was also an oblong uterine collection of 18 * 2 cm communicating with the anastomotic ileal loop through a fistula (Fig. 1).Fig. 1 Abdominal-pelvic CT-scan. a: Tissular mass of the left pericolic gutter. b: Mesenteric lymph node with necrotic center.c: Uterine collection communicating with the anastomotic ileal loop.
Fig. 1
We decided then to perform a CT-scan-guided biopsy of the tissular mass. Pathology examination findings were suggestive of peritoneal tuberculosis. However, no formal diagnosis could be set on these pathological results. Moreover, CT-Scan guided drainage of the uterine collection was performed and has brought pus. Radiological treatment was associated with broad-spectrum antibiotics combined with resuscitation. Bacteriological examination of the purulent fluid collected isolated a multi-sensitive Escherichia Coli allowing adaptation of antibiotic therapy.
The patient was therefore put on anti-tuberculosis treatment, complicated on Day eight by a drug-induced hepatitis. Several attempts to reintroduce anti-tuberculosis therapy have failed.
A proctoscopy was compulsory to explore the remnant part of the rectum and the ileorectal anastomosis. It showed multiple ulcerations at the level of the anastomosis with no other abnormalities noticed during the exam.
Faced with the absence of clinical, biological and radiological improvement during three weeks of management, a university hospital assistant decided to operate the patient with the aim of performing surgical drainage of the collection with eventual resection of the fistulized ileorectal anastomosis.
Through a median incision, we found a pelvic shield made of small agglutinated handles clogging an anastomotic hemi-circumferential dehiscence that feeds a collection of 3 cm (Fig. 2). There was also a whitish 2 cm nodule at the level of the right pericolic gutter and a mesenteric lymph node of 6 cm that were resected for pathological study.Fig. 2 Anastomotic dehiscence.
Fig. 2
We therefore decided to perform a resection of the ileorectal anastomosis, with closure of the rectal stump and preparation of a right iliac terminal ileostomy. We left in place a wide drainage in the pelvis.
Histological examination of the specimen concluded that there was a morphological and immunohistochemical aspect consistent with small intestinal T lymphoma of the NOS type (CD3 +, CD30 +, ALK-) without any argument in favor of associated tuberculosis disease (Fig. 3).Fig. 3 Pathological findings of resected specimen. a: Hematoxylin Eosin x 10: intestinal mucosa site of a diffuse lymphoid proliferation. b: Hematoxylin Eosin x 40: pleomorphic lymphoid cells, sometimes large, with atypical nuclei. c: Immunohistochemistry x 40: tumor cells express CD3 intensely.
Fig. 3
The parietal nodule and the mesenteric mass removed are free from any tumor proliferation or tuberculosis involvement.
The evolution was favorable and post-operative course was uneventful.
The patient was discharged on Day 10 postoperatively, and was referred to oncology department in order to benefit from adjuvant treatment. Six months follow up showed no recurrence under anthracycline-containing chemotherapy (CHOP: cyclophosphamide, doxorubicin, vincristine and prednisone).
3 Discussion
The association of cancer and CD is well documented. Many studies confirmed that patients with long-standing IBD have an increased risk of developing colorectal cancer [3]. The results vary widely between different studies. Jess et al. [4] reported a meta-analysis of intestinal cancer risk in crohn’s disease based on population-based studies revealing an overall increased risk of both colorectal cancers and small bowel cancers among patients with CD with standardized incidence ratios (SIR) ranging from 0.9 to 2.2. These findings stress the importance of endoscopic follow-up and treatment of patients with operated or not IBD.
Although the type of lymphoma most frequently described with immunosuppressants is large cell B lymphoma, non-Hodgkin's T lymphoma has been described in individuals with IBD with a demonstrated combination of therapy or treatment with Azathioprine alone.
Digestive T cell lymphomas represent 13%–17% of all gastrointestinal lymphomas [5]. They almost all occur in the small intestine especially the jejunum but remain less frequent than B lymphomas in this location [5,6].
The onset of a malignant lymphoma during the course of the CD is a very rare finding. Almost all papers reported are case reports [7]. Crohn’s disease has long been suspected in the genesis of non-Hodgkin’s lymphoma of the digestive tract. However, most studies have failed to demonstrate this claim.
Two large-scale Swedish studies have failed to identify CD as a risk factor for lymphoma [8,9]. On the other hand, a recent American study [10] identified crohn’s disease as a risk factor for non-Hodgkin’s lymphoma but this study gathered a population of elderly patients with severe forms of the disease.
Immunosuppressive therapies used to control CD such as thiopurines have now been shown to be a risk factor for non-Hodgkin's lymphoma. This risk is increased in male patients and the elderly [11].
The risk of non-Hodgkin's lymphoma can be overlooked by the clinician in the face of the significant improvement in quality and life expectancy in young subjects whose Crohn’s disease is kept in remission thanks to maintenance therapy based on Azathopirine [12].
Maintaining such a level of immunosuppression is associated with a carcinological risk. Thus, the use of thiopurines is clearly associated with a risk of developing lymphoma [13]. In 2011, 43 cases of lymphoma were described among the 16,023 patients treated with immunosuppressants for IBD [13]. The type of lymphoma most often diagnosed was large cell B lymphoma (44%), then follicular lymphoma (14%) then Hodgkin's lymphoma (12%).
In addition, the use of azathioprine or 6-mercaptopurine increased the risk of developing lymphoma by 4–5. On the other hand, the correlation between the occurrence of lymphoma and the use of an anti TNF is more disputed due to the use, often in parallel, of anti TNF and thiopurines in most patients [14]. A meta-analysis of 26 studies had described 13 cases of non-Hodgkin's lymphoma in adults treated with anti TNF for CD. Compared to the risk in the general population of developing lymphoma (1.9 per 10,000 person-years), the risk under anti TNF therapy was 3 times higher (3.2 per 10,000 person-years). Nevertheless, among the cases, 66% were also on thiopurines at the time of the diagnosis of lymphoma.
Finally, the TREAT study [15] is the only prospective study that continues to compare the side effects of infliximab with those of other therapies in more than 6000 patients treated for CD since 1999. The last update of this study in 2014 did not report any correlation between the use of infliximab and the risk of neoplasia but confirmed that immunosuppressive treatments, alone or in combination with biotherapies, increased the carcinogenic risk with odds with respective ratios of 4.19 and 3.33.
Similarly, Herrinton et al. reported that combotherapy increased the risk of developing lymphoma by a factor of 6 compared to the risk of the general population [13].
Non-Hodgkin's lymphomas can be complicated by intestinal perforation, especially after the initiation of anti-tumor chemotherapy, but the perforations can complicate the natural history of a lymphoma. These perforations most often occur in the small intestine and generally require emergency surgery [16]. Perforation is also known as a rare acute surgical emergency complicating the natural history of the CD, occurring in 1–3% of cases [17]. However, in other cases, perforation of a cancer, endoscopic perforation or anastomotic failure may occur.
In our patient, the perforation happened at the level of the ileo-rectal anastomosis which was the seat of lymphoma complicating the CD.
Surgical resection is currently the standard treatment with a mortality of less than 4% compared to 41% of mortality observed in the past after simple sutures of the perforation [18]. We opted for a resection of the ileo-rectal anastomosis with closure of the rectal stump and preparation of an ileostomy associated with wide drainage of the pelvis given the peritoneal contamination and the immunocompromised site. The restoration of delayed digestive continuity was necessary in our view.
4 Conclusion
The appearance of lymphoma occurred in this case, in a young patient put on Thiopurines for 6 years with an evolution towards degeneration is relatively rapid compared to what is generally reported in the literature. The non-Hodgkin's lymphoma discovered fortuitously in pathology study was responsible for an anastomotic dehiscence which was blocked by the small handles carrying out a real plastron. To our knowledge, no publication has dealt with a case of dehiscence of an anastomosis at 3 years of follow-up due to degeneration in T lymphoma which makes this case all the more interesting.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
None.
Ethical approval
Not applicable.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Anis Haddad: Performed Surgery.
Ahmed Ben Mahmoud: Writing - Original draft.
Houcine Maghrebi: Supervision.
Baya Chelly: Data interpretation of the pathological findings.
Mohamed Jouini: Supervision.
Montasser Jameleddine Kacem: Supervision - Reviewing.
Registration of research studies
Not applicable.
Guarantor
Ahmed Ben Mahmoud.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgement
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33429357 | 18,817,709 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acinetobacter bacteraemia'. | Pneumocystis jiroveci pneumonia, Nocardia brasiliensis, and Mycobacterium tuberculosis co-infection in a myasthenia gravis patient: A case report.
BACKGROUND
Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junctions that leads to fluctuating weakness and disabling fatigability. Due to difficulty in breathing caused by weakness of the respiratory muscles, patients with MG are more susceptible to pneumonia and other respiratory infections. As many patients with MG are given immunosuppressive therapy, this makes them more prone to infections. However, coinfection with 3 pathogens is very rare.
Here, we report the case of a 41-year-old gentleman with MG who was receiving long-term steroid therapy. He presented with a cough with pale brown expectoration that occurred without obvious inducement, severe pain in the scapula, as well as swelling and weakness of both legs. Despite undergoing treatment, but his symptoms did not improve, prompting two additional hospital admissions over a period of several months.
METHODS
Bronchoscopy and bronchoalveolar lavage (BAL) were performed, revealing the presence of Pneumocystis jirovecii , Nocardia brasiliensis, and Mycobacterium tuberculosis (MTB). N brasiliensis was identified by positive modified acid-fast Kinyoun staining as well as a positive colony culture identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry from the BAL sample. MTB was confirmed using GeneXpert, and due to the limitations of the culture conditions, methenamine silver stain was used to confirm Pneumocystis jirovecii. Next-generation sequencing (NGS) assay of the BAL samples also confirmed these pathogens.
METHODS
The patient was transferred to a designated tuberculosis hospital and received anti-infective and anti-TB treatment.
RESULTS
During treatment at the designated hospital, the patient developed gastrointestinal bleeding and impaired liver function. One month later, he developed multiple organ failure, consolidation of the left lower lung, and pan-drug resistant bacteremia. He refused further treatment and was discharged.
CONCLUSIONS
In conclusion, physicians should be aware of the predisposition of MG patients to co-infections, especially patients with metabolic disorders, to avoid inadequate treatment and poor patient outcomes. Due to the limitations of culture conditions, NGS should be considered as a new technique for identifying pathogens.
1 Introduction
Pneumocystis jirovecii, which causes pneumonia, and Mycobacterium tuberculosis are the most commonly identified infections in patients with myasthenia gravis (MG).[1,2]Nocardia species are potential opportunistic pathogens that are prevalent in people with compromised cell-mediated immunity. However, concurrent infection with these two pathogens is a rare event in immunocompromised individuals. The rarity of concurrent infection leads to the possibility that the detection of one pathogen may lead to low suspicion of the presence of a second infection. Thus, this may lead to inadequate treatment and poor patient outcomes. Additionally, since patients with co-infections are mostly immunocompromised individuals, an overlooked diagnosis can worsen the clinical outcome. Herein, we present an unusual case of a patient with MG who was receiving long-term steroid therapy combined with additional antimetabolite immunosuppressives and developed co-infections with Pneumocystis jiroveci, N brasiliensis, and Mycobacterium tuberculosis.
2 Case description
2.1 Ethics statement
According to the hospital protocol, no formal ethics approval was required for this study. The patient agreed and provided written informed consent for publication of this report and any accompanying images.
2.2 Case introduction
A 41-year-old man with a past medical history of type 2 diabetes mellitus and hyperlipidemia had been diagnosed with MG and underwent a surgical thoracotomy for thymoma 4 years ago. He was subsequently started on methylprednisolone and also received intravenous immunoglobulin. In August 2018, he was admitted to the hospital with respiratory obstruction and discharged after symptom alleviation. The symptoms recurred one month later, but they were again relieved on symptomatic treatment; thus, the patient was again discharged. Nevertheless, the symptoms persisted, prompting two additional hospital admissions over a period of several months. In November 2018, he was re-admitted with a cough with pale brown expectoration that occurred with no obvious inducement. This was accompanied by severe pain in the scapula and swelling of and weakness in both legs. The patient was initially treated with methylprednisolone 24 mg daily, which was later increased to 120 mg after re-admission. Despite these interventions, his symptoms persisted; 3 days after admission, the patient developed dyspnea and respiratory distress, with the maintenance of an upright posture required for breathing. His oxygen saturation was 75%, and he was transferred to the intensive care unit (ICU) for further treatment. He was started on broad-spectrum antibiotics including Sulperazon and voriconazole. Bedside chest radiographs showed diffuse hyperdense shadows in both lungs. Bronchoscopy was performed to rule out atypical infections such as P jiroveci. In addition, bacterial cultures, fungal cultures, and acid-fast bacilli cultures were performed on the bronchoalveolar lavage (BAL) samples, which were also delivered to the Beijing Genomics Institution (BGI) for next-generation sequencing (NGS). During this period, a prior BAL culture was analyzed, using the Zeihl-Neelsen acid-fast stain and the modified acid-fast Kinyoun stain, and showed positivity for Mycobacterium tuberculosis and N brasiliensis. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) of the colony culture identified the pathogen as N brasiliensis. Silver stain was positive for budding yeast (Fig. 1), which was identified as P jiroveci. Several days later, these results were confirmed by NGS. Subsequently, the patient was transferred to a designated tuberculosis hospital.
Figure 1 Sliver stain positive, original magnification × 40.
During hospitalization, the patient was treated with methylprednisolone 40 mg daily, anti-bacterial therapy (injections of sulfamethoxazole, Sulperazon, and linezolid), anti-fungal therapy (injections of voriconazole), and anti-TB therapy, including isoniazid, rifampicin, pyrazinamide, and ethambutol. On hospital day 15, the patient developed gastrointestinal hemorrhage and liver dysfunction. Therefore, the treatment was combined with liver-protecting agents and hemostatic therapy. On hospital day 23, he developed fever and shortness of breath. A chest computed tomography (CT) scan demonstrated consolidation of the left lower lung, and bacteremia caused by a multi-drug resistant Acinetobacter baumanii was diagnosed based on a positive blood culture. Consequently, the antibacterial agent was changed to tigecycline injection. However, the treatment was not effective. The patient refused further treatment and was discharged due to further clinical deterioration, including multiple organ failure, on hospital day 30.
3 Discussion
Although MG is a relatively rare condition, several patients with MG receive immunosuppressive therapy, with corticosteroids being the most commonly used immunosuppressive drugs. Tindall et al suggested that corticosteroids may reduce both the serum AChR antibody levels and the AChR reactivity of peripheral blood lymphocytes.[3] Corticosteroids can inhibit the effects of lymphocytes, monocyte chemotaxis, and peripheral monocytes, including their bactericidal activity and the production of interleukin-1 and tumor necrosis factor-α. This can interfere with cell-mediated immunity, resulting in reduced host resistance to infections.[4] The symptoms of MG can be aggravated by stress, surgery, various autoimmune or rheumatological diseases, thyroid dysfunction, and infectious diseases. In addition, systemic corticosteroids, especially when combined with other antimetabolite immunosuppressives, may increase the risk of opportunistic infections.
Previous studies have shown an association between the occurrence of TB and use of corticosteroids in some diseases that require steroid treatment.[5,6] TB may arise by transmission from actively infected individuals or by the reactivation of a quiescent focus. As many patients with MG require immunosuppressive therapy, they are highly susceptible to contracting TB. Pulmonary TB can also exacerbate MG because of the respiratory distress in patients with MG. Some case reports have shown that concurrent TB can cause acute deterioration of MG.[7] Ou et al analyzed the risk factors for TB in patients with MG by univariate Cox regression analysis and revealed that the risk factors are: age ≥ 60 years, presence of chronic obstructive pulmonary disease and/or underlying malignancy, use of corticosteroids, and use of high-dose pyridostigmine.[2]
P jiroveci pneumonia (PJP) is an opportunistic infection with a high mortality rate that is seen in patients receiving immunosuppressive therapy. P jiroveci lives almost exclusively in the pulmonary alveoli and adheres to the alveolar epithelium. Intra-alveolar macrophages serve as the primary host defense against P jiroveci, and macrophage deficiency or dysfunction can lead to infection.[8] The most common underlying rheumatologic conditions associated with PJP are inflammatory myopathy, systemic lupus erythematosus (SLE), and granulomatosis with polyangiitis (GPA). A commonly cited recommendation based mainly on retrospective studies is to consider PJP prophylaxis in patients who are on ≥20 mg prednisone for ≥2 to 4 weeks.[7,9]
Pulmonary nocardiosis is a severe and uncommon opportunistic infection caused by Nocardia species. As potential opportunistic pathogens, Nocardia species are prevalent in individuals with compromised cell-mediated immunity. Nocardia does not belong to the normal human flora and is seldom a contaminant in tissue cultures.[10] It is found in soil, decaying plants, and dust particles.[11] The immunocompetence of the host determines the rate and course of infection. High-dose prolonged corticosteroid therapy is a known independent risk factor for infection with Nocardia because it suppresses Th1 cellular immunity.[10]
On conducting a literature review with the articles retrieved using the search terms P jiroveci pneumonia, N brasiliensis, and Mycobacterium tuberculosis on PubMed, there were some case reports on the co-existence of TB and P jiroveci pneumonia in MG patients, but co-infection with P jiroveci, N brasiliensis, and Mycobacterium tuberculosis in MG patients was rarely mentioned. In our case, the patient had a past medical history of type 2 diabetes mellitus and hyperlipidemia and had recently received immunosuppressive therapy with a high dose of methylprednisolone for four years. Additionally, he had undergone surgical thoracotomy for thymoma, further increasing the risk of opportunistic infections. It is essential to highlight this case given that most medical practitioners frequently manage patients with immune-compromised states, such as those on chronic steroid therapy. Identification of each of the underlying causative organisms is essential because this has significant implications for treatment. The application of new techniques for diagnosing pathogens, such as NGS, should be considered, particularly when the culture conditions are limited. Since co-infection is rare, when one infection is identified, most health professionals will have a low suspicion for an additional co-infection. This may lead to inadequate treatment and poor patient outcome. Hence, this case report is important since it can aid in increasing awareness among general practitioners.
Author contributions
Conceptualization: Jiahui Hou.
Methodology: Junmin Cao.
Validation: Ying Yu.
Writing – original draft: Jiahui Hou.
Writing – review & editing: Panli Tan.
Abbreviations: BAL = bronchoscopy and bronchoalveolar lavage, MALDI-TOF MS = the matrix-assisted laser desorption ionization-time of flight mass spectrometry, MG = myasthenia gravis, MTB = Mycobacterium tuberculosis, NGS = the next-generation sequencing, PJP = pneumocystis jiroveci pneumonia.
How to cite this article: Hou J, Cao J, Tan P, Yu Y. Pneumocystis jiroveci pneumonia, Nocardia brasiliensis, and Mycobacterium tuberculosis co-infection in a myasthenia gravis patient: A case report. Medicine. 2021;100:1(e24245).
The consent was obtained by all participants in this study.
The work was sponsored by the Natural Science Foundation of Zhejiang Province (No. LGF20H080004).
All authors have no potential conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | CEFOPERAZONE SODIUM\SULBACTAM SODIUM, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LINEZOLID, METHYLPREDNISOLONE, PYRAZINAMIDE, RIFAMPIN, SULFAMETHOXAZOLE, VORICONAZOLE | DrugsGivenReaction | CC BY | 33429828 | 18,961,450 | 2021-01-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Multiple organ dysfunction syndrome'. | Pneumocystis jiroveci pneumonia, Nocardia brasiliensis, and Mycobacterium tuberculosis co-infection in a myasthenia gravis patient: A case report.
BACKGROUND
Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junctions that leads to fluctuating weakness and disabling fatigability. Due to difficulty in breathing caused by weakness of the respiratory muscles, patients with MG are more susceptible to pneumonia and other respiratory infections. As many patients with MG are given immunosuppressive therapy, this makes them more prone to infections. However, coinfection with 3 pathogens is very rare.
Here, we report the case of a 41-year-old gentleman with MG who was receiving long-term steroid therapy. He presented with a cough with pale brown expectoration that occurred without obvious inducement, severe pain in the scapula, as well as swelling and weakness of both legs. Despite undergoing treatment, but his symptoms did not improve, prompting two additional hospital admissions over a period of several months.
METHODS
Bronchoscopy and bronchoalveolar lavage (BAL) were performed, revealing the presence of Pneumocystis jirovecii , Nocardia brasiliensis, and Mycobacterium tuberculosis (MTB). N brasiliensis was identified by positive modified acid-fast Kinyoun staining as well as a positive colony culture identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry from the BAL sample. MTB was confirmed using GeneXpert, and due to the limitations of the culture conditions, methenamine silver stain was used to confirm Pneumocystis jirovecii. Next-generation sequencing (NGS) assay of the BAL samples also confirmed these pathogens.
METHODS
The patient was transferred to a designated tuberculosis hospital and received anti-infective and anti-TB treatment.
RESULTS
During treatment at the designated hospital, the patient developed gastrointestinal bleeding and impaired liver function. One month later, he developed multiple organ failure, consolidation of the left lower lung, and pan-drug resistant bacteremia. He refused further treatment and was discharged.
CONCLUSIONS
In conclusion, physicians should be aware of the predisposition of MG patients to co-infections, especially patients with metabolic disorders, to avoid inadequate treatment and poor patient outcomes. Due to the limitations of culture conditions, NGS should be considered as a new technique for identifying pathogens.
1 Introduction
Pneumocystis jirovecii, which causes pneumonia, and Mycobacterium tuberculosis are the most commonly identified infections in patients with myasthenia gravis (MG).[1,2]Nocardia species are potential opportunistic pathogens that are prevalent in people with compromised cell-mediated immunity. However, concurrent infection with these two pathogens is a rare event in immunocompromised individuals. The rarity of concurrent infection leads to the possibility that the detection of one pathogen may lead to low suspicion of the presence of a second infection. Thus, this may lead to inadequate treatment and poor patient outcomes. Additionally, since patients with co-infections are mostly immunocompromised individuals, an overlooked diagnosis can worsen the clinical outcome. Herein, we present an unusual case of a patient with MG who was receiving long-term steroid therapy combined with additional antimetabolite immunosuppressives and developed co-infections with Pneumocystis jiroveci, N brasiliensis, and Mycobacterium tuberculosis.
2 Case description
2.1 Ethics statement
According to the hospital protocol, no formal ethics approval was required for this study. The patient agreed and provided written informed consent for publication of this report and any accompanying images.
2.2 Case introduction
A 41-year-old man with a past medical history of type 2 diabetes mellitus and hyperlipidemia had been diagnosed with MG and underwent a surgical thoracotomy for thymoma 4 years ago. He was subsequently started on methylprednisolone and also received intravenous immunoglobulin. In August 2018, he was admitted to the hospital with respiratory obstruction and discharged after symptom alleviation. The symptoms recurred one month later, but they were again relieved on symptomatic treatment; thus, the patient was again discharged. Nevertheless, the symptoms persisted, prompting two additional hospital admissions over a period of several months. In November 2018, he was re-admitted with a cough with pale brown expectoration that occurred with no obvious inducement. This was accompanied by severe pain in the scapula and swelling of and weakness in both legs. The patient was initially treated with methylprednisolone 24 mg daily, which was later increased to 120 mg after re-admission. Despite these interventions, his symptoms persisted; 3 days after admission, the patient developed dyspnea and respiratory distress, with the maintenance of an upright posture required for breathing. His oxygen saturation was 75%, and he was transferred to the intensive care unit (ICU) for further treatment. He was started on broad-spectrum antibiotics including Sulperazon and voriconazole. Bedside chest radiographs showed diffuse hyperdense shadows in both lungs. Bronchoscopy was performed to rule out atypical infections such as P jiroveci. In addition, bacterial cultures, fungal cultures, and acid-fast bacilli cultures were performed on the bronchoalveolar lavage (BAL) samples, which were also delivered to the Beijing Genomics Institution (BGI) for next-generation sequencing (NGS). During this period, a prior BAL culture was analyzed, using the Zeihl-Neelsen acid-fast stain and the modified acid-fast Kinyoun stain, and showed positivity for Mycobacterium tuberculosis and N brasiliensis. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) of the colony culture identified the pathogen as N brasiliensis. Silver stain was positive for budding yeast (Fig. 1), which was identified as P jiroveci. Several days later, these results were confirmed by NGS. Subsequently, the patient was transferred to a designated tuberculosis hospital.
Figure 1 Sliver stain positive, original magnification × 40.
During hospitalization, the patient was treated with methylprednisolone 40 mg daily, anti-bacterial therapy (injections of sulfamethoxazole, Sulperazon, and linezolid), anti-fungal therapy (injections of voriconazole), and anti-TB therapy, including isoniazid, rifampicin, pyrazinamide, and ethambutol. On hospital day 15, the patient developed gastrointestinal hemorrhage and liver dysfunction. Therefore, the treatment was combined with liver-protecting agents and hemostatic therapy. On hospital day 23, he developed fever and shortness of breath. A chest computed tomography (CT) scan demonstrated consolidation of the left lower lung, and bacteremia caused by a multi-drug resistant Acinetobacter baumanii was diagnosed based on a positive blood culture. Consequently, the antibacterial agent was changed to tigecycline injection. However, the treatment was not effective. The patient refused further treatment and was discharged due to further clinical deterioration, including multiple organ failure, on hospital day 30.
3 Discussion
Although MG is a relatively rare condition, several patients with MG receive immunosuppressive therapy, with corticosteroids being the most commonly used immunosuppressive drugs. Tindall et al suggested that corticosteroids may reduce both the serum AChR antibody levels and the AChR reactivity of peripheral blood lymphocytes.[3] Corticosteroids can inhibit the effects of lymphocytes, monocyte chemotaxis, and peripheral monocytes, including their bactericidal activity and the production of interleukin-1 and tumor necrosis factor-α. This can interfere with cell-mediated immunity, resulting in reduced host resistance to infections.[4] The symptoms of MG can be aggravated by stress, surgery, various autoimmune or rheumatological diseases, thyroid dysfunction, and infectious diseases. In addition, systemic corticosteroids, especially when combined with other antimetabolite immunosuppressives, may increase the risk of opportunistic infections.
Previous studies have shown an association between the occurrence of TB and use of corticosteroids in some diseases that require steroid treatment.[5,6] TB may arise by transmission from actively infected individuals or by the reactivation of a quiescent focus. As many patients with MG require immunosuppressive therapy, they are highly susceptible to contracting TB. Pulmonary TB can also exacerbate MG because of the respiratory distress in patients with MG. Some case reports have shown that concurrent TB can cause acute deterioration of MG.[7] Ou et al analyzed the risk factors for TB in patients with MG by univariate Cox regression analysis and revealed that the risk factors are: age ≥ 60 years, presence of chronic obstructive pulmonary disease and/or underlying malignancy, use of corticosteroids, and use of high-dose pyridostigmine.[2]
P jiroveci pneumonia (PJP) is an opportunistic infection with a high mortality rate that is seen in patients receiving immunosuppressive therapy. P jiroveci lives almost exclusively in the pulmonary alveoli and adheres to the alveolar epithelium. Intra-alveolar macrophages serve as the primary host defense against P jiroveci, and macrophage deficiency or dysfunction can lead to infection.[8] The most common underlying rheumatologic conditions associated with PJP are inflammatory myopathy, systemic lupus erythematosus (SLE), and granulomatosis with polyangiitis (GPA). A commonly cited recommendation based mainly on retrospective studies is to consider PJP prophylaxis in patients who are on ≥20 mg prednisone for ≥2 to 4 weeks.[7,9]
Pulmonary nocardiosis is a severe and uncommon opportunistic infection caused by Nocardia species. As potential opportunistic pathogens, Nocardia species are prevalent in individuals with compromised cell-mediated immunity. Nocardia does not belong to the normal human flora and is seldom a contaminant in tissue cultures.[10] It is found in soil, decaying plants, and dust particles.[11] The immunocompetence of the host determines the rate and course of infection. High-dose prolonged corticosteroid therapy is a known independent risk factor for infection with Nocardia because it suppresses Th1 cellular immunity.[10]
On conducting a literature review with the articles retrieved using the search terms P jiroveci pneumonia, N brasiliensis, and Mycobacterium tuberculosis on PubMed, there were some case reports on the co-existence of TB and P jiroveci pneumonia in MG patients, but co-infection with P jiroveci, N brasiliensis, and Mycobacterium tuberculosis in MG patients was rarely mentioned. In our case, the patient had a past medical history of type 2 diabetes mellitus and hyperlipidemia and had recently received immunosuppressive therapy with a high dose of methylprednisolone for four years. Additionally, he had undergone surgical thoracotomy for thymoma, further increasing the risk of opportunistic infections. It is essential to highlight this case given that most medical practitioners frequently manage patients with immune-compromised states, such as those on chronic steroid therapy. Identification of each of the underlying causative organisms is essential because this has significant implications for treatment. The application of new techniques for diagnosing pathogens, such as NGS, should be considered, particularly when the culture conditions are limited. Since co-infection is rare, when one infection is identified, most health professionals will have a low suspicion for an additional co-infection. This may lead to inadequate treatment and poor patient outcome. Hence, this case report is important since it can aid in increasing awareness among general practitioners.
Author contributions
Conceptualization: Jiahui Hou.
Methodology: Junmin Cao.
Validation: Ying Yu.
Writing – original draft: Jiahui Hou.
Writing – review & editing: Panli Tan.
Abbreviations: BAL = bronchoscopy and bronchoalveolar lavage, MALDI-TOF MS = the matrix-assisted laser desorption ionization-time of flight mass spectrometry, MG = myasthenia gravis, MTB = Mycobacterium tuberculosis, NGS = the next-generation sequencing, PJP = pneumocystis jiroveci pneumonia.
How to cite this article: Hou J, Cao J, Tan P, Yu Y. Pneumocystis jiroveci pneumonia, Nocardia brasiliensis, and Mycobacterium tuberculosis co-infection in a myasthenia gravis patient: A case report. Medicine. 2021;100:1(e24245).
The consent was obtained by all participants in this study.
The work was sponsored by the Natural Science Foundation of Zhejiang Province (No. LGF20H080004).
All authors have no potential conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | CEFOPERAZONE SODIUM\SULBACTAM SODIUM, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LINEZOLID, METHYLPREDNISOLONE, PYRAZINAMIDE, RIFAMPIN, SULFAMETHOXAZOLE, VORICONAZOLE | DrugsGivenReaction | CC BY | 33429828 | 18,961,450 | 2021-01-08 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | Pneumocystis jiroveci pneumonia, Nocardia brasiliensis, and Mycobacterium tuberculosis co-infection in a myasthenia gravis patient: A case report.
BACKGROUND
Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junctions that leads to fluctuating weakness and disabling fatigability. Due to difficulty in breathing caused by weakness of the respiratory muscles, patients with MG are more susceptible to pneumonia and other respiratory infections. As many patients with MG are given immunosuppressive therapy, this makes them more prone to infections. However, coinfection with 3 pathogens is very rare.
Here, we report the case of a 41-year-old gentleman with MG who was receiving long-term steroid therapy. He presented with a cough with pale brown expectoration that occurred without obvious inducement, severe pain in the scapula, as well as swelling and weakness of both legs. Despite undergoing treatment, but his symptoms did not improve, prompting two additional hospital admissions over a period of several months.
METHODS
Bronchoscopy and bronchoalveolar lavage (BAL) were performed, revealing the presence of Pneumocystis jirovecii , Nocardia brasiliensis, and Mycobacterium tuberculosis (MTB). N brasiliensis was identified by positive modified acid-fast Kinyoun staining as well as a positive colony culture identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry from the BAL sample. MTB was confirmed using GeneXpert, and due to the limitations of the culture conditions, methenamine silver stain was used to confirm Pneumocystis jirovecii. Next-generation sequencing (NGS) assay of the BAL samples also confirmed these pathogens.
METHODS
The patient was transferred to a designated tuberculosis hospital and received anti-infective and anti-TB treatment.
RESULTS
During treatment at the designated hospital, the patient developed gastrointestinal bleeding and impaired liver function. One month later, he developed multiple organ failure, consolidation of the left lower lung, and pan-drug resistant bacteremia. He refused further treatment and was discharged.
CONCLUSIONS
In conclusion, physicians should be aware of the predisposition of MG patients to co-infections, especially patients with metabolic disorders, to avoid inadequate treatment and poor patient outcomes. Due to the limitations of culture conditions, NGS should be considered as a new technique for identifying pathogens.
1 Introduction
Pneumocystis jirovecii, which causes pneumonia, and Mycobacterium tuberculosis are the most commonly identified infections in patients with myasthenia gravis (MG).[1,2]Nocardia species are potential opportunistic pathogens that are prevalent in people with compromised cell-mediated immunity. However, concurrent infection with these two pathogens is a rare event in immunocompromised individuals. The rarity of concurrent infection leads to the possibility that the detection of one pathogen may lead to low suspicion of the presence of a second infection. Thus, this may lead to inadequate treatment and poor patient outcomes. Additionally, since patients with co-infections are mostly immunocompromised individuals, an overlooked diagnosis can worsen the clinical outcome. Herein, we present an unusual case of a patient with MG who was receiving long-term steroid therapy combined with additional antimetabolite immunosuppressives and developed co-infections with Pneumocystis jiroveci, N brasiliensis, and Mycobacterium tuberculosis.
2 Case description
2.1 Ethics statement
According to the hospital protocol, no formal ethics approval was required for this study. The patient agreed and provided written informed consent for publication of this report and any accompanying images.
2.2 Case introduction
A 41-year-old man with a past medical history of type 2 diabetes mellitus and hyperlipidemia had been diagnosed with MG and underwent a surgical thoracotomy for thymoma 4 years ago. He was subsequently started on methylprednisolone and also received intravenous immunoglobulin. In August 2018, he was admitted to the hospital with respiratory obstruction and discharged after symptom alleviation. The symptoms recurred one month later, but they were again relieved on symptomatic treatment; thus, the patient was again discharged. Nevertheless, the symptoms persisted, prompting two additional hospital admissions over a period of several months. In November 2018, he was re-admitted with a cough with pale brown expectoration that occurred with no obvious inducement. This was accompanied by severe pain in the scapula and swelling of and weakness in both legs. The patient was initially treated with methylprednisolone 24 mg daily, which was later increased to 120 mg after re-admission. Despite these interventions, his symptoms persisted; 3 days after admission, the patient developed dyspnea and respiratory distress, with the maintenance of an upright posture required for breathing. His oxygen saturation was 75%, and he was transferred to the intensive care unit (ICU) for further treatment. He was started on broad-spectrum antibiotics including Sulperazon and voriconazole. Bedside chest radiographs showed diffuse hyperdense shadows in both lungs. Bronchoscopy was performed to rule out atypical infections such as P jiroveci. In addition, bacterial cultures, fungal cultures, and acid-fast bacilli cultures were performed on the bronchoalveolar lavage (BAL) samples, which were also delivered to the Beijing Genomics Institution (BGI) for next-generation sequencing (NGS). During this period, a prior BAL culture was analyzed, using the Zeihl-Neelsen acid-fast stain and the modified acid-fast Kinyoun stain, and showed positivity for Mycobacterium tuberculosis and N brasiliensis. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) of the colony culture identified the pathogen as N brasiliensis. Silver stain was positive for budding yeast (Fig. 1), which was identified as P jiroveci. Several days later, these results were confirmed by NGS. Subsequently, the patient was transferred to a designated tuberculosis hospital.
Figure 1 Sliver stain positive, original magnification × 40.
During hospitalization, the patient was treated with methylprednisolone 40 mg daily, anti-bacterial therapy (injections of sulfamethoxazole, Sulperazon, and linezolid), anti-fungal therapy (injections of voriconazole), and anti-TB therapy, including isoniazid, rifampicin, pyrazinamide, and ethambutol. On hospital day 15, the patient developed gastrointestinal hemorrhage and liver dysfunction. Therefore, the treatment was combined with liver-protecting agents and hemostatic therapy. On hospital day 23, he developed fever and shortness of breath. A chest computed tomography (CT) scan demonstrated consolidation of the left lower lung, and bacteremia caused by a multi-drug resistant Acinetobacter baumanii was diagnosed based on a positive blood culture. Consequently, the antibacterial agent was changed to tigecycline injection. However, the treatment was not effective. The patient refused further treatment and was discharged due to further clinical deterioration, including multiple organ failure, on hospital day 30.
3 Discussion
Although MG is a relatively rare condition, several patients with MG receive immunosuppressive therapy, with corticosteroids being the most commonly used immunosuppressive drugs. Tindall et al suggested that corticosteroids may reduce both the serum AChR antibody levels and the AChR reactivity of peripheral blood lymphocytes.[3] Corticosteroids can inhibit the effects of lymphocytes, monocyte chemotaxis, and peripheral monocytes, including their bactericidal activity and the production of interleukin-1 and tumor necrosis factor-α. This can interfere with cell-mediated immunity, resulting in reduced host resistance to infections.[4] The symptoms of MG can be aggravated by stress, surgery, various autoimmune or rheumatological diseases, thyroid dysfunction, and infectious diseases. In addition, systemic corticosteroids, especially when combined with other antimetabolite immunosuppressives, may increase the risk of opportunistic infections.
Previous studies have shown an association between the occurrence of TB and use of corticosteroids in some diseases that require steroid treatment.[5,6] TB may arise by transmission from actively infected individuals or by the reactivation of a quiescent focus. As many patients with MG require immunosuppressive therapy, they are highly susceptible to contracting TB. Pulmonary TB can also exacerbate MG because of the respiratory distress in patients with MG. Some case reports have shown that concurrent TB can cause acute deterioration of MG.[7] Ou et al analyzed the risk factors for TB in patients with MG by univariate Cox regression analysis and revealed that the risk factors are: age ≥ 60 years, presence of chronic obstructive pulmonary disease and/or underlying malignancy, use of corticosteroids, and use of high-dose pyridostigmine.[2]
P jiroveci pneumonia (PJP) is an opportunistic infection with a high mortality rate that is seen in patients receiving immunosuppressive therapy. P jiroveci lives almost exclusively in the pulmonary alveoli and adheres to the alveolar epithelium. Intra-alveolar macrophages serve as the primary host defense against P jiroveci, and macrophage deficiency or dysfunction can lead to infection.[8] The most common underlying rheumatologic conditions associated with PJP are inflammatory myopathy, systemic lupus erythematosus (SLE), and granulomatosis with polyangiitis (GPA). A commonly cited recommendation based mainly on retrospective studies is to consider PJP prophylaxis in patients who are on ≥20 mg prednisone for ≥2 to 4 weeks.[7,9]
Pulmonary nocardiosis is a severe and uncommon opportunistic infection caused by Nocardia species. As potential opportunistic pathogens, Nocardia species are prevalent in individuals with compromised cell-mediated immunity. Nocardia does not belong to the normal human flora and is seldom a contaminant in tissue cultures.[10] It is found in soil, decaying plants, and dust particles.[11] The immunocompetence of the host determines the rate and course of infection. High-dose prolonged corticosteroid therapy is a known independent risk factor for infection with Nocardia because it suppresses Th1 cellular immunity.[10]
On conducting a literature review with the articles retrieved using the search terms P jiroveci pneumonia, N brasiliensis, and Mycobacterium tuberculosis on PubMed, there were some case reports on the co-existence of TB and P jiroveci pneumonia in MG patients, but co-infection with P jiroveci, N brasiliensis, and Mycobacterium tuberculosis in MG patients was rarely mentioned. In our case, the patient had a past medical history of type 2 diabetes mellitus and hyperlipidemia and had recently received immunosuppressive therapy with a high dose of methylprednisolone for four years. Additionally, he had undergone surgical thoracotomy for thymoma, further increasing the risk of opportunistic infections. It is essential to highlight this case given that most medical practitioners frequently manage patients with immune-compromised states, such as those on chronic steroid therapy. Identification of each of the underlying causative organisms is essential because this has significant implications for treatment. The application of new techniques for diagnosing pathogens, such as NGS, should be considered, particularly when the culture conditions are limited. Since co-infection is rare, when one infection is identified, most health professionals will have a low suspicion for an additional co-infection. This may lead to inadequate treatment and poor patient outcome. Hence, this case report is important since it can aid in increasing awareness among general practitioners.
Author contributions
Conceptualization: Jiahui Hou.
Methodology: Junmin Cao.
Validation: Ying Yu.
Writing – original draft: Jiahui Hou.
Writing – review & editing: Panli Tan.
Abbreviations: BAL = bronchoscopy and bronchoalveolar lavage, MALDI-TOF MS = the matrix-assisted laser desorption ionization-time of flight mass spectrometry, MG = myasthenia gravis, MTB = Mycobacterium tuberculosis, NGS = the next-generation sequencing, PJP = pneumocystis jiroveci pneumonia.
How to cite this article: Hou J, Cao J, Tan P, Yu Y. Pneumocystis jiroveci pneumonia, Nocardia brasiliensis, and Mycobacterium tuberculosis co-infection in a myasthenia gravis patient: A case report. Medicine. 2021;100:1(e24245).
The consent was obtained by all participants in this study.
The work was sponsored by the Natural Science Foundation of Zhejiang Province (No. LGF20H080004).
All authors have no potential conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | 40 mg (milligrams). | DrugDosage | CC BY | 33429828 | 18,961,450 | 2021-01-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chest pain'. | IgG4-related nephritis and interstitial pulmonary disease complicated by invasive pulmonary fungal infection: a case report.
IgG4-related kidney disease (IgG4-RKD) can affect multiple organs, which was first reported as a complication or extra-organ manifestation of autoimmune pancreatitis in 2004. It is characterized by abundant IgG4-positive plasma cells infiltration in tissues involved.
A 69-year-old man presented with cough and renal dysfunction with medical history of hypertension and diabetes. Pathological findings revealed interstitial nephritis and he was initially diagnosed with IgG4-RKD. Prednisone helped the patient to get a remission of cough and an obvious decrease of IgG4 level. However, he developed invasive pulmonary fungal infection while steroid theatment. Anti-fungal therapy was initiated after lung puncture (around cavitary lung lesion). Hemodialysis had been conducted because of renal failure and he got rid of it 2 months later. Methylprednisolone was decreased to 8 mg/day for maintenance therapy. Anti-fungal infection continued for 4 months after discharge home. On the 4th month of follow-up, Chest CT revealed no progression of lung lesions.
The corticosteroids are the first-line therapy of IgG4-RD and a rapid response helps to confirm the diagnosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control.
Background
IgG4-related disease (IgG4-RD) is an inflammatory and fibrotic disease which was first described in the pancreas and was called autoimmune pancreatitis (AIP) in 2001 [1]. Its concept has been recognized worldwide since then that this systemic disease involved multiple organs or tissues characterized by elevated serum IgG4 level and IgG4 positive plasma cells infiltration in the affected tissues, leading to fibrosis eventually [2–6]. The prevalence of IgG4-RD in Japan was estimated as 0.28–1.08/100,000 people in 2012 [7].
IgG4-related tubulointerstitial nephritis (IgG4-TIN), is one of the frequent pathological changes of IgG4-related kidney disease (IgG4-RKD), accounting for about 15–25% of all IgG-RD [4, 8]. IgG4-related TIN shows a range of histologic appearances including (A) acute interstitial nephritis with minimal fibrosis; (B) a more cellular inflammatory pattern in the setting of expansile fibrosis; and (C) a very fibrotic, pauci-cellular pattern [7]. The diagnosis criteria of IgG4-RKD were proposed by the Japanese Society of Nephrology [9] and a work group of North America [7], respectively. IgG4-related kidney lesions were often associated with extrarenal disease, such as chronic sclerosing inflammation of the lacrimal gland, salivary gland [10] and lung [11].
Patients with IgG4-RKD have an increased risk of infection than general population. IgG4-TIN can be accompanied by eosinophilic lung disease [12] and pneumonia [13]. Here, we present a case of IgG4-RKD and lung interstitial lesions who developed invasive pulmonary fungal infection (IPFI) during treatment of glucocorticoid combined with immunosuppressive agents.
Case presentation
A 69-year-old male was admitted to the hospital in 2019 January 5th because of gradually aggravated edema and cough. His medical history included hypertension, arrhythmia and diabetes. On 2019 May 8th, he had experienced cough and phlegm with temperature around 38 ~ 39 °C. Laboratory tests were presented in Table 1. 18F-FDG-PET/CT showed interstitial pneumonia in both lungs. There was also elevated uptake abnormality in the upper kidney observed. Cefperazone-Sulbactam, doxycycline hydrochloride, imipenem, and linezolid were given. Because of no improvement, he took oral prednisone 24 mg per day. The body temperature recovered to normal and lower limb edema was alleviated after one week. On 2019 June 13th ,serum creatinine 157.7 umol/L (Fig. 1); and serum albumin, 24.9 g/L. Chest computed tomography (CT) scan showed that honeycomb-like changes considering interstitial inflammation and bilateral pleural effusion (Fig. 1A).
Table 1 Laboratory data performed before and after treatment
ITEMS Beforetherapy Steroidtherapyfor 1month Steroid therapy for2 months Steroid therapy for3 months Steroid therapy for4 months
White blood cell count(*10^9/L) 15.4 21.11 8.24 11.66 13.28
Hemoglobin(g/L) 129 108 84 98 101
Platelet count(*10^9/L) 323 285 100 273 176
C-reaction protein (CRP)(mg/L) 90 58.1 32 79.8 18.9
Erythrocyte sedimentation rate(mm/H) 120 60 / / /
Serum nitrogen (mmol/L) 10.2 24.71 24.18 30.33 14.5
Serum creatinine (umol/L) 64.6 232.8 212.4 187.2 100.7
Serum albumin(g/L) 24.2 32 30 27.6 21.2
Urine RBC(/ul) / 42.6 10.9 3
Urine protein creatine ratio(mg/g) 48.5
24 h urine protein (g) 0.721 0.62 0.61 0.45 0.49
ANCA-MPO (RU/ml) 35.1 12.7 8.6
ANCA-PR3 (RU/ml) 6.7 4.9 4.7
CD4+ / CD8 + lymphocyte 0.81 / / / 1.9
ABG Before therapy Steroid therapy for 2 months
PH 7.201 7.498
PCO2(mmHg) 20 31.6
PO2(mmHg) 117 49
SpO2 (%) 98 88
K(mmol/L) 5.4 4.1
HCO3-(mmol/L) 7.8 24.5
BE(mmol/L) -20 1
ANCA-MPO Myeloperoxidase-antineutrophil cytoplasmic antibody, ANCA-PR3 proteinase 3, ABG Arterial Blood Gas, / not available
Fig. 1 Chest CT showed interstitial inflammation and bilateral pleural effusion before therapy (a). After glucocorticoids admission, obvious absorption of interstitial inflammation and pleural effusion on both sides were found (b). Infection of both lungs with a left lower lobe cavity before anti-infection therapy (c). After anti-infection therapy, no increase boarder of lung lesions (d)
He went to Nephrology Department on 2019 July 2nd for further treatment. Laboratory results were presented in Table 1. Urine RBC 42.6/ul; Urine protein: creatine ratio (uPCR) 48.5 mg/g; Serum IgG4 level was elevated at 3.42 g/L (Normal range: 0.03–2.10 g/L). Anti-myeloperoxidase anti-neutrophil cytoplasmic antibody level was elevated at 35.1Ru/ml (Normal range:<20 Ru/ml). However, serum immunoglobulin A(IgA), IgG and IgM level were normal. Furthermore, the patient was negative for anti-double-stranded antibody, antinuclear antibody, anti-Sjogren’s syndrome A antibody, anti-Sjogren’s syndrome B antibody and anti-proteinase 3. Ultrasound displayed large-sized kidneys with uniform echo frequency and clear corticomedullary boundaries. Chest CT revealed obvious absorption of interstitial inflammation and pleural effusion on both sides, there were also multiple nodules in both lungs (Fig. 1b).
Histopathology of the kidney biopsy shows proliferation of glomerular mesangial cells, diffuse and irregular thickening of basement membrane (Fig. 2a). The tubulointerstitium shows marked injury. Patchy foci fibrosis and inflammatory cells infiltration were prominent in the interstitium (Fig. 2b, c). Immunofluorescence staining shows that IgG, IgM, IgA, C1q, C3 and C4 were negative in the granular mesangial area. Immunohistological analysis revealed numerous CD20-positive B cells ((D), × 400) and dense infiltration of CD138-positive plasma cells ((E), × 400), with an IgG4+/IgG+ plasma cell ratio being > 40% ((F), × 400). Electron microscopy demonstrated that there were no electron-dense deposits in the glomeruli (Fig. 3).
Fig. 2 Renal histopathological result showed almost normal glomeruli, massively infiltrating cells, and abundant interstitial fibrosis under the light microscopy. a The glomerulus showed glomerular mesangial cells proliferation and diffuse and irregular thickening of basement membrane (HE staining, × 200). b, c A mass of plasma cells and fibrotic fibers (HE staining, × 400) can be observed in the interstitium. d, e Immunohistological analysis revealed mostly CD20-positive B cells (× 400) and CD138-positive plasma cells (× 400) in the interstitium. f Immunohistochemistry for IgG4 shows abundant positive plasma cells (coloured brown) (× 400)
Fig. 3 No electron-dense deposits are observed under electron microscopy. a Abundant plasma cells (× 2000) infiltrated in renal interstitium. b Detachment and partial atrophy of the microvilli of renal tubular epithelial cells as well as edema, infiltration of lymphocytes/monocytes, and fibrosis in renal interstitium. There are no electron-dense deposits in the glomeruli (× 2000). c Proliferation of glomerular mesangial cells and interstitial cells (× 2000). d Diffuse and irregular thickening of basement membrane (× 12,000)
Based on these findings, he had been diagnosed as IgG4-related renal disease. Oral prednisone (40 mg/day) and cyclophosphamide (CTX, 0.4 g) were prescribed by intravenous infusion. The patient had been followed up every month after the treatment (Table 1). He presented with intermittent fever for more than 20 days and acute onset of left pleuritic chest pain with dry cough for 10 days. Negative results were found in aerobic or anaerobic blood culture. Chest CT showed recent infection of both lungs with left upper lung cavity (Fig. 1c). At June 28th he developed hemoptysis and type 1 respiratory failure (Table 2). The results of relevant tests are shown in Table 1. In order to differentiate between IgG4-RLD and IPFI, left upper lung puncture was conducted and showed that interstitial collagen fibrosis with acute and chronic inflammatory cell infiltration, focal fibrous necrosis and exudation, and small alveolar cell response. Fungal spores were also found in lung puncture specimen. Filamentous fungi can be seen in sputum culture. Immunohistochemistry test revealed that most plasma cells in the lung interstitium were positive for CD38 (+), CD138 (+), IgG (+) (Fig. 4). IgG positive plasma cells < 40%, IgG4 positive plasma cells < 10/HPF, which does not meet the pathological diagnostic criteria of IgG4 related diseases. The diagnosis of IPFI was definite. After then, the patient was initiated on voriconazole and caspofungin to anti-fungal infection, and prednisolone was decreased to 30 mg per day.
Table 2 Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ [2, 14, 15]
Criterion
Histology (i)The specimen pathology shows the dense lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis, the infiltration of IgG4-positive cells, and IgG cells more than IgG4 cells ratio of 40%;
Imaging (ii)clinical/radiological examination showing characteristic diffuse or localized swelling or masses in single or multiple organs;
Serology (iii) serum IgG4 concentration > 135 mg/dL;
(iv)Inflammatory markers such as white blood cells count and C-reactive protein concentrations are not elevated, despite the degree of lesions, their spread on imaging analysis and massive cellular infiltration on pathological examination;
Other organ involvement (v)Characteristic findings of IgG4-RD in other organs, including autoimmune pancreatitis, lung involvement, et al.
Treatment (vi)response to steroids.
All 3 criteria (i + ii + iii) are needed for definite diagnosis of IgG4-RD
Fig. 4 Histopathological findings of the pulmonary tissue (light microscopy: HE). a Pulmonary tissue shows fibrotic changes of the interstitium (× 100) in the lung. b Cell and tissue reactions and cellulosic exudation were observed in alveoli (× 200). c, d Giant cell, interstitial edema, collagen fiber hyperplasia and masson body were observed in the specimen (× 200). e, f Immunohistological analysis revealed CD38-positive plasmacyte (coloured brown) (E × 400) and CD138-positive plasmacyte (coloured brown) infiltration (F × 400). g IgG immunostaining shows IgG-positive plasmacyte (coloured brown) infiltration (× 400). h IgG4 immunostaining shows IgG4-positive plasmacyte (coloured brown) infiltration in the lung (× 400)
With anti-infection and immunosuppressive treatment for 2 weeks, serum CRP and IgG4 level had been considerably decreased to 2.94 mg/L and 1.57 g/L, respectively. Voriconazole 200 mg bid and Methylprednisolone 30 mg/day were continued after discharge home. After treatment for one month, a repeat CT scan showed no progression of lung lesions (Fig. 1D). CD4+/CD8+ lymphocyte: 1.9. The patient had been followed up for 4 months. In the most recent follow-up examination, the serum creatinine level decreased to 101 umol/L and he got rid of hemodialysis (Fig. 5). He is currently undergoing tapered prednisolone treatment.
Fig. 5 Dynamic changes of renal function before and after treatment in the patient with IgG4-RKD
Discussion and conclusions
This patient is characterized by serum IgG4 elevation, positive MPO-ANCA, which suggested the possibility of co-occurrence/concurrence of AAV and IgG4‐RD on his first visit from his serological presentation. Diagnosis of IgG4-RD requires particular pathological, serological and clinical features [2, 14, 15] (listed in Table 2). This patient presented with serum IgG4 elevation, hematuria, proteinuria, elevated uptake abnormality of the upper kidney observed in 18F-FDG-PET/CT, progressive kidney failure and interstitial lung disease. Histopathology of kidney biopsy showing typical lymphoplasmacytic infiltration and fibrosis enriched in IgG4-positive plasma cells, and infiltration of IgG4 + plasma cells with IgG4+/IgG+ plasma cells ratio greater than 40% and a total of ≥ 10 IgG4 + plasma cells per high-power field (HPF) indicated the diagnosis of IgG4-RKD.
Given the elevated MPO-ANCA and CRP, AAV related nephritis was a possible differential diagnosis (Proposed diagnostic criteria for kidney involvement in AAV listed in Table 3 [16]). In this case, pathological findings did not show renal crescentic glomerulonephritis or vasculitis, thus, anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-AAV) was not firstly considered according to the Chapel Hill Consensus Conference nomenclature criteria for AAV [16]; However, Some ANCA positive patients may present with interstitial nephritis without severe glomerulopathy, and whether his initial interstitial lung disease was related to IgG4 or AAV or both was not determined. Some reports suggested a possible pathogenic effect of ANCA-IgG4 [17, 18]. Serum IgG4 increase and IgG4-positive cell infiltration in the organ can also be seen in AAV [19, 20]. Distinguishing between these diseases is essential for treatment planning [20], because IgG4-RD responds well to steroid therapy alone, while AAV often requires concomitant immunosuppressant use. His initial interstitial lung disease was improved (Fig. 1) with prednisone therapy alone for one month favored the diagnosis of IgG4-RLD. Kim et al. [21] described that a steroid trial was useful for differentiating and response to steroid therapy is recommended to be added to the diagnostic criteria. Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ listed in Table 2. Therefore, we preferred his diagnosis of IgG4-RD.
Table 3 Proposed diagnostic criteria for kidney involvement in AAV [16]
clinical manifestations a rapidly progressive GN with a decline in kidney function accompanied by sub–nephrotic-range proteinuria, microscopic hematuria, and hypertension over days to a few months
Serology Anti-MPO antibody or anti-PR3 antibody positive
Pathological findings pauci-immune focal necrotizing crescentic GN
Rare patients with AAV have a prominent tubulointerstitial nephritis, which can be associated with vasculitis of the vasa recta
A diagnosis of AAV incorporates the integration of clinical features, ANCA serology, and tissue pathology as needed
Since kidney involvement was firstly reported in a patient with IgG4-RD in 2004 [22], many similar cases have been described [23–25]. A cross-sectional study reported in 2010 revealed all kidney lesions were associated with extrarenal disease among 114 patients with IgG4-related disease [26]. Several clinicopathologic studies reported IgG4-RD with both kidney and lung involvement [5, 14, 27–30]. In kidney its characteristic manifestation is TIN with multiple extrarenal tissue damage [14, 31], which is easily apparent with a chronic or rapid progressive renal function decline [23]. In lung, this may present as nodules with spiculated margins mimicking primary pulmonary malignancy [28, 32], multiple ground glass opacities (GGO) mimicking interstitial lung disease [14], alveolar interstitial type, and bronchovascular type [33].
However, he developed intermittent fever, acute onset of left pleuritic chest pain and an emerging lung lesion after steroid use for one month. IgG4-RLD has been classified into four categories based on CT. Our case was the GGO type. This also was the primary feature of IPFI [34] of which most common chest CT signs are nodules, consolidation and GGO. This patient had several high-risk factors of IPFI such as old age, long-term use of glucocorticoids, repeated hospitalization, etc. [35]. However,it is difficult to distinguish between IgG4-related lung disease (IgG4-RLD) and IPFI (Table 3). Lung puncture pathology is key standard. Thus, sputum culture and pathogenic examination were repeated and infiltration of IgG4-positive plasma cells was not found. The lung tissue specimen showed fungal spores which supported the diagnosis of IPFI. The differential diagnosis of IgG4-RLD and IPFI were listed in Table 4 [34, 36, 37].
Table 4 Differences between IgG4-RLD and IPFI [34, 36, 37]
Items IgG4-RLD IPFI
Clinical manifestations multi-system injuries dry cough and fever,no specific
Laboratory tests Serum IgG4 elevation CRP and (or) PCT elevation,G/GM positive
Imaging nodules, multiple ground glass opacities (GGO),alveolar interstitial type, and bronchovascular type nodules, consolidation and ground-glass opacity(GGO)
Pathology Mainly IgG4
With plasma cell infiltration and often with interstitial damage
fungal spores with hyphae can be observed, pulmonary fibrosis and inflammatory cell infiltration
Treatment protocol Systemic glucocorticoids anti-infection
Systemic glucocorticoids are recommended as the first-line approach of renal injury in untreated IgG4-RD [31]. A moderate initial dose of oral prednisolone for induction is 0.6 mg/kg daily for 2–4 weeks. The maintenance dose of steroid therapy is given after remission as 2.5-5 mg daily over a period of 2–3 months [2]. However, treatment with exogenous glucocorticoids comes with a number of risks such as avascular necrosis, osteoporosis, glaucoma, cardiovascular disease, worse glucose tolerance and diabetes. The risk of infection is of utmost concern and is well-documented [36, 38]. A Japanese study including 459 AIP patients reported pneumonia occurred in 3 patients treated with steroid [13]. Optimizing the nutritional state of patients, reducing its dose, duration and number of immunosuppressants are recommended to help prevent infection. In the present case, we have to decrease the dosage of immunosuppressive drugs after then, nevertheless, IgG4-RLD were aggravated and renal failure developed during dosage decrease.
Since not every patient can be recover from renal disfunction, maintenance hemodialysis become necessary in patients with irreversible renal failure due to IgG4-RKD [4, 39]. And in this case, the patient experienced a short-time hemodialysis because of azotemia, which partly due to deteriorating renal function, steroids use or (and) infection. Improvements in pulmonary lesions and kidney function were observed after 4 months and were maintained with a dose of 8.0 mg/day prednisone. Thus, the dosage of steroid and immunosuppressant should be reduced for the therapy of the elderly patients with IgG4 related diseases. In addition, it has been reported that relapse of IgG4-related lesions, including kidney damage, occurred in 20% of treated patients with IgG4-RKD during maintenance treatment [39]. Thus, long-term follow-up for this patient are required and a well prognosis is expected.
Taken together, IgG4-RKD is an immune-mediated condition that can affect not only kidney but also several other organs, leading to a dense lymphoplasmacytic infiltration dominant in IgG4-positive plasma cells with fibrosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control (Fig. 6).
Fig. 6 Flow diagram of the patient’s disease progression and treatment
Abbreviations
IgG4-RKDIgG4-related kidney disease
AIPAutoimmune pancreatitis
IgG4-TINIgG4-related tubulointerstitial nephritis
IPFIInvasive pulmonary fungal infection
CTChest computed tomography
uPCRUrine protein: creatine ratio
IgGSerum immunoglobulin G
CTXCyclophosphamide
MPO-ANCAAnti-myeloperoxidase anti-neutrophil cytoplasmic antibody
ANCA-AAVAnti-neutrophil cytoplasmic antibody associated vasculitis
GGOMultiple ground glass opacities
IgG4-RLDIgG4-related lung disease
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the Department of Pathology, Jiangsu province Hospital, for pulmonary pathology.
Authors’ contributions
YLX reviewed the patient’s clinical data, performed the literature search, and wrote the initial draft of the manuscript. YYH and KL assisted in the preparation of the manuscript contributed to data collection and interpretation and critically reviewed the manuscript. JQ, and JFZ provide the pathology of renal biopsy. XFZ performed the immunohistochemical studies. TFY conducted pulmonary puncture and provide the possibility of lung pathology. GY and XQX carried out analysis of patient’s clinical course, outcomes and interpretation of findings, and provided critical review comments for the manuscript. NNW and CYX had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, and provided critical review comments for the manuscript. All authors read and approved the final manuscript.
Funding
The research was financially supported by the National Natural Science Foundation of China (81570666), International Society of Nephrology (ISN) Clinical Research Program (18-01-0247), Jiangsu Province Key Medical Personnel Project (ZDRCA2016002). The funders had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, provided critical review comments and also submission for the manuscript.
Availability of data and materials
The datasets used during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | CYCLOPHOSPHAMIDE, PREDNISONE | DrugsGivenReaction | CC BY | 33430791 | 18,792,998 | 2021-01-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemoptysis'. | IgG4-related nephritis and interstitial pulmonary disease complicated by invasive pulmonary fungal infection: a case report.
IgG4-related kidney disease (IgG4-RKD) can affect multiple organs, which was first reported as a complication or extra-organ manifestation of autoimmune pancreatitis in 2004. It is characterized by abundant IgG4-positive plasma cells infiltration in tissues involved.
A 69-year-old man presented with cough and renal dysfunction with medical history of hypertension and diabetes. Pathological findings revealed interstitial nephritis and he was initially diagnosed with IgG4-RKD. Prednisone helped the patient to get a remission of cough and an obvious decrease of IgG4 level. However, he developed invasive pulmonary fungal infection while steroid theatment. Anti-fungal therapy was initiated after lung puncture (around cavitary lung lesion). Hemodialysis had been conducted because of renal failure and he got rid of it 2 months later. Methylprednisolone was decreased to 8 mg/day for maintenance therapy. Anti-fungal infection continued for 4 months after discharge home. On the 4th month of follow-up, Chest CT revealed no progression of lung lesions.
The corticosteroids are the first-line therapy of IgG4-RD and a rapid response helps to confirm the diagnosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control.
Background
IgG4-related disease (IgG4-RD) is an inflammatory and fibrotic disease which was first described in the pancreas and was called autoimmune pancreatitis (AIP) in 2001 [1]. Its concept has been recognized worldwide since then that this systemic disease involved multiple organs or tissues characterized by elevated serum IgG4 level and IgG4 positive plasma cells infiltration in the affected tissues, leading to fibrosis eventually [2–6]. The prevalence of IgG4-RD in Japan was estimated as 0.28–1.08/100,000 people in 2012 [7].
IgG4-related tubulointerstitial nephritis (IgG4-TIN), is one of the frequent pathological changes of IgG4-related kidney disease (IgG4-RKD), accounting for about 15–25% of all IgG-RD [4, 8]. IgG4-related TIN shows a range of histologic appearances including (A) acute interstitial nephritis with minimal fibrosis; (B) a more cellular inflammatory pattern in the setting of expansile fibrosis; and (C) a very fibrotic, pauci-cellular pattern [7]. The diagnosis criteria of IgG4-RKD were proposed by the Japanese Society of Nephrology [9] and a work group of North America [7], respectively. IgG4-related kidney lesions were often associated with extrarenal disease, such as chronic sclerosing inflammation of the lacrimal gland, salivary gland [10] and lung [11].
Patients with IgG4-RKD have an increased risk of infection than general population. IgG4-TIN can be accompanied by eosinophilic lung disease [12] and pneumonia [13]. Here, we present a case of IgG4-RKD and lung interstitial lesions who developed invasive pulmonary fungal infection (IPFI) during treatment of glucocorticoid combined with immunosuppressive agents.
Case presentation
A 69-year-old male was admitted to the hospital in 2019 January 5th because of gradually aggravated edema and cough. His medical history included hypertension, arrhythmia and diabetes. On 2019 May 8th, he had experienced cough and phlegm with temperature around 38 ~ 39 °C. Laboratory tests were presented in Table 1. 18F-FDG-PET/CT showed interstitial pneumonia in both lungs. There was also elevated uptake abnormality in the upper kidney observed. Cefperazone-Sulbactam, doxycycline hydrochloride, imipenem, and linezolid were given. Because of no improvement, he took oral prednisone 24 mg per day. The body temperature recovered to normal and lower limb edema was alleviated after one week. On 2019 June 13th ,serum creatinine 157.7 umol/L (Fig. 1); and serum albumin, 24.9 g/L. Chest computed tomography (CT) scan showed that honeycomb-like changes considering interstitial inflammation and bilateral pleural effusion (Fig. 1A).
Table 1 Laboratory data performed before and after treatment
ITEMS Beforetherapy Steroidtherapyfor 1month Steroid therapy for2 months Steroid therapy for3 months Steroid therapy for4 months
White blood cell count(*10^9/L) 15.4 21.11 8.24 11.66 13.28
Hemoglobin(g/L) 129 108 84 98 101
Platelet count(*10^9/L) 323 285 100 273 176
C-reaction protein (CRP)(mg/L) 90 58.1 32 79.8 18.9
Erythrocyte sedimentation rate(mm/H) 120 60 / / /
Serum nitrogen (mmol/L) 10.2 24.71 24.18 30.33 14.5
Serum creatinine (umol/L) 64.6 232.8 212.4 187.2 100.7
Serum albumin(g/L) 24.2 32 30 27.6 21.2
Urine RBC(/ul) / 42.6 10.9 3
Urine protein creatine ratio(mg/g) 48.5
24 h urine protein (g) 0.721 0.62 0.61 0.45 0.49
ANCA-MPO (RU/ml) 35.1 12.7 8.6
ANCA-PR3 (RU/ml) 6.7 4.9 4.7
CD4+ / CD8 + lymphocyte 0.81 / / / 1.9
ABG Before therapy Steroid therapy for 2 months
PH 7.201 7.498
PCO2(mmHg) 20 31.6
PO2(mmHg) 117 49
SpO2 (%) 98 88
K(mmol/L) 5.4 4.1
HCO3-(mmol/L) 7.8 24.5
BE(mmol/L) -20 1
ANCA-MPO Myeloperoxidase-antineutrophil cytoplasmic antibody, ANCA-PR3 proteinase 3, ABG Arterial Blood Gas, / not available
Fig. 1 Chest CT showed interstitial inflammation and bilateral pleural effusion before therapy (a). After glucocorticoids admission, obvious absorption of interstitial inflammation and pleural effusion on both sides were found (b). Infection of both lungs with a left lower lobe cavity before anti-infection therapy (c). After anti-infection therapy, no increase boarder of lung lesions (d)
He went to Nephrology Department on 2019 July 2nd for further treatment. Laboratory results were presented in Table 1. Urine RBC 42.6/ul; Urine protein: creatine ratio (uPCR) 48.5 mg/g; Serum IgG4 level was elevated at 3.42 g/L (Normal range: 0.03–2.10 g/L). Anti-myeloperoxidase anti-neutrophil cytoplasmic antibody level was elevated at 35.1Ru/ml (Normal range:<20 Ru/ml). However, serum immunoglobulin A(IgA), IgG and IgM level were normal. Furthermore, the patient was negative for anti-double-stranded antibody, antinuclear antibody, anti-Sjogren’s syndrome A antibody, anti-Sjogren’s syndrome B antibody and anti-proteinase 3. Ultrasound displayed large-sized kidneys with uniform echo frequency and clear corticomedullary boundaries. Chest CT revealed obvious absorption of interstitial inflammation and pleural effusion on both sides, there were also multiple nodules in both lungs (Fig. 1b).
Histopathology of the kidney biopsy shows proliferation of glomerular mesangial cells, diffuse and irregular thickening of basement membrane (Fig. 2a). The tubulointerstitium shows marked injury. Patchy foci fibrosis and inflammatory cells infiltration were prominent in the interstitium (Fig. 2b, c). Immunofluorescence staining shows that IgG, IgM, IgA, C1q, C3 and C4 were negative in the granular mesangial area. Immunohistological analysis revealed numerous CD20-positive B cells ((D), × 400) and dense infiltration of CD138-positive plasma cells ((E), × 400), with an IgG4+/IgG+ plasma cell ratio being > 40% ((F), × 400). Electron microscopy demonstrated that there were no electron-dense deposits in the glomeruli (Fig. 3).
Fig. 2 Renal histopathological result showed almost normal glomeruli, massively infiltrating cells, and abundant interstitial fibrosis under the light microscopy. a The glomerulus showed glomerular mesangial cells proliferation and diffuse and irregular thickening of basement membrane (HE staining, × 200). b, c A mass of plasma cells and fibrotic fibers (HE staining, × 400) can be observed in the interstitium. d, e Immunohistological analysis revealed mostly CD20-positive B cells (× 400) and CD138-positive plasma cells (× 400) in the interstitium. f Immunohistochemistry for IgG4 shows abundant positive plasma cells (coloured brown) (× 400)
Fig. 3 No electron-dense deposits are observed under electron microscopy. a Abundant plasma cells (× 2000) infiltrated in renal interstitium. b Detachment and partial atrophy of the microvilli of renal tubular epithelial cells as well as edema, infiltration of lymphocytes/monocytes, and fibrosis in renal interstitium. There are no electron-dense deposits in the glomeruli (× 2000). c Proliferation of glomerular mesangial cells and interstitial cells (× 2000). d Diffuse and irregular thickening of basement membrane (× 12,000)
Based on these findings, he had been diagnosed as IgG4-related renal disease. Oral prednisone (40 mg/day) and cyclophosphamide (CTX, 0.4 g) were prescribed by intravenous infusion. The patient had been followed up every month after the treatment (Table 1). He presented with intermittent fever for more than 20 days and acute onset of left pleuritic chest pain with dry cough for 10 days. Negative results were found in aerobic or anaerobic blood culture. Chest CT showed recent infection of both lungs with left upper lung cavity (Fig. 1c). At June 28th he developed hemoptysis and type 1 respiratory failure (Table 2). The results of relevant tests are shown in Table 1. In order to differentiate between IgG4-RLD and IPFI, left upper lung puncture was conducted and showed that interstitial collagen fibrosis with acute and chronic inflammatory cell infiltration, focal fibrous necrosis and exudation, and small alveolar cell response. Fungal spores were also found in lung puncture specimen. Filamentous fungi can be seen in sputum culture. Immunohistochemistry test revealed that most plasma cells in the lung interstitium were positive for CD38 (+), CD138 (+), IgG (+) (Fig. 4). IgG positive plasma cells < 40%, IgG4 positive plasma cells < 10/HPF, which does not meet the pathological diagnostic criteria of IgG4 related diseases. The diagnosis of IPFI was definite. After then, the patient was initiated on voriconazole and caspofungin to anti-fungal infection, and prednisolone was decreased to 30 mg per day.
Table 2 Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ [2, 14, 15]
Criterion
Histology (i)The specimen pathology shows the dense lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis, the infiltration of IgG4-positive cells, and IgG cells more than IgG4 cells ratio of 40%;
Imaging (ii)clinical/radiological examination showing characteristic diffuse or localized swelling or masses in single or multiple organs;
Serology (iii) serum IgG4 concentration > 135 mg/dL;
(iv)Inflammatory markers such as white blood cells count and C-reactive protein concentrations are not elevated, despite the degree of lesions, their spread on imaging analysis and massive cellular infiltration on pathological examination;
Other organ involvement (v)Characteristic findings of IgG4-RD in other organs, including autoimmune pancreatitis, lung involvement, et al.
Treatment (vi)response to steroids.
All 3 criteria (i + ii + iii) are needed for definite diagnosis of IgG4-RD
Fig. 4 Histopathological findings of the pulmonary tissue (light microscopy: HE). a Pulmonary tissue shows fibrotic changes of the interstitium (× 100) in the lung. b Cell and tissue reactions and cellulosic exudation were observed in alveoli (× 200). c, d Giant cell, interstitial edema, collagen fiber hyperplasia and masson body were observed in the specimen (× 200). e, f Immunohistological analysis revealed CD38-positive plasmacyte (coloured brown) (E × 400) and CD138-positive plasmacyte (coloured brown) infiltration (F × 400). g IgG immunostaining shows IgG-positive plasmacyte (coloured brown) infiltration (× 400). h IgG4 immunostaining shows IgG4-positive plasmacyte (coloured brown) infiltration in the lung (× 400)
With anti-infection and immunosuppressive treatment for 2 weeks, serum CRP and IgG4 level had been considerably decreased to 2.94 mg/L and 1.57 g/L, respectively. Voriconazole 200 mg bid and Methylprednisolone 30 mg/day were continued after discharge home. After treatment for one month, a repeat CT scan showed no progression of lung lesions (Fig. 1D). CD4+/CD8+ lymphocyte: 1.9. The patient had been followed up for 4 months. In the most recent follow-up examination, the serum creatinine level decreased to 101 umol/L and he got rid of hemodialysis (Fig. 5). He is currently undergoing tapered prednisolone treatment.
Fig. 5 Dynamic changes of renal function before and after treatment in the patient with IgG4-RKD
Discussion and conclusions
This patient is characterized by serum IgG4 elevation, positive MPO-ANCA, which suggested the possibility of co-occurrence/concurrence of AAV and IgG4‐RD on his first visit from his serological presentation. Diagnosis of IgG4-RD requires particular pathological, serological and clinical features [2, 14, 15] (listed in Table 2). This patient presented with serum IgG4 elevation, hematuria, proteinuria, elevated uptake abnormality of the upper kidney observed in 18F-FDG-PET/CT, progressive kidney failure and interstitial lung disease. Histopathology of kidney biopsy showing typical lymphoplasmacytic infiltration and fibrosis enriched in IgG4-positive plasma cells, and infiltration of IgG4 + plasma cells with IgG4+/IgG+ plasma cells ratio greater than 40% and a total of ≥ 10 IgG4 + plasma cells per high-power field (HPF) indicated the diagnosis of IgG4-RKD.
Given the elevated MPO-ANCA and CRP, AAV related nephritis was a possible differential diagnosis (Proposed diagnostic criteria for kidney involvement in AAV listed in Table 3 [16]). In this case, pathological findings did not show renal crescentic glomerulonephritis or vasculitis, thus, anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-AAV) was not firstly considered according to the Chapel Hill Consensus Conference nomenclature criteria for AAV [16]; However, Some ANCA positive patients may present with interstitial nephritis without severe glomerulopathy, and whether his initial interstitial lung disease was related to IgG4 or AAV or both was not determined. Some reports suggested a possible pathogenic effect of ANCA-IgG4 [17, 18]. Serum IgG4 increase and IgG4-positive cell infiltration in the organ can also be seen in AAV [19, 20]. Distinguishing between these diseases is essential for treatment planning [20], because IgG4-RD responds well to steroid therapy alone, while AAV often requires concomitant immunosuppressant use. His initial interstitial lung disease was improved (Fig. 1) with prednisone therapy alone for one month favored the diagnosis of IgG4-RLD. Kim et al. [21] described that a steroid trial was useful for differentiating and response to steroid therapy is recommended to be added to the diagnostic criteria. Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ listed in Table 2. Therefore, we preferred his diagnosis of IgG4-RD.
Table 3 Proposed diagnostic criteria for kidney involvement in AAV [16]
clinical manifestations a rapidly progressive GN with a decline in kidney function accompanied by sub–nephrotic-range proteinuria, microscopic hematuria, and hypertension over days to a few months
Serology Anti-MPO antibody or anti-PR3 antibody positive
Pathological findings pauci-immune focal necrotizing crescentic GN
Rare patients with AAV have a prominent tubulointerstitial nephritis, which can be associated with vasculitis of the vasa recta
A diagnosis of AAV incorporates the integration of clinical features, ANCA serology, and tissue pathology as needed
Since kidney involvement was firstly reported in a patient with IgG4-RD in 2004 [22], many similar cases have been described [23–25]. A cross-sectional study reported in 2010 revealed all kidney lesions were associated with extrarenal disease among 114 patients with IgG4-related disease [26]. Several clinicopathologic studies reported IgG4-RD with both kidney and lung involvement [5, 14, 27–30]. In kidney its characteristic manifestation is TIN with multiple extrarenal tissue damage [14, 31], which is easily apparent with a chronic or rapid progressive renal function decline [23]. In lung, this may present as nodules with spiculated margins mimicking primary pulmonary malignancy [28, 32], multiple ground glass opacities (GGO) mimicking interstitial lung disease [14], alveolar interstitial type, and bronchovascular type [33].
However, he developed intermittent fever, acute onset of left pleuritic chest pain and an emerging lung lesion after steroid use for one month. IgG4-RLD has been classified into four categories based on CT. Our case was the GGO type. This also was the primary feature of IPFI [34] of which most common chest CT signs are nodules, consolidation and GGO. This patient had several high-risk factors of IPFI such as old age, long-term use of glucocorticoids, repeated hospitalization, etc. [35]. However,it is difficult to distinguish between IgG4-related lung disease (IgG4-RLD) and IPFI (Table 3). Lung puncture pathology is key standard. Thus, sputum culture and pathogenic examination were repeated and infiltration of IgG4-positive plasma cells was not found. The lung tissue specimen showed fungal spores which supported the diagnosis of IPFI. The differential diagnosis of IgG4-RLD and IPFI were listed in Table 4 [34, 36, 37].
Table 4 Differences between IgG4-RLD and IPFI [34, 36, 37]
Items IgG4-RLD IPFI
Clinical manifestations multi-system injuries dry cough and fever,no specific
Laboratory tests Serum IgG4 elevation CRP and (or) PCT elevation,G/GM positive
Imaging nodules, multiple ground glass opacities (GGO),alveolar interstitial type, and bronchovascular type nodules, consolidation and ground-glass opacity(GGO)
Pathology Mainly IgG4
With plasma cell infiltration and often with interstitial damage
fungal spores with hyphae can be observed, pulmonary fibrosis and inflammatory cell infiltration
Treatment protocol Systemic glucocorticoids anti-infection
Systemic glucocorticoids are recommended as the first-line approach of renal injury in untreated IgG4-RD [31]. A moderate initial dose of oral prednisolone for induction is 0.6 mg/kg daily for 2–4 weeks. The maintenance dose of steroid therapy is given after remission as 2.5-5 mg daily over a period of 2–3 months [2]. However, treatment with exogenous glucocorticoids comes with a number of risks such as avascular necrosis, osteoporosis, glaucoma, cardiovascular disease, worse glucose tolerance and diabetes. The risk of infection is of utmost concern and is well-documented [36, 38]. A Japanese study including 459 AIP patients reported pneumonia occurred in 3 patients treated with steroid [13]. Optimizing the nutritional state of patients, reducing its dose, duration and number of immunosuppressants are recommended to help prevent infection. In the present case, we have to decrease the dosage of immunosuppressive drugs after then, nevertheless, IgG4-RLD were aggravated and renal failure developed during dosage decrease.
Since not every patient can be recover from renal disfunction, maintenance hemodialysis become necessary in patients with irreversible renal failure due to IgG4-RKD [4, 39]. And in this case, the patient experienced a short-time hemodialysis because of azotemia, which partly due to deteriorating renal function, steroids use or (and) infection. Improvements in pulmonary lesions and kidney function were observed after 4 months and were maintained with a dose of 8.0 mg/day prednisone. Thus, the dosage of steroid and immunosuppressant should be reduced for the therapy of the elderly patients with IgG4 related diseases. In addition, it has been reported that relapse of IgG4-related lesions, including kidney damage, occurred in 20% of treated patients with IgG4-RKD during maintenance treatment [39]. Thus, long-term follow-up for this patient are required and a well prognosis is expected.
Taken together, IgG4-RKD is an immune-mediated condition that can affect not only kidney but also several other organs, leading to a dense lymphoplasmacytic infiltration dominant in IgG4-positive plasma cells with fibrosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control (Fig. 6).
Fig. 6 Flow diagram of the patient’s disease progression and treatment
Abbreviations
IgG4-RKDIgG4-related kidney disease
AIPAutoimmune pancreatitis
IgG4-TINIgG4-related tubulointerstitial nephritis
IPFIInvasive pulmonary fungal infection
CTChest computed tomography
uPCRUrine protein: creatine ratio
IgGSerum immunoglobulin G
CTXCyclophosphamide
MPO-ANCAAnti-myeloperoxidase anti-neutrophil cytoplasmic antibody
ANCA-AAVAnti-neutrophil cytoplasmic antibody associated vasculitis
GGOMultiple ground glass opacities
IgG4-RLDIgG4-related lung disease
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the Department of Pathology, Jiangsu province Hospital, for pulmonary pathology.
Authors’ contributions
YLX reviewed the patient’s clinical data, performed the literature search, and wrote the initial draft of the manuscript. YYH and KL assisted in the preparation of the manuscript contributed to data collection and interpretation and critically reviewed the manuscript. JQ, and JFZ provide the pathology of renal biopsy. XFZ performed the immunohistochemical studies. TFY conducted pulmonary puncture and provide the possibility of lung pathology. GY and XQX carried out analysis of patient’s clinical course, outcomes and interpretation of findings, and provided critical review comments for the manuscript. NNW and CYX had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, and provided critical review comments for the manuscript. All authors read and approved the final manuscript.
Funding
The research was financially supported by the National Natural Science Foundation of China (81570666), International Society of Nephrology (ISN) Clinical Research Program (18-01-0247), Jiangsu Province Key Medical Personnel Project (ZDRCA2016002). The funders had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, provided critical review comments and also submission for the manuscript.
Availability of data and materials
The datasets used during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | CYCLOPHOSPHAMIDE, PREDNISONE | DrugsGivenReaction | CC BY | 33430791 | 18,792,998 | 2021-01-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lower respiratory tract infection fungal'. | IgG4-related nephritis and interstitial pulmonary disease complicated by invasive pulmonary fungal infection: a case report.
IgG4-related kidney disease (IgG4-RKD) can affect multiple organs, which was first reported as a complication or extra-organ manifestation of autoimmune pancreatitis in 2004. It is characterized by abundant IgG4-positive plasma cells infiltration in tissues involved.
A 69-year-old man presented with cough and renal dysfunction with medical history of hypertension and diabetes. Pathological findings revealed interstitial nephritis and he was initially diagnosed with IgG4-RKD. Prednisone helped the patient to get a remission of cough and an obvious decrease of IgG4 level. However, he developed invasive pulmonary fungal infection while steroid theatment. Anti-fungal therapy was initiated after lung puncture (around cavitary lung lesion). Hemodialysis had been conducted because of renal failure and he got rid of it 2 months later. Methylprednisolone was decreased to 8 mg/day for maintenance therapy. Anti-fungal infection continued for 4 months after discharge home. On the 4th month of follow-up, Chest CT revealed no progression of lung lesions.
The corticosteroids are the first-line therapy of IgG4-RD and a rapid response helps to confirm the diagnosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control.
Background
IgG4-related disease (IgG4-RD) is an inflammatory and fibrotic disease which was first described in the pancreas and was called autoimmune pancreatitis (AIP) in 2001 [1]. Its concept has been recognized worldwide since then that this systemic disease involved multiple organs or tissues characterized by elevated serum IgG4 level and IgG4 positive plasma cells infiltration in the affected tissues, leading to fibrosis eventually [2–6]. The prevalence of IgG4-RD in Japan was estimated as 0.28–1.08/100,000 people in 2012 [7].
IgG4-related tubulointerstitial nephritis (IgG4-TIN), is one of the frequent pathological changes of IgG4-related kidney disease (IgG4-RKD), accounting for about 15–25% of all IgG-RD [4, 8]. IgG4-related TIN shows a range of histologic appearances including (A) acute interstitial nephritis with minimal fibrosis; (B) a more cellular inflammatory pattern in the setting of expansile fibrosis; and (C) a very fibrotic, pauci-cellular pattern [7]. The diagnosis criteria of IgG4-RKD were proposed by the Japanese Society of Nephrology [9] and a work group of North America [7], respectively. IgG4-related kidney lesions were often associated with extrarenal disease, such as chronic sclerosing inflammation of the lacrimal gland, salivary gland [10] and lung [11].
Patients with IgG4-RKD have an increased risk of infection than general population. IgG4-TIN can be accompanied by eosinophilic lung disease [12] and pneumonia [13]. Here, we present a case of IgG4-RKD and lung interstitial lesions who developed invasive pulmonary fungal infection (IPFI) during treatment of glucocorticoid combined with immunosuppressive agents.
Case presentation
A 69-year-old male was admitted to the hospital in 2019 January 5th because of gradually aggravated edema and cough. His medical history included hypertension, arrhythmia and diabetes. On 2019 May 8th, he had experienced cough and phlegm with temperature around 38 ~ 39 °C. Laboratory tests were presented in Table 1. 18F-FDG-PET/CT showed interstitial pneumonia in both lungs. There was also elevated uptake abnormality in the upper kidney observed. Cefperazone-Sulbactam, doxycycline hydrochloride, imipenem, and linezolid were given. Because of no improvement, he took oral prednisone 24 mg per day. The body temperature recovered to normal and lower limb edema was alleviated after one week. On 2019 June 13th ,serum creatinine 157.7 umol/L (Fig. 1); and serum albumin, 24.9 g/L. Chest computed tomography (CT) scan showed that honeycomb-like changes considering interstitial inflammation and bilateral pleural effusion (Fig. 1A).
Table 1 Laboratory data performed before and after treatment
ITEMS Beforetherapy Steroidtherapyfor 1month Steroid therapy for2 months Steroid therapy for3 months Steroid therapy for4 months
White blood cell count(*10^9/L) 15.4 21.11 8.24 11.66 13.28
Hemoglobin(g/L) 129 108 84 98 101
Platelet count(*10^9/L) 323 285 100 273 176
C-reaction protein (CRP)(mg/L) 90 58.1 32 79.8 18.9
Erythrocyte sedimentation rate(mm/H) 120 60 / / /
Serum nitrogen (mmol/L) 10.2 24.71 24.18 30.33 14.5
Serum creatinine (umol/L) 64.6 232.8 212.4 187.2 100.7
Serum albumin(g/L) 24.2 32 30 27.6 21.2
Urine RBC(/ul) / 42.6 10.9 3
Urine protein creatine ratio(mg/g) 48.5
24 h urine protein (g) 0.721 0.62 0.61 0.45 0.49
ANCA-MPO (RU/ml) 35.1 12.7 8.6
ANCA-PR3 (RU/ml) 6.7 4.9 4.7
CD4+ / CD8 + lymphocyte 0.81 / / / 1.9
ABG Before therapy Steroid therapy for 2 months
PH 7.201 7.498
PCO2(mmHg) 20 31.6
PO2(mmHg) 117 49
SpO2 (%) 98 88
K(mmol/L) 5.4 4.1
HCO3-(mmol/L) 7.8 24.5
BE(mmol/L) -20 1
ANCA-MPO Myeloperoxidase-antineutrophil cytoplasmic antibody, ANCA-PR3 proteinase 3, ABG Arterial Blood Gas, / not available
Fig. 1 Chest CT showed interstitial inflammation and bilateral pleural effusion before therapy (a). After glucocorticoids admission, obvious absorption of interstitial inflammation and pleural effusion on both sides were found (b). Infection of both lungs with a left lower lobe cavity before anti-infection therapy (c). After anti-infection therapy, no increase boarder of lung lesions (d)
He went to Nephrology Department on 2019 July 2nd for further treatment. Laboratory results were presented in Table 1. Urine RBC 42.6/ul; Urine protein: creatine ratio (uPCR) 48.5 mg/g; Serum IgG4 level was elevated at 3.42 g/L (Normal range: 0.03–2.10 g/L). Anti-myeloperoxidase anti-neutrophil cytoplasmic antibody level was elevated at 35.1Ru/ml (Normal range:<20 Ru/ml). However, serum immunoglobulin A(IgA), IgG and IgM level were normal. Furthermore, the patient was negative for anti-double-stranded antibody, antinuclear antibody, anti-Sjogren’s syndrome A antibody, anti-Sjogren’s syndrome B antibody and anti-proteinase 3. Ultrasound displayed large-sized kidneys with uniform echo frequency and clear corticomedullary boundaries. Chest CT revealed obvious absorption of interstitial inflammation and pleural effusion on both sides, there were also multiple nodules in both lungs (Fig. 1b).
Histopathology of the kidney biopsy shows proliferation of glomerular mesangial cells, diffuse and irregular thickening of basement membrane (Fig. 2a). The tubulointerstitium shows marked injury. Patchy foci fibrosis and inflammatory cells infiltration were prominent in the interstitium (Fig. 2b, c). Immunofluorescence staining shows that IgG, IgM, IgA, C1q, C3 and C4 were negative in the granular mesangial area. Immunohistological analysis revealed numerous CD20-positive B cells ((D), × 400) and dense infiltration of CD138-positive plasma cells ((E), × 400), with an IgG4+/IgG+ plasma cell ratio being > 40% ((F), × 400). Electron microscopy demonstrated that there were no electron-dense deposits in the glomeruli (Fig. 3).
Fig. 2 Renal histopathological result showed almost normal glomeruli, massively infiltrating cells, and abundant interstitial fibrosis under the light microscopy. a The glomerulus showed glomerular mesangial cells proliferation and diffuse and irregular thickening of basement membrane (HE staining, × 200). b, c A mass of plasma cells and fibrotic fibers (HE staining, × 400) can be observed in the interstitium. d, e Immunohistological analysis revealed mostly CD20-positive B cells (× 400) and CD138-positive plasma cells (× 400) in the interstitium. f Immunohistochemistry for IgG4 shows abundant positive plasma cells (coloured brown) (× 400)
Fig. 3 No electron-dense deposits are observed under electron microscopy. a Abundant plasma cells (× 2000) infiltrated in renal interstitium. b Detachment and partial atrophy of the microvilli of renal tubular epithelial cells as well as edema, infiltration of lymphocytes/monocytes, and fibrosis in renal interstitium. There are no electron-dense deposits in the glomeruli (× 2000). c Proliferation of glomerular mesangial cells and interstitial cells (× 2000). d Diffuse and irregular thickening of basement membrane (× 12,000)
Based on these findings, he had been diagnosed as IgG4-related renal disease. Oral prednisone (40 mg/day) and cyclophosphamide (CTX, 0.4 g) were prescribed by intravenous infusion. The patient had been followed up every month after the treatment (Table 1). He presented with intermittent fever for more than 20 days and acute onset of left pleuritic chest pain with dry cough for 10 days. Negative results were found in aerobic or anaerobic blood culture. Chest CT showed recent infection of both lungs with left upper lung cavity (Fig. 1c). At June 28th he developed hemoptysis and type 1 respiratory failure (Table 2). The results of relevant tests are shown in Table 1. In order to differentiate between IgG4-RLD and IPFI, left upper lung puncture was conducted and showed that interstitial collagen fibrosis with acute and chronic inflammatory cell infiltration, focal fibrous necrosis and exudation, and small alveolar cell response. Fungal spores were also found in lung puncture specimen. Filamentous fungi can be seen in sputum culture. Immunohistochemistry test revealed that most plasma cells in the lung interstitium were positive for CD38 (+), CD138 (+), IgG (+) (Fig. 4). IgG positive plasma cells < 40%, IgG4 positive plasma cells < 10/HPF, which does not meet the pathological diagnostic criteria of IgG4 related diseases. The diagnosis of IPFI was definite. After then, the patient was initiated on voriconazole and caspofungin to anti-fungal infection, and prednisolone was decreased to 30 mg per day.
Table 2 Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ [2, 14, 15]
Criterion
Histology (i)The specimen pathology shows the dense lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis, the infiltration of IgG4-positive cells, and IgG cells more than IgG4 cells ratio of 40%;
Imaging (ii)clinical/radiological examination showing characteristic diffuse or localized swelling or masses in single or multiple organs;
Serology (iii) serum IgG4 concentration > 135 mg/dL;
(iv)Inflammatory markers such as white blood cells count and C-reactive protein concentrations are not elevated, despite the degree of lesions, their spread on imaging analysis and massive cellular infiltration on pathological examination;
Other organ involvement (v)Characteristic findings of IgG4-RD in other organs, including autoimmune pancreatitis, lung involvement, et al.
Treatment (vi)response to steroids.
All 3 criteria (i + ii + iii) are needed for definite diagnosis of IgG4-RD
Fig. 4 Histopathological findings of the pulmonary tissue (light microscopy: HE). a Pulmonary tissue shows fibrotic changes of the interstitium (× 100) in the lung. b Cell and tissue reactions and cellulosic exudation were observed in alveoli (× 200). c, d Giant cell, interstitial edema, collagen fiber hyperplasia and masson body were observed in the specimen (× 200). e, f Immunohistological analysis revealed CD38-positive plasmacyte (coloured brown) (E × 400) and CD138-positive plasmacyte (coloured brown) infiltration (F × 400). g IgG immunostaining shows IgG-positive plasmacyte (coloured brown) infiltration (× 400). h IgG4 immunostaining shows IgG4-positive plasmacyte (coloured brown) infiltration in the lung (× 400)
With anti-infection and immunosuppressive treatment for 2 weeks, serum CRP and IgG4 level had been considerably decreased to 2.94 mg/L and 1.57 g/L, respectively. Voriconazole 200 mg bid and Methylprednisolone 30 mg/day were continued after discharge home. After treatment for one month, a repeat CT scan showed no progression of lung lesions (Fig. 1D). CD4+/CD8+ lymphocyte: 1.9. The patient had been followed up for 4 months. In the most recent follow-up examination, the serum creatinine level decreased to 101 umol/L and he got rid of hemodialysis (Fig. 5). He is currently undergoing tapered prednisolone treatment.
Fig. 5 Dynamic changes of renal function before and after treatment in the patient with IgG4-RKD
Discussion and conclusions
This patient is characterized by serum IgG4 elevation, positive MPO-ANCA, which suggested the possibility of co-occurrence/concurrence of AAV and IgG4‐RD on his first visit from his serological presentation. Diagnosis of IgG4-RD requires particular pathological, serological and clinical features [2, 14, 15] (listed in Table 2). This patient presented with serum IgG4 elevation, hematuria, proteinuria, elevated uptake abnormality of the upper kidney observed in 18F-FDG-PET/CT, progressive kidney failure and interstitial lung disease. Histopathology of kidney biopsy showing typical lymphoplasmacytic infiltration and fibrosis enriched in IgG4-positive plasma cells, and infiltration of IgG4 + plasma cells with IgG4+/IgG+ plasma cells ratio greater than 40% and a total of ≥ 10 IgG4 + plasma cells per high-power field (HPF) indicated the diagnosis of IgG4-RKD.
Given the elevated MPO-ANCA and CRP, AAV related nephritis was a possible differential diagnosis (Proposed diagnostic criteria for kidney involvement in AAV listed in Table 3 [16]). In this case, pathological findings did not show renal crescentic glomerulonephritis or vasculitis, thus, anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-AAV) was not firstly considered according to the Chapel Hill Consensus Conference nomenclature criteria for AAV [16]; However, Some ANCA positive patients may present with interstitial nephritis without severe glomerulopathy, and whether his initial interstitial lung disease was related to IgG4 or AAV or both was not determined. Some reports suggested a possible pathogenic effect of ANCA-IgG4 [17, 18]. Serum IgG4 increase and IgG4-positive cell infiltration in the organ can also be seen in AAV [19, 20]. Distinguishing between these diseases is essential for treatment planning [20], because IgG4-RD responds well to steroid therapy alone, while AAV often requires concomitant immunosuppressant use. His initial interstitial lung disease was improved (Fig. 1) with prednisone therapy alone for one month favored the diagnosis of IgG4-RLD. Kim et al. [21] described that a steroid trial was useful for differentiating and response to steroid therapy is recommended to be added to the diagnostic criteria. Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ listed in Table 2. Therefore, we preferred his diagnosis of IgG4-RD.
Table 3 Proposed diagnostic criteria for kidney involvement in AAV [16]
clinical manifestations a rapidly progressive GN with a decline in kidney function accompanied by sub–nephrotic-range proteinuria, microscopic hematuria, and hypertension over days to a few months
Serology Anti-MPO antibody or anti-PR3 antibody positive
Pathological findings pauci-immune focal necrotizing crescentic GN
Rare patients with AAV have a prominent tubulointerstitial nephritis, which can be associated with vasculitis of the vasa recta
A diagnosis of AAV incorporates the integration of clinical features, ANCA serology, and tissue pathology as needed
Since kidney involvement was firstly reported in a patient with IgG4-RD in 2004 [22], many similar cases have been described [23–25]. A cross-sectional study reported in 2010 revealed all kidney lesions were associated with extrarenal disease among 114 patients with IgG4-related disease [26]. Several clinicopathologic studies reported IgG4-RD with both kidney and lung involvement [5, 14, 27–30]. In kidney its characteristic manifestation is TIN with multiple extrarenal tissue damage [14, 31], which is easily apparent with a chronic or rapid progressive renal function decline [23]. In lung, this may present as nodules with spiculated margins mimicking primary pulmonary malignancy [28, 32], multiple ground glass opacities (GGO) mimicking interstitial lung disease [14], alveolar interstitial type, and bronchovascular type [33].
However, he developed intermittent fever, acute onset of left pleuritic chest pain and an emerging lung lesion after steroid use for one month. IgG4-RLD has been classified into four categories based on CT. Our case was the GGO type. This also was the primary feature of IPFI [34] of which most common chest CT signs are nodules, consolidation and GGO. This patient had several high-risk factors of IPFI such as old age, long-term use of glucocorticoids, repeated hospitalization, etc. [35]. However,it is difficult to distinguish between IgG4-related lung disease (IgG4-RLD) and IPFI (Table 3). Lung puncture pathology is key standard. Thus, sputum culture and pathogenic examination were repeated and infiltration of IgG4-positive plasma cells was not found. The lung tissue specimen showed fungal spores which supported the diagnosis of IPFI. The differential diagnosis of IgG4-RLD and IPFI were listed in Table 4 [34, 36, 37].
Table 4 Differences between IgG4-RLD and IPFI [34, 36, 37]
Items IgG4-RLD IPFI
Clinical manifestations multi-system injuries dry cough and fever,no specific
Laboratory tests Serum IgG4 elevation CRP and (or) PCT elevation,G/GM positive
Imaging nodules, multiple ground glass opacities (GGO),alveolar interstitial type, and bronchovascular type nodules, consolidation and ground-glass opacity(GGO)
Pathology Mainly IgG4
With plasma cell infiltration and often with interstitial damage
fungal spores with hyphae can be observed, pulmonary fibrosis and inflammatory cell infiltration
Treatment protocol Systemic glucocorticoids anti-infection
Systemic glucocorticoids are recommended as the first-line approach of renal injury in untreated IgG4-RD [31]. A moderate initial dose of oral prednisolone for induction is 0.6 mg/kg daily for 2–4 weeks. The maintenance dose of steroid therapy is given after remission as 2.5-5 mg daily over a period of 2–3 months [2]. However, treatment with exogenous glucocorticoids comes with a number of risks such as avascular necrosis, osteoporosis, glaucoma, cardiovascular disease, worse glucose tolerance and diabetes. The risk of infection is of utmost concern and is well-documented [36, 38]. A Japanese study including 459 AIP patients reported pneumonia occurred in 3 patients treated with steroid [13]. Optimizing the nutritional state of patients, reducing its dose, duration and number of immunosuppressants are recommended to help prevent infection. In the present case, we have to decrease the dosage of immunosuppressive drugs after then, nevertheless, IgG4-RLD were aggravated and renal failure developed during dosage decrease.
Since not every patient can be recover from renal disfunction, maintenance hemodialysis become necessary in patients with irreversible renal failure due to IgG4-RKD [4, 39]. And in this case, the patient experienced a short-time hemodialysis because of azotemia, which partly due to deteriorating renal function, steroids use or (and) infection. Improvements in pulmonary lesions and kidney function were observed after 4 months and were maintained with a dose of 8.0 mg/day prednisone. Thus, the dosage of steroid and immunosuppressant should be reduced for the therapy of the elderly patients with IgG4 related diseases. In addition, it has been reported that relapse of IgG4-related lesions, including kidney damage, occurred in 20% of treated patients with IgG4-RKD during maintenance treatment [39]. Thus, long-term follow-up for this patient are required and a well prognosis is expected.
Taken together, IgG4-RKD is an immune-mediated condition that can affect not only kidney but also several other organs, leading to a dense lymphoplasmacytic infiltration dominant in IgG4-positive plasma cells with fibrosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control (Fig. 6).
Fig. 6 Flow diagram of the patient’s disease progression and treatment
Abbreviations
IgG4-RKDIgG4-related kidney disease
AIPAutoimmune pancreatitis
IgG4-TINIgG4-related tubulointerstitial nephritis
IPFIInvasive pulmonary fungal infection
CTChest computed tomography
uPCRUrine protein: creatine ratio
IgGSerum immunoglobulin G
CTXCyclophosphamide
MPO-ANCAAnti-myeloperoxidase anti-neutrophil cytoplasmic antibody
ANCA-AAVAnti-neutrophil cytoplasmic antibody associated vasculitis
GGOMultiple ground glass opacities
IgG4-RLDIgG4-related lung disease
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the Department of Pathology, Jiangsu province Hospital, for pulmonary pathology.
Authors’ contributions
YLX reviewed the patient’s clinical data, performed the literature search, and wrote the initial draft of the manuscript. YYH and KL assisted in the preparation of the manuscript contributed to data collection and interpretation and critically reviewed the manuscript. JQ, and JFZ provide the pathology of renal biopsy. XFZ performed the immunohistochemical studies. TFY conducted pulmonary puncture and provide the possibility of lung pathology. GY and XQX carried out analysis of patient’s clinical course, outcomes and interpretation of findings, and provided critical review comments for the manuscript. NNW and CYX had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, and provided critical review comments for the manuscript. All authors read and approved the final manuscript.
Funding
The research was financially supported by the National Natural Science Foundation of China (81570666), International Society of Nephrology (ISN) Clinical Research Program (18-01-0247), Jiangsu Province Key Medical Personnel Project (ZDRCA2016002). The funders had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, provided critical review comments and also submission for the manuscript.
Availability of data and materials
The datasets used during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | CYCLOPHOSPHAMIDE, PREDNISONE | DrugsGivenReaction | CC BY | 33430791 | 18,792,998 | 2021-01-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory failure'. | IgG4-related nephritis and interstitial pulmonary disease complicated by invasive pulmonary fungal infection: a case report.
IgG4-related kidney disease (IgG4-RKD) can affect multiple organs, which was first reported as a complication or extra-organ manifestation of autoimmune pancreatitis in 2004. It is characterized by abundant IgG4-positive plasma cells infiltration in tissues involved.
A 69-year-old man presented with cough and renal dysfunction with medical history of hypertension and diabetes. Pathological findings revealed interstitial nephritis and he was initially diagnosed with IgG4-RKD. Prednisone helped the patient to get a remission of cough and an obvious decrease of IgG4 level. However, he developed invasive pulmonary fungal infection while steroid theatment. Anti-fungal therapy was initiated after lung puncture (around cavitary lung lesion). Hemodialysis had been conducted because of renal failure and he got rid of it 2 months later. Methylprednisolone was decreased to 8 mg/day for maintenance therapy. Anti-fungal infection continued for 4 months after discharge home. On the 4th month of follow-up, Chest CT revealed no progression of lung lesions.
The corticosteroids are the first-line therapy of IgG4-RD and a rapid response helps to confirm the diagnosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control.
Background
IgG4-related disease (IgG4-RD) is an inflammatory and fibrotic disease which was first described in the pancreas and was called autoimmune pancreatitis (AIP) in 2001 [1]. Its concept has been recognized worldwide since then that this systemic disease involved multiple organs or tissues characterized by elevated serum IgG4 level and IgG4 positive plasma cells infiltration in the affected tissues, leading to fibrosis eventually [2–6]. The prevalence of IgG4-RD in Japan was estimated as 0.28–1.08/100,000 people in 2012 [7].
IgG4-related tubulointerstitial nephritis (IgG4-TIN), is one of the frequent pathological changes of IgG4-related kidney disease (IgG4-RKD), accounting for about 15–25% of all IgG-RD [4, 8]. IgG4-related TIN shows a range of histologic appearances including (A) acute interstitial nephritis with minimal fibrosis; (B) a more cellular inflammatory pattern in the setting of expansile fibrosis; and (C) a very fibrotic, pauci-cellular pattern [7]. The diagnosis criteria of IgG4-RKD were proposed by the Japanese Society of Nephrology [9] and a work group of North America [7], respectively. IgG4-related kidney lesions were often associated with extrarenal disease, such as chronic sclerosing inflammation of the lacrimal gland, salivary gland [10] and lung [11].
Patients with IgG4-RKD have an increased risk of infection than general population. IgG4-TIN can be accompanied by eosinophilic lung disease [12] and pneumonia [13]. Here, we present a case of IgG4-RKD and lung interstitial lesions who developed invasive pulmonary fungal infection (IPFI) during treatment of glucocorticoid combined with immunosuppressive agents.
Case presentation
A 69-year-old male was admitted to the hospital in 2019 January 5th because of gradually aggravated edema and cough. His medical history included hypertension, arrhythmia and diabetes. On 2019 May 8th, he had experienced cough and phlegm with temperature around 38 ~ 39 °C. Laboratory tests were presented in Table 1. 18F-FDG-PET/CT showed interstitial pneumonia in both lungs. There was also elevated uptake abnormality in the upper kidney observed. Cefperazone-Sulbactam, doxycycline hydrochloride, imipenem, and linezolid were given. Because of no improvement, he took oral prednisone 24 mg per day. The body temperature recovered to normal and lower limb edema was alleviated after one week. On 2019 June 13th ,serum creatinine 157.7 umol/L (Fig. 1); and serum albumin, 24.9 g/L. Chest computed tomography (CT) scan showed that honeycomb-like changes considering interstitial inflammation and bilateral pleural effusion (Fig. 1A).
Table 1 Laboratory data performed before and after treatment
ITEMS Beforetherapy Steroidtherapyfor 1month Steroid therapy for2 months Steroid therapy for3 months Steroid therapy for4 months
White blood cell count(*10^9/L) 15.4 21.11 8.24 11.66 13.28
Hemoglobin(g/L) 129 108 84 98 101
Platelet count(*10^9/L) 323 285 100 273 176
C-reaction protein (CRP)(mg/L) 90 58.1 32 79.8 18.9
Erythrocyte sedimentation rate(mm/H) 120 60 / / /
Serum nitrogen (mmol/L) 10.2 24.71 24.18 30.33 14.5
Serum creatinine (umol/L) 64.6 232.8 212.4 187.2 100.7
Serum albumin(g/L) 24.2 32 30 27.6 21.2
Urine RBC(/ul) / 42.6 10.9 3
Urine protein creatine ratio(mg/g) 48.5
24 h urine protein (g) 0.721 0.62 0.61 0.45 0.49
ANCA-MPO (RU/ml) 35.1 12.7 8.6
ANCA-PR3 (RU/ml) 6.7 4.9 4.7
CD4+ / CD8 + lymphocyte 0.81 / / / 1.9
ABG Before therapy Steroid therapy for 2 months
PH 7.201 7.498
PCO2(mmHg) 20 31.6
PO2(mmHg) 117 49
SpO2 (%) 98 88
K(mmol/L) 5.4 4.1
HCO3-(mmol/L) 7.8 24.5
BE(mmol/L) -20 1
ANCA-MPO Myeloperoxidase-antineutrophil cytoplasmic antibody, ANCA-PR3 proteinase 3, ABG Arterial Blood Gas, / not available
Fig. 1 Chest CT showed interstitial inflammation and bilateral pleural effusion before therapy (a). After glucocorticoids admission, obvious absorption of interstitial inflammation and pleural effusion on both sides were found (b). Infection of both lungs with a left lower lobe cavity before anti-infection therapy (c). After anti-infection therapy, no increase boarder of lung lesions (d)
He went to Nephrology Department on 2019 July 2nd for further treatment. Laboratory results were presented in Table 1. Urine RBC 42.6/ul; Urine protein: creatine ratio (uPCR) 48.5 mg/g; Serum IgG4 level was elevated at 3.42 g/L (Normal range: 0.03–2.10 g/L). Anti-myeloperoxidase anti-neutrophil cytoplasmic antibody level was elevated at 35.1Ru/ml (Normal range:<20 Ru/ml). However, serum immunoglobulin A(IgA), IgG and IgM level were normal. Furthermore, the patient was negative for anti-double-stranded antibody, antinuclear antibody, anti-Sjogren’s syndrome A antibody, anti-Sjogren’s syndrome B antibody and anti-proteinase 3. Ultrasound displayed large-sized kidneys with uniform echo frequency and clear corticomedullary boundaries. Chest CT revealed obvious absorption of interstitial inflammation and pleural effusion on both sides, there were also multiple nodules in both lungs (Fig. 1b).
Histopathology of the kidney biopsy shows proliferation of glomerular mesangial cells, diffuse and irregular thickening of basement membrane (Fig. 2a). The tubulointerstitium shows marked injury. Patchy foci fibrosis and inflammatory cells infiltration were prominent in the interstitium (Fig. 2b, c). Immunofluorescence staining shows that IgG, IgM, IgA, C1q, C3 and C4 were negative in the granular mesangial area. Immunohistological analysis revealed numerous CD20-positive B cells ((D), × 400) and dense infiltration of CD138-positive plasma cells ((E), × 400), with an IgG4+/IgG+ plasma cell ratio being > 40% ((F), × 400). Electron microscopy demonstrated that there were no electron-dense deposits in the glomeruli (Fig. 3).
Fig. 2 Renal histopathological result showed almost normal glomeruli, massively infiltrating cells, and abundant interstitial fibrosis under the light microscopy. a The glomerulus showed glomerular mesangial cells proliferation and diffuse and irregular thickening of basement membrane (HE staining, × 200). b, c A mass of plasma cells and fibrotic fibers (HE staining, × 400) can be observed in the interstitium. d, e Immunohistological analysis revealed mostly CD20-positive B cells (× 400) and CD138-positive plasma cells (× 400) in the interstitium. f Immunohistochemistry for IgG4 shows abundant positive plasma cells (coloured brown) (× 400)
Fig. 3 No electron-dense deposits are observed under electron microscopy. a Abundant plasma cells (× 2000) infiltrated in renal interstitium. b Detachment and partial atrophy of the microvilli of renal tubular epithelial cells as well as edema, infiltration of lymphocytes/monocytes, and fibrosis in renal interstitium. There are no electron-dense deposits in the glomeruli (× 2000). c Proliferation of glomerular mesangial cells and interstitial cells (× 2000). d Diffuse and irregular thickening of basement membrane (× 12,000)
Based on these findings, he had been diagnosed as IgG4-related renal disease. Oral prednisone (40 mg/day) and cyclophosphamide (CTX, 0.4 g) were prescribed by intravenous infusion. The patient had been followed up every month after the treatment (Table 1). He presented with intermittent fever for more than 20 days and acute onset of left pleuritic chest pain with dry cough for 10 days. Negative results were found in aerobic or anaerobic blood culture. Chest CT showed recent infection of both lungs with left upper lung cavity (Fig. 1c). At June 28th he developed hemoptysis and type 1 respiratory failure (Table 2). The results of relevant tests are shown in Table 1. In order to differentiate between IgG4-RLD and IPFI, left upper lung puncture was conducted and showed that interstitial collagen fibrosis with acute and chronic inflammatory cell infiltration, focal fibrous necrosis and exudation, and small alveolar cell response. Fungal spores were also found in lung puncture specimen. Filamentous fungi can be seen in sputum culture. Immunohistochemistry test revealed that most plasma cells in the lung interstitium were positive for CD38 (+), CD138 (+), IgG (+) (Fig. 4). IgG positive plasma cells < 40%, IgG4 positive plasma cells < 10/HPF, which does not meet the pathological diagnostic criteria of IgG4 related diseases. The diagnosis of IPFI was definite. After then, the patient was initiated on voriconazole and caspofungin to anti-fungal infection, and prednisolone was decreased to 30 mg per day.
Table 2 Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ [2, 14, 15]
Criterion
Histology (i)The specimen pathology shows the dense lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis, the infiltration of IgG4-positive cells, and IgG cells more than IgG4 cells ratio of 40%;
Imaging (ii)clinical/radiological examination showing characteristic diffuse or localized swelling or masses in single or multiple organs;
Serology (iii) serum IgG4 concentration > 135 mg/dL;
(iv)Inflammatory markers such as white blood cells count and C-reactive protein concentrations are not elevated, despite the degree of lesions, their spread on imaging analysis and massive cellular infiltration on pathological examination;
Other organ involvement (v)Characteristic findings of IgG4-RD in other organs, including autoimmune pancreatitis, lung involvement, et al.
Treatment (vi)response to steroids.
All 3 criteria (i + ii + iii) are needed for definite diagnosis of IgG4-RD
Fig. 4 Histopathological findings of the pulmonary tissue (light microscopy: HE). a Pulmonary tissue shows fibrotic changes of the interstitium (× 100) in the lung. b Cell and tissue reactions and cellulosic exudation were observed in alveoli (× 200). c, d Giant cell, interstitial edema, collagen fiber hyperplasia and masson body were observed in the specimen (× 200). e, f Immunohistological analysis revealed CD38-positive plasmacyte (coloured brown) (E × 400) and CD138-positive plasmacyte (coloured brown) infiltration (F × 400). g IgG immunostaining shows IgG-positive plasmacyte (coloured brown) infiltration (× 400). h IgG4 immunostaining shows IgG4-positive plasmacyte (coloured brown) infiltration in the lung (× 400)
With anti-infection and immunosuppressive treatment for 2 weeks, serum CRP and IgG4 level had been considerably decreased to 2.94 mg/L and 1.57 g/L, respectively. Voriconazole 200 mg bid and Methylprednisolone 30 mg/day were continued after discharge home. After treatment for one month, a repeat CT scan showed no progression of lung lesions (Fig. 1D). CD4+/CD8+ lymphocyte: 1.9. The patient had been followed up for 4 months. In the most recent follow-up examination, the serum creatinine level decreased to 101 umol/L and he got rid of hemodialysis (Fig. 5). He is currently undergoing tapered prednisolone treatment.
Fig. 5 Dynamic changes of renal function before and after treatment in the patient with IgG4-RKD
Discussion and conclusions
This patient is characterized by serum IgG4 elevation, positive MPO-ANCA, which suggested the possibility of co-occurrence/concurrence of AAV and IgG4‐RD on his first visit from his serological presentation. Diagnosis of IgG4-RD requires particular pathological, serological and clinical features [2, 14, 15] (listed in Table 2). This patient presented with serum IgG4 elevation, hematuria, proteinuria, elevated uptake abnormality of the upper kidney observed in 18F-FDG-PET/CT, progressive kidney failure and interstitial lung disease. Histopathology of kidney biopsy showing typical lymphoplasmacytic infiltration and fibrosis enriched in IgG4-positive plasma cells, and infiltration of IgG4 + plasma cells with IgG4+/IgG+ plasma cells ratio greater than 40% and a total of ≥ 10 IgG4 + plasma cells per high-power field (HPF) indicated the diagnosis of IgG4-RKD.
Given the elevated MPO-ANCA and CRP, AAV related nephritis was a possible differential diagnosis (Proposed diagnostic criteria for kidney involvement in AAV listed in Table 3 [16]). In this case, pathological findings did not show renal crescentic glomerulonephritis or vasculitis, thus, anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-AAV) was not firstly considered according to the Chapel Hill Consensus Conference nomenclature criteria for AAV [16]; However, Some ANCA positive patients may present with interstitial nephritis without severe glomerulopathy, and whether his initial interstitial lung disease was related to IgG4 or AAV or both was not determined. Some reports suggested a possible pathogenic effect of ANCA-IgG4 [17, 18]. Serum IgG4 increase and IgG4-positive cell infiltration in the organ can also be seen in AAV [19, 20]. Distinguishing between these diseases is essential for treatment planning [20], because IgG4-RD responds well to steroid therapy alone, while AAV often requires concomitant immunosuppressant use. His initial interstitial lung disease was improved (Fig. 1) with prednisone therapy alone for one month favored the diagnosis of IgG4-RLD. Kim et al. [21] described that a steroid trial was useful for differentiating and response to steroid therapy is recommended to be added to the diagnostic criteria. Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ listed in Table 2. Therefore, we preferred his diagnosis of IgG4-RD.
Table 3 Proposed diagnostic criteria for kidney involvement in AAV [16]
clinical manifestations a rapidly progressive GN with a decline in kidney function accompanied by sub–nephrotic-range proteinuria, microscopic hematuria, and hypertension over days to a few months
Serology Anti-MPO antibody or anti-PR3 antibody positive
Pathological findings pauci-immune focal necrotizing crescentic GN
Rare patients with AAV have a prominent tubulointerstitial nephritis, which can be associated with vasculitis of the vasa recta
A diagnosis of AAV incorporates the integration of clinical features, ANCA serology, and tissue pathology as needed
Since kidney involvement was firstly reported in a patient with IgG4-RD in 2004 [22], many similar cases have been described [23–25]. A cross-sectional study reported in 2010 revealed all kidney lesions were associated with extrarenal disease among 114 patients with IgG4-related disease [26]. Several clinicopathologic studies reported IgG4-RD with both kidney and lung involvement [5, 14, 27–30]. In kidney its characteristic manifestation is TIN with multiple extrarenal tissue damage [14, 31], which is easily apparent with a chronic or rapid progressive renal function decline [23]. In lung, this may present as nodules with spiculated margins mimicking primary pulmonary malignancy [28, 32], multiple ground glass opacities (GGO) mimicking interstitial lung disease [14], alveolar interstitial type, and bronchovascular type [33].
However, he developed intermittent fever, acute onset of left pleuritic chest pain and an emerging lung lesion after steroid use for one month. IgG4-RLD has been classified into four categories based on CT. Our case was the GGO type. This also was the primary feature of IPFI [34] of which most common chest CT signs are nodules, consolidation and GGO. This patient had several high-risk factors of IPFI such as old age, long-term use of glucocorticoids, repeated hospitalization, etc. [35]. However,it is difficult to distinguish between IgG4-related lung disease (IgG4-RLD) and IPFI (Table 3). Lung puncture pathology is key standard. Thus, sputum culture and pathogenic examination were repeated and infiltration of IgG4-positive plasma cells was not found. The lung tissue specimen showed fungal spores which supported the diagnosis of IPFI. The differential diagnosis of IgG4-RLD and IPFI were listed in Table 4 [34, 36, 37].
Table 4 Differences between IgG4-RLD and IPFI [34, 36, 37]
Items IgG4-RLD IPFI
Clinical manifestations multi-system injuries dry cough and fever,no specific
Laboratory tests Serum IgG4 elevation CRP and (or) PCT elevation,G/GM positive
Imaging nodules, multiple ground glass opacities (GGO),alveolar interstitial type, and bronchovascular type nodules, consolidation and ground-glass opacity(GGO)
Pathology Mainly IgG4
With plasma cell infiltration and often with interstitial damage
fungal spores with hyphae can be observed, pulmonary fibrosis and inflammatory cell infiltration
Treatment protocol Systemic glucocorticoids anti-infection
Systemic glucocorticoids are recommended as the first-line approach of renal injury in untreated IgG4-RD [31]. A moderate initial dose of oral prednisolone for induction is 0.6 mg/kg daily for 2–4 weeks. The maintenance dose of steroid therapy is given after remission as 2.5-5 mg daily over a period of 2–3 months [2]. However, treatment with exogenous glucocorticoids comes with a number of risks such as avascular necrosis, osteoporosis, glaucoma, cardiovascular disease, worse glucose tolerance and diabetes. The risk of infection is of utmost concern and is well-documented [36, 38]. A Japanese study including 459 AIP patients reported pneumonia occurred in 3 patients treated with steroid [13]. Optimizing the nutritional state of patients, reducing its dose, duration and number of immunosuppressants are recommended to help prevent infection. In the present case, we have to decrease the dosage of immunosuppressive drugs after then, nevertheless, IgG4-RLD were aggravated and renal failure developed during dosage decrease.
Since not every patient can be recover from renal disfunction, maintenance hemodialysis become necessary in patients with irreversible renal failure due to IgG4-RKD [4, 39]. And in this case, the patient experienced a short-time hemodialysis because of azotemia, which partly due to deteriorating renal function, steroids use or (and) infection. Improvements in pulmonary lesions and kidney function were observed after 4 months and were maintained with a dose of 8.0 mg/day prednisone. Thus, the dosage of steroid and immunosuppressant should be reduced for the therapy of the elderly patients with IgG4 related diseases. In addition, it has been reported that relapse of IgG4-related lesions, including kidney damage, occurred in 20% of treated patients with IgG4-RKD during maintenance treatment [39]. Thus, long-term follow-up for this patient are required and a well prognosis is expected.
Taken together, IgG4-RKD is an immune-mediated condition that can affect not only kidney but also several other organs, leading to a dense lymphoplasmacytic infiltration dominant in IgG4-positive plasma cells with fibrosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control (Fig. 6).
Fig. 6 Flow diagram of the patient’s disease progression and treatment
Abbreviations
IgG4-RKDIgG4-related kidney disease
AIPAutoimmune pancreatitis
IgG4-TINIgG4-related tubulointerstitial nephritis
IPFIInvasive pulmonary fungal infection
CTChest computed tomography
uPCRUrine protein: creatine ratio
IgGSerum immunoglobulin G
CTXCyclophosphamide
MPO-ANCAAnti-myeloperoxidase anti-neutrophil cytoplasmic antibody
ANCA-AAVAnti-neutrophil cytoplasmic antibody associated vasculitis
GGOMultiple ground glass opacities
IgG4-RLDIgG4-related lung disease
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the Department of Pathology, Jiangsu province Hospital, for pulmonary pathology.
Authors’ contributions
YLX reviewed the patient’s clinical data, performed the literature search, and wrote the initial draft of the manuscript. YYH and KL assisted in the preparation of the manuscript contributed to data collection and interpretation and critically reviewed the manuscript. JQ, and JFZ provide the pathology of renal biopsy. XFZ performed the immunohistochemical studies. TFY conducted pulmonary puncture and provide the possibility of lung pathology. GY and XQX carried out analysis of patient’s clinical course, outcomes and interpretation of findings, and provided critical review comments for the manuscript. NNW and CYX had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, and provided critical review comments for the manuscript. All authors read and approved the final manuscript.
Funding
The research was financially supported by the National Natural Science Foundation of China (81570666), International Society of Nephrology (ISN) Clinical Research Program (18-01-0247), Jiangsu Province Key Medical Personnel Project (ZDRCA2016002). The funders had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, provided critical review comments and also submission for the manuscript.
Availability of data and materials
The datasets used during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | CYCLOPHOSPHAMIDE, PREDNISONE | DrugsGivenReaction | CC BY | 33430791 | 18,792,998 | 2021-01-11 |
What was the administration route of drug 'CYCLOPHOSPHAMIDE'? | IgG4-related nephritis and interstitial pulmonary disease complicated by invasive pulmonary fungal infection: a case report.
IgG4-related kidney disease (IgG4-RKD) can affect multiple organs, which was first reported as a complication or extra-organ manifestation of autoimmune pancreatitis in 2004. It is characterized by abundant IgG4-positive plasma cells infiltration in tissues involved.
A 69-year-old man presented with cough and renal dysfunction with medical history of hypertension and diabetes. Pathological findings revealed interstitial nephritis and he was initially diagnosed with IgG4-RKD. Prednisone helped the patient to get a remission of cough and an obvious decrease of IgG4 level. However, he developed invasive pulmonary fungal infection while steroid theatment. Anti-fungal therapy was initiated after lung puncture (around cavitary lung lesion). Hemodialysis had been conducted because of renal failure and he got rid of it 2 months later. Methylprednisolone was decreased to 8 mg/day for maintenance therapy. Anti-fungal infection continued for 4 months after discharge home. On the 4th month of follow-up, Chest CT revealed no progression of lung lesions.
The corticosteroids are the first-line therapy of IgG4-RD and a rapid response helps to confirm the diagnosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control.
Background
IgG4-related disease (IgG4-RD) is an inflammatory and fibrotic disease which was first described in the pancreas and was called autoimmune pancreatitis (AIP) in 2001 [1]. Its concept has been recognized worldwide since then that this systemic disease involved multiple organs or tissues characterized by elevated serum IgG4 level and IgG4 positive plasma cells infiltration in the affected tissues, leading to fibrosis eventually [2–6]. The prevalence of IgG4-RD in Japan was estimated as 0.28–1.08/100,000 people in 2012 [7].
IgG4-related tubulointerstitial nephritis (IgG4-TIN), is one of the frequent pathological changes of IgG4-related kidney disease (IgG4-RKD), accounting for about 15–25% of all IgG-RD [4, 8]. IgG4-related TIN shows a range of histologic appearances including (A) acute interstitial nephritis with minimal fibrosis; (B) a more cellular inflammatory pattern in the setting of expansile fibrosis; and (C) a very fibrotic, pauci-cellular pattern [7]. The diagnosis criteria of IgG4-RKD were proposed by the Japanese Society of Nephrology [9] and a work group of North America [7], respectively. IgG4-related kidney lesions were often associated with extrarenal disease, such as chronic sclerosing inflammation of the lacrimal gland, salivary gland [10] and lung [11].
Patients with IgG4-RKD have an increased risk of infection than general population. IgG4-TIN can be accompanied by eosinophilic lung disease [12] and pneumonia [13]. Here, we present a case of IgG4-RKD and lung interstitial lesions who developed invasive pulmonary fungal infection (IPFI) during treatment of glucocorticoid combined with immunosuppressive agents.
Case presentation
A 69-year-old male was admitted to the hospital in 2019 January 5th because of gradually aggravated edema and cough. His medical history included hypertension, arrhythmia and diabetes. On 2019 May 8th, he had experienced cough and phlegm with temperature around 38 ~ 39 °C. Laboratory tests were presented in Table 1. 18F-FDG-PET/CT showed interstitial pneumonia in both lungs. There was also elevated uptake abnormality in the upper kidney observed. Cefperazone-Sulbactam, doxycycline hydrochloride, imipenem, and linezolid were given. Because of no improvement, he took oral prednisone 24 mg per day. The body temperature recovered to normal and lower limb edema was alleviated after one week. On 2019 June 13th ,serum creatinine 157.7 umol/L (Fig. 1); and serum albumin, 24.9 g/L. Chest computed tomography (CT) scan showed that honeycomb-like changes considering interstitial inflammation and bilateral pleural effusion (Fig. 1A).
Table 1 Laboratory data performed before and after treatment
ITEMS Beforetherapy Steroidtherapyfor 1month Steroid therapy for2 months Steroid therapy for3 months Steroid therapy for4 months
White blood cell count(*10^9/L) 15.4 21.11 8.24 11.66 13.28
Hemoglobin(g/L) 129 108 84 98 101
Platelet count(*10^9/L) 323 285 100 273 176
C-reaction protein (CRP)(mg/L) 90 58.1 32 79.8 18.9
Erythrocyte sedimentation rate(mm/H) 120 60 / / /
Serum nitrogen (mmol/L) 10.2 24.71 24.18 30.33 14.5
Serum creatinine (umol/L) 64.6 232.8 212.4 187.2 100.7
Serum albumin(g/L) 24.2 32 30 27.6 21.2
Urine RBC(/ul) / 42.6 10.9 3
Urine protein creatine ratio(mg/g) 48.5
24 h urine protein (g) 0.721 0.62 0.61 0.45 0.49
ANCA-MPO (RU/ml) 35.1 12.7 8.6
ANCA-PR3 (RU/ml) 6.7 4.9 4.7
CD4+ / CD8 + lymphocyte 0.81 / / / 1.9
ABG Before therapy Steroid therapy for 2 months
PH 7.201 7.498
PCO2(mmHg) 20 31.6
PO2(mmHg) 117 49
SpO2 (%) 98 88
K(mmol/L) 5.4 4.1
HCO3-(mmol/L) 7.8 24.5
BE(mmol/L) -20 1
ANCA-MPO Myeloperoxidase-antineutrophil cytoplasmic antibody, ANCA-PR3 proteinase 3, ABG Arterial Blood Gas, / not available
Fig. 1 Chest CT showed interstitial inflammation and bilateral pleural effusion before therapy (a). After glucocorticoids admission, obvious absorption of interstitial inflammation and pleural effusion on both sides were found (b). Infection of both lungs with a left lower lobe cavity before anti-infection therapy (c). After anti-infection therapy, no increase boarder of lung lesions (d)
He went to Nephrology Department on 2019 July 2nd for further treatment. Laboratory results were presented in Table 1. Urine RBC 42.6/ul; Urine protein: creatine ratio (uPCR) 48.5 mg/g; Serum IgG4 level was elevated at 3.42 g/L (Normal range: 0.03–2.10 g/L). Anti-myeloperoxidase anti-neutrophil cytoplasmic antibody level was elevated at 35.1Ru/ml (Normal range:<20 Ru/ml). However, serum immunoglobulin A(IgA), IgG and IgM level were normal. Furthermore, the patient was negative for anti-double-stranded antibody, antinuclear antibody, anti-Sjogren’s syndrome A antibody, anti-Sjogren’s syndrome B antibody and anti-proteinase 3. Ultrasound displayed large-sized kidneys with uniform echo frequency and clear corticomedullary boundaries. Chest CT revealed obvious absorption of interstitial inflammation and pleural effusion on both sides, there were also multiple nodules in both lungs (Fig. 1b).
Histopathology of the kidney biopsy shows proliferation of glomerular mesangial cells, diffuse and irregular thickening of basement membrane (Fig. 2a). The tubulointerstitium shows marked injury. Patchy foci fibrosis and inflammatory cells infiltration were prominent in the interstitium (Fig. 2b, c). Immunofluorescence staining shows that IgG, IgM, IgA, C1q, C3 and C4 were negative in the granular mesangial area. Immunohistological analysis revealed numerous CD20-positive B cells ((D), × 400) and dense infiltration of CD138-positive plasma cells ((E), × 400), with an IgG4+/IgG+ plasma cell ratio being > 40% ((F), × 400). Electron microscopy demonstrated that there were no electron-dense deposits in the glomeruli (Fig. 3).
Fig. 2 Renal histopathological result showed almost normal glomeruli, massively infiltrating cells, and abundant interstitial fibrosis under the light microscopy. a The glomerulus showed glomerular mesangial cells proliferation and diffuse and irregular thickening of basement membrane (HE staining, × 200). b, c A mass of plasma cells and fibrotic fibers (HE staining, × 400) can be observed in the interstitium. d, e Immunohistological analysis revealed mostly CD20-positive B cells (× 400) and CD138-positive plasma cells (× 400) in the interstitium. f Immunohistochemistry for IgG4 shows abundant positive plasma cells (coloured brown) (× 400)
Fig. 3 No electron-dense deposits are observed under electron microscopy. a Abundant plasma cells (× 2000) infiltrated in renal interstitium. b Detachment and partial atrophy of the microvilli of renal tubular epithelial cells as well as edema, infiltration of lymphocytes/monocytes, and fibrosis in renal interstitium. There are no electron-dense deposits in the glomeruli (× 2000). c Proliferation of glomerular mesangial cells and interstitial cells (× 2000). d Diffuse and irregular thickening of basement membrane (× 12,000)
Based on these findings, he had been diagnosed as IgG4-related renal disease. Oral prednisone (40 mg/day) and cyclophosphamide (CTX, 0.4 g) were prescribed by intravenous infusion. The patient had been followed up every month after the treatment (Table 1). He presented with intermittent fever for more than 20 days and acute onset of left pleuritic chest pain with dry cough for 10 days. Negative results were found in aerobic or anaerobic blood culture. Chest CT showed recent infection of both lungs with left upper lung cavity (Fig. 1c). At June 28th he developed hemoptysis and type 1 respiratory failure (Table 2). The results of relevant tests are shown in Table 1. In order to differentiate between IgG4-RLD and IPFI, left upper lung puncture was conducted and showed that interstitial collagen fibrosis with acute and chronic inflammatory cell infiltration, focal fibrous necrosis and exudation, and small alveolar cell response. Fungal spores were also found in lung puncture specimen. Filamentous fungi can be seen in sputum culture. Immunohistochemistry test revealed that most plasma cells in the lung interstitium were positive for CD38 (+), CD138 (+), IgG (+) (Fig. 4). IgG positive plasma cells < 40%, IgG4 positive plasma cells < 10/HPF, which does not meet the pathological diagnostic criteria of IgG4 related diseases. The diagnosis of IPFI was definite. After then, the patient was initiated on voriconazole and caspofungin to anti-fungal infection, and prednisolone was decreased to 30 mg per day.
Table 2 Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ [2, 14, 15]
Criterion
Histology (i)The specimen pathology shows the dense lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis, the infiltration of IgG4-positive cells, and IgG cells more than IgG4 cells ratio of 40%;
Imaging (ii)clinical/radiological examination showing characteristic diffuse or localized swelling or masses in single or multiple organs;
Serology (iii) serum IgG4 concentration > 135 mg/dL;
(iv)Inflammatory markers such as white blood cells count and C-reactive protein concentrations are not elevated, despite the degree of lesions, their spread on imaging analysis and massive cellular infiltration on pathological examination;
Other organ involvement (v)Characteristic findings of IgG4-RD in other organs, including autoimmune pancreatitis, lung involvement, et al.
Treatment (vi)response to steroids.
All 3 criteria (i + ii + iii) are needed for definite diagnosis of IgG4-RD
Fig. 4 Histopathological findings of the pulmonary tissue (light microscopy: HE). a Pulmonary tissue shows fibrotic changes of the interstitium (× 100) in the lung. b Cell and tissue reactions and cellulosic exudation were observed in alveoli (× 200). c, d Giant cell, interstitial edema, collagen fiber hyperplasia and masson body were observed in the specimen (× 200). e, f Immunohistological analysis revealed CD38-positive plasmacyte (coloured brown) (E × 400) and CD138-positive plasmacyte (coloured brown) infiltration (F × 400). g IgG immunostaining shows IgG-positive plasmacyte (coloured brown) infiltration (× 400). h IgG4 immunostaining shows IgG4-positive plasmacyte (coloured brown) infiltration in the lung (× 400)
With anti-infection and immunosuppressive treatment for 2 weeks, serum CRP and IgG4 level had been considerably decreased to 2.94 mg/L and 1.57 g/L, respectively. Voriconazole 200 mg bid and Methylprednisolone 30 mg/day were continued after discharge home. After treatment for one month, a repeat CT scan showed no progression of lung lesions (Fig. 1D). CD4+/CD8+ lymphocyte: 1.9. The patient had been followed up for 4 months. In the most recent follow-up examination, the serum creatinine level decreased to 101 umol/L and he got rid of hemodialysis (Fig. 5). He is currently undergoing tapered prednisolone treatment.
Fig. 5 Dynamic changes of renal function before and after treatment in the patient with IgG4-RKD
Discussion and conclusions
This patient is characterized by serum IgG4 elevation, positive MPO-ANCA, which suggested the possibility of co-occurrence/concurrence of AAV and IgG4‐RD on his first visit from his serological presentation. Diagnosis of IgG4-RD requires particular pathological, serological and clinical features [2, 14, 15] (listed in Table 2). This patient presented with serum IgG4 elevation, hematuria, proteinuria, elevated uptake abnormality of the upper kidney observed in 18F-FDG-PET/CT, progressive kidney failure and interstitial lung disease. Histopathology of kidney biopsy showing typical lymphoplasmacytic infiltration and fibrosis enriched in IgG4-positive plasma cells, and infiltration of IgG4 + plasma cells with IgG4+/IgG+ plasma cells ratio greater than 40% and a total of ≥ 10 IgG4 + plasma cells per high-power field (HPF) indicated the diagnosis of IgG4-RKD.
Given the elevated MPO-ANCA and CRP, AAV related nephritis was a possible differential diagnosis (Proposed diagnostic criteria for kidney involvement in AAV listed in Table 3 [16]). In this case, pathological findings did not show renal crescentic glomerulonephritis or vasculitis, thus, anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-AAV) was not firstly considered according to the Chapel Hill Consensus Conference nomenclature criteria for AAV [16]; However, Some ANCA positive patients may present with interstitial nephritis without severe glomerulopathy, and whether his initial interstitial lung disease was related to IgG4 or AAV or both was not determined. Some reports suggested a possible pathogenic effect of ANCA-IgG4 [17, 18]. Serum IgG4 increase and IgG4-positive cell infiltration in the organ can also be seen in AAV [19, 20]. Distinguishing between these diseases is essential for treatment planning [20], because IgG4-RD responds well to steroid therapy alone, while AAV often requires concomitant immunosuppressant use. His initial interstitial lung disease was improved (Fig. 1) with prednisone therapy alone for one month favored the diagnosis of IgG4-RLD. Kim et al. [21] described that a steroid trial was useful for differentiating and response to steroid therapy is recommended to be added to the diagnostic criteria. Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ listed in Table 2. Therefore, we preferred his diagnosis of IgG4-RD.
Table 3 Proposed diagnostic criteria for kidney involvement in AAV [16]
clinical manifestations a rapidly progressive GN with a decline in kidney function accompanied by sub–nephrotic-range proteinuria, microscopic hematuria, and hypertension over days to a few months
Serology Anti-MPO antibody or anti-PR3 antibody positive
Pathological findings pauci-immune focal necrotizing crescentic GN
Rare patients with AAV have a prominent tubulointerstitial nephritis, which can be associated with vasculitis of the vasa recta
A diagnosis of AAV incorporates the integration of clinical features, ANCA serology, and tissue pathology as needed
Since kidney involvement was firstly reported in a patient with IgG4-RD in 2004 [22], many similar cases have been described [23–25]. A cross-sectional study reported in 2010 revealed all kidney lesions were associated with extrarenal disease among 114 patients with IgG4-related disease [26]. Several clinicopathologic studies reported IgG4-RD with both kidney and lung involvement [5, 14, 27–30]. In kidney its characteristic manifestation is TIN with multiple extrarenal tissue damage [14, 31], which is easily apparent with a chronic or rapid progressive renal function decline [23]. In lung, this may present as nodules with spiculated margins mimicking primary pulmonary malignancy [28, 32], multiple ground glass opacities (GGO) mimicking interstitial lung disease [14], alveolar interstitial type, and bronchovascular type [33].
However, he developed intermittent fever, acute onset of left pleuritic chest pain and an emerging lung lesion after steroid use for one month. IgG4-RLD has been classified into four categories based on CT. Our case was the GGO type. This also was the primary feature of IPFI [34] of which most common chest CT signs are nodules, consolidation and GGO. This patient had several high-risk factors of IPFI such as old age, long-term use of glucocorticoids, repeated hospitalization, etc. [35]. However,it is difficult to distinguish between IgG4-related lung disease (IgG4-RLD) and IPFI (Table 3). Lung puncture pathology is key standard. Thus, sputum culture and pathogenic examination were repeated and infiltration of IgG4-positive plasma cells was not found. The lung tissue specimen showed fungal spores which supported the diagnosis of IPFI. The differential diagnosis of IgG4-RLD and IPFI were listed in Table 4 [34, 36, 37].
Table 4 Differences between IgG4-RLD and IPFI [34, 36, 37]
Items IgG4-RLD IPFI
Clinical manifestations multi-system injuries dry cough and fever,no specific
Laboratory tests Serum IgG4 elevation CRP and (or) PCT elevation,G/GM positive
Imaging nodules, multiple ground glass opacities (GGO),alveolar interstitial type, and bronchovascular type nodules, consolidation and ground-glass opacity(GGO)
Pathology Mainly IgG4
With plasma cell infiltration and often with interstitial damage
fungal spores with hyphae can be observed, pulmonary fibrosis and inflammatory cell infiltration
Treatment protocol Systemic glucocorticoids anti-infection
Systemic glucocorticoids are recommended as the first-line approach of renal injury in untreated IgG4-RD [31]. A moderate initial dose of oral prednisolone for induction is 0.6 mg/kg daily for 2–4 weeks. The maintenance dose of steroid therapy is given after remission as 2.5-5 mg daily over a period of 2–3 months [2]. However, treatment with exogenous glucocorticoids comes with a number of risks such as avascular necrosis, osteoporosis, glaucoma, cardiovascular disease, worse glucose tolerance and diabetes. The risk of infection is of utmost concern and is well-documented [36, 38]. A Japanese study including 459 AIP patients reported pneumonia occurred in 3 patients treated with steroid [13]. Optimizing the nutritional state of patients, reducing its dose, duration and number of immunosuppressants are recommended to help prevent infection. In the present case, we have to decrease the dosage of immunosuppressive drugs after then, nevertheless, IgG4-RLD were aggravated and renal failure developed during dosage decrease.
Since not every patient can be recover from renal disfunction, maintenance hemodialysis become necessary in patients with irreversible renal failure due to IgG4-RKD [4, 39]. And in this case, the patient experienced a short-time hemodialysis because of azotemia, which partly due to deteriorating renal function, steroids use or (and) infection. Improvements in pulmonary lesions and kidney function were observed after 4 months and were maintained with a dose of 8.0 mg/day prednisone. Thus, the dosage of steroid and immunosuppressant should be reduced for the therapy of the elderly patients with IgG4 related diseases. In addition, it has been reported that relapse of IgG4-related lesions, including kidney damage, occurred in 20% of treated patients with IgG4-RKD during maintenance treatment [39]. Thus, long-term follow-up for this patient are required and a well prognosis is expected.
Taken together, IgG4-RKD is an immune-mediated condition that can affect not only kidney but also several other organs, leading to a dense lymphoplasmacytic infiltration dominant in IgG4-positive plasma cells with fibrosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control (Fig. 6).
Fig. 6 Flow diagram of the patient’s disease progression and treatment
Abbreviations
IgG4-RKDIgG4-related kidney disease
AIPAutoimmune pancreatitis
IgG4-TINIgG4-related tubulointerstitial nephritis
IPFIInvasive pulmonary fungal infection
CTChest computed tomography
uPCRUrine protein: creatine ratio
IgGSerum immunoglobulin G
CTXCyclophosphamide
MPO-ANCAAnti-myeloperoxidase anti-neutrophil cytoplasmic antibody
ANCA-AAVAnti-neutrophil cytoplasmic antibody associated vasculitis
GGOMultiple ground glass opacities
IgG4-RLDIgG4-related lung disease
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the Department of Pathology, Jiangsu province Hospital, for pulmonary pathology.
Authors’ contributions
YLX reviewed the patient’s clinical data, performed the literature search, and wrote the initial draft of the manuscript. YYH and KL assisted in the preparation of the manuscript contributed to data collection and interpretation and critically reviewed the manuscript. JQ, and JFZ provide the pathology of renal biopsy. XFZ performed the immunohistochemical studies. TFY conducted pulmonary puncture and provide the possibility of lung pathology. GY and XQX carried out analysis of patient’s clinical course, outcomes and interpretation of findings, and provided critical review comments for the manuscript. NNW and CYX had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, and provided critical review comments for the manuscript. All authors read and approved the final manuscript.
Funding
The research was financially supported by the National Natural Science Foundation of China (81570666), International Society of Nephrology (ISN) Clinical Research Program (18-01-0247), Jiangsu Province Key Medical Personnel Project (ZDRCA2016002). The funders had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, provided critical review comments and also submission for the manuscript.
Availability of data and materials
The datasets used during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33430791 | 18,792,998 | 2021-01-11 |
What was the administration route of drug 'PREDNISONE'? | IgG4-related nephritis and interstitial pulmonary disease complicated by invasive pulmonary fungal infection: a case report.
IgG4-related kidney disease (IgG4-RKD) can affect multiple organs, which was first reported as a complication or extra-organ manifestation of autoimmune pancreatitis in 2004. It is characterized by abundant IgG4-positive plasma cells infiltration in tissues involved.
A 69-year-old man presented with cough and renal dysfunction with medical history of hypertension and diabetes. Pathological findings revealed interstitial nephritis and he was initially diagnosed with IgG4-RKD. Prednisone helped the patient to get a remission of cough and an obvious decrease of IgG4 level. However, he developed invasive pulmonary fungal infection while steroid theatment. Anti-fungal therapy was initiated after lung puncture (around cavitary lung lesion). Hemodialysis had been conducted because of renal failure and he got rid of it 2 months later. Methylprednisolone was decreased to 8 mg/day for maintenance therapy. Anti-fungal infection continued for 4 months after discharge home. On the 4th month of follow-up, Chest CT revealed no progression of lung lesions.
The corticosteroids are the first-line therapy of IgG4-RD and a rapid response helps to confirm the diagnosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control.
Background
IgG4-related disease (IgG4-RD) is an inflammatory and fibrotic disease which was first described in the pancreas and was called autoimmune pancreatitis (AIP) in 2001 [1]. Its concept has been recognized worldwide since then that this systemic disease involved multiple organs or tissues characterized by elevated serum IgG4 level and IgG4 positive plasma cells infiltration in the affected tissues, leading to fibrosis eventually [2–6]. The prevalence of IgG4-RD in Japan was estimated as 0.28–1.08/100,000 people in 2012 [7].
IgG4-related tubulointerstitial nephritis (IgG4-TIN), is one of the frequent pathological changes of IgG4-related kidney disease (IgG4-RKD), accounting for about 15–25% of all IgG-RD [4, 8]. IgG4-related TIN shows a range of histologic appearances including (A) acute interstitial nephritis with minimal fibrosis; (B) a more cellular inflammatory pattern in the setting of expansile fibrosis; and (C) a very fibrotic, pauci-cellular pattern [7]. The diagnosis criteria of IgG4-RKD were proposed by the Japanese Society of Nephrology [9] and a work group of North America [7], respectively. IgG4-related kidney lesions were often associated with extrarenal disease, such as chronic sclerosing inflammation of the lacrimal gland, salivary gland [10] and lung [11].
Patients with IgG4-RKD have an increased risk of infection than general population. IgG4-TIN can be accompanied by eosinophilic lung disease [12] and pneumonia [13]. Here, we present a case of IgG4-RKD and lung interstitial lesions who developed invasive pulmonary fungal infection (IPFI) during treatment of glucocorticoid combined with immunosuppressive agents.
Case presentation
A 69-year-old male was admitted to the hospital in 2019 January 5th because of gradually aggravated edema and cough. His medical history included hypertension, arrhythmia and diabetes. On 2019 May 8th, he had experienced cough and phlegm with temperature around 38 ~ 39 °C. Laboratory tests were presented in Table 1. 18F-FDG-PET/CT showed interstitial pneumonia in both lungs. There was also elevated uptake abnormality in the upper kidney observed. Cefperazone-Sulbactam, doxycycline hydrochloride, imipenem, and linezolid were given. Because of no improvement, he took oral prednisone 24 mg per day. The body temperature recovered to normal and lower limb edema was alleviated after one week. On 2019 June 13th ,serum creatinine 157.7 umol/L (Fig. 1); and serum albumin, 24.9 g/L. Chest computed tomography (CT) scan showed that honeycomb-like changes considering interstitial inflammation and bilateral pleural effusion (Fig. 1A).
Table 1 Laboratory data performed before and after treatment
ITEMS Beforetherapy Steroidtherapyfor 1month Steroid therapy for2 months Steroid therapy for3 months Steroid therapy for4 months
White blood cell count(*10^9/L) 15.4 21.11 8.24 11.66 13.28
Hemoglobin(g/L) 129 108 84 98 101
Platelet count(*10^9/L) 323 285 100 273 176
C-reaction protein (CRP)(mg/L) 90 58.1 32 79.8 18.9
Erythrocyte sedimentation rate(mm/H) 120 60 / / /
Serum nitrogen (mmol/L) 10.2 24.71 24.18 30.33 14.5
Serum creatinine (umol/L) 64.6 232.8 212.4 187.2 100.7
Serum albumin(g/L) 24.2 32 30 27.6 21.2
Urine RBC(/ul) / 42.6 10.9 3
Urine protein creatine ratio(mg/g) 48.5
24 h urine protein (g) 0.721 0.62 0.61 0.45 0.49
ANCA-MPO (RU/ml) 35.1 12.7 8.6
ANCA-PR3 (RU/ml) 6.7 4.9 4.7
CD4+ / CD8 + lymphocyte 0.81 / / / 1.9
ABG Before therapy Steroid therapy for 2 months
PH 7.201 7.498
PCO2(mmHg) 20 31.6
PO2(mmHg) 117 49
SpO2 (%) 98 88
K(mmol/L) 5.4 4.1
HCO3-(mmol/L) 7.8 24.5
BE(mmol/L) -20 1
ANCA-MPO Myeloperoxidase-antineutrophil cytoplasmic antibody, ANCA-PR3 proteinase 3, ABG Arterial Blood Gas, / not available
Fig. 1 Chest CT showed interstitial inflammation and bilateral pleural effusion before therapy (a). After glucocorticoids admission, obvious absorption of interstitial inflammation and pleural effusion on both sides were found (b). Infection of both lungs with a left lower lobe cavity before anti-infection therapy (c). After anti-infection therapy, no increase boarder of lung lesions (d)
He went to Nephrology Department on 2019 July 2nd for further treatment. Laboratory results were presented in Table 1. Urine RBC 42.6/ul; Urine protein: creatine ratio (uPCR) 48.5 mg/g; Serum IgG4 level was elevated at 3.42 g/L (Normal range: 0.03–2.10 g/L). Anti-myeloperoxidase anti-neutrophil cytoplasmic antibody level was elevated at 35.1Ru/ml (Normal range:<20 Ru/ml). However, serum immunoglobulin A(IgA), IgG and IgM level were normal. Furthermore, the patient was negative for anti-double-stranded antibody, antinuclear antibody, anti-Sjogren’s syndrome A antibody, anti-Sjogren’s syndrome B antibody and anti-proteinase 3. Ultrasound displayed large-sized kidneys with uniform echo frequency and clear corticomedullary boundaries. Chest CT revealed obvious absorption of interstitial inflammation and pleural effusion on both sides, there were also multiple nodules in both lungs (Fig. 1b).
Histopathology of the kidney biopsy shows proliferation of glomerular mesangial cells, diffuse and irregular thickening of basement membrane (Fig. 2a). The tubulointerstitium shows marked injury. Patchy foci fibrosis and inflammatory cells infiltration were prominent in the interstitium (Fig. 2b, c). Immunofluorescence staining shows that IgG, IgM, IgA, C1q, C3 and C4 were negative in the granular mesangial area. Immunohistological analysis revealed numerous CD20-positive B cells ((D), × 400) and dense infiltration of CD138-positive plasma cells ((E), × 400), with an IgG4+/IgG+ plasma cell ratio being > 40% ((F), × 400). Electron microscopy demonstrated that there were no electron-dense deposits in the glomeruli (Fig. 3).
Fig. 2 Renal histopathological result showed almost normal glomeruli, massively infiltrating cells, and abundant interstitial fibrosis under the light microscopy. a The glomerulus showed glomerular mesangial cells proliferation and diffuse and irregular thickening of basement membrane (HE staining, × 200). b, c A mass of plasma cells and fibrotic fibers (HE staining, × 400) can be observed in the interstitium. d, e Immunohistological analysis revealed mostly CD20-positive B cells (× 400) and CD138-positive plasma cells (× 400) in the interstitium. f Immunohistochemistry for IgG4 shows abundant positive plasma cells (coloured brown) (× 400)
Fig. 3 No electron-dense deposits are observed under electron microscopy. a Abundant plasma cells (× 2000) infiltrated in renal interstitium. b Detachment and partial atrophy of the microvilli of renal tubular epithelial cells as well as edema, infiltration of lymphocytes/monocytes, and fibrosis in renal interstitium. There are no electron-dense deposits in the glomeruli (× 2000). c Proliferation of glomerular mesangial cells and interstitial cells (× 2000). d Diffuse and irregular thickening of basement membrane (× 12,000)
Based on these findings, he had been diagnosed as IgG4-related renal disease. Oral prednisone (40 mg/day) and cyclophosphamide (CTX, 0.4 g) were prescribed by intravenous infusion. The patient had been followed up every month after the treatment (Table 1). He presented with intermittent fever for more than 20 days and acute onset of left pleuritic chest pain with dry cough for 10 days. Negative results were found in aerobic or anaerobic blood culture. Chest CT showed recent infection of both lungs with left upper lung cavity (Fig. 1c). At June 28th he developed hemoptysis and type 1 respiratory failure (Table 2). The results of relevant tests are shown in Table 1. In order to differentiate between IgG4-RLD and IPFI, left upper lung puncture was conducted and showed that interstitial collagen fibrosis with acute and chronic inflammatory cell infiltration, focal fibrous necrosis and exudation, and small alveolar cell response. Fungal spores were also found in lung puncture specimen. Filamentous fungi can be seen in sputum culture. Immunohistochemistry test revealed that most plasma cells in the lung interstitium were positive for CD38 (+), CD138 (+), IgG (+) (Fig. 4). IgG positive plasma cells < 40%, IgG4 positive plasma cells < 10/HPF, which does not meet the pathological diagnostic criteria of IgG4 related diseases. The diagnosis of IPFI was definite. After then, the patient was initiated on voriconazole and caspofungin to anti-fungal infection, and prednisolone was decreased to 30 mg per day.
Table 2 Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ [2, 14, 15]
Criterion
Histology (i)The specimen pathology shows the dense lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis, the infiltration of IgG4-positive cells, and IgG cells more than IgG4 cells ratio of 40%;
Imaging (ii)clinical/radiological examination showing characteristic diffuse or localized swelling or masses in single or multiple organs;
Serology (iii) serum IgG4 concentration > 135 mg/dL;
(iv)Inflammatory markers such as white blood cells count and C-reactive protein concentrations are not elevated, despite the degree of lesions, their spread on imaging analysis and massive cellular infiltration on pathological examination;
Other organ involvement (v)Characteristic findings of IgG4-RD in other organs, including autoimmune pancreatitis, lung involvement, et al.
Treatment (vi)response to steroids.
All 3 criteria (i + ii + iii) are needed for definite diagnosis of IgG4-RD
Fig. 4 Histopathological findings of the pulmonary tissue (light microscopy: HE). a Pulmonary tissue shows fibrotic changes of the interstitium (× 100) in the lung. b Cell and tissue reactions and cellulosic exudation were observed in alveoli (× 200). c, d Giant cell, interstitial edema, collagen fiber hyperplasia and masson body were observed in the specimen (× 200). e, f Immunohistological analysis revealed CD38-positive plasmacyte (coloured brown) (E × 400) and CD138-positive plasmacyte (coloured brown) infiltration (F × 400). g IgG immunostaining shows IgG-positive plasmacyte (coloured brown) infiltration (× 400). h IgG4 immunostaining shows IgG4-positive plasmacyte (coloured brown) infiltration in the lung (× 400)
With anti-infection and immunosuppressive treatment for 2 weeks, serum CRP and IgG4 level had been considerably decreased to 2.94 mg/L and 1.57 g/L, respectively. Voriconazole 200 mg bid and Methylprednisolone 30 mg/day were continued after discharge home. After treatment for one month, a repeat CT scan showed no progression of lung lesions (Fig. 1D). CD4+/CD8+ lymphocyte: 1.9. The patient had been followed up for 4 months. In the most recent follow-up examination, the serum creatinine level decreased to 101 umol/L and he got rid of hemodialysis (Fig. 5). He is currently undergoing tapered prednisolone treatment.
Fig. 5 Dynamic changes of renal function before and after treatment in the patient with IgG4-RKD
Discussion and conclusions
This patient is characterized by serum IgG4 elevation, positive MPO-ANCA, which suggested the possibility of co-occurrence/concurrence of AAV and IgG4‐RD on his first visit from his serological presentation. Diagnosis of IgG4-RD requires particular pathological, serological and clinical features [2, 14, 15] (listed in Table 2). This patient presented with serum IgG4 elevation, hematuria, proteinuria, elevated uptake abnormality of the upper kidney observed in 18F-FDG-PET/CT, progressive kidney failure and interstitial lung disease. Histopathology of kidney biopsy showing typical lymphoplasmacytic infiltration and fibrosis enriched in IgG4-positive plasma cells, and infiltration of IgG4 + plasma cells with IgG4+/IgG+ plasma cells ratio greater than 40% and a total of ≥ 10 IgG4 + plasma cells per high-power field (HPF) indicated the diagnosis of IgG4-RKD.
Given the elevated MPO-ANCA and CRP, AAV related nephritis was a possible differential diagnosis (Proposed diagnostic criteria for kidney involvement in AAV listed in Table 3 [16]). In this case, pathological findings did not show renal crescentic glomerulonephritis or vasculitis, thus, anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-AAV) was not firstly considered according to the Chapel Hill Consensus Conference nomenclature criteria for AAV [16]; However, Some ANCA positive patients may present with interstitial nephritis without severe glomerulopathy, and whether his initial interstitial lung disease was related to IgG4 or AAV or both was not determined. Some reports suggested a possible pathogenic effect of ANCA-IgG4 [17, 18]. Serum IgG4 increase and IgG4-positive cell infiltration in the organ can also be seen in AAV [19, 20]. Distinguishing between these diseases is essential for treatment planning [20], because IgG4-RD responds well to steroid therapy alone, while AAV often requires concomitant immunosuppressant use. His initial interstitial lung disease was improved (Fig. 1) with prednisone therapy alone for one month favored the diagnosis of IgG4-RLD. Kim et al. [21] described that a steroid trial was useful for differentiating and response to steroid therapy is recommended to be added to the diagnostic criteria. Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ listed in Table 2. Therefore, we preferred his diagnosis of IgG4-RD.
Table 3 Proposed diagnostic criteria for kidney involvement in AAV [16]
clinical manifestations a rapidly progressive GN with a decline in kidney function accompanied by sub–nephrotic-range proteinuria, microscopic hematuria, and hypertension over days to a few months
Serology Anti-MPO antibody or anti-PR3 antibody positive
Pathological findings pauci-immune focal necrotizing crescentic GN
Rare patients with AAV have a prominent tubulointerstitial nephritis, which can be associated with vasculitis of the vasa recta
A diagnosis of AAV incorporates the integration of clinical features, ANCA serology, and tissue pathology as needed
Since kidney involvement was firstly reported in a patient with IgG4-RD in 2004 [22], many similar cases have been described [23–25]. A cross-sectional study reported in 2010 revealed all kidney lesions were associated with extrarenal disease among 114 patients with IgG4-related disease [26]. Several clinicopathologic studies reported IgG4-RD with both kidney and lung involvement [5, 14, 27–30]. In kidney its characteristic manifestation is TIN with multiple extrarenal tissue damage [14, 31], which is easily apparent with a chronic or rapid progressive renal function decline [23]. In lung, this may present as nodules with spiculated margins mimicking primary pulmonary malignancy [28, 32], multiple ground glass opacities (GGO) mimicking interstitial lung disease [14], alveolar interstitial type, and bronchovascular type [33].
However, he developed intermittent fever, acute onset of left pleuritic chest pain and an emerging lung lesion after steroid use for one month. IgG4-RLD has been classified into four categories based on CT. Our case was the GGO type. This also was the primary feature of IPFI [34] of which most common chest CT signs are nodules, consolidation and GGO. This patient had several high-risk factors of IPFI such as old age, long-term use of glucocorticoids, repeated hospitalization, etc. [35]. However,it is difficult to distinguish between IgG4-related lung disease (IgG4-RLD) and IPFI (Table 3). Lung puncture pathology is key standard. Thus, sputum culture and pathogenic examination were repeated and infiltration of IgG4-positive plasma cells was not found. The lung tissue specimen showed fungal spores which supported the diagnosis of IPFI. The differential diagnosis of IgG4-RLD and IPFI were listed in Table 4 [34, 36, 37].
Table 4 Differences between IgG4-RLD and IPFI [34, 36, 37]
Items IgG4-RLD IPFI
Clinical manifestations multi-system injuries dry cough and fever,no specific
Laboratory tests Serum IgG4 elevation CRP and (or) PCT elevation,G/GM positive
Imaging nodules, multiple ground glass opacities (GGO),alveolar interstitial type, and bronchovascular type nodules, consolidation and ground-glass opacity(GGO)
Pathology Mainly IgG4
With plasma cell infiltration and often with interstitial damage
fungal spores with hyphae can be observed, pulmonary fibrosis and inflammatory cell infiltration
Treatment protocol Systemic glucocorticoids anti-infection
Systemic glucocorticoids are recommended as the first-line approach of renal injury in untreated IgG4-RD [31]. A moderate initial dose of oral prednisolone for induction is 0.6 mg/kg daily for 2–4 weeks. The maintenance dose of steroid therapy is given after remission as 2.5-5 mg daily over a period of 2–3 months [2]. However, treatment with exogenous glucocorticoids comes with a number of risks such as avascular necrosis, osteoporosis, glaucoma, cardiovascular disease, worse glucose tolerance and diabetes. The risk of infection is of utmost concern and is well-documented [36, 38]. A Japanese study including 459 AIP patients reported pneumonia occurred in 3 patients treated with steroid [13]. Optimizing the nutritional state of patients, reducing its dose, duration and number of immunosuppressants are recommended to help prevent infection. In the present case, we have to decrease the dosage of immunosuppressive drugs after then, nevertheless, IgG4-RLD were aggravated and renal failure developed during dosage decrease.
Since not every patient can be recover from renal disfunction, maintenance hemodialysis become necessary in patients with irreversible renal failure due to IgG4-RKD [4, 39]. And in this case, the patient experienced a short-time hemodialysis because of azotemia, which partly due to deteriorating renal function, steroids use or (and) infection. Improvements in pulmonary lesions and kidney function were observed after 4 months and were maintained with a dose of 8.0 mg/day prednisone. Thus, the dosage of steroid and immunosuppressant should be reduced for the therapy of the elderly patients with IgG4 related diseases. In addition, it has been reported that relapse of IgG4-related lesions, including kidney damage, occurred in 20% of treated patients with IgG4-RKD during maintenance treatment [39]. Thus, long-term follow-up for this patient are required and a well prognosis is expected.
Taken together, IgG4-RKD is an immune-mediated condition that can affect not only kidney but also several other organs, leading to a dense lymphoplasmacytic infiltration dominant in IgG4-positive plasma cells with fibrosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control (Fig. 6).
Fig. 6 Flow diagram of the patient’s disease progression and treatment
Abbreviations
IgG4-RKDIgG4-related kidney disease
AIPAutoimmune pancreatitis
IgG4-TINIgG4-related tubulointerstitial nephritis
IPFIInvasive pulmonary fungal infection
CTChest computed tomography
uPCRUrine protein: creatine ratio
IgGSerum immunoglobulin G
CTXCyclophosphamide
MPO-ANCAAnti-myeloperoxidase anti-neutrophil cytoplasmic antibody
ANCA-AAVAnti-neutrophil cytoplasmic antibody associated vasculitis
GGOMultiple ground glass opacities
IgG4-RLDIgG4-related lung disease
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the Department of Pathology, Jiangsu province Hospital, for pulmonary pathology.
Authors’ contributions
YLX reviewed the patient’s clinical data, performed the literature search, and wrote the initial draft of the manuscript. YYH and KL assisted in the preparation of the manuscript contributed to data collection and interpretation and critically reviewed the manuscript. JQ, and JFZ provide the pathology of renal biopsy. XFZ performed the immunohistochemical studies. TFY conducted pulmonary puncture and provide the possibility of lung pathology. GY and XQX carried out analysis of patient’s clinical course, outcomes and interpretation of findings, and provided critical review comments for the manuscript. NNW and CYX had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, and provided critical review comments for the manuscript. All authors read and approved the final manuscript.
Funding
The research was financially supported by the National Natural Science Foundation of China (81570666), International Society of Nephrology (ISN) Clinical Research Program (18-01-0247), Jiangsu Province Key Medical Personnel Project (ZDRCA2016002). The funders had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, provided critical review comments and also submission for the manuscript.
Availability of data and materials
The datasets used during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33430791 | 18,792,998 | 2021-01-11 |
What was the dosage of drug 'CYCLOPHOSPHAMIDE'? | IgG4-related nephritis and interstitial pulmonary disease complicated by invasive pulmonary fungal infection: a case report.
IgG4-related kidney disease (IgG4-RKD) can affect multiple organs, which was first reported as a complication or extra-organ manifestation of autoimmune pancreatitis in 2004. It is characterized by abundant IgG4-positive plasma cells infiltration in tissues involved.
A 69-year-old man presented with cough and renal dysfunction with medical history of hypertension and diabetes. Pathological findings revealed interstitial nephritis and he was initially diagnosed with IgG4-RKD. Prednisone helped the patient to get a remission of cough and an obvious decrease of IgG4 level. However, he developed invasive pulmonary fungal infection while steroid theatment. Anti-fungal therapy was initiated after lung puncture (around cavitary lung lesion). Hemodialysis had been conducted because of renal failure and he got rid of it 2 months later. Methylprednisolone was decreased to 8 mg/day for maintenance therapy. Anti-fungal infection continued for 4 months after discharge home. On the 4th month of follow-up, Chest CT revealed no progression of lung lesions.
The corticosteroids are the first-line therapy of IgG4-RD and a rapid response helps to confirm the diagnosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control.
Background
IgG4-related disease (IgG4-RD) is an inflammatory and fibrotic disease which was first described in the pancreas and was called autoimmune pancreatitis (AIP) in 2001 [1]. Its concept has been recognized worldwide since then that this systemic disease involved multiple organs or tissues characterized by elevated serum IgG4 level and IgG4 positive plasma cells infiltration in the affected tissues, leading to fibrosis eventually [2–6]. The prevalence of IgG4-RD in Japan was estimated as 0.28–1.08/100,000 people in 2012 [7].
IgG4-related tubulointerstitial nephritis (IgG4-TIN), is one of the frequent pathological changes of IgG4-related kidney disease (IgG4-RKD), accounting for about 15–25% of all IgG-RD [4, 8]. IgG4-related TIN shows a range of histologic appearances including (A) acute interstitial nephritis with minimal fibrosis; (B) a more cellular inflammatory pattern in the setting of expansile fibrosis; and (C) a very fibrotic, pauci-cellular pattern [7]. The diagnosis criteria of IgG4-RKD were proposed by the Japanese Society of Nephrology [9] and a work group of North America [7], respectively. IgG4-related kidney lesions were often associated with extrarenal disease, such as chronic sclerosing inflammation of the lacrimal gland, salivary gland [10] and lung [11].
Patients with IgG4-RKD have an increased risk of infection than general population. IgG4-TIN can be accompanied by eosinophilic lung disease [12] and pneumonia [13]. Here, we present a case of IgG4-RKD and lung interstitial lesions who developed invasive pulmonary fungal infection (IPFI) during treatment of glucocorticoid combined with immunosuppressive agents.
Case presentation
A 69-year-old male was admitted to the hospital in 2019 January 5th because of gradually aggravated edema and cough. His medical history included hypertension, arrhythmia and diabetes. On 2019 May 8th, he had experienced cough and phlegm with temperature around 38 ~ 39 °C. Laboratory tests were presented in Table 1. 18F-FDG-PET/CT showed interstitial pneumonia in both lungs. There was also elevated uptake abnormality in the upper kidney observed. Cefperazone-Sulbactam, doxycycline hydrochloride, imipenem, and linezolid were given. Because of no improvement, he took oral prednisone 24 mg per day. The body temperature recovered to normal and lower limb edema was alleviated after one week. On 2019 June 13th ,serum creatinine 157.7 umol/L (Fig. 1); and serum albumin, 24.9 g/L. Chest computed tomography (CT) scan showed that honeycomb-like changes considering interstitial inflammation and bilateral pleural effusion (Fig. 1A).
Table 1 Laboratory data performed before and after treatment
ITEMS Beforetherapy Steroidtherapyfor 1month Steroid therapy for2 months Steroid therapy for3 months Steroid therapy for4 months
White blood cell count(*10^9/L) 15.4 21.11 8.24 11.66 13.28
Hemoglobin(g/L) 129 108 84 98 101
Platelet count(*10^9/L) 323 285 100 273 176
C-reaction protein (CRP)(mg/L) 90 58.1 32 79.8 18.9
Erythrocyte sedimentation rate(mm/H) 120 60 / / /
Serum nitrogen (mmol/L) 10.2 24.71 24.18 30.33 14.5
Serum creatinine (umol/L) 64.6 232.8 212.4 187.2 100.7
Serum albumin(g/L) 24.2 32 30 27.6 21.2
Urine RBC(/ul) / 42.6 10.9 3
Urine protein creatine ratio(mg/g) 48.5
24 h urine protein (g) 0.721 0.62 0.61 0.45 0.49
ANCA-MPO (RU/ml) 35.1 12.7 8.6
ANCA-PR3 (RU/ml) 6.7 4.9 4.7
CD4+ / CD8 + lymphocyte 0.81 / / / 1.9
ABG Before therapy Steroid therapy for 2 months
PH 7.201 7.498
PCO2(mmHg) 20 31.6
PO2(mmHg) 117 49
SpO2 (%) 98 88
K(mmol/L) 5.4 4.1
HCO3-(mmol/L) 7.8 24.5
BE(mmol/L) -20 1
ANCA-MPO Myeloperoxidase-antineutrophil cytoplasmic antibody, ANCA-PR3 proteinase 3, ABG Arterial Blood Gas, / not available
Fig. 1 Chest CT showed interstitial inflammation and bilateral pleural effusion before therapy (a). After glucocorticoids admission, obvious absorption of interstitial inflammation and pleural effusion on both sides were found (b). Infection of both lungs with a left lower lobe cavity before anti-infection therapy (c). After anti-infection therapy, no increase boarder of lung lesions (d)
He went to Nephrology Department on 2019 July 2nd for further treatment. Laboratory results were presented in Table 1. Urine RBC 42.6/ul; Urine protein: creatine ratio (uPCR) 48.5 mg/g; Serum IgG4 level was elevated at 3.42 g/L (Normal range: 0.03–2.10 g/L). Anti-myeloperoxidase anti-neutrophil cytoplasmic antibody level was elevated at 35.1Ru/ml (Normal range:<20 Ru/ml). However, serum immunoglobulin A(IgA), IgG and IgM level were normal. Furthermore, the patient was negative for anti-double-stranded antibody, antinuclear antibody, anti-Sjogren’s syndrome A antibody, anti-Sjogren’s syndrome B antibody and anti-proteinase 3. Ultrasound displayed large-sized kidneys with uniform echo frequency and clear corticomedullary boundaries. Chest CT revealed obvious absorption of interstitial inflammation and pleural effusion on both sides, there were also multiple nodules in both lungs (Fig. 1b).
Histopathology of the kidney biopsy shows proliferation of glomerular mesangial cells, diffuse and irregular thickening of basement membrane (Fig. 2a). The tubulointerstitium shows marked injury. Patchy foci fibrosis and inflammatory cells infiltration were prominent in the interstitium (Fig. 2b, c). Immunofluorescence staining shows that IgG, IgM, IgA, C1q, C3 and C4 were negative in the granular mesangial area. Immunohistological analysis revealed numerous CD20-positive B cells ((D), × 400) and dense infiltration of CD138-positive plasma cells ((E), × 400), with an IgG4+/IgG+ plasma cell ratio being > 40% ((F), × 400). Electron microscopy demonstrated that there were no electron-dense deposits in the glomeruli (Fig. 3).
Fig. 2 Renal histopathological result showed almost normal glomeruli, massively infiltrating cells, and abundant interstitial fibrosis under the light microscopy. a The glomerulus showed glomerular mesangial cells proliferation and diffuse and irregular thickening of basement membrane (HE staining, × 200). b, c A mass of plasma cells and fibrotic fibers (HE staining, × 400) can be observed in the interstitium. d, e Immunohistological analysis revealed mostly CD20-positive B cells (× 400) and CD138-positive plasma cells (× 400) in the interstitium. f Immunohistochemistry for IgG4 shows abundant positive plasma cells (coloured brown) (× 400)
Fig. 3 No electron-dense deposits are observed under electron microscopy. a Abundant plasma cells (× 2000) infiltrated in renal interstitium. b Detachment and partial atrophy of the microvilli of renal tubular epithelial cells as well as edema, infiltration of lymphocytes/monocytes, and fibrosis in renal interstitium. There are no electron-dense deposits in the glomeruli (× 2000). c Proliferation of glomerular mesangial cells and interstitial cells (× 2000). d Diffuse and irregular thickening of basement membrane (× 12,000)
Based on these findings, he had been diagnosed as IgG4-related renal disease. Oral prednisone (40 mg/day) and cyclophosphamide (CTX, 0.4 g) were prescribed by intravenous infusion. The patient had been followed up every month after the treatment (Table 1). He presented with intermittent fever for more than 20 days and acute onset of left pleuritic chest pain with dry cough for 10 days. Negative results were found in aerobic or anaerobic blood culture. Chest CT showed recent infection of both lungs with left upper lung cavity (Fig. 1c). At June 28th he developed hemoptysis and type 1 respiratory failure (Table 2). The results of relevant tests are shown in Table 1. In order to differentiate between IgG4-RLD and IPFI, left upper lung puncture was conducted and showed that interstitial collagen fibrosis with acute and chronic inflammatory cell infiltration, focal fibrous necrosis and exudation, and small alveolar cell response. Fungal spores were also found in lung puncture specimen. Filamentous fungi can be seen in sputum culture. Immunohistochemistry test revealed that most plasma cells in the lung interstitium were positive for CD38 (+), CD138 (+), IgG (+) (Fig. 4). IgG positive plasma cells < 40%, IgG4 positive plasma cells < 10/HPF, which does not meet the pathological diagnostic criteria of IgG4 related diseases. The diagnosis of IPFI was definite. After then, the patient was initiated on voriconazole and caspofungin to anti-fungal infection, and prednisolone was decreased to 30 mg per day.
Table 2 Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ [2, 14, 15]
Criterion
Histology (i)The specimen pathology shows the dense lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis, the infiltration of IgG4-positive cells, and IgG cells more than IgG4 cells ratio of 40%;
Imaging (ii)clinical/radiological examination showing characteristic diffuse or localized swelling or masses in single or multiple organs;
Serology (iii) serum IgG4 concentration > 135 mg/dL;
(iv)Inflammatory markers such as white blood cells count and C-reactive protein concentrations are not elevated, despite the degree of lesions, their spread on imaging analysis and massive cellular infiltration on pathological examination;
Other organ involvement (v)Characteristic findings of IgG4-RD in other organs, including autoimmune pancreatitis, lung involvement, et al.
Treatment (vi)response to steroids.
All 3 criteria (i + ii + iii) are needed for definite diagnosis of IgG4-RD
Fig. 4 Histopathological findings of the pulmonary tissue (light microscopy: HE). a Pulmonary tissue shows fibrotic changes of the interstitium (× 100) in the lung. b Cell and tissue reactions and cellulosic exudation were observed in alveoli (× 200). c, d Giant cell, interstitial edema, collagen fiber hyperplasia and masson body were observed in the specimen (× 200). e, f Immunohistological analysis revealed CD38-positive plasmacyte (coloured brown) (E × 400) and CD138-positive plasmacyte (coloured brown) infiltration (F × 400). g IgG immunostaining shows IgG-positive plasmacyte (coloured brown) infiltration (× 400). h IgG4 immunostaining shows IgG4-positive plasmacyte (coloured brown) infiltration in the lung (× 400)
With anti-infection and immunosuppressive treatment for 2 weeks, serum CRP and IgG4 level had been considerably decreased to 2.94 mg/L and 1.57 g/L, respectively. Voriconazole 200 mg bid and Methylprednisolone 30 mg/day were continued after discharge home. After treatment for one month, a repeat CT scan showed no progression of lung lesions (Fig. 1D). CD4+/CD8+ lymphocyte: 1.9. The patient had been followed up for 4 months. In the most recent follow-up examination, the serum creatinine level decreased to 101 umol/L and he got rid of hemodialysis (Fig. 5). He is currently undergoing tapered prednisolone treatment.
Fig. 5 Dynamic changes of renal function before and after treatment in the patient with IgG4-RKD
Discussion and conclusions
This patient is characterized by serum IgG4 elevation, positive MPO-ANCA, which suggested the possibility of co-occurrence/concurrence of AAV and IgG4‐RD on his first visit from his serological presentation. Diagnosis of IgG4-RD requires particular pathological, serological and clinical features [2, 14, 15] (listed in Table 2). This patient presented with serum IgG4 elevation, hematuria, proteinuria, elevated uptake abnormality of the upper kidney observed in 18F-FDG-PET/CT, progressive kidney failure and interstitial lung disease. Histopathology of kidney biopsy showing typical lymphoplasmacytic infiltration and fibrosis enriched in IgG4-positive plasma cells, and infiltration of IgG4 + plasma cells with IgG4+/IgG+ plasma cells ratio greater than 40% and a total of ≥ 10 IgG4 + plasma cells per high-power field (HPF) indicated the diagnosis of IgG4-RKD.
Given the elevated MPO-ANCA and CRP, AAV related nephritis was a possible differential diagnosis (Proposed diagnostic criteria for kidney involvement in AAV listed in Table 3 [16]). In this case, pathological findings did not show renal crescentic glomerulonephritis or vasculitis, thus, anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-AAV) was not firstly considered according to the Chapel Hill Consensus Conference nomenclature criteria for AAV [16]; However, Some ANCA positive patients may present with interstitial nephritis without severe glomerulopathy, and whether his initial interstitial lung disease was related to IgG4 or AAV or both was not determined. Some reports suggested a possible pathogenic effect of ANCA-IgG4 [17, 18]. Serum IgG4 increase and IgG4-positive cell infiltration in the organ can also be seen in AAV [19, 20]. Distinguishing between these diseases is essential for treatment planning [20], because IgG4-RD responds well to steroid therapy alone, while AAV often requires concomitant immunosuppressant use. His initial interstitial lung disease was improved (Fig. 1) with prednisone therapy alone for one month favored the diagnosis of IgG4-RLD. Kim et al. [21] described that a steroid trial was useful for differentiating and response to steroid therapy is recommended to be added to the diagnostic criteria. Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ listed in Table 2. Therefore, we preferred his diagnosis of IgG4-RD.
Table 3 Proposed diagnostic criteria for kidney involvement in AAV [16]
clinical manifestations a rapidly progressive GN with a decline in kidney function accompanied by sub–nephrotic-range proteinuria, microscopic hematuria, and hypertension over days to a few months
Serology Anti-MPO antibody or anti-PR3 antibody positive
Pathological findings pauci-immune focal necrotizing crescentic GN
Rare patients with AAV have a prominent tubulointerstitial nephritis, which can be associated with vasculitis of the vasa recta
A diagnosis of AAV incorporates the integration of clinical features, ANCA serology, and tissue pathology as needed
Since kidney involvement was firstly reported in a patient with IgG4-RD in 2004 [22], many similar cases have been described [23–25]. A cross-sectional study reported in 2010 revealed all kidney lesions were associated with extrarenal disease among 114 patients with IgG4-related disease [26]. Several clinicopathologic studies reported IgG4-RD with both kidney and lung involvement [5, 14, 27–30]. In kidney its characteristic manifestation is TIN with multiple extrarenal tissue damage [14, 31], which is easily apparent with a chronic or rapid progressive renal function decline [23]. In lung, this may present as nodules with spiculated margins mimicking primary pulmonary malignancy [28, 32], multiple ground glass opacities (GGO) mimicking interstitial lung disease [14], alveolar interstitial type, and bronchovascular type [33].
However, he developed intermittent fever, acute onset of left pleuritic chest pain and an emerging lung lesion after steroid use for one month. IgG4-RLD has been classified into four categories based on CT. Our case was the GGO type. This also was the primary feature of IPFI [34] of which most common chest CT signs are nodules, consolidation and GGO. This patient had several high-risk factors of IPFI such as old age, long-term use of glucocorticoids, repeated hospitalization, etc. [35]. However,it is difficult to distinguish between IgG4-related lung disease (IgG4-RLD) and IPFI (Table 3). Lung puncture pathology is key standard. Thus, sputum culture and pathogenic examination were repeated and infiltration of IgG4-positive plasma cells was not found. The lung tissue specimen showed fungal spores which supported the diagnosis of IPFI. The differential diagnosis of IgG4-RLD and IPFI were listed in Table 4 [34, 36, 37].
Table 4 Differences between IgG4-RLD and IPFI [34, 36, 37]
Items IgG4-RLD IPFI
Clinical manifestations multi-system injuries dry cough and fever,no specific
Laboratory tests Serum IgG4 elevation CRP and (or) PCT elevation,G/GM positive
Imaging nodules, multiple ground glass opacities (GGO),alveolar interstitial type, and bronchovascular type nodules, consolidation and ground-glass opacity(GGO)
Pathology Mainly IgG4
With plasma cell infiltration and often with interstitial damage
fungal spores with hyphae can be observed, pulmonary fibrosis and inflammatory cell infiltration
Treatment protocol Systemic glucocorticoids anti-infection
Systemic glucocorticoids are recommended as the first-line approach of renal injury in untreated IgG4-RD [31]. A moderate initial dose of oral prednisolone for induction is 0.6 mg/kg daily for 2–4 weeks. The maintenance dose of steroid therapy is given after remission as 2.5-5 mg daily over a period of 2–3 months [2]. However, treatment with exogenous glucocorticoids comes with a number of risks such as avascular necrosis, osteoporosis, glaucoma, cardiovascular disease, worse glucose tolerance and diabetes. The risk of infection is of utmost concern and is well-documented [36, 38]. A Japanese study including 459 AIP patients reported pneumonia occurred in 3 patients treated with steroid [13]. Optimizing the nutritional state of patients, reducing its dose, duration and number of immunosuppressants are recommended to help prevent infection. In the present case, we have to decrease the dosage of immunosuppressive drugs after then, nevertheless, IgG4-RLD were aggravated and renal failure developed during dosage decrease.
Since not every patient can be recover from renal disfunction, maintenance hemodialysis become necessary in patients with irreversible renal failure due to IgG4-RKD [4, 39]. And in this case, the patient experienced a short-time hemodialysis because of azotemia, which partly due to deteriorating renal function, steroids use or (and) infection. Improvements in pulmonary lesions and kidney function were observed after 4 months and were maintained with a dose of 8.0 mg/day prednisone. Thus, the dosage of steroid and immunosuppressant should be reduced for the therapy of the elderly patients with IgG4 related diseases. In addition, it has been reported that relapse of IgG4-related lesions, including kidney damage, occurred in 20% of treated patients with IgG4-RKD during maintenance treatment [39]. Thus, long-term follow-up for this patient are required and a well prognosis is expected.
Taken together, IgG4-RKD is an immune-mediated condition that can affect not only kidney but also several other organs, leading to a dense lymphoplasmacytic infiltration dominant in IgG4-positive plasma cells with fibrosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control (Fig. 6).
Fig. 6 Flow diagram of the patient’s disease progression and treatment
Abbreviations
IgG4-RKDIgG4-related kidney disease
AIPAutoimmune pancreatitis
IgG4-TINIgG4-related tubulointerstitial nephritis
IPFIInvasive pulmonary fungal infection
CTChest computed tomography
uPCRUrine protein: creatine ratio
IgGSerum immunoglobulin G
CTXCyclophosphamide
MPO-ANCAAnti-myeloperoxidase anti-neutrophil cytoplasmic antibody
ANCA-AAVAnti-neutrophil cytoplasmic antibody associated vasculitis
GGOMultiple ground glass opacities
IgG4-RLDIgG4-related lung disease
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the Department of Pathology, Jiangsu province Hospital, for pulmonary pathology.
Authors’ contributions
YLX reviewed the patient’s clinical data, performed the literature search, and wrote the initial draft of the manuscript. YYH and KL assisted in the preparation of the manuscript contributed to data collection and interpretation and critically reviewed the manuscript. JQ, and JFZ provide the pathology of renal biopsy. XFZ performed the immunohistochemical studies. TFY conducted pulmonary puncture and provide the possibility of lung pathology. GY and XQX carried out analysis of patient’s clinical course, outcomes and interpretation of findings, and provided critical review comments for the manuscript. NNW and CYX had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, and provided critical review comments for the manuscript. All authors read and approved the final manuscript.
Funding
The research was financially supported by the National Natural Science Foundation of China (81570666), International Society of Nephrology (ISN) Clinical Research Program (18-01-0247), Jiangsu Province Key Medical Personnel Project (ZDRCA2016002). The funders had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, provided critical review comments and also submission for the manuscript.
Availability of data and materials
The datasets used during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | .4 g (grams). | DrugDosage | CC BY | 33430791 | 18,792,998 | 2021-01-11 |
What was the outcome of reaction 'Chest pain'? | IgG4-related nephritis and interstitial pulmonary disease complicated by invasive pulmonary fungal infection: a case report.
IgG4-related kidney disease (IgG4-RKD) can affect multiple organs, which was first reported as a complication or extra-organ manifestation of autoimmune pancreatitis in 2004. It is characterized by abundant IgG4-positive plasma cells infiltration in tissues involved.
A 69-year-old man presented with cough and renal dysfunction with medical history of hypertension and diabetes. Pathological findings revealed interstitial nephritis and he was initially diagnosed with IgG4-RKD. Prednisone helped the patient to get a remission of cough and an obvious decrease of IgG4 level. However, he developed invasive pulmonary fungal infection while steroid theatment. Anti-fungal therapy was initiated after lung puncture (around cavitary lung lesion). Hemodialysis had been conducted because of renal failure and he got rid of it 2 months later. Methylprednisolone was decreased to 8 mg/day for maintenance therapy. Anti-fungal infection continued for 4 months after discharge home. On the 4th month of follow-up, Chest CT revealed no progression of lung lesions.
The corticosteroids are the first-line therapy of IgG4-RD and a rapid response helps to confirm the diagnosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control.
Background
IgG4-related disease (IgG4-RD) is an inflammatory and fibrotic disease which was first described in the pancreas and was called autoimmune pancreatitis (AIP) in 2001 [1]. Its concept has been recognized worldwide since then that this systemic disease involved multiple organs or tissues characterized by elevated serum IgG4 level and IgG4 positive plasma cells infiltration in the affected tissues, leading to fibrosis eventually [2–6]. The prevalence of IgG4-RD in Japan was estimated as 0.28–1.08/100,000 people in 2012 [7].
IgG4-related tubulointerstitial nephritis (IgG4-TIN), is one of the frequent pathological changes of IgG4-related kidney disease (IgG4-RKD), accounting for about 15–25% of all IgG-RD [4, 8]. IgG4-related TIN shows a range of histologic appearances including (A) acute interstitial nephritis with minimal fibrosis; (B) a more cellular inflammatory pattern in the setting of expansile fibrosis; and (C) a very fibrotic, pauci-cellular pattern [7]. The diagnosis criteria of IgG4-RKD were proposed by the Japanese Society of Nephrology [9] and a work group of North America [7], respectively. IgG4-related kidney lesions were often associated with extrarenal disease, such as chronic sclerosing inflammation of the lacrimal gland, salivary gland [10] and lung [11].
Patients with IgG4-RKD have an increased risk of infection than general population. IgG4-TIN can be accompanied by eosinophilic lung disease [12] and pneumonia [13]. Here, we present a case of IgG4-RKD and lung interstitial lesions who developed invasive pulmonary fungal infection (IPFI) during treatment of glucocorticoid combined with immunosuppressive agents.
Case presentation
A 69-year-old male was admitted to the hospital in 2019 January 5th because of gradually aggravated edema and cough. His medical history included hypertension, arrhythmia and diabetes. On 2019 May 8th, he had experienced cough and phlegm with temperature around 38 ~ 39 °C. Laboratory tests were presented in Table 1. 18F-FDG-PET/CT showed interstitial pneumonia in both lungs. There was also elevated uptake abnormality in the upper kidney observed. Cefperazone-Sulbactam, doxycycline hydrochloride, imipenem, and linezolid were given. Because of no improvement, he took oral prednisone 24 mg per day. The body temperature recovered to normal and lower limb edema was alleviated after one week. On 2019 June 13th ,serum creatinine 157.7 umol/L (Fig. 1); and serum albumin, 24.9 g/L. Chest computed tomography (CT) scan showed that honeycomb-like changes considering interstitial inflammation and bilateral pleural effusion (Fig. 1A).
Table 1 Laboratory data performed before and after treatment
ITEMS Beforetherapy Steroidtherapyfor 1month Steroid therapy for2 months Steroid therapy for3 months Steroid therapy for4 months
White blood cell count(*10^9/L) 15.4 21.11 8.24 11.66 13.28
Hemoglobin(g/L) 129 108 84 98 101
Platelet count(*10^9/L) 323 285 100 273 176
C-reaction protein (CRP)(mg/L) 90 58.1 32 79.8 18.9
Erythrocyte sedimentation rate(mm/H) 120 60 / / /
Serum nitrogen (mmol/L) 10.2 24.71 24.18 30.33 14.5
Serum creatinine (umol/L) 64.6 232.8 212.4 187.2 100.7
Serum albumin(g/L) 24.2 32 30 27.6 21.2
Urine RBC(/ul) / 42.6 10.9 3
Urine protein creatine ratio(mg/g) 48.5
24 h urine protein (g) 0.721 0.62 0.61 0.45 0.49
ANCA-MPO (RU/ml) 35.1 12.7 8.6
ANCA-PR3 (RU/ml) 6.7 4.9 4.7
CD4+ / CD8 + lymphocyte 0.81 / / / 1.9
ABG Before therapy Steroid therapy for 2 months
PH 7.201 7.498
PCO2(mmHg) 20 31.6
PO2(mmHg) 117 49
SpO2 (%) 98 88
K(mmol/L) 5.4 4.1
HCO3-(mmol/L) 7.8 24.5
BE(mmol/L) -20 1
ANCA-MPO Myeloperoxidase-antineutrophil cytoplasmic antibody, ANCA-PR3 proteinase 3, ABG Arterial Blood Gas, / not available
Fig. 1 Chest CT showed interstitial inflammation and bilateral pleural effusion before therapy (a). After glucocorticoids admission, obvious absorption of interstitial inflammation and pleural effusion on both sides were found (b). Infection of both lungs with a left lower lobe cavity before anti-infection therapy (c). After anti-infection therapy, no increase boarder of lung lesions (d)
He went to Nephrology Department on 2019 July 2nd for further treatment. Laboratory results were presented in Table 1. Urine RBC 42.6/ul; Urine protein: creatine ratio (uPCR) 48.5 mg/g; Serum IgG4 level was elevated at 3.42 g/L (Normal range: 0.03–2.10 g/L). Anti-myeloperoxidase anti-neutrophil cytoplasmic antibody level was elevated at 35.1Ru/ml (Normal range:<20 Ru/ml). However, serum immunoglobulin A(IgA), IgG and IgM level were normal. Furthermore, the patient was negative for anti-double-stranded antibody, antinuclear antibody, anti-Sjogren’s syndrome A antibody, anti-Sjogren’s syndrome B antibody and anti-proteinase 3. Ultrasound displayed large-sized kidneys with uniform echo frequency and clear corticomedullary boundaries. Chest CT revealed obvious absorption of interstitial inflammation and pleural effusion on both sides, there were also multiple nodules in both lungs (Fig. 1b).
Histopathology of the kidney biopsy shows proliferation of glomerular mesangial cells, diffuse and irregular thickening of basement membrane (Fig. 2a). The tubulointerstitium shows marked injury. Patchy foci fibrosis and inflammatory cells infiltration were prominent in the interstitium (Fig. 2b, c). Immunofluorescence staining shows that IgG, IgM, IgA, C1q, C3 and C4 were negative in the granular mesangial area. Immunohistological analysis revealed numerous CD20-positive B cells ((D), × 400) and dense infiltration of CD138-positive plasma cells ((E), × 400), with an IgG4+/IgG+ plasma cell ratio being > 40% ((F), × 400). Electron microscopy demonstrated that there were no electron-dense deposits in the glomeruli (Fig. 3).
Fig. 2 Renal histopathological result showed almost normal glomeruli, massively infiltrating cells, and abundant interstitial fibrosis under the light microscopy. a The glomerulus showed glomerular mesangial cells proliferation and diffuse and irregular thickening of basement membrane (HE staining, × 200). b, c A mass of plasma cells and fibrotic fibers (HE staining, × 400) can be observed in the interstitium. d, e Immunohistological analysis revealed mostly CD20-positive B cells (× 400) and CD138-positive plasma cells (× 400) in the interstitium. f Immunohistochemistry for IgG4 shows abundant positive plasma cells (coloured brown) (× 400)
Fig. 3 No electron-dense deposits are observed under electron microscopy. a Abundant plasma cells (× 2000) infiltrated in renal interstitium. b Detachment and partial atrophy of the microvilli of renal tubular epithelial cells as well as edema, infiltration of lymphocytes/monocytes, and fibrosis in renal interstitium. There are no electron-dense deposits in the glomeruli (× 2000). c Proliferation of glomerular mesangial cells and interstitial cells (× 2000). d Diffuse and irregular thickening of basement membrane (× 12,000)
Based on these findings, he had been diagnosed as IgG4-related renal disease. Oral prednisone (40 mg/day) and cyclophosphamide (CTX, 0.4 g) were prescribed by intravenous infusion. The patient had been followed up every month after the treatment (Table 1). He presented with intermittent fever for more than 20 days and acute onset of left pleuritic chest pain with dry cough for 10 days. Negative results were found in aerobic or anaerobic blood culture. Chest CT showed recent infection of both lungs with left upper lung cavity (Fig. 1c). At June 28th he developed hemoptysis and type 1 respiratory failure (Table 2). The results of relevant tests are shown in Table 1. In order to differentiate between IgG4-RLD and IPFI, left upper lung puncture was conducted and showed that interstitial collagen fibrosis with acute and chronic inflammatory cell infiltration, focal fibrous necrosis and exudation, and small alveolar cell response. Fungal spores were also found in lung puncture specimen. Filamentous fungi can be seen in sputum culture. Immunohistochemistry test revealed that most plasma cells in the lung interstitium were positive for CD38 (+), CD138 (+), IgG (+) (Fig. 4). IgG positive plasma cells < 40%, IgG4 positive plasma cells < 10/HPF, which does not meet the pathological diagnostic criteria of IgG4 related diseases. The diagnosis of IPFI was definite. After then, the patient was initiated on voriconazole and caspofungin to anti-fungal infection, and prednisolone was decreased to 30 mg per day.
Table 2 Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ [2, 14, 15]
Criterion
Histology (i)The specimen pathology shows the dense lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis, the infiltration of IgG4-positive cells, and IgG cells more than IgG4 cells ratio of 40%;
Imaging (ii)clinical/radiological examination showing characteristic diffuse or localized swelling or masses in single or multiple organs;
Serology (iii) serum IgG4 concentration > 135 mg/dL;
(iv)Inflammatory markers such as white blood cells count and C-reactive protein concentrations are not elevated, despite the degree of lesions, their spread on imaging analysis and massive cellular infiltration on pathological examination;
Other organ involvement (v)Characteristic findings of IgG4-RD in other organs, including autoimmune pancreatitis, lung involvement, et al.
Treatment (vi)response to steroids.
All 3 criteria (i + ii + iii) are needed for definite diagnosis of IgG4-RD
Fig. 4 Histopathological findings of the pulmonary tissue (light microscopy: HE). a Pulmonary tissue shows fibrotic changes of the interstitium (× 100) in the lung. b Cell and tissue reactions and cellulosic exudation were observed in alveoli (× 200). c, d Giant cell, interstitial edema, collagen fiber hyperplasia and masson body were observed in the specimen (× 200). e, f Immunohistological analysis revealed CD38-positive plasmacyte (coloured brown) (E × 400) and CD138-positive plasmacyte (coloured brown) infiltration (F × 400). g IgG immunostaining shows IgG-positive plasmacyte (coloured brown) infiltration (× 400). h IgG4 immunostaining shows IgG4-positive plasmacyte (coloured brown) infiltration in the lung (× 400)
With anti-infection and immunosuppressive treatment for 2 weeks, serum CRP and IgG4 level had been considerably decreased to 2.94 mg/L and 1.57 g/L, respectively. Voriconazole 200 mg bid and Methylprednisolone 30 mg/day were continued after discharge home. After treatment for one month, a repeat CT scan showed no progression of lung lesions (Fig. 1D). CD4+/CD8+ lymphocyte: 1.9. The patient had been followed up for 4 months. In the most recent follow-up examination, the serum creatinine level decreased to 101 umol/L and he got rid of hemodialysis (Fig. 5). He is currently undergoing tapered prednisolone treatment.
Fig. 5 Dynamic changes of renal function before and after treatment in the patient with IgG4-RKD
Discussion and conclusions
This patient is characterized by serum IgG4 elevation, positive MPO-ANCA, which suggested the possibility of co-occurrence/concurrence of AAV and IgG4‐RD on his first visit from his serological presentation. Diagnosis of IgG4-RD requires particular pathological, serological and clinical features [2, 14, 15] (listed in Table 2). This patient presented with serum IgG4 elevation, hematuria, proteinuria, elevated uptake abnormality of the upper kidney observed in 18F-FDG-PET/CT, progressive kidney failure and interstitial lung disease. Histopathology of kidney biopsy showing typical lymphoplasmacytic infiltration and fibrosis enriched in IgG4-positive plasma cells, and infiltration of IgG4 + plasma cells with IgG4+/IgG+ plasma cells ratio greater than 40% and a total of ≥ 10 IgG4 + plasma cells per high-power field (HPF) indicated the diagnosis of IgG4-RKD.
Given the elevated MPO-ANCA and CRP, AAV related nephritis was a possible differential diagnosis (Proposed diagnostic criteria for kidney involvement in AAV listed in Table 3 [16]). In this case, pathological findings did not show renal crescentic glomerulonephritis or vasculitis, thus, anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-AAV) was not firstly considered according to the Chapel Hill Consensus Conference nomenclature criteria for AAV [16]; However, Some ANCA positive patients may present with interstitial nephritis without severe glomerulopathy, and whether his initial interstitial lung disease was related to IgG4 or AAV or both was not determined. Some reports suggested a possible pathogenic effect of ANCA-IgG4 [17, 18]. Serum IgG4 increase and IgG4-positive cell infiltration in the organ can also be seen in AAV [19, 20]. Distinguishing between these diseases is essential for treatment planning [20], because IgG4-RD responds well to steroid therapy alone, while AAV often requires concomitant immunosuppressant use. His initial interstitial lung disease was improved (Fig. 1) with prednisone therapy alone for one month favored the diagnosis of IgG4-RLD. Kim et al. [21] described that a steroid trial was useful for differentiating and response to steroid therapy is recommended to be added to the diagnostic criteria. Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ listed in Table 2. Therefore, we preferred his diagnosis of IgG4-RD.
Table 3 Proposed diagnostic criteria for kidney involvement in AAV [16]
clinical manifestations a rapidly progressive GN with a decline in kidney function accompanied by sub–nephrotic-range proteinuria, microscopic hematuria, and hypertension over days to a few months
Serology Anti-MPO antibody or anti-PR3 antibody positive
Pathological findings pauci-immune focal necrotizing crescentic GN
Rare patients with AAV have a prominent tubulointerstitial nephritis, which can be associated with vasculitis of the vasa recta
A diagnosis of AAV incorporates the integration of clinical features, ANCA serology, and tissue pathology as needed
Since kidney involvement was firstly reported in a patient with IgG4-RD in 2004 [22], many similar cases have been described [23–25]. A cross-sectional study reported in 2010 revealed all kidney lesions were associated with extrarenal disease among 114 patients with IgG4-related disease [26]. Several clinicopathologic studies reported IgG4-RD with both kidney and lung involvement [5, 14, 27–30]. In kidney its characteristic manifestation is TIN with multiple extrarenal tissue damage [14, 31], which is easily apparent with a chronic or rapid progressive renal function decline [23]. In lung, this may present as nodules with spiculated margins mimicking primary pulmonary malignancy [28, 32], multiple ground glass opacities (GGO) mimicking interstitial lung disease [14], alveolar interstitial type, and bronchovascular type [33].
However, he developed intermittent fever, acute onset of left pleuritic chest pain and an emerging lung lesion after steroid use for one month. IgG4-RLD has been classified into four categories based on CT. Our case was the GGO type. This also was the primary feature of IPFI [34] of which most common chest CT signs are nodules, consolidation and GGO. This patient had several high-risk factors of IPFI such as old age, long-term use of glucocorticoids, repeated hospitalization, etc. [35]. However,it is difficult to distinguish between IgG4-related lung disease (IgG4-RLD) and IPFI (Table 3). Lung puncture pathology is key standard. Thus, sputum culture and pathogenic examination were repeated and infiltration of IgG4-positive plasma cells was not found. The lung tissue specimen showed fungal spores which supported the diagnosis of IPFI. The differential diagnosis of IgG4-RLD and IPFI were listed in Table 4 [34, 36, 37].
Table 4 Differences between IgG4-RLD and IPFI [34, 36, 37]
Items IgG4-RLD IPFI
Clinical manifestations multi-system injuries dry cough and fever,no specific
Laboratory tests Serum IgG4 elevation CRP and (or) PCT elevation,G/GM positive
Imaging nodules, multiple ground glass opacities (GGO),alveolar interstitial type, and bronchovascular type nodules, consolidation and ground-glass opacity(GGO)
Pathology Mainly IgG4
With plasma cell infiltration and often with interstitial damage
fungal spores with hyphae can be observed, pulmonary fibrosis and inflammatory cell infiltration
Treatment protocol Systemic glucocorticoids anti-infection
Systemic glucocorticoids are recommended as the first-line approach of renal injury in untreated IgG4-RD [31]. A moderate initial dose of oral prednisolone for induction is 0.6 mg/kg daily for 2–4 weeks. The maintenance dose of steroid therapy is given after remission as 2.5-5 mg daily over a period of 2–3 months [2]. However, treatment with exogenous glucocorticoids comes with a number of risks such as avascular necrosis, osteoporosis, glaucoma, cardiovascular disease, worse glucose tolerance and diabetes. The risk of infection is of utmost concern and is well-documented [36, 38]. A Japanese study including 459 AIP patients reported pneumonia occurred in 3 patients treated with steroid [13]. Optimizing the nutritional state of patients, reducing its dose, duration and number of immunosuppressants are recommended to help prevent infection. In the present case, we have to decrease the dosage of immunosuppressive drugs after then, nevertheless, IgG4-RLD were aggravated and renal failure developed during dosage decrease.
Since not every patient can be recover from renal disfunction, maintenance hemodialysis become necessary in patients with irreversible renal failure due to IgG4-RKD [4, 39]. And in this case, the patient experienced a short-time hemodialysis because of azotemia, which partly due to deteriorating renal function, steroids use or (and) infection. Improvements in pulmonary lesions and kidney function were observed after 4 months and were maintained with a dose of 8.0 mg/day prednisone. Thus, the dosage of steroid and immunosuppressant should be reduced for the therapy of the elderly patients with IgG4 related diseases. In addition, it has been reported that relapse of IgG4-related lesions, including kidney damage, occurred in 20% of treated patients with IgG4-RKD during maintenance treatment [39]. Thus, long-term follow-up for this patient are required and a well prognosis is expected.
Taken together, IgG4-RKD is an immune-mediated condition that can affect not only kidney but also several other organs, leading to a dense lymphoplasmacytic infiltration dominant in IgG4-positive plasma cells with fibrosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control (Fig. 6).
Fig. 6 Flow diagram of the patient’s disease progression and treatment
Abbreviations
IgG4-RKDIgG4-related kidney disease
AIPAutoimmune pancreatitis
IgG4-TINIgG4-related tubulointerstitial nephritis
IPFIInvasive pulmonary fungal infection
CTChest computed tomography
uPCRUrine protein: creatine ratio
IgGSerum immunoglobulin G
CTXCyclophosphamide
MPO-ANCAAnti-myeloperoxidase anti-neutrophil cytoplasmic antibody
ANCA-AAVAnti-neutrophil cytoplasmic antibody associated vasculitis
GGOMultiple ground glass opacities
IgG4-RLDIgG4-related lung disease
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the Department of Pathology, Jiangsu province Hospital, for pulmonary pathology.
Authors’ contributions
YLX reviewed the patient’s clinical data, performed the literature search, and wrote the initial draft of the manuscript. YYH and KL assisted in the preparation of the manuscript contributed to data collection and interpretation and critically reviewed the manuscript. JQ, and JFZ provide the pathology of renal biopsy. XFZ performed the immunohistochemical studies. TFY conducted pulmonary puncture and provide the possibility of lung pathology. GY and XQX carried out analysis of patient’s clinical course, outcomes and interpretation of findings, and provided critical review comments for the manuscript. NNW and CYX had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, and provided critical review comments for the manuscript. All authors read and approved the final manuscript.
Funding
The research was financially supported by the National Natural Science Foundation of China (81570666), International Society of Nephrology (ISN) Clinical Research Program (18-01-0247), Jiangsu Province Key Medical Personnel Project (ZDRCA2016002). The funders had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, provided critical review comments and also submission for the manuscript.
Availability of data and materials
The datasets used during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33430791 | 18,792,998 | 2021-01-11 |
What was the outcome of reaction 'Haemoptysis'? | IgG4-related nephritis and interstitial pulmonary disease complicated by invasive pulmonary fungal infection: a case report.
IgG4-related kidney disease (IgG4-RKD) can affect multiple organs, which was first reported as a complication or extra-organ manifestation of autoimmune pancreatitis in 2004. It is characterized by abundant IgG4-positive plasma cells infiltration in tissues involved.
A 69-year-old man presented with cough and renal dysfunction with medical history of hypertension and diabetes. Pathological findings revealed interstitial nephritis and he was initially diagnosed with IgG4-RKD. Prednisone helped the patient to get a remission of cough and an obvious decrease of IgG4 level. However, he developed invasive pulmonary fungal infection while steroid theatment. Anti-fungal therapy was initiated after lung puncture (around cavitary lung lesion). Hemodialysis had been conducted because of renal failure and he got rid of it 2 months later. Methylprednisolone was decreased to 8 mg/day for maintenance therapy. Anti-fungal infection continued for 4 months after discharge home. On the 4th month of follow-up, Chest CT revealed no progression of lung lesions.
The corticosteroids are the first-line therapy of IgG4-RD and a rapid response helps to confirm the diagnosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control.
Background
IgG4-related disease (IgG4-RD) is an inflammatory and fibrotic disease which was first described in the pancreas and was called autoimmune pancreatitis (AIP) in 2001 [1]. Its concept has been recognized worldwide since then that this systemic disease involved multiple organs or tissues characterized by elevated serum IgG4 level and IgG4 positive plasma cells infiltration in the affected tissues, leading to fibrosis eventually [2–6]. The prevalence of IgG4-RD in Japan was estimated as 0.28–1.08/100,000 people in 2012 [7].
IgG4-related tubulointerstitial nephritis (IgG4-TIN), is one of the frequent pathological changes of IgG4-related kidney disease (IgG4-RKD), accounting for about 15–25% of all IgG-RD [4, 8]. IgG4-related TIN shows a range of histologic appearances including (A) acute interstitial nephritis with minimal fibrosis; (B) a more cellular inflammatory pattern in the setting of expansile fibrosis; and (C) a very fibrotic, pauci-cellular pattern [7]. The diagnosis criteria of IgG4-RKD were proposed by the Japanese Society of Nephrology [9] and a work group of North America [7], respectively. IgG4-related kidney lesions were often associated with extrarenal disease, such as chronic sclerosing inflammation of the lacrimal gland, salivary gland [10] and lung [11].
Patients with IgG4-RKD have an increased risk of infection than general population. IgG4-TIN can be accompanied by eosinophilic lung disease [12] and pneumonia [13]. Here, we present a case of IgG4-RKD and lung interstitial lesions who developed invasive pulmonary fungal infection (IPFI) during treatment of glucocorticoid combined with immunosuppressive agents.
Case presentation
A 69-year-old male was admitted to the hospital in 2019 January 5th because of gradually aggravated edema and cough. His medical history included hypertension, arrhythmia and diabetes. On 2019 May 8th, he had experienced cough and phlegm with temperature around 38 ~ 39 °C. Laboratory tests were presented in Table 1. 18F-FDG-PET/CT showed interstitial pneumonia in both lungs. There was also elevated uptake abnormality in the upper kidney observed. Cefperazone-Sulbactam, doxycycline hydrochloride, imipenem, and linezolid were given. Because of no improvement, he took oral prednisone 24 mg per day. The body temperature recovered to normal and lower limb edema was alleviated after one week. On 2019 June 13th ,serum creatinine 157.7 umol/L (Fig. 1); and serum albumin, 24.9 g/L. Chest computed tomography (CT) scan showed that honeycomb-like changes considering interstitial inflammation and bilateral pleural effusion (Fig. 1A).
Table 1 Laboratory data performed before and after treatment
ITEMS Beforetherapy Steroidtherapyfor 1month Steroid therapy for2 months Steroid therapy for3 months Steroid therapy for4 months
White blood cell count(*10^9/L) 15.4 21.11 8.24 11.66 13.28
Hemoglobin(g/L) 129 108 84 98 101
Platelet count(*10^9/L) 323 285 100 273 176
C-reaction protein (CRP)(mg/L) 90 58.1 32 79.8 18.9
Erythrocyte sedimentation rate(mm/H) 120 60 / / /
Serum nitrogen (mmol/L) 10.2 24.71 24.18 30.33 14.5
Serum creatinine (umol/L) 64.6 232.8 212.4 187.2 100.7
Serum albumin(g/L) 24.2 32 30 27.6 21.2
Urine RBC(/ul) / 42.6 10.9 3
Urine protein creatine ratio(mg/g) 48.5
24 h urine protein (g) 0.721 0.62 0.61 0.45 0.49
ANCA-MPO (RU/ml) 35.1 12.7 8.6
ANCA-PR3 (RU/ml) 6.7 4.9 4.7
CD4+ / CD8 + lymphocyte 0.81 / / / 1.9
ABG Before therapy Steroid therapy for 2 months
PH 7.201 7.498
PCO2(mmHg) 20 31.6
PO2(mmHg) 117 49
SpO2 (%) 98 88
K(mmol/L) 5.4 4.1
HCO3-(mmol/L) 7.8 24.5
BE(mmol/L) -20 1
ANCA-MPO Myeloperoxidase-antineutrophil cytoplasmic antibody, ANCA-PR3 proteinase 3, ABG Arterial Blood Gas, / not available
Fig. 1 Chest CT showed interstitial inflammation and bilateral pleural effusion before therapy (a). After glucocorticoids admission, obvious absorption of interstitial inflammation and pleural effusion on both sides were found (b). Infection of both lungs with a left lower lobe cavity before anti-infection therapy (c). After anti-infection therapy, no increase boarder of lung lesions (d)
He went to Nephrology Department on 2019 July 2nd for further treatment. Laboratory results were presented in Table 1. Urine RBC 42.6/ul; Urine protein: creatine ratio (uPCR) 48.5 mg/g; Serum IgG4 level was elevated at 3.42 g/L (Normal range: 0.03–2.10 g/L). Anti-myeloperoxidase anti-neutrophil cytoplasmic antibody level was elevated at 35.1Ru/ml (Normal range:<20 Ru/ml). However, serum immunoglobulin A(IgA), IgG and IgM level were normal. Furthermore, the patient was negative for anti-double-stranded antibody, antinuclear antibody, anti-Sjogren’s syndrome A antibody, anti-Sjogren’s syndrome B antibody and anti-proteinase 3. Ultrasound displayed large-sized kidneys with uniform echo frequency and clear corticomedullary boundaries. Chest CT revealed obvious absorption of interstitial inflammation and pleural effusion on both sides, there were also multiple nodules in both lungs (Fig. 1b).
Histopathology of the kidney biopsy shows proliferation of glomerular mesangial cells, diffuse and irregular thickening of basement membrane (Fig. 2a). The tubulointerstitium shows marked injury. Patchy foci fibrosis and inflammatory cells infiltration were prominent in the interstitium (Fig. 2b, c). Immunofluorescence staining shows that IgG, IgM, IgA, C1q, C3 and C4 were negative in the granular mesangial area. Immunohistological analysis revealed numerous CD20-positive B cells ((D), × 400) and dense infiltration of CD138-positive plasma cells ((E), × 400), with an IgG4+/IgG+ plasma cell ratio being > 40% ((F), × 400). Electron microscopy demonstrated that there were no electron-dense deposits in the glomeruli (Fig. 3).
Fig. 2 Renal histopathological result showed almost normal glomeruli, massively infiltrating cells, and abundant interstitial fibrosis under the light microscopy. a The glomerulus showed glomerular mesangial cells proliferation and diffuse and irregular thickening of basement membrane (HE staining, × 200). b, c A mass of plasma cells and fibrotic fibers (HE staining, × 400) can be observed in the interstitium. d, e Immunohistological analysis revealed mostly CD20-positive B cells (× 400) and CD138-positive plasma cells (× 400) in the interstitium. f Immunohistochemistry for IgG4 shows abundant positive plasma cells (coloured brown) (× 400)
Fig. 3 No electron-dense deposits are observed under electron microscopy. a Abundant plasma cells (× 2000) infiltrated in renal interstitium. b Detachment and partial atrophy of the microvilli of renal tubular epithelial cells as well as edema, infiltration of lymphocytes/monocytes, and fibrosis in renal interstitium. There are no electron-dense deposits in the glomeruli (× 2000). c Proliferation of glomerular mesangial cells and interstitial cells (× 2000). d Diffuse and irregular thickening of basement membrane (× 12,000)
Based on these findings, he had been diagnosed as IgG4-related renal disease. Oral prednisone (40 mg/day) and cyclophosphamide (CTX, 0.4 g) were prescribed by intravenous infusion. The patient had been followed up every month after the treatment (Table 1). He presented with intermittent fever for more than 20 days and acute onset of left pleuritic chest pain with dry cough for 10 days. Negative results were found in aerobic or anaerobic blood culture. Chest CT showed recent infection of both lungs with left upper lung cavity (Fig. 1c). At June 28th he developed hemoptysis and type 1 respiratory failure (Table 2). The results of relevant tests are shown in Table 1. In order to differentiate between IgG4-RLD and IPFI, left upper lung puncture was conducted and showed that interstitial collagen fibrosis with acute and chronic inflammatory cell infiltration, focal fibrous necrosis and exudation, and small alveolar cell response. Fungal spores were also found in lung puncture specimen. Filamentous fungi can be seen in sputum culture. Immunohistochemistry test revealed that most plasma cells in the lung interstitium were positive for CD38 (+), CD138 (+), IgG (+) (Fig. 4). IgG positive plasma cells < 40%, IgG4 positive plasma cells < 10/HPF, which does not meet the pathological diagnostic criteria of IgG4 related diseases. The diagnosis of IPFI was definite. After then, the patient was initiated on voriconazole and caspofungin to anti-fungal infection, and prednisolone was decreased to 30 mg per day.
Table 2 Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ [2, 14, 15]
Criterion
Histology (i)The specimen pathology shows the dense lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis, the infiltration of IgG4-positive cells, and IgG cells more than IgG4 cells ratio of 40%;
Imaging (ii)clinical/radiological examination showing characteristic diffuse or localized swelling or masses in single or multiple organs;
Serology (iii) serum IgG4 concentration > 135 mg/dL;
(iv)Inflammatory markers such as white blood cells count and C-reactive protein concentrations are not elevated, despite the degree of lesions, their spread on imaging analysis and massive cellular infiltration on pathological examination;
Other organ involvement (v)Characteristic findings of IgG4-RD in other organs, including autoimmune pancreatitis, lung involvement, et al.
Treatment (vi)response to steroids.
All 3 criteria (i + ii + iii) are needed for definite diagnosis of IgG4-RD
Fig. 4 Histopathological findings of the pulmonary tissue (light microscopy: HE). a Pulmonary tissue shows fibrotic changes of the interstitium (× 100) in the lung. b Cell and tissue reactions and cellulosic exudation were observed in alveoli (× 200). c, d Giant cell, interstitial edema, collagen fiber hyperplasia and masson body were observed in the specimen (× 200). e, f Immunohistological analysis revealed CD38-positive plasmacyte (coloured brown) (E × 400) and CD138-positive plasmacyte (coloured brown) infiltration (F × 400). g IgG immunostaining shows IgG-positive plasmacyte (coloured brown) infiltration (× 400). h IgG4 immunostaining shows IgG4-positive plasmacyte (coloured brown) infiltration in the lung (× 400)
With anti-infection and immunosuppressive treatment for 2 weeks, serum CRP and IgG4 level had been considerably decreased to 2.94 mg/L and 1.57 g/L, respectively. Voriconazole 200 mg bid and Methylprednisolone 30 mg/day were continued after discharge home. After treatment for one month, a repeat CT scan showed no progression of lung lesions (Fig. 1D). CD4+/CD8+ lymphocyte: 1.9. The patient had been followed up for 4 months. In the most recent follow-up examination, the serum creatinine level decreased to 101 umol/L and he got rid of hemodialysis (Fig. 5). He is currently undergoing tapered prednisolone treatment.
Fig. 5 Dynamic changes of renal function before and after treatment in the patient with IgG4-RKD
Discussion and conclusions
This patient is characterized by serum IgG4 elevation, positive MPO-ANCA, which suggested the possibility of co-occurrence/concurrence of AAV and IgG4‐RD on his first visit from his serological presentation. Diagnosis of IgG4-RD requires particular pathological, serological and clinical features [2, 14, 15] (listed in Table 2). This patient presented with serum IgG4 elevation, hematuria, proteinuria, elevated uptake abnormality of the upper kidney observed in 18F-FDG-PET/CT, progressive kidney failure and interstitial lung disease. Histopathology of kidney biopsy showing typical lymphoplasmacytic infiltration and fibrosis enriched in IgG4-positive plasma cells, and infiltration of IgG4 + plasma cells with IgG4+/IgG+ plasma cells ratio greater than 40% and a total of ≥ 10 IgG4 + plasma cells per high-power field (HPF) indicated the diagnosis of IgG4-RKD.
Given the elevated MPO-ANCA and CRP, AAV related nephritis was a possible differential diagnosis (Proposed diagnostic criteria for kidney involvement in AAV listed in Table 3 [16]). In this case, pathological findings did not show renal crescentic glomerulonephritis or vasculitis, thus, anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-AAV) was not firstly considered according to the Chapel Hill Consensus Conference nomenclature criteria for AAV [16]; However, Some ANCA positive patients may present with interstitial nephritis without severe glomerulopathy, and whether his initial interstitial lung disease was related to IgG4 or AAV or both was not determined. Some reports suggested a possible pathogenic effect of ANCA-IgG4 [17, 18]. Serum IgG4 increase and IgG4-positive cell infiltration in the organ can also be seen in AAV [19, 20]. Distinguishing between these diseases is essential for treatment planning [20], because IgG4-RD responds well to steroid therapy alone, while AAV often requires concomitant immunosuppressant use. His initial interstitial lung disease was improved (Fig. 1) with prednisone therapy alone for one month favored the diagnosis of IgG4-RLD. Kim et al. [21] described that a steroid trial was useful for differentiating and response to steroid therapy is recommended to be added to the diagnostic criteria. Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ listed in Table 2. Therefore, we preferred his diagnosis of IgG4-RD.
Table 3 Proposed diagnostic criteria for kidney involvement in AAV [16]
clinical manifestations a rapidly progressive GN with a decline in kidney function accompanied by sub–nephrotic-range proteinuria, microscopic hematuria, and hypertension over days to a few months
Serology Anti-MPO antibody or anti-PR3 antibody positive
Pathological findings pauci-immune focal necrotizing crescentic GN
Rare patients with AAV have a prominent tubulointerstitial nephritis, which can be associated with vasculitis of the vasa recta
A diagnosis of AAV incorporates the integration of clinical features, ANCA serology, and tissue pathology as needed
Since kidney involvement was firstly reported in a patient with IgG4-RD in 2004 [22], many similar cases have been described [23–25]. A cross-sectional study reported in 2010 revealed all kidney lesions were associated with extrarenal disease among 114 patients with IgG4-related disease [26]. Several clinicopathologic studies reported IgG4-RD with both kidney and lung involvement [5, 14, 27–30]. In kidney its characteristic manifestation is TIN with multiple extrarenal tissue damage [14, 31], which is easily apparent with a chronic or rapid progressive renal function decline [23]. In lung, this may present as nodules with spiculated margins mimicking primary pulmonary malignancy [28, 32], multiple ground glass opacities (GGO) mimicking interstitial lung disease [14], alveolar interstitial type, and bronchovascular type [33].
However, he developed intermittent fever, acute onset of left pleuritic chest pain and an emerging lung lesion after steroid use for one month. IgG4-RLD has been classified into four categories based on CT. Our case was the GGO type. This also was the primary feature of IPFI [34] of which most common chest CT signs are nodules, consolidation and GGO. This patient had several high-risk factors of IPFI such as old age, long-term use of glucocorticoids, repeated hospitalization, etc. [35]. However,it is difficult to distinguish between IgG4-related lung disease (IgG4-RLD) and IPFI (Table 3). Lung puncture pathology is key standard. Thus, sputum culture and pathogenic examination were repeated and infiltration of IgG4-positive plasma cells was not found. The lung tissue specimen showed fungal spores which supported the diagnosis of IPFI. The differential diagnosis of IgG4-RLD and IPFI were listed in Table 4 [34, 36, 37].
Table 4 Differences between IgG4-RLD and IPFI [34, 36, 37]
Items IgG4-RLD IPFI
Clinical manifestations multi-system injuries dry cough and fever,no specific
Laboratory tests Serum IgG4 elevation CRP and (or) PCT elevation,G/GM positive
Imaging nodules, multiple ground glass opacities (GGO),alveolar interstitial type, and bronchovascular type nodules, consolidation and ground-glass opacity(GGO)
Pathology Mainly IgG4
With plasma cell infiltration and often with interstitial damage
fungal spores with hyphae can be observed, pulmonary fibrosis and inflammatory cell infiltration
Treatment protocol Systemic glucocorticoids anti-infection
Systemic glucocorticoids are recommended as the first-line approach of renal injury in untreated IgG4-RD [31]. A moderate initial dose of oral prednisolone for induction is 0.6 mg/kg daily for 2–4 weeks. The maintenance dose of steroid therapy is given after remission as 2.5-5 mg daily over a period of 2–3 months [2]. However, treatment with exogenous glucocorticoids comes with a number of risks such as avascular necrosis, osteoporosis, glaucoma, cardiovascular disease, worse glucose tolerance and diabetes. The risk of infection is of utmost concern and is well-documented [36, 38]. A Japanese study including 459 AIP patients reported pneumonia occurred in 3 patients treated with steroid [13]. Optimizing the nutritional state of patients, reducing its dose, duration and number of immunosuppressants are recommended to help prevent infection. In the present case, we have to decrease the dosage of immunosuppressive drugs after then, nevertheless, IgG4-RLD were aggravated and renal failure developed during dosage decrease.
Since not every patient can be recover from renal disfunction, maintenance hemodialysis become necessary in patients with irreversible renal failure due to IgG4-RKD [4, 39]. And in this case, the patient experienced a short-time hemodialysis because of azotemia, which partly due to deteriorating renal function, steroids use or (and) infection. Improvements in pulmonary lesions and kidney function were observed after 4 months and were maintained with a dose of 8.0 mg/day prednisone. Thus, the dosage of steroid and immunosuppressant should be reduced for the therapy of the elderly patients with IgG4 related diseases. In addition, it has been reported that relapse of IgG4-related lesions, including kidney damage, occurred in 20% of treated patients with IgG4-RKD during maintenance treatment [39]. Thus, long-term follow-up for this patient are required and a well prognosis is expected.
Taken together, IgG4-RKD is an immune-mediated condition that can affect not only kidney but also several other organs, leading to a dense lymphoplasmacytic infiltration dominant in IgG4-positive plasma cells with fibrosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control (Fig. 6).
Fig. 6 Flow diagram of the patient’s disease progression and treatment
Abbreviations
IgG4-RKDIgG4-related kidney disease
AIPAutoimmune pancreatitis
IgG4-TINIgG4-related tubulointerstitial nephritis
IPFIInvasive pulmonary fungal infection
CTChest computed tomography
uPCRUrine protein: creatine ratio
IgGSerum immunoglobulin G
CTXCyclophosphamide
MPO-ANCAAnti-myeloperoxidase anti-neutrophil cytoplasmic antibody
ANCA-AAVAnti-neutrophil cytoplasmic antibody associated vasculitis
GGOMultiple ground glass opacities
IgG4-RLDIgG4-related lung disease
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the Department of Pathology, Jiangsu province Hospital, for pulmonary pathology.
Authors’ contributions
YLX reviewed the patient’s clinical data, performed the literature search, and wrote the initial draft of the manuscript. YYH and KL assisted in the preparation of the manuscript contributed to data collection and interpretation and critically reviewed the manuscript. JQ, and JFZ provide the pathology of renal biopsy. XFZ performed the immunohistochemical studies. TFY conducted pulmonary puncture and provide the possibility of lung pathology. GY and XQX carried out analysis of patient’s clinical course, outcomes and interpretation of findings, and provided critical review comments for the manuscript. NNW and CYX had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, and provided critical review comments for the manuscript. All authors read and approved the final manuscript.
Funding
The research was financially supported by the National Natural Science Foundation of China (81570666), International Society of Nephrology (ISN) Clinical Research Program (18-01-0247), Jiangsu Province Key Medical Personnel Project (ZDRCA2016002). The funders had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, provided critical review comments and also submission for the manuscript.
Availability of data and materials
The datasets used during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33430791 | 18,792,998 | 2021-01-11 |
What was the outcome of reaction 'Lower respiratory tract infection fungal'? | IgG4-related nephritis and interstitial pulmonary disease complicated by invasive pulmonary fungal infection: a case report.
IgG4-related kidney disease (IgG4-RKD) can affect multiple organs, which was first reported as a complication or extra-organ manifestation of autoimmune pancreatitis in 2004. It is characterized by abundant IgG4-positive plasma cells infiltration in tissues involved.
A 69-year-old man presented with cough and renal dysfunction with medical history of hypertension and diabetes. Pathological findings revealed interstitial nephritis and he was initially diagnosed with IgG4-RKD. Prednisone helped the patient to get a remission of cough and an obvious decrease of IgG4 level. However, he developed invasive pulmonary fungal infection while steroid theatment. Anti-fungal therapy was initiated after lung puncture (around cavitary lung lesion). Hemodialysis had been conducted because of renal failure and he got rid of it 2 months later. Methylprednisolone was decreased to 8 mg/day for maintenance therapy. Anti-fungal infection continued for 4 months after discharge home. On the 4th month of follow-up, Chest CT revealed no progression of lung lesions.
The corticosteroids are the first-line therapy of IgG4-RD and a rapid response helps to confirm the diagnosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control.
Background
IgG4-related disease (IgG4-RD) is an inflammatory and fibrotic disease which was first described in the pancreas and was called autoimmune pancreatitis (AIP) in 2001 [1]. Its concept has been recognized worldwide since then that this systemic disease involved multiple organs or tissues characterized by elevated serum IgG4 level and IgG4 positive plasma cells infiltration in the affected tissues, leading to fibrosis eventually [2–6]. The prevalence of IgG4-RD in Japan was estimated as 0.28–1.08/100,000 people in 2012 [7].
IgG4-related tubulointerstitial nephritis (IgG4-TIN), is one of the frequent pathological changes of IgG4-related kidney disease (IgG4-RKD), accounting for about 15–25% of all IgG-RD [4, 8]. IgG4-related TIN shows a range of histologic appearances including (A) acute interstitial nephritis with minimal fibrosis; (B) a more cellular inflammatory pattern in the setting of expansile fibrosis; and (C) a very fibrotic, pauci-cellular pattern [7]. The diagnosis criteria of IgG4-RKD were proposed by the Japanese Society of Nephrology [9] and a work group of North America [7], respectively. IgG4-related kidney lesions were often associated with extrarenal disease, such as chronic sclerosing inflammation of the lacrimal gland, salivary gland [10] and lung [11].
Patients with IgG4-RKD have an increased risk of infection than general population. IgG4-TIN can be accompanied by eosinophilic lung disease [12] and pneumonia [13]. Here, we present a case of IgG4-RKD and lung interstitial lesions who developed invasive pulmonary fungal infection (IPFI) during treatment of glucocorticoid combined with immunosuppressive agents.
Case presentation
A 69-year-old male was admitted to the hospital in 2019 January 5th because of gradually aggravated edema and cough. His medical history included hypertension, arrhythmia and diabetes. On 2019 May 8th, he had experienced cough and phlegm with temperature around 38 ~ 39 °C. Laboratory tests were presented in Table 1. 18F-FDG-PET/CT showed interstitial pneumonia in both lungs. There was also elevated uptake abnormality in the upper kidney observed. Cefperazone-Sulbactam, doxycycline hydrochloride, imipenem, and linezolid were given. Because of no improvement, he took oral prednisone 24 mg per day. The body temperature recovered to normal and lower limb edema was alleviated after one week. On 2019 June 13th ,serum creatinine 157.7 umol/L (Fig. 1); and serum albumin, 24.9 g/L. Chest computed tomography (CT) scan showed that honeycomb-like changes considering interstitial inflammation and bilateral pleural effusion (Fig. 1A).
Table 1 Laboratory data performed before and after treatment
ITEMS Beforetherapy Steroidtherapyfor 1month Steroid therapy for2 months Steroid therapy for3 months Steroid therapy for4 months
White blood cell count(*10^9/L) 15.4 21.11 8.24 11.66 13.28
Hemoglobin(g/L) 129 108 84 98 101
Platelet count(*10^9/L) 323 285 100 273 176
C-reaction protein (CRP)(mg/L) 90 58.1 32 79.8 18.9
Erythrocyte sedimentation rate(mm/H) 120 60 / / /
Serum nitrogen (mmol/L) 10.2 24.71 24.18 30.33 14.5
Serum creatinine (umol/L) 64.6 232.8 212.4 187.2 100.7
Serum albumin(g/L) 24.2 32 30 27.6 21.2
Urine RBC(/ul) / 42.6 10.9 3
Urine protein creatine ratio(mg/g) 48.5
24 h urine protein (g) 0.721 0.62 0.61 0.45 0.49
ANCA-MPO (RU/ml) 35.1 12.7 8.6
ANCA-PR3 (RU/ml) 6.7 4.9 4.7
CD4+ / CD8 + lymphocyte 0.81 / / / 1.9
ABG Before therapy Steroid therapy for 2 months
PH 7.201 7.498
PCO2(mmHg) 20 31.6
PO2(mmHg) 117 49
SpO2 (%) 98 88
K(mmol/L) 5.4 4.1
HCO3-(mmol/L) 7.8 24.5
BE(mmol/L) -20 1
ANCA-MPO Myeloperoxidase-antineutrophil cytoplasmic antibody, ANCA-PR3 proteinase 3, ABG Arterial Blood Gas, / not available
Fig. 1 Chest CT showed interstitial inflammation and bilateral pleural effusion before therapy (a). After glucocorticoids admission, obvious absorption of interstitial inflammation and pleural effusion on both sides were found (b). Infection of both lungs with a left lower lobe cavity before anti-infection therapy (c). After anti-infection therapy, no increase boarder of lung lesions (d)
He went to Nephrology Department on 2019 July 2nd for further treatment. Laboratory results were presented in Table 1. Urine RBC 42.6/ul; Urine protein: creatine ratio (uPCR) 48.5 mg/g; Serum IgG4 level was elevated at 3.42 g/L (Normal range: 0.03–2.10 g/L). Anti-myeloperoxidase anti-neutrophil cytoplasmic antibody level was elevated at 35.1Ru/ml (Normal range:<20 Ru/ml). However, serum immunoglobulin A(IgA), IgG and IgM level were normal. Furthermore, the patient was negative for anti-double-stranded antibody, antinuclear antibody, anti-Sjogren’s syndrome A antibody, anti-Sjogren’s syndrome B antibody and anti-proteinase 3. Ultrasound displayed large-sized kidneys with uniform echo frequency and clear corticomedullary boundaries. Chest CT revealed obvious absorption of interstitial inflammation and pleural effusion on both sides, there were also multiple nodules in both lungs (Fig. 1b).
Histopathology of the kidney biopsy shows proliferation of glomerular mesangial cells, diffuse and irregular thickening of basement membrane (Fig. 2a). The tubulointerstitium shows marked injury. Patchy foci fibrosis and inflammatory cells infiltration were prominent in the interstitium (Fig. 2b, c). Immunofluorescence staining shows that IgG, IgM, IgA, C1q, C3 and C4 were negative in the granular mesangial area. Immunohistological analysis revealed numerous CD20-positive B cells ((D), × 400) and dense infiltration of CD138-positive plasma cells ((E), × 400), with an IgG4+/IgG+ plasma cell ratio being > 40% ((F), × 400). Electron microscopy demonstrated that there were no electron-dense deposits in the glomeruli (Fig. 3).
Fig. 2 Renal histopathological result showed almost normal glomeruli, massively infiltrating cells, and abundant interstitial fibrosis under the light microscopy. a The glomerulus showed glomerular mesangial cells proliferation and diffuse and irregular thickening of basement membrane (HE staining, × 200). b, c A mass of plasma cells and fibrotic fibers (HE staining, × 400) can be observed in the interstitium. d, e Immunohistological analysis revealed mostly CD20-positive B cells (× 400) and CD138-positive plasma cells (× 400) in the interstitium. f Immunohistochemistry for IgG4 shows abundant positive plasma cells (coloured brown) (× 400)
Fig. 3 No electron-dense deposits are observed under electron microscopy. a Abundant plasma cells (× 2000) infiltrated in renal interstitium. b Detachment and partial atrophy of the microvilli of renal tubular epithelial cells as well as edema, infiltration of lymphocytes/monocytes, and fibrosis in renal interstitium. There are no electron-dense deposits in the glomeruli (× 2000). c Proliferation of glomerular mesangial cells and interstitial cells (× 2000). d Diffuse and irregular thickening of basement membrane (× 12,000)
Based on these findings, he had been diagnosed as IgG4-related renal disease. Oral prednisone (40 mg/day) and cyclophosphamide (CTX, 0.4 g) were prescribed by intravenous infusion. The patient had been followed up every month after the treatment (Table 1). He presented with intermittent fever for more than 20 days and acute onset of left pleuritic chest pain with dry cough for 10 days. Negative results were found in aerobic or anaerobic blood culture. Chest CT showed recent infection of both lungs with left upper lung cavity (Fig. 1c). At June 28th he developed hemoptysis and type 1 respiratory failure (Table 2). The results of relevant tests are shown in Table 1. In order to differentiate between IgG4-RLD and IPFI, left upper lung puncture was conducted and showed that interstitial collagen fibrosis with acute and chronic inflammatory cell infiltration, focal fibrous necrosis and exudation, and small alveolar cell response. Fungal spores were also found in lung puncture specimen. Filamentous fungi can be seen in sputum culture. Immunohistochemistry test revealed that most plasma cells in the lung interstitium were positive for CD38 (+), CD138 (+), IgG (+) (Fig. 4). IgG positive plasma cells < 40%, IgG4 positive plasma cells < 10/HPF, which does not meet the pathological diagnostic criteria of IgG4 related diseases. The diagnosis of IPFI was definite. After then, the patient was initiated on voriconazole and caspofungin to anti-fungal infection, and prednisolone was decreased to 30 mg per day.
Table 2 Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ [2, 14, 15]
Criterion
Histology (i)The specimen pathology shows the dense lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis, the infiltration of IgG4-positive cells, and IgG cells more than IgG4 cells ratio of 40%;
Imaging (ii)clinical/radiological examination showing characteristic diffuse or localized swelling or masses in single or multiple organs;
Serology (iii) serum IgG4 concentration > 135 mg/dL;
(iv)Inflammatory markers such as white blood cells count and C-reactive protein concentrations are not elevated, despite the degree of lesions, their spread on imaging analysis and massive cellular infiltration on pathological examination;
Other organ involvement (v)Characteristic findings of IgG4-RD in other organs, including autoimmune pancreatitis, lung involvement, et al.
Treatment (vi)response to steroids.
All 3 criteria (i + ii + iii) are needed for definite diagnosis of IgG4-RD
Fig. 4 Histopathological findings of the pulmonary tissue (light microscopy: HE). a Pulmonary tissue shows fibrotic changes of the interstitium (× 100) in the lung. b Cell and tissue reactions and cellulosic exudation were observed in alveoli (× 200). c, d Giant cell, interstitial edema, collagen fiber hyperplasia and masson body were observed in the specimen (× 200). e, f Immunohistological analysis revealed CD38-positive plasmacyte (coloured brown) (E × 400) and CD138-positive plasmacyte (coloured brown) infiltration (F × 400). g IgG immunostaining shows IgG-positive plasmacyte (coloured brown) infiltration (× 400). h IgG4 immunostaining shows IgG4-positive plasmacyte (coloured brown) infiltration in the lung (× 400)
With anti-infection and immunosuppressive treatment for 2 weeks, serum CRP and IgG4 level had been considerably decreased to 2.94 mg/L and 1.57 g/L, respectively. Voriconazole 200 mg bid and Methylprednisolone 30 mg/day were continued after discharge home. After treatment for one month, a repeat CT scan showed no progression of lung lesions (Fig. 1D). CD4+/CD8+ lymphocyte: 1.9. The patient had been followed up for 4 months. In the most recent follow-up examination, the serum creatinine level decreased to 101 umol/L and he got rid of hemodialysis (Fig. 5). He is currently undergoing tapered prednisolone treatment.
Fig. 5 Dynamic changes of renal function before and after treatment in the patient with IgG4-RKD
Discussion and conclusions
This patient is characterized by serum IgG4 elevation, positive MPO-ANCA, which suggested the possibility of co-occurrence/concurrence of AAV and IgG4‐RD on his first visit from his serological presentation. Diagnosis of IgG4-RD requires particular pathological, serological and clinical features [2, 14, 15] (listed in Table 2). This patient presented with serum IgG4 elevation, hematuria, proteinuria, elevated uptake abnormality of the upper kidney observed in 18F-FDG-PET/CT, progressive kidney failure and interstitial lung disease. Histopathology of kidney biopsy showing typical lymphoplasmacytic infiltration and fibrosis enriched in IgG4-positive plasma cells, and infiltration of IgG4 + plasma cells with IgG4+/IgG+ plasma cells ratio greater than 40% and a total of ≥ 10 IgG4 + plasma cells per high-power field (HPF) indicated the diagnosis of IgG4-RKD.
Given the elevated MPO-ANCA and CRP, AAV related nephritis was a possible differential diagnosis (Proposed diagnostic criteria for kidney involvement in AAV listed in Table 3 [16]). In this case, pathological findings did not show renal crescentic glomerulonephritis or vasculitis, thus, anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-AAV) was not firstly considered according to the Chapel Hill Consensus Conference nomenclature criteria for AAV [16]; However, Some ANCA positive patients may present with interstitial nephritis without severe glomerulopathy, and whether his initial interstitial lung disease was related to IgG4 or AAV or both was not determined. Some reports suggested a possible pathogenic effect of ANCA-IgG4 [17, 18]. Serum IgG4 increase and IgG4-positive cell infiltration in the organ can also be seen in AAV [19, 20]. Distinguishing between these diseases is essential for treatment planning [20], because IgG4-RD responds well to steroid therapy alone, while AAV often requires concomitant immunosuppressant use. His initial interstitial lung disease was improved (Fig. 1) with prednisone therapy alone for one month favored the diagnosis of IgG4-RLD. Kim et al. [21] described that a steroid trial was useful for differentiating and response to steroid therapy is recommended to be added to the diagnostic criteria. Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ listed in Table 2. Therefore, we preferred his diagnosis of IgG4-RD.
Table 3 Proposed diagnostic criteria for kidney involvement in AAV [16]
clinical manifestations a rapidly progressive GN with a decline in kidney function accompanied by sub–nephrotic-range proteinuria, microscopic hematuria, and hypertension over days to a few months
Serology Anti-MPO antibody or anti-PR3 antibody positive
Pathological findings pauci-immune focal necrotizing crescentic GN
Rare patients with AAV have a prominent tubulointerstitial nephritis, which can be associated with vasculitis of the vasa recta
A diagnosis of AAV incorporates the integration of clinical features, ANCA serology, and tissue pathology as needed
Since kidney involvement was firstly reported in a patient with IgG4-RD in 2004 [22], many similar cases have been described [23–25]. A cross-sectional study reported in 2010 revealed all kidney lesions were associated with extrarenal disease among 114 patients with IgG4-related disease [26]. Several clinicopathologic studies reported IgG4-RD with both kidney and lung involvement [5, 14, 27–30]. In kidney its characteristic manifestation is TIN with multiple extrarenal tissue damage [14, 31], which is easily apparent with a chronic or rapid progressive renal function decline [23]. In lung, this may present as nodules with spiculated margins mimicking primary pulmonary malignancy [28, 32], multiple ground glass opacities (GGO) mimicking interstitial lung disease [14], alveolar interstitial type, and bronchovascular type [33].
However, he developed intermittent fever, acute onset of left pleuritic chest pain and an emerging lung lesion after steroid use for one month. IgG4-RLD has been classified into four categories based on CT. Our case was the GGO type. This also was the primary feature of IPFI [34] of which most common chest CT signs are nodules, consolidation and GGO. This patient had several high-risk factors of IPFI such as old age, long-term use of glucocorticoids, repeated hospitalization, etc. [35]. However,it is difficult to distinguish between IgG4-related lung disease (IgG4-RLD) and IPFI (Table 3). Lung puncture pathology is key standard. Thus, sputum culture and pathogenic examination were repeated and infiltration of IgG4-positive plasma cells was not found. The lung tissue specimen showed fungal spores which supported the diagnosis of IPFI. The differential diagnosis of IgG4-RLD and IPFI were listed in Table 4 [34, 36, 37].
Table 4 Differences between IgG4-RLD and IPFI [34, 36, 37]
Items IgG4-RLD IPFI
Clinical manifestations multi-system injuries dry cough and fever,no specific
Laboratory tests Serum IgG4 elevation CRP and (or) PCT elevation,G/GM positive
Imaging nodules, multiple ground glass opacities (GGO),alveolar interstitial type, and bronchovascular type nodules, consolidation and ground-glass opacity(GGO)
Pathology Mainly IgG4
With plasma cell infiltration and often with interstitial damage
fungal spores with hyphae can be observed, pulmonary fibrosis and inflammatory cell infiltration
Treatment protocol Systemic glucocorticoids anti-infection
Systemic glucocorticoids are recommended as the first-line approach of renal injury in untreated IgG4-RD [31]. A moderate initial dose of oral prednisolone for induction is 0.6 mg/kg daily for 2–4 weeks. The maintenance dose of steroid therapy is given after remission as 2.5-5 mg daily over a period of 2–3 months [2]. However, treatment with exogenous glucocorticoids comes with a number of risks such as avascular necrosis, osteoporosis, glaucoma, cardiovascular disease, worse glucose tolerance and diabetes. The risk of infection is of utmost concern and is well-documented [36, 38]. A Japanese study including 459 AIP patients reported pneumonia occurred in 3 patients treated with steroid [13]. Optimizing the nutritional state of patients, reducing its dose, duration and number of immunosuppressants are recommended to help prevent infection. In the present case, we have to decrease the dosage of immunosuppressive drugs after then, nevertheless, IgG4-RLD were aggravated and renal failure developed during dosage decrease.
Since not every patient can be recover from renal disfunction, maintenance hemodialysis become necessary in patients with irreversible renal failure due to IgG4-RKD [4, 39]. And in this case, the patient experienced a short-time hemodialysis because of azotemia, which partly due to deteriorating renal function, steroids use or (and) infection. Improvements in pulmonary lesions and kidney function were observed after 4 months and were maintained with a dose of 8.0 mg/day prednisone. Thus, the dosage of steroid and immunosuppressant should be reduced for the therapy of the elderly patients with IgG4 related diseases. In addition, it has been reported that relapse of IgG4-related lesions, including kidney damage, occurred in 20% of treated patients with IgG4-RKD during maintenance treatment [39]. Thus, long-term follow-up for this patient are required and a well prognosis is expected.
Taken together, IgG4-RKD is an immune-mediated condition that can affect not only kidney but also several other organs, leading to a dense lymphoplasmacytic infiltration dominant in IgG4-positive plasma cells with fibrosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control (Fig. 6).
Fig. 6 Flow diagram of the patient’s disease progression and treatment
Abbreviations
IgG4-RKDIgG4-related kidney disease
AIPAutoimmune pancreatitis
IgG4-TINIgG4-related tubulointerstitial nephritis
IPFIInvasive pulmonary fungal infection
CTChest computed tomography
uPCRUrine protein: creatine ratio
IgGSerum immunoglobulin G
CTXCyclophosphamide
MPO-ANCAAnti-myeloperoxidase anti-neutrophil cytoplasmic antibody
ANCA-AAVAnti-neutrophil cytoplasmic antibody associated vasculitis
GGOMultiple ground glass opacities
IgG4-RLDIgG4-related lung disease
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the Department of Pathology, Jiangsu province Hospital, for pulmonary pathology.
Authors’ contributions
YLX reviewed the patient’s clinical data, performed the literature search, and wrote the initial draft of the manuscript. YYH and KL assisted in the preparation of the manuscript contributed to data collection and interpretation and critically reviewed the manuscript. JQ, and JFZ provide the pathology of renal biopsy. XFZ performed the immunohistochemical studies. TFY conducted pulmonary puncture and provide the possibility of lung pathology. GY and XQX carried out analysis of patient’s clinical course, outcomes and interpretation of findings, and provided critical review comments for the manuscript. NNW and CYX had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, and provided critical review comments for the manuscript. All authors read and approved the final manuscript.
Funding
The research was financially supported by the National Natural Science Foundation of China (81570666), International Society of Nephrology (ISN) Clinical Research Program (18-01-0247), Jiangsu Province Key Medical Personnel Project (ZDRCA2016002). The funders had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, provided critical review comments and also submission for the manuscript.
Availability of data and materials
The datasets used during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33430791 | 18,792,998 | 2021-01-11 |
What was the outcome of reaction 'Respiratory failure'? | IgG4-related nephritis and interstitial pulmonary disease complicated by invasive pulmonary fungal infection: a case report.
IgG4-related kidney disease (IgG4-RKD) can affect multiple organs, which was first reported as a complication or extra-organ manifestation of autoimmune pancreatitis in 2004. It is characterized by abundant IgG4-positive plasma cells infiltration in tissues involved.
A 69-year-old man presented with cough and renal dysfunction with medical history of hypertension and diabetes. Pathological findings revealed interstitial nephritis and he was initially diagnosed with IgG4-RKD. Prednisone helped the patient to get a remission of cough and an obvious decrease of IgG4 level. However, he developed invasive pulmonary fungal infection while steroid theatment. Anti-fungal therapy was initiated after lung puncture (around cavitary lung lesion). Hemodialysis had been conducted because of renal failure and he got rid of it 2 months later. Methylprednisolone was decreased to 8 mg/day for maintenance therapy. Anti-fungal infection continued for 4 months after discharge home. On the 4th month of follow-up, Chest CT revealed no progression of lung lesions.
The corticosteroids are the first-line therapy of IgG4-RD and a rapid response helps to confirm the diagnosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control.
Background
IgG4-related disease (IgG4-RD) is an inflammatory and fibrotic disease which was first described in the pancreas and was called autoimmune pancreatitis (AIP) in 2001 [1]. Its concept has been recognized worldwide since then that this systemic disease involved multiple organs or tissues characterized by elevated serum IgG4 level and IgG4 positive plasma cells infiltration in the affected tissues, leading to fibrosis eventually [2–6]. The prevalence of IgG4-RD in Japan was estimated as 0.28–1.08/100,000 people in 2012 [7].
IgG4-related tubulointerstitial nephritis (IgG4-TIN), is one of the frequent pathological changes of IgG4-related kidney disease (IgG4-RKD), accounting for about 15–25% of all IgG-RD [4, 8]. IgG4-related TIN shows a range of histologic appearances including (A) acute interstitial nephritis with minimal fibrosis; (B) a more cellular inflammatory pattern in the setting of expansile fibrosis; and (C) a very fibrotic, pauci-cellular pattern [7]. The diagnosis criteria of IgG4-RKD were proposed by the Japanese Society of Nephrology [9] and a work group of North America [7], respectively. IgG4-related kidney lesions were often associated with extrarenal disease, such as chronic sclerosing inflammation of the lacrimal gland, salivary gland [10] and lung [11].
Patients with IgG4-RKD have an increased risk of infection than general population. IgG4-TIN can be accompanied by eosinophilic lung disease [12] and pneumonia [13]. Here, we present a case of IgG4-RKD and lung interstitial lesions who developed invasive pulmonary fungal infection (IPFI) during treatment of glucocorticoid combined with immunosuppressive agents.
Case presentation
A 69-year-old male was admitted to the hospital in 2019 January 5th because of gradually aggravated edema and cough. His medical history included hypertension, arrhythmia and diabetes. On 2019 May 8th, he had experienced cough and phlegm with temperature around 38 ~ 39 °C. Laboratory tests were presented in Table 1. 18F-FDG-PET/CT showed interstitial pneumonia in both lungs. There was also elevated uptake abnormality in the upper kidney observed. Cefperazone-Sulbactam, doxycycline hydrochloride, imipenem, and linezolid were given. Because of no improvement, he took oral prednisone 24 mg per day. The body temperature recovered to normal and lower limb edema was alleviated after one week. On 2019 June 13th ,serum creatinine 157.7 umol/L (Fig. 1); and serum albumin, 24.9 g/L. Chest computed tomography (CT) scan showed that honeycomb-like changes considering interstitial inflammation and bilateral pleural effusion (Fig. 1A).
Table 1 Laboratory data performed before and after treatment
ITEMS Beforetherapy Steroidtherapyfor 1month Steroid therapy for2 months Steroid therapy for3 months Steroid therapy for4 months
White blood cell count(*10^9/L) 15.4 21.11 8.24 11.66 13.28
Hemoglobin(g/L) 129 108 84 98 101
Platelet count(*10^9/L) 323 285 100 273 176
C-reaction protein (CRP)(mg/L) 90 58.1 32 79.8 18.9
Erythrocyte sedimentation rate(mm/H) 120 60 / / /
Serum nitrogen (mmol/L) 10.2 24.71 24.18 30.33 14.5
Serum creatinine (umol/L) 64.6 232.8 212.4 187.2 100.7
Serum albumin(g/L) 24.2 32 30 27.6 21.2
Urine RBC(/ul) / 42.6 10.9 3
Urine protein creatine ratio(mg/g) 48.5
24 h urine protein (g) 0.721 0.62 0.61 0.45 0.49
ANCA-MPO (RU/ml) 35.1 12.7 8.6
ANCA-PR3 (RU/ml) 6.7 4.9 4.7
CD4+ / CD8 + lymphocyte 0.81 / / / 1.9
ABG Before therapy Steroid therapy for 2 months
PH 7.201 7.498
PCO2(mmHg) 20 31.6
PO2(mmHg) 117 49
SpO2 (%) 98 88
K(mmol/L) 5.4 4.1
HCO3-(mmol/L) 7.8 24.5
BE(mmol/L) -20 1
ANCA-MPO Myeloperoxidase-antineutrophil cytoplasmic antibody, ANCA-PR3 proteinase 3, ABG Arterial Blood Gas, / not available
Fig. 1 Chest CT showed interstitial inflammation and bilateral pleural effusion before therapy (a). After glucocorticoids admission, obvious absorption of interstitial inflammation and pleural effusion on both sides were found (b). Infection of both lungs with a left lower lobe cavity before anti-infection therapy (c). After anti-infection therapy, no increase boarder of lung lesions (d)
He went to Nephrology Department on 2019 July 2nd for further treatment. Laboratory results were presented in Table 1. Urine RBC 42.6/ul; Urine protein: creatine ratio (uPCR) 48.5 mg/g; Serum IgG4 level was elevated at 3.42 g/L (Normal range: 0.03–2.10 g/L). Anti-myeloperoxidase anti-neutrophil cytoplasmic antibody level was elevated at 35.1Ru/ml (Normal range:<20 Ru/ml). However, serum immunoglobulin A(IgA), IgG and IgM level were normal. Furthermore, the patient was negative for anti-double-stranded antibody, antinuclear antibody, anti-Sjogren’s syndrome A antibody, anti-Sjogren’s syndrome B antibody and anti-proteinase 3. Ultrasound displayed large-sized kidneys with uniform echo frequency and clear corticomedullary boundaries. Chest CT revealed obvious absorption of interstitial inflammation and pleural effusion on both sides, there were also multiple nodules in both lungs (Fig. 1b).
Histopathology of the kidney biopsy shows proliferation of glomerular mesangial cells, diffuse and irregular thickening of basement membrane (Fig. 2a). The tubulointerstitium shows marked injury. Patchy foci fibrosis and inflammatory cells infiltration were prominent in the interstitium (Fig. 2b, c). Immunofluorescence staining shows that IgG, IgM, IgA, C1q, C3 and C4 were negative in the granular mesangial area. Immunohistological analysis revealed numerous CD20-positive B cells ((D), × 400) and dense infiltration of CD138-positive plasma cells ((E), × 400), with an IgG4+/IgG+ plasma cell ratio being > 40% ((F), × 400). Electron microscopy demonstrated that there were no electron-dense deposits in the glomeruli (Fig. 3).
Fig. 2 Renal histopathological result showed almost normal glomeruli, massively infiltrating cells, and abundant interstitial fibrosis under the light microscopy. a The glomerulus showed glomerular mesangial cells proliferation and diffuse and irregular thickening of basement membrane (HE staining, × 200). b, c A mass of plasma cells and fibrotic fibers (HE staining, × 400) can be observed in the interstitium. d, e Immunohistological analysis revealed mostly CD20-positive B cells (× 400) and CD138-positive plasma cells (× 400) in the interstitium. f Immunohistochemistry for IgG4 shows abundant positive plasma cells (coloured brown) (× 400)
Fig. 3 No electron-dense deposits are observed under electron microscopy. a Abundant plasma cells (× 2000) infiltrated in renal interstitium. b Detachment and partial atrophy of the microvilli of renal tubular epithelial cells as well as edema, infiltration of lymphocytes/monocytes, and fibrosis in renal interstitium. There are no electron-dense deposits in the glomeruli (× 2000). c Proliferation of glomerular mesangial cells and interstitial cells (× 2000). d Diffuse and irregular thickening of basement membrane (× 12,000)
Based on these findings, he had been diagnosed as IgG4-related renal disease. Oral prednisone (40 mg/day) and cyclophosphamide (CTX, 0.4 g) were prescribed by intravenous infusion. The patient had been followed up every month after the treatment (Table 1). He presented with intermittent fever for more than 20 days and acute onset of left pleuritic chest pain with dry cough for 10 days. Negative results were found in aerobic or anaerobic blood culture. Chest CT showed recent infection of both lungs with left upper lung cavity (Fig. 1c). At June 28th he developed hemoptysis and type 1 respiratory failure (Table 2). The results of relevant tests are shown in Table 1. In order to differentiate between IgG4-RLD and IPFI, left upper lung puncture was conducted and showed that interstitial collagen fibrosis with acute and chronic inflammatory cell infiltration, focal fibrous necrosis and exudation, and small alveolar cell response. Fungal spores were also found in lung puncture specimen. Filamentous fungi can be seen in sputum culture. Immunohistochemistry test revealed that most plasma cells in the lung interstitium were positive for CD38 (+), CD138 (+), IgG (+) (Fig. 4). IgG positive plasma cells < 40%, IgG4 positive plasma cells < 10/HPF, which does not meet the pathological diagnostic criteria of IgG4 related diseases. The diagnosis of IPFI was definite. After then, the patient was initiated on voriconazole and caspofungin to anti-fungal infection, and prednisolone was decreased to 30 mg per day.
Table 2 Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ [2, 14, 15]
Criterion
Histology (i)The specimen pathology shows the dense lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis, the infiltration of IgG4-positive cells, and IgG cells more than IgG4 cells ratio of 40%;
Imaging (ii)clinical/radiological examination showing characteristic diffuse or localized swelling or masses in single or multiple organs;
Serology (iii) serum IgG4 concentration > 135 mg/dL;
(iv)Inflammatory markers such as white blood cells count and C-reactive protein concentrations are not elevated, despite the degree of lesions, their spread on imaging analysis and massive cellular infiltration on pathological examination;
Other organ involvement (v)Characteristic findings of IgG4-RD in other organs, including autoimmune pancreatitis, lung involvement, et al.
Treatment (vi)response to steroids.
All 3 criteria (i + ii + iii) are needed for definite diagnosis of IgG4-RD
Fig. 4 Histopathological findings of the pulmonary tissue (light microscopy: HE). a Pulmonary tissue shows fibrotic changes of the interstitium (× 100) in the lung. b Cell and tissue reactions and cellulosic exudation were observed in alveoli (× 200). c, d Giant cell, interstitial edema, collagen fiber hyperplasia and masson body were observed in the specimen (× 200). e, f Immunohistological analysis revealed CD38-positive plasmacyte (coloured brown) (E × 400) and CD138-positive plasmacyte (coloured brown) infiltration (F × 400). g IgG immunostaining shows IgG-positive plasmacyte (coloured brown) infiltration (× 400). h IgG4 immunostaining shows IgG4-positive plasmacyte (coloured brown) infiltration in the lung (× 400)
With anti-infection and immunosuppressive treatment for 2 weeks, serum CRP and IgG4 level had been considerably decreased to 2.94 mg/L and 1.57 g/L, respectively. Voriconazole 200 mg bid and Methylprednisolone 30 mg/day were continued after discharge home. After treatment for one month, a repeat CT scan showed no progression of lung lesions (Fig. 1D). CD4+/CD8+ lymphocyte: 1.9. The patient had been followed up for 4 months. In the most recent follow-up examination, the serum creatinine level decreased to 101 umol/L and he got rid of hemodialysis (Fig. 5). He is currently undergoing tapered prednisolone treatment.
Fig. 5 Dynamic changes of renal function before and after treatment in the patient with IgG4-RKD
Discussion and conclusions
This patient is characterized by serum IgG4 elevation, positive MPO-ANCA, which suggested the possibility of co-occurrence/concurrence of AAV and IgG4‐RD on his first visit from his serological presentation. Diagnosis of IgG4-RD requires particular pathological, serological and clinical features [2, 14, 15] (listed in Table 2). This patient presented with serum IgG4 elevation, hematuria, proteinuria, elevated uptake abnormality of the upper kidney observed in 18F-FDG-PET/CT, progressive kidney failure and interstitial lung disease. Histopathology of kidney biopsy showing typical lymphoplasmacytic infiltration and fibrosis enriched in IgG4-positive plasma cells, and infiltration of IgG4 + plasma cells with IgG4+/IgG+ plasma cells ratio greater than 40% and a total of ≥ 10 IgG4 + plasma cells per high-power field (HPF) indicated the diagnosis of IgG4-RKD.
Given the elevated MPO-ANCA and CRP, AAV related nephritis was a possible differential diagnosis (Proposed diagnostic criteria for kidney involvement in AAV listed in Table 3 [16]). In this case, pathological findings did not show renal crescentic glomerulonephritis or vasculitis, thus, anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-AAV) was not firstly considered according to the Chapel Hill Consensus Conference nomenclature criteria for AAV [16]; However, Some ANCA positive patients may present with interstitial nephritis without severe glomerulopathy, and whether his initial interstitial lung disease was related to IgG4 or AAV or both was not determined. Some reports suggested a possible pathogenic effect of ANCA-IgG4 [17, 18]. Serum IgG4 increase and IgG4-positive cell infiltration in the organ can also be seen in AAV [19, 20]. Distinguishing between these diseases is essential for treatment planning [20], because IgG4-RD responds well to steroid therapy alone, while AAV often requires concomitant immunosuppressant use. His initial interstitial lung disease was improved (Fig. 1) with prednisone therapy alone for one month favored the diagnosis of IgG4-RLD. Kim et al. [21] described that a steroid trial was useful for differentiating and response to steroid therapy is recommended to be added to the diagnostic criteria. Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ listed in Table 2. Therefore, we preferred his diagnosis of IgG4-RD.
Table 3 Proposed diagnostic criteria for kidney involvement in AAV [16]
clinical manifestations a rapidly progressive GN with a decline in kidney function accompanied by sub–nephrotic-range proteinuria, microscopic hematuria, and hypertension over days to a few months
Serology Anti-MPO antibody or anti-PR3 antibody positive
Pathological findings pauci-immune focal necrotizing crescentic GN
Rare patients with AAV have a prominent tubulointerstitial nephritis, which can be associated with vasculitis of the vasa recta
A diagnosis of AAV incorporates the integration of clinical features, ANCA serology, and tissue pathology as needed
Since kidney involvement was firstly reported in a patient with IgG4-RD in 2004 [22], many similar cases have been described [23–25]. A cross-sectional study reported in 2010 revealed all kidney lesions were associated with extrarenal disease among 114 patients with IgG4-related disease [26]. Several clinicopathologic studies reported IgG4-RD with both kidney and lung involvement [5, 14, 27–30]. In kidney its characteristic manifestation is TIN with multiple extrarenal tissue damage [14, 31], which is easily apparent with a chronic or rapid progressive renal function decline [23]. In lung, this may present as nodules with spiculated margins mimicking primary pulmonary malignancy [28, 32], multiple ground glass opacities (GGO) mimicking interstitial lung disease [14], alveolar interstitial type, and bronchovascular type [33].
However, he developed intermittent fever, acute onset of left pleuritic chest pain and an emerging lung lesion after steroid use for one month. IgG4-RLD has been classified into four categories based on CT. Our case was the GGO type. This also was the primary feature of IPFI [34] of which most common chest CT signs are nodules, consolidation and GGO. This patient had several high-risk factors of IPFI such as old age, long-term use of glucocorticoids, repeated hospitalization, etc. [35]. However,it is difficult to distinguish between IgG4-related lung disease (IgG4-RLD) and IPFI (Table 3). Lung puncture pathology is key standard. Thus, sputum culture and pathogenic examination were repeated and infiltration of IgG4-positive plasma cells was not found. The lung tissue specimen showed fungal spores which supported the diagnosis of IPFI. The differential diagnosis of IgG4-RLD and IPFI were listed in Table 4 [34, 36, 37].
Table 4 Differences between IgG4-RLD and IPFI [34, 36, 37]
Items IgG4-RLD IPFI
Clinical manifestations multi-system injuries dry cough and fever,no specific
Laboratory tests Serum IgG4 elevation CRP and (or) PCT elevation,G/GM positive
Imaging nodules, multiple ground glass opacities (GGO),alveolar interstitial type, and bronchovascular type nodules, consolidation and ground-glass opacity(GGO)
Pathology Mainly IgG4
With plasma cell infiltration and often with interstitial damage
fungal spores with hyphae can be observed, pulmonary fibrosis and inflammatory cell infiltration
Treatment protocol Systemic glucocorticoids anti-infection
Systemic glucocorticoids are recommended as the first-line approach of renal injury in untreated IgG4-RD [31]. A moderate initial dose of oral prednisolone for induction is 0.6 mg/kg daily for 2–4 weeks. The maintenance dose of steroid therapy is given after remission as 2.5-5 mg daily over a period of 2–3 months [2]. However, treatment with exogenous glucocorticoids comes with a number of risks such as avascular necrosis, osteoporosis, glaucoma, cardiovascular disease, worse glucose tolerance and diabetes. The risk of infection is of utmost concern and is well-documented [36, 38]. A Japanese study including 459 AIP patients reported pneumonia occurred in 3 patients treated with steroid [13]. Optimizing the nutritional state of patients, reducing its dose, duration and number of immunosuppressants are recommended to help prevent infection. In the present case, we have to decrease the dosage of immunosuppressive drugs after then, nevertheless, IgG4-RLD were aggravated and renal failure developed during dosage decrease.
Since not every patient can be recover from renal disfunction, maintenance hemodialysis become necessary in patients with irreversible renal failure due to IgG4-RKD [4, 39]. And in this case, the patient experienced a short-time hemodialysis because of azotemia, which partly due to deteriorating renal function, steroids use or (and) infection. Improvements in pulmonary lesions and kidney function were observed after 4 months and were maintained with a dose of 8.0 mg/day prednisone. Thus, the dosage of steroid and immunosuppressant should be reduced for the therapy of the elderly patients with IgG4 related diseases. In addition, it has been reported that relapse of IgG4-related lesions, including kidney damage, occurred in 20% of treated patients with IgG4-RKD during maintenance treatment [39]. Thus, long-term follow-up for this patient are required and a well prognosis is expected.
Taken together, IgG4-RKD is an immune-mediated condition that can affect not only kidney but also several other organs, leading to a dense lymphoplasmacytic infiltration dominant in IgG4-positive plasma cells with fibrosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control (Fig. 6).
Fig. 6 Flow diagram of the patient’s disease progression and treatment
Abbreviations
IgG4-RKDIgG4-related kidney disease
AIPAutoimmune pancreatitis
IgG4-TINIgG4-related tubulointerstitial nephritis
IPFIInvasive pulmonary fungal infection
CTChest computed tomography
uPCRUrine protein: creatine ratio
IgGSerum immunoglobulin G
CTXCyclophosphamide
MPO-ANCAAnti-myeloperoxidase anti-neutrophil cytoplasmic antibody
ANCA-AAVAnti-neutrophil cytoplasmic antibody associated vasculitis
GGOMultiple ground glass opacities
IgG4-RLDIgG4-related lung disease
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We sincerely thank the Department of Pathology, Jiangsu province Hospital, for pulmonary pathology.
Authors’ contributions
YLX reviewed the patient’s clinical data, performed the literature search, and wrote the initial draft of the manuscript. YYH and KL assisted in the preparation of the manuscript contributed to data collection and interpretation and critically reviewed the manuscript. JQ, and JFZ provide the pathology of renal biopsy. XFZ performed the immunohistochemical studies. TFY conducted pulmonary puncture and provide the possibility of lung pathology. GY and XQX carried out analysis of patient’s clinical course, outcomes and interpretation of findings, and provided critical review comments for the manuscript. NNW and CYX had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, and provided critical review comments for the manuscript. All authors read and approved the final manuscript.
Funding
The research was financially supported by the National Natural Science Foundation of China (81570666), International Society of Nephrology (ISN) Clinical Research Program (18-01-0247), Jiangsu Province Key Medical Personnel Project (ZDRCA2016002). The funders had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, provided critical review comments and also submission for the manuscript.
Availability of data and materials
The datasets used during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33430791 | 18,792,998 | 2021-01-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Osmotic demyelination syndrome'. | Effective treatment of osmotic demyelination syndrome with plasmapheresis: a case report and review of the literature.
BACKGROUND
Treatment options for chronic osmotic demyelination syndrome are limited to case reports and only a very few show complete recovery. We report a case of complete recovery of chronic osmotic demyelination syndrome with plasmapheresis.
METHODS
A 43-year-old Sri Lankan man presented with fever, repeated vomiting, unsteady gait, increased tonicity of his right upper limb and paucity of speech for three days. He was treated in the local hospital with antibiotics and antivirals as per central nervous system infection. He had hyponatraemia, which was rapidly corrected with hypertonic saline from 97 to 119 mmol/L. He was transferred to our hospital because of progressive reduction of consciousness, rapidly worsening rigidity and bradykinesia of all four limbs and worsening dysarthria and bradyphrenia. Magnetic resonance imaging of the brain was compatible with osmotic demyelination syndrome. He was commenced on plasmapheresis twenty-two days after rapid correction of sodium. He regained independent mobility with complete resolution of rigidity, bradykinesia and speech dysfunction after five cycles of alternate day plasmapheresis.
CONCLUSIONS
Plasmapheresis can be considered as an effective treatment modality in chronic osmotic demyelination syndrome.
Background
Rapid correction of hyponatraemia is associated with osmotic demyelination syndrome (ODS), which is a demyelinating disorder of the central nervous system (CNS) [1]. Brain adapts to chronic hyponatraemia by extracellular movement of osmotically active organic and inorganic particles [2]. During rapid correction of hyponatraemia, organic osmolytes cannot re-enter the intracellular compartment as rapidly as ionic movement creating an osmotic disequilibrium [2]. This causes shrinkage of brain cells including astrocytes and oligodendrocytes causing accelerated apoptosis leading to disruption of the blood brain barrier and demyelination [3]. Consequently, symptoms related to pontine and extra-pontine demyelination typically occurs after two to six days of rapid sodium correction [4]. Traditionally, established ODS is considered to be associated with a poor prognosis [4]. Apart from supportive therapy, sodium re-lowering therapy has shown to be beneficial in the acute stage [5]. However, successful outcome of chronic ODS is limited to a few case reports [6, 7]. Out of the experimental therapies, plasmapheresis alone or in combination with other treatment modalities has shown variable benefit [6, 7, 8, 9, 10, 11]. We report a case of complete clinical and radiological recovery of ODS with plasmapheresis, initiated twenty-two days after rapid sodium correction.
Case presentation
A 43-year-old Sri Lankan man with type 2 diabetes mellitus and hypertension presented with fever for 3 days which was associated with arthralgia, myalgia, dry cough and headache, but without features of meningism. Fever resolved after 3 days and he was well except for arthralgia and myalgia. After 1 week of resolution of fever he developed recurrent episodes of vomiting followed by development of an unsteady gait with increased tonicity of his right upper limb and paucity of speech. There was no history of altered level of consciousness, involuntary movements or seizures. He was admitted to the local hospital with above symptoms on the 12th day of his illness. On admission to the local hospital he was afebrile, pulse rate was 104 bpm and blood pressure was 130/80 mmHg. His Glasgow coma scale score (GCS) was 15/15, pupils were equally reactive to light and there was no neck stiffness. During the hospital stay he had resurgence of fever with worsening rigidity and difficulty in walking. He was noted to have a sodium of 97 mmol/L, which was corrected with hypertonic saline up to 119 mmol/L. His haematological and biochemical investigations done at local hospital are shown in Table 1. After 4 days of sodium correction he developed reduced level of consciousness, bradykinesia and tremors of both upper and lower limbs symmetrically. His speech remained sparse and there were no seizures. Non contrast computed tomography (NCCT) brain was normal. Cerebro-spinal fluid (CSF) analysis was not done. He was transferred to the National Hospital of Sri Lanka (NHSL), Colombo on the 22nd day of his illness for further management.Table 1. Haematological and biochemical parameters of the patient at the local hospital.
Laboratory parameter Value Reference range
Haematology
Total white cell count (cells/µL) 17,140 4000–11,000
Neutrophil count (cells/µL) 13,026 1500–8000
Lymphocyte count (cells/µL) 2802 1000–4800
Haemoglobin level (g/dL) 14.2 13.5–17.5
Platelet count (platelets/µL) 352,000 150,000–450,000
Erythrocyte sedimentation rate (mm/1st hour) 6
Biochemistry
C-reactive protein (mg/L) 28 < 6
Serum creatinine (µmol/L) 98 60–110
Serum potassium (mmol/L) 4.1 3.5–5.1
Serum osmolality (mOsm/kg) 214 275–295
Urine osmolality (mOsm/kg) 632 300–900
Urine sodium (mmol/L) 51 < 20
Serum 9 am cortisol (nmol/L) 380 > 300
Serum thyroid stimulating hormone (mIU/L) 1.16 0.4–4
There was no history of recent travel, animal contact, familial movement disorders, past history of psychiatric disorders or exposure to toxic substances including methanol, ethylene glycol or cyanide. He was a non-smoker and consumed alcohol occasionally at social events.
On examination, his body mass index was 24.2 kg/m2, afebrile and there was no neck stiffness. GCS was 11/15 (best motor reponse—6, best verbal response—2, and eye opening—3). He had features of Parkinsonism including bradykinesia, rigidity and tremors symmetrically involving both upper and lower limbs. Increased muscle tone and hyper-reflexia were noted in all four limbs with bilateral extensor plantar responses. He had ignition failure and a narrow-based shuffling gait. Speech was sparse with an expressionless face (see Additional file 1 for video 1). Cardiovascular, respiratory and abdominal examinations were normal.
His haematological and biochemical investigations done at NHSL are shown in Table 2.Table 2. Haematological and biochemical parameters of the patient at National Hospital of Sri Lanka
Laboratory parameter Value Reference range
Haematology
Total white cell count (cells/µL) 9820 4000–11,000
Neutrophil count (cells/µL) 7430 1500–8000
Lymphocyte count (cells/µL) 1550 1000–4800
Haemoglobin level (g/dL) 12.9 13.5–17.5
Platelet count (platelets/µL) 319,000 150,000–450,000
Erythrocyte sedimentation rate (mm/1st hour) 6
Biochemistry
C-reactive protein (mg/L) 38 < 6
Serum creatinine (µmol/L) 88 60–110
Serum sodium (mmol/L) 138 135–148
Serum potassium (mmol/L) 3.99 3.5–5.1
Creatine phosphokinase (U/L) 123 39–308
Aspartate aminotransferase (U/L) 31 10–40
Alanine aminotransferase (U/L) 23 7–56
Alkaline phosphatase (U/L) 66 53–128
Screening for sepsis including urine full report, urine/ blood cultures and chest radiograph were unremarkable. Variation of his serum sodium levels are shown in the Fig. 1. Sodium level was 138 mmol/L on admission to our hospital. NCCT brain was normal. CSF analysis on the 23rd day of the illness, was normal except for an elevated level of protein. Antibodies against Japanese encephalitis, polymerase chain reaction of Herpes simplex virus and Mycobacterium tuberculosis were negative. Magnetic resonance imaging (MRI) of the brain showed bilateral symmetrical T2 FLAIR (fluid-attenuated inversion recovery) high signal involving caudate, lentiform nuclei, thalami and external capsules. Furthermore, the characteristic central trident shaped T2 FLAIR high signal area was evident in the pons (Fig. 2). A diagnosis of ODS was made based on the history of rapid sodium correction and abnormalities detected on the cranial MRI.Fig. 1 Temporal variation of serum sodium levels. The graph shows rapid sodium correction from a trough of 97 to 119 mmol/L.
Fig. 2 MRI brain before plasmapheresis. a Bilateral symmetrical T2-FLAIR high signal involving caudate, lentiform nuclei, thalami and external capsules; b central trident shaped T2-FLAIR high signal area in the pons (yellow arrow).
As infection in the CNS was suspected intravenous ceftriaxone and aciclovir were administered for fourteen days. Parkinsonism was treated symptomatically with co-careldopa and benzhexol. Intubation was not needed and he was fed via a naso-gastric feeding tube. In order to reverse the effects of ODS, sodium re-lowering therapy was attempted with 5% dextrose but failed to achieve clinical improvement and induce target hyponatraemia. Thus, the patient was initiated on alternate day plasmapheresis with a total plasma exchange volume of 11,132 mL. There was improvement of his rigidity, tremors and bradykinesia with plasmapheresis but without improvement in his speech and gait initially. However, at the end of five cycles there was complete neurological recovery (see Additional file 2 for video 2). Variation of sodium level with sodium re-lowering therapy and plasmapheresis is shown in Fig. 3. Neurological reassessment done three months after discharge showed sustained complete recovery and repeat MRI brain showed complete resolution at five months (Fig. 4; Additional file 3: Timeline).Fig. 3 Temporal variation of serum sodium levels with sodium re-lowering therapy and plasmapheresis.
Fig. 4 MRI brain five months after plasmapheresis. The images shows complete resolution of changes observed in Fig. 2.
Discussion
We report a case of chronic ODS that showed complete clinical and radiological resolution with plasmapheresis. The initial clinical presentation of our patient to the local hospital with fever and repeated vomiting followed by unsteady gait, increased tone of the right upper limb and paucity of speech suggested a CNS infection involving the basal ganglia. This clinical presentation was consistent with a CNS infection such as acute encephalitis with predilection to basal ganglia. Flaviviruses such as Japanese encephalitis and West Nile virus are known to cause encephalitis with basal ganglia involvement, although a number of other viruses, toxoplasmosis and tuberculosis may also cause a similar syndrome. [12, 13].
The cause of the hyponatraemia detected at the local hospital was probably multifactorial, contributed by sodium loss through vomiting and syndrome of inappropriate anti-diuretic hormone secretion due to CNS infection. This had been rapidly corrected during the hospital stay. Rapid correction of hyponatraemia is known to cause ODS [1]. The clinical course with predominant extrapyramidal symptoms could be explained either by the progressive CNS infection or concurrent development of ODS. However, T2 FLAIR MRI images showing symmetrical high intensity lesions in the caudate, lentiform nuclei and bilateral thalami with sparing of globus pallidus and the typical trident shaped T2 high intensity lesion in the pons favour ODS [14].
Apart from supportive care, there is no proven treatment for established ODS. Re-lowering of sodium using 5% dextrose and desmopressin have shown benefit in treating ODS in animal models, but data in humans is limited to case reports and case series [5, 15]. However, successful reversal of neurological manifestations had only being achieved with early re-induction of hyponatraemia. Although sodium re-lowering was initially started in our patient to treat ODS, it was soon discontinued due to the lack of any clinical improvement. Other treatments modalities reported for ODS included administration of thyrotrophic releasing hormone, corticosteroids [16], immunoglobulins [17] and plasmapheresis. These had been used alone or in combination and the outcomes had been variable [11].
Plasmapheresis is an extracorporeal treatment aimed to remove circulating pathologic or toxic substances from the circulation, in order to halt the progression of a disease process. There are several case reports describing plasmapheresis used alone or in combination with other treatment modalities but the reported outcomes have been variable (Table 3).Table 3. Summary of case reports describing plasmapheresis used to treat ODS.
Age and gender of the patient Clinical features MRI findings Day of initiation of plasmapheresis No. of cycles/volume exchanged Outcome References
Pontine Extra-pontine Clinical Radiological
29 F Tetraparesis, areflexia, bulbar dysfunction + − NA 24,700 mL Partial Unchanged [8]
20 F Spastic tetraparesis, bulbar dysfunction + − NA 5243 mL Partial Unchanged [8]
30 F Tetraparesis, pseudo-bulbar palsy, nystagmus + − NA 18,270 mL Complete Unchanged [8]
59 F Pseudo-bulbar palsy, flaccid tetraplegia, ophthalmoplegia, hyper-reflexia + − A week after the onset of neurological manifestations 37,300 mL Partial Unchanged [9]
40 F Tetraparesis, pseudo-bulbar palsy, diplopia + − Immediately after MRI confirmation of ODS 4394 mL Partial NA [10]
71 F Spastic tetraparesis, hyper-reflexia, dysphagia + + 23rd day after rapid sodium correction 3840 mL Complete The signals were reduced in size but remained [6]
50 F Drowsy, spastic tetraparesis, areflexia, bulbar dysfunction + − 20th day after the onset of neurological manifestations 7 cycles Complete NA (7)
F female, NA data not available, + presence of changes, − absence of changes
The pathogenesis of ODS is incompletely understood. It is believed that chronic hyponatraemia is associated with movement of osmotically active particles out in to the extracellular compartment to prevent swelling of astrocytes. However, when the hyponatraemia is rapidly corrected, organic osmolytes cannot re-enter to maintain intracellular osmolarity, as fast as the extracellular osmolarity is increased by infusion of sodium. This results in shrinkage of astrocytes and oligodendrocytes resulting in their apoptosis, inflammation and disruption of blood-brain barrier leading to demyelination [2, 18]. Hence, brain areas which have slowest uptake of osmolytes such as central pons (30–50%), extra-pontine areas (20–50%) or both (30–50%) are the worst affected [19]. There is also evidence for the role of an undefined myelinotoxin released due to osmotic stress contributing to myelinolysis [8].
An unknown myelinotoxic substance in plasma has been postulated to mediate ODS [6]. This substance is thought to gain access into the CNS by damage to the blood brain barrier and is the possible mechanism of prolonged and ongoing neurotoxicity [6]. Efficacy of plasmapheresis in ODS is thought to be related to removal of pro-inflammatory, high molecular weight myelinotoxins from the circulation [8].
Chronic established ODS was traditionally considered to have a poor neurological outcome. Mortality associated with ODS has been reported in up to 31% of patients while another 31% have been reported to require lifelong supportive therapy [20]. In contrast, our case report highlights the benefit of plasmapheresis in established ODS even when initiated later in the course of the disease.
Conclusion
Although chronic established ODS has been considered to be associated with a poor outcome, this case report highlights that plasmapheresis may remain effective in reversing ODS several weeks after the initial osmotic insult.
Supplementary information
Additional file 1:
Video 1. Demonstration of clinical features of the patient before initiating plasmapheresis.
Additional file 2:
Video 2. Demonstration of complete neurological recovery of the patient at the end of plasmapheresis.
Additional file 3:
Timeline. Summary of the important clinical events of the patient shown in a timeline.
Abbreviations
ODSOsmotic demyelination syndrome
CNSCentral nervous system
GCSGlasgow coma scale
NHSLNational Hospital of Sri Lanka
CSFCerebrospinal fluid
MRIMagnetic resonance imaging
FLAIRFluid-attenuated inversion recovery
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary information accompanies this paper at 10.1186/s13256-020-02573-9.
Acknowledgements
We thank the team of transfusion medicine, National Hospital of Sri Lanka, Colombo, Sri Lanka for timely arrangement of plasmapheresis.
Authors’ contributions
All authors contributed equally to the management of the patient and contributed to the drafting of the manuscript. TC revised the manuscript critically and prepared the final version. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All necessary data and material are provided.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the
Editor-in-Chief of this journal.
Competing interests
Authors declare that they have no competing interests. | SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33430956 | 19,115,896 | 2021-01-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Altered state of consciousness'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ascites'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bacteraemia'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, DARATUMUMAB, DEXAMETHASONE, DOXORUBICIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,486,304 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytomegalovirus nephritis'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug level increased'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoalbuminaemia'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoxia'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myeloma cast nephropathy'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nephropathy toxic'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Overdose'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pancytopenia'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Plasmacytoma'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pleural effusion'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyelonephritis acute'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, DARATUMUMAB, DEXAMETHASONE, DOXORUBICIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,486,304 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxic encephalopathy'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tubulointerstitial nephritis'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, CARFILZOMIB, CEFAZOLIN SODIUM, CEFEPIME HYDROCHLORIDE, CEFTAZIDIME, DARATUMUMAB, DEXAMETHASONE ACETATE, LENALIDOMIDE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Urinary tract infection'. | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | BORTEZOMIB, DARATUMUMAB, DEXAMETHASONE, DOXORUBICIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33431732 | 19,486,304 | 2021-06-01 |
What was the dosage of drug 'DEXAMETHASONE'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | INTERMEDIATE?DOSE | DrugDosageText | CC BY-NC-ND | 33431732 | 19,486,304 | 2021-06-01 |
What was the outcome of reaction 'Acute kidney injury'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Altered state of consciousness'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Ascites'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Cytomegalovirus nephritis'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Cytomegalovirus viraemia'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Drug level increased'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Hypoalbuminaemia'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Hypoxia'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Myeloma cast nephropathy'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Nephropathy toxic'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Overdose'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Pancytopenia'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Plasmacytoma'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Pleural effusion'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Toxic encephalopathy'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Toxicity to various agents'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
What was the outcome of reaction 'Tubulointerstitial nephritis'? | Vancomycin Intoxication and Cefepime-induced Encephalopathy Treated by Abdominal Drainage of Massive Ascites in Addition to Online Hemodiafiltration.
A patient with recurrent plasmacytoma with massive ascites exhibited vancomycin intoxication and cefepime-induced encephalopathy due to renal dysfunction. The ascitic accumulation of these drugs was suspected because of the refractory intoxicated state. To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was performed in addition to online hemodiafiltration. If patients with renal dysfunction and massive ascites develop vancomycin intoxication and cefepime-induced encephalopathy that cannot be improved by drug discontinuation, physicians should suspect ascitic accumulation and evaluate the ascitic concentration. Furthermore, if a high accumulation in massive ascites occurs, physicians should perform abdominal drainage along with blood purification.
Introduction
Antibiotics are either eliminated in active form through the kidney or metabolized through the liver. Therefore, it is necessary to adjust the antibiotic dosage and frequency of administration in patients with renal or hepatic failure (1,2). If symptoms of intoxication due to antibiotic overdose are suspected by physicians, they should monitor the blood concentration, discontinue the suspected drugs, administer antidotes, or perform blood purification (3,4). However, to our knowledge, there have been no reports focusing on the transfer and accumulation of suspected drugs into body fluids other than blood.
We herein report a case of plasmacytoma with massive ascites where vancomycin (VCM) and cefepime (CFPM) were administered as acute pyelonephritis developed along with bacteremia during chemotherapy, and subsequently, VCM intoxication and CFPM-induced encephalopathy (CIE) occurred due to renal dysfunction, resulting in the accumulation of these drugs in ascites.
Case Report
A 55-year-old man, with a history of plasmacytoma, was admitted to the hematology department of our hospital due to its recurrence. He had initially complained of a mass at his anterior chest a year and a half before. Based on the biopsy of the chest lesion, he was diagnosed with plasmacytoma. Positron emission tomography-computed tomography (PET-CT) revealed an increased 18F-fluorodeoxyglucose uptake in his anterior chest, upper thoracic spine, lumbar spine, sacrum, and both scapulae. The spinal lesions caused lower limb paralysis and bladder disturbance, which were difficult to improve with spinal surgery. Several types of chemotherapy (two cycles of vincristine, doxorubicin, and dexamethasone; two cycles of bortezomib, lenalidomide, and dexamethasone; and 11 cycles of pomalidomide, cyclophosphamide, and dexamethasone) controlled exacerbation of plasmacytoma, but lower limb paralysis and bladder disturbance continued.
The patient visited our hospital with a new complaint of abdominal distention. Computed tomography (CT) revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (Fig. 1a, b). The cytological examination of ascites revealed atypical plasma cells, suggesting recurrence of plasmacytoma.
Figure 1. CT imaging. (a, b) Abdominal CT captured on admission revealed massive ascites with a low Hounsfield unit value and multiple intraperitoneal lesions (white arrows). (c, d) Follow-up CT revealed shrinkage of the lesions (white arrows) (c: day 40, d: day 54).
On day 2 of admission, daratumumab, bortezomib, and dexamethasone were initiated; however, he developed acute pyelonephritis with bacteremia on day 8, and ceftazidime (CAZ) was initiated. His body temperature decreased from day 9 to day 10; however, it increased again on day 11, and antibiotics escalation (from CAZ to CFPM) was performed. As the causative bacteria, Klebsiella pneumoniae, was proven to be sensitive to cefazolin (CEZ), antibiotics de-escalation (from CFPM to CEZ) was performed on day 16, but his body temperature increased again on day 21 and did not decrease despite repeated escalation of antibiotics (from CEZ to CFPM). Based on urinary culture on day 21, urinary tract infection due to Enterococcus faecium was suspected, so VCM was added to CFPM on day 24.
Follow-up CT to evaluate the state of plasmacytoma demonstrated progressive disease, so as a stronger regimen, carfilzomib, lenalidomide, and dexamethasone were initiated on day 25. On day 26, acute kidney injury (AKI) was observed. On day 29, aggravation of AKI and high serum levels of VCM were observed, so VCM was discontinued, and infusion of crystalloid was initiated. On day 30, consciousness disorder was observed, and the patient was referred to the nephrology department with suspicion of uremia.
His body height was 176.4 cm, body weight 61.7 kg, blood pressure 100/62 mmHg, heart rate 80 beats/min, body temperature 37.2°C, respiratory rate 16 beats/min, blood oxygen saturation level 98% with oxygen administered at 2 L/min, and Glasgow Coma Scale E4V4M5. A physical examination revealed abdominal distention; however, an examination of the other parts of the body was unremarkable. No lung rales or heart murmurs were detected on chest auscultation. Laboratory findings revealed renal dysfunction, pancytopenia, hypoalbuminemia, high serum levels of VCM, and high urinary levels of β2-microglobulin (β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) (Table). The possibility of prerenal and postrenal AKI was considered limited as a cause of renal dysfunction, since laboratory findings did not show a low fractional excretion of sodium or urea nitrogen; echocardiography did not reveal collapse of the inferior vena cava (IVC), left ventricular asynergy, or valvular dysfunction; and abdominal CT revealed no evidence of expansion of the renal pelvises. The possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, uncontrolled urinary tract infection, uremia, and thrombotic thrombocytopenic purpura (TTP) were considered limited as a cause of consciousness disorder, since head CT and magnetic resonance imaging (MRI) revealed no evidence of intracranial lesions, an examination of the cerebrospinal fluid (CSF) revealed no evidence of cell proliferation or atypical cells, a sufficient amount of antibiotics effective against the causative bacteria had been administered, and the laboratory findings did not show high anion gap metabolic acidosis, decreased serum haptoglobin levels, or decreased activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) (Table). It was therefore suspected that AKI had developed due to myeloma kidney and VCM intoxication, since the laboratory findings showed high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG. Simultaneously, it was also suspected that consciousness disorder might have developed due to CIE, since a large amount of CFPM had been administered in the presence of renal dysfunction. Indeed, electroencephalography (EEG) showed triphasic waves but not epileptic waves, consistent with drug-induced encephalopathy.
Table. Laboratory Findings on the Patient Referral to the Nephrology Department.
Blood cell count Coagulation Venous blood gas
WBC 1,860 /μL PT-INR 1.27 pH 7.39
RBC 2.48×106 /μL APTT 35.7 s pCO2 40.1 mmHg
Hb 8.1 g/dL Fibrinogen 396 mg/dL pO2 74.1 mmHg
Hct 24.0 % D-dimer 0.79 µg/mL HCO3- 23.9 mmol/L
Plt 3.3×104 /μL Drug monitoring Base excess -0.9 mmol/L
Blood chemistry VCM levels 47.1 µg/mL Anion gap 7.8 mmol/L
CRP 4.44 mg/dL Immunochemistry Lactate 0.69 mmol/L
TP 3.4 g/dL IgG 213 mg/dL
Alb 1.6 g/dL IgA 21 mg/dL Urinalysis
AST 29 U/L IgM 3 mg/dL pH 1.008
ALT 14 U/L IgG4 8.9 mg/dL Protein (1+)
LDH 276 U/L Free light chain κ 6.4 mg/dL 4.17 g/gCre
T-Bil 0.3 mg/dL Free light chain λ 1,044 mg/dL Occult blood (1+)
BUN 69.4 mg/dL Bence-Jones protein Positive RBC 5-9 /HPF
Cre 3.24 mg/dL ADAMTS13-activity 49 % WBC 5-9 /HPF
eGFR 16.97 mL/min ANA Less than ×40 titer Granular casts few/LPF
Na 128 mEq/L MPO-ANCA Negative Dysmorphic RBC Negative
K 5.0 mEq/L PR3-ANCA Negative UN 182 mg/dL
Cl 97 mEq/L Anti-GBM antibody Negative Na 58 mEq/L
Ca 10.1 mg/dL ACE 16.1 IU/L Cl 69 mEq/L
Mg 3.7 mg/dL EBV-VCA IgM Less than ×10 titer Cre 15.4 mg/dL
iP 5.2 mg/dL EBV-VCA IgG ×40 titer NAG 141.4 U/L
UA 5.3 mg/dL EBNA ×20 titer β2MG 53,948 µg/L
Haptoglobin 97 mg/dL CMV antigenemia Positive Bence-Jones protein Positive
β2MG 38.1 mg/L NH3 22 µg/dL
eGFR: estimated glomerular filtration rate, β2MG: β2-microglobulin, VCM: vancomycin, ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13, ANA: antinuclear antibody, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ACE: angiotensin-converting enzyme, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, NAG: N-acetyl-beta-D-glucosaminidase
To improve his VCM intoxication and CIE, VCM and CFPM were discontinued on day 29; however, there was no trend of decreased serum levels of VCM or consciousness recovery. Thus, on day 32, online hemodiafiltration (OHDF) was conducted to remove these drugs. An ascites examination revealed high ascitic concentrations of VCM, suggesting a refractory intoxicated state of the patient due to the accumulation of VCM and CFPM in massive ascites.
To remove these drugs that had accumulated in the blood and ascites, abdominal drainage was also performed in addition to OHDF. After performing OHDF thrice and abdominal drainage twice, the serum and ascitic levels of VCM decreased to 10-15 μg/mL. Every session was pre-dilution and the volume of substitutes was 72 L/session in OHDF. Furthermore, the consciousness of the patient recovered (from E4V4M5 on day 30 to E4V5M6 on day 37), and triphasic waves captured on the first EEG disappeared in the second EEG on day 40. Follow-up CT demonstrated progressive disease (Fig. 1c), so a stronger regimen of bortezomib, doxorubicin, and intermediate-dose dexamethasone was introduced on day 40.
Despite the successful removal of VCM, aggravated renal dysfunction and low urine output continued, resulting in hypoxia due to pleural effusion unresponsive to diuretic therapy. On day 40, thrice weekly sessions of hemodialysis (HD) were introduced. The patient developed cytomegalovirus (CMV) viremia on day 43, so ganciclovir was administered until negative conversion of CMV antigenemia. A significant improvement in the renal function was noted from day 47, and HD was discontinued on day 52. Follow-up CT captured on day 54 demonstrated a partial response (Fig. 1d), and blood tests revealed a decrease in the amount of free light chains, suggesting that the new regimen initiated on day 40 was effective against recurrent plasmacytoma. Therefore, the next cycle of the regimen was initiated on day 65.
A schematic outline of the clinical course is shown in Fig. 2.
Figure 2. The clinical course. Cre: serum creatinine level, UV: urine volume, CAZ: ceftazidime, CFPM: cefepime, CEZ: cefazolin, VCM: vancomycin, HD: hemodialysis, OHDF: online hemodiafiltration, DVd: daratumumab, bortezomib, and dexamethasone, KRd: carfilzomib, lenalidomide, and dexamethasone, iPAD: bortezomib, doxorubicin, and intermediate-dose dexamethasone, sVCM: serum concentration of vancomycin, aVCM: ascitic concentration of vancomycin
Discussion
We herein report a patient with recurrent plasmacytoma to whom VCM and CFPM were administered because of the development of acute pyelonephritis with bacteremia during chemotherapy, and subsequently VCM intoxication and CIE occurred in the presence of renal dysfunction. Abdominal drainage was performed in addition to OHDF, as the possibility of accumulation of these drugs in massive ascites was suspected, leading to the successful treatment of VCM intoxication and CIE. We searched for the phrases “vancomycin/poisoning” [MeSH terms], “cefepime/adverse effects” [MeSH terms] in PubMed, and, to our knowledge, this is the first report to describe the transfer and accumulation of these drugs into ascites in a patient with VCM intoxication and CIE.
The pharmacokinetic characteristics of VCM are an approximately 80-90% excretion via urine, with a volume of distribution (Vd) of approximately 0.4-1.0 L/kg. In contrast, approximately 80% of CFPM is excreted via the urine, with a Vd of approximately 0.2 L/kg (5-7). VCM and CFPM were presumed to have a high transferability to ascites, since the ascitic concentrations of these drugs were increased after intravenous administration in patients with peritoneal dialysis and abdominal surgery (8-10), and the intravenous administration of these drugs was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients (11,12). In the present case, a large amount of newly developed ascites led to the diagnosis of recurrent plasmacytoma, so the patient was at risk of the ascitic accumulation of VCM and CFPM due to the high transferability to ascites. In addition, the risk of ascitic accumulation was increased because of the low urinary excretion of VCM and CFPM due to AKI. An ascites examination resulted in the early detection of the ascitic accumulation of these drugs.
The removal efficiency of a drug by HD mainly depends on its molecular weight, protein binding, Vd, and water solubility. Drugs satisfying the pharmacokinetic properties of a low molecular weight, low protein binding, low Vd, and high water solubility have a high removal efficiency by HD, while those without any of these properties have a low removal efficiency by HD. The removal of drugs less dialysable in HD requires the administration of antidotes or other techniques of blood purification, such as hemodiafiltration, plasma exchange, or plasma absorption (13). VCM has a relatively high molecular weight of 1,450 g/mol, protein binding of approximately 10-50%, low Vd of approximately 0.4-1.0 L/kg, and high water solubility, while CFPM has a relatively low molecular weight of 571.5 g/mol, protein binding of approximately 16-19%, low Vd of approximately 0.2 L/kg, and high water solubility (5-7,14). VCM was estimated to have a lower removal efficiency in HD than CFPM, as its molecular weight was higher than that of CFPM, although both drugs have low protein binding, low Vd, and high water solubility. In general, OHDF is more effective than HD at removing drugs of medium molecular weight. As reported previously, OHDF was effective in removing VCM (15); OHDF was therefore performed in the present case to remove both VCM and CFPM. However, an ascites examination suggested the accumulation of these drugs in massive ascites. The intoxicated state of the patient was presumed to be refractory due to the blood and ascitic accumulation, abdominal drainage was therefore performed in addition to OHDF to remove these drugs efficiently, resulting in the successful improvement of VCM intoxication and CIE.
In this case, myeloma kidney and drug-induced nephropathy were suspected as the primary causes of AKI and CIE as the primary cause of consciousness disorder. Prerenal and postrenal AKI were ruled out as the causes of AKI, since urine tests did not show a low fractional excretion of sodium or urea nitrogen, echocardiography did not reveal the collapse of the IVC, left ventricular asynergy, or valvular dysfunction, and abdominal CT revealed no evidence of expansion of the renal pelvises. High urinary levels of β2MG and NAG suggested the presence of tubulointerstitial damage of the kidneys. Laboratory findings did not support the possibility of systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, IgG4-related disease, ANCA-associated vasculitis, anti-glomerular basement membrane disease, or hyperuricemia. Uncontrolled urinary tract infection was also ruled out, as a sufficient amount of antibiotics effective against the causative bacteria had been administered. It was finally concluded that myeloma kidney and VCM-induced nephropathy were the primary causes of AKI, as the patient developed refractory plasmacytoma with high serum levels of free light chains, and a high serum level of VCM was observed. Despite the introduction of a stronger regimen for plasmacytoma, discontinuation of VCM, OHDF, and abdominal drainage, rapidly progressive renal dysfunction was observed, resulting in the introduction of HD on day 40. The low urine output initially continued; however, the renal function started to improve on day 47, and HD was discontinued on day 52.
On the other hand, the laboratory findings did not support the possibility of abnormal blood sugar levels, electrolyte imbalance, hyperammonemia, or TTP as a cause of consciousness disorder. Imaging findings, the examination of the CSF, and the EEG did not support the possibility of stroke, meningoencephalitis, plasmacytoma invasion to the central nervous system, or epilepsy. Uremia was also ruled out as well, since consciousness disorder remained for several days even after the improvement of azotemia by OHDF. CIE was suspected as the primary cause of consciousness disorder, as a large amount of CFPM had been administered in the presence of renal dysfunction. Discontinuation of CFPM, OHDF, and abdominal drainage were performed to improve CIE, leading to an improvement in consciousness disorder.
Several differences were noted between a typical case of CIE and that observed in this case. The clinical characteristics of CIE are a median onset of approximately 4-5 days after CFPM initiation, improvement of neurotoxicity symptoms several days after treatment, including blood purification, and renal dysfunction (16,17). In contrast, the present case had a relatively long period from CFPM initiation (day 21) to the onset of CIE (day 30) and a relatively long period from CFPM discontinuation (day 29) to the improvement in consciousness disorder (day 37), atypical as a clinical course of CIE. The atypical course of CIE in this case may have been due to massive ascites acting as a kind of “buffer agent”. CFPM concentrations in the CSF might not increase easily due to its high transferability into ascites; however, once the concentration in the CSF rose to the degree that the patient developed CIE, the concentration might have remained unchanged due to the marked accumulation in ascites, resulting in prolonged CIE.
In this case report, four clinical problems remained to be discussed. First, there was no direct proof of CIE or the CFPM accumulation in ascites, as the CFPM concentrations in the blood, ascites, and CSF could not be examined due to the lack of insurance coverage in Japan. However, the discussion concerning the pharmacokinetics of CFPM in this case is valid, since other etiologies of consciousness disorder were ruled out, the consciousness disorder and EEG findings were improved after the treatment according to CIE, CFPM had high transferability into ascites according to previous reports that ascitic concentrations of CFPM were increased after its intravenous administration in patients with peritoneal dialysis and abdominal surgery, and the administration of CFPM was effective against peritonitis in peritoneal dialysis patients and spontaneous bacterial peritonitis in liver cirrhosis patients. Second, abdominal drainage may not have been needed to improve VCM intoxication and CIE. The intoxicated state of the patient could have been treated by OHDF alone without abdominal drainage; however, more sessions of OHDF would have been required to remove these drugs that were accumulated in blood and massive ascites. Third, the definitive diagnosis of AKI was not confirmed, as performing a renal biopsy was difficult due to the low platelet count. Recurrent plasmacytoma with high serum levels of free light chains and VCM and high urinary levels of β2MG and NAG suggested the possibility of myeloma kidney and VCM-induced nephropathy, while CMV viremia also suggested the possibility of CMV nephropathy. Furthermore, carfilzomib-related AKI was not ruled out (18). Fourth, lenalidomide-related encephalopathy was not ruled out. Lenalidomide-related neurological and psychiatric disorders, such as headache, dizziness, tremor, peripheral neuropathy, or anxiety may occur, although consciousness disorder is a rare complication (19-27). Ischemic stroke and progressive multifocal leukoencephalopathy are reported to be lenalidomide-related encephalopathies detectable with head MRI (28,29). Since head MRI showed no abnormal findings in this case, the possibility of lenalidomide-related encephalopathy was considered limited.
In summary, we herein report a case of recurrent plasmacytoma developing VCM intoxication and CIE due to VCM and CFPM overdose in the presence of renal dysfunction, resulting in the transfer and accumulation of these drugs into massive ascites. If patients with an impaired renal function and massive ascites develop VCM intoxication and CIE, physicians should consider the possibility of these agents' transfer and accumulation into ascites and evaluate the ascitic concentration of the suspected drugs. Furthermore, if the high accumulation of drugs in massive ascites occurs, to reduce the number of sessions of blood purification, physicians should consider performing abdominal drainage in addition to blood purification.
Informed consent was obtained from all individual participants included in the study.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33431732 | 19,478,242 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thyroiditis'. | Clinical Studies on Potassium Iodide-induced Painless Thyroiditis in 11 Graves' Disease Patients.
Objective Painless thyroiditis (PT) is characterized by transient hyperthyroidism with a low 99mTc uptake. We herein describe 11 cases of PT that occurred during treatment with potassium iodide (KI) for Graves' disease (GD). Methods From August 2016 to December 2018, 11 women with GD who developed PT during treatment with KI were enrolled. Of these patients, 10 discontinued antithyroid drug (ATD) because of side effects and began KI, and 1 patient switched from thiamazole to KI because she was planning a pregnancy. The mean patient age was 40.1 years old. Thyroid function tests, thyroid autoantibodies including anti thyroglobulin antibody (TgAb), anti-thyroperoxidase antibody (TPOAb), and M22-TRAb, and the 99mTc uptake were evaluated at the time of PT. Results All 11 women patients presented with transient thyrotoxicosis in which 99mTc scans revealed a low uptake of 0.34±0.15% (normal 0.70-1.02%). M22-TRAb was absent in all cases except for one (2.4 IU/L), whereas TgAb and TPOAb were present in 10 and 6 cases, respectively. Ten patients returned to a euthyroid status without passing through the post-hypothyroid phase, and one patient underwent total thyroidectomy during the euthyroid phase of PT. Only four patients require beta-blocker therapy. All patients with KI-induced PT except 1 displayed GD remission during a mean observation period of 23.3 months, and 1 patient had recurrence of GD after PT. Conclusion We encountered 11 GD patients who developed PT during treatment with KI, which was initiated after ATD had been discontinued due to side effects.
Introduction
The administration of stable iodine to hyperthyroid patients provides a clinical benefit (1-3). In Japan, where the iodine intake is sufficient, among hyperthyroid patients with antithyroid drug (ATD)-associated side effects, potassium iodide (KI) therapy is effective in two-thirds of cases, and about 40% of patients experience remission after KI therapy alone (4). In patients with mild Graves' disease (GD), KI is a possible alternative initial treatment for this condition (5).
Painless thyroiditis (PT also called silent thyroiditis) can be subclassified into the sporadic type (unrelated to pregnancy), postpartum thyroiditis, gestational PT (6), exogenous PT, and others.
We herein report cases of KI-induced PT that occurred during treatment for GD, mostly after the cessation of ATD due to side effects.
Materials and Methods
From August 2016 to December 2018, 11 patients who met the eligibility criteria and gave their written informed consent were enrolled in the study. The study cohort comprised 11 women who developed PT during treatment with KI at 50 mg or 100 mg daily (50 mg KI is equivalent to 38.2 mg inorganic iodide; Nichiiko, Tokyo, Japan) for GD. These patients were outpatients of the Kamijo Thyroid Clinic, and the median age at the diagnosis was 40 years old (range, 21-56 years old). Ten GD patients discontinued thionamide due to side effects and began to take KI. The remaining patient discontinued methylmercaptoimidazole (MMI) and switched to KI because she was planning a pregnancy.
Tests (normal ranges in parentheses) were performed with an electrochemiluminescence immunoassay (Roche Diagnostics, Mannheim, Germany) for free thyroxine (FT4) (0.80 to 1.90 ng/dL), free triiodothyronine (FT3) (2.00-4.40 pg/mL), and thyrotropin (TSH) (0.45-4.50 μU/mL). The thyroid weight was estimated by the previously reported method (7). The normal range of female thyroid weight is 15 to 25 g. The cut-off values of anti-thyroperoxidase antibody (TPOAb) and anti-thyroglobulin antibody (TgAb) were 30 and 40 IU/L, respectively, and the values were calculated by a receiver operating characteristic (ROC) analysis based on patients with Hashimoto's disease and normal controls pathologically diagnosed according to resected tissue (data not shown). The M22-TRAb levels were measured with the inhibition assay kit Elecsys anti-TSH receptor assay (Roche Diagnostic) according to the manufacturer's instructions (8). This assay detects M22-TRAb via the inhibition of a monoclonal antibody (M22), which binds to the extracellular domain of porcine TSH receptor. M22-TRAb was considered present when the value exceeded 2.0 IU/L (8). The intra- and inter-assay coefficients of variation for M22-TRAb in 4 different serum samples ranged from 0.8-9.4% and 1.3-22.0%, respectively. The 20-minute uptake of 99mTc pertechnetate was assessed immediately after thyrotoxicosis was diagnosed. According to the ROC analysis with untreated GD (n=1,234) and PT (n=679), the 99mTc uptake cut-off value was to be 1.02%. The sensitivity and specificity of the optimal cut-off value were 99.8% and 100%, respectively. When the 99mTc uptake is <0.70%, all thyrotoxic patients are considered to have PT. Thus, the reference range is 0.70% to 1.02%.
The diagnosis of PT was based on 1) a transient increase in FT3 and FT4 with suppressed TSH (<0.01 μU/mL), 2) a painless thyroid gland, and 3) a marked decrease in the thyroid 99mTc uptake. In all cases, PT occurred during treatment with KI. None of the 11 patients were using levothyroxine or amiodarone at the time of the diagnosis.
Results
Enrollment and characteristics of patients with KI-induced PT
Table 1 summarizes the clinical and laboratory findings of the 11 patients. The dose of KI at the diagnosis of PT was 52.1±19.3 (mean±standard deviation) mg daily (range, 38.2-76.4). Routine blood work detected evidence of thyrotoxicosis approximately 18.5±14.5 months (range, 2.0-45.0) after the initiation of KI therapy.
Table 1. Summary of the Clinical and Laboratory Findings and Thyroid Tests at the Diagnosis of PT in 11 Patients with KI-induced PT.
Case No. Age (years) Reason for use of KI KI dose (mg) FT4 levels (N: 0.80-1.90 ng/dL) FT3 levels (N: 2.00-4.40 pg/mL) TSH levels (N: 0.45-4.50 μU/mL) Thyroid weight (10-25 g) 99mTc uptake (N: 0.70-1.02%) M22-TRAb (N: ≤2.0 IU/L) TPOAb (N: <30 IU/mL) TgAb (N:<40 IU/mL)
1 29 Side effect of PTU 38.2 2.74 6.51 <0.01 26 0.59 0.3 597.1 775
2 21 Side effect of MMI 76.4 3.81 10.34 <0.01 43 0.27 0.5 92.2 72.7
3 38 Side effect of MMI 38.2 3.06 8.53 <0.01 36 0.21 2.4 17.4 2,023
4 55 Side effect of MMI 76.4 2.04 6.67 <0.01 25 0.30 0.3 <5.0 301.4
5 56 Side effect of MMI 38.2 2.34 4.5 <0.01 23 0.33 0.7 126.2 1,035
6 53 Side effect of MMI 38.2 4.74 14.77 <0.01 35 0.65 0.3 600 496.3
7 37 Side effect of MMI and PTU 38.2 4.64 10.63 <0.01 34 0.26 1.3 14.6 68.3
8 38 Planning a pregnancy 38.2 2.34 5.73 <0.01 33 0.29 0.3 <5.0 301.4
9 34 Side effect of MMI 76.4 2.77 6.55 <0.01 36 0.21 0.6 536.3 684.4
10 52 Side effect of MMI 38.2 2.51 5.51 <0.01 34 0.39 0.3 119.7 4,000
11 28 Side effect of MMI 76.4 2.01 5.05 <0.01 50 0.20 1.9 12.8 19.5
Mean±standard deviation 52.1±19.3 3.00±0.98 7.71±3.10 34.1±7.0 0.34±0.15
Range 38.2-76.4 2.01-4.74 4.50-14.77 23-50 0.20-0.65
PT: painless thyroiditis, KI: potassium iodide, PTU: propylthiouracil, MMI: methylmercaptoimidazole, TPOAb: anti-thyroperoxidase antibody, TgAb: anti-thyroglobulin antibody
Blood tests revealed suppressed TSH (<0.01 μU/mL) along with elevated FT4 (3.00±0.98 ng/dL (mean±standard deviation) (normal, 0.80-1.90 ng/dL) and FT3 (7.71±3.10 pg/mL (normal, 2.00-4.40 pg/mL). During the thyrotoxic phase, serologic tests and a thyroid scan with 99mTc were performed in all 11 patients. M22-TRAb was negative except in 1 patient whose value (2.4 IU/L) was just above the reference range (normal: <2.0 IU/L). Six patients (54.5%) had elevated TPOAb (>30 IU/mL), and 10 (90.9%) had elevated TgAb (>40 IU/mL). The thyroid weights were mildly enlarged [34.1±7.0 g (normal, 15-25g)]. A thyroid scan with 99mTc revealed a decreased uptake at 0.34±0.15% (reference range, 0.80-1.20%). The thyroid images obtained by 99mTc scan in all patients with KI-induced PT showed an extremely diminished uptake by the thyroid, although a dark structure was visible in the salivary glands, consistent with PT, as shown in Fig. 1.
Figure 1. 99mTc thyroid scan showing an extremely diminished uptake by the thyroid, although a dark structure is visible in the salivary glands.
KI treatment was promptly discontinued after the diagnosis of PT in all patients. During the thyrotoxic phase, 8 patients (73%) were symptomatic, with palpitations being the most common symptom, followed by shortness of breath, tremors, perspiration, heat intolerance, and fatigue. Four patients required temporary β-blocker therapy. No specific therapeutic intervention was required for these patients because their thyroid dysfunction resolved spontaneously.
Timeline of PT
The details of the clinical course and prognosis of the 11 patients are shown in Table 2. The mean period from thyrotoxicosis to euthyroidism was 72.7±45.9 days (range, 34-174 days). The FT4 levels at 100.4±30.0 days prior to PT were normal at 1.43±0.22 ng/dL (range, 1.00-1.70 ng/dL). The euthyroid condition remained in 9 patients for 315.2±44.1 days (range, 84-558 days) after PT. No hypothyroidism following thyrotoxicosis was observed.
Table 2. The Clinical Course and Prognosis of KI-induced PT.
Case No. FT4 value (months: mos) prior to PT Months to PT from KI initiation FT4 values at PT β-blocker Days to spontaneous normalization FT4 values at normalization Hypothyroid phase Prognosis after PT
1 1.56 (2 mos) 2 2.74 Not 54 0.98 no Total thyroidectomy immediately after recovery from PT
2 1.53 (2 mos) 24 3.81 Pr 132 1.51 no GD remission for 14 mos
3 1.53 (2 mos) 6 3.06 Not 41 1.49 no GD remission for 24 mos
4 1.06 (2 mos) 36 2.04 Not 34 1.00 no GD remission for 24 mos
5 1.58 (4 mos) 12 2.34 Not 41 1.30 no GD recurred 49 days after recovery from PT
6 1.23 (3 mos) 10 4.74 Not 48 0.81 no GD remission for 26 mos
7 1.29 (3 mos) 45 4.64 Not 45 1.67 no GD remission for 34 mos
8 1.31 (4 mos) 36 6.89 Pr 84 1.22 no GD remission for 22 mos
9 1.78 (4 mos) 16 2.77 Not 108 1.53 no GD remission for 22 mos
10 1.26 (4 mos) 9 2.51 Pr 44 1.31 no GD remission for 36 mos
11 1.70 (2 mos) 12 2.01 Pr 174 0.94 no GD remission for 8 mos
Mean± standard deviation 1.44±0.22 (2.9±0.9) 18.9±14.0 3.41±1.49 73.2±46.1 1.25±0.29
Range 1.06-1.78 (2.0-4.0) 2.0-45.0 (2.01-6.89) (34-174) (0.81-1.67)
KI: potassium iodide, PT: painless thyroiditis, Pr: prescribed, Not: not prescribed, GD: Graves’ disease
In case 5 only, GD recurred 49 days after PT, as shown in Table 2. Case 1 who was planning a pregnancy underwent total thyroidectomy immediately after recovery from PT, as described in detail below.
Pathological findings
Case 1 stopped propylthiouracil (PTU) because of myeloperoxidase-anti-neutrophil cytoplasmic antibody [MPO-ANCA: 14.3 IU/mL (normal, <3.5)]-associated general arthralgia and started KI (50 mg daily). Seventy-seven days after the initiation of KI, she developed PT. The patient received no therapy, and 54 days later she was clinically euthyroid with FT3 2.31 pg/mL, FT4 0.98 ng/dL, and TSH <0.01 μU/mL. She therefore underwent total thyroidectomy 71 days later, as previously decided. The histology of the resected thyroid showed cells in the papillary folds that extended into the lumen of the follicles (Fig. 2a), consistent with GD and disrupted thyroid follicles (Fig. 2b). No oxyphilia or evidence of granulomatous thyroiditis was seen.
Figure 2. Pathology of the resected thyroid gland in a 29-year-old female Graves’ disease patient with KI-induced painless thyroiditis. The cells are present in the papillary folds and extend into the lumen of the follicles [arrow in (a)] and (b) disrupted follicles [arrowhead in (b)] (Hematoxylin and Eosin staining, ×20).
Discussion
To our knowledge, the present study is the first case study of patients who developed PT during treatment with KI for GD. Ten patients started KI because of discontinuation of ATD due to side effects. At the diagnosis of the thyrotoxic phase of PT, the mean 99mTc scintigram was 0.34% (range 0.20-0.60%), and all patients spontaneously achieved clinical and biochemical euthyroidism, consistent with PT. In this study, no hypothyroidism following thyrotoxicosis was observed. More recently in 2020, outside of our observation period, two patients with KI-induced PT showed spontaneous resolution with subsequent hypothyroidism. One of these two patients is currently receiving levothyroxine (data unshown).
Interestingly, 60.7% of cases of PT that occurred in GD patients, directly recovered to a euthyroid status without passing through the hypothyroid phase, in contrast with 40% of cases of PT in Hashimoto's thyroiditis patients (6). Regarding the spontaneous remission of GD, Codaccioni et al. (9) reported that treatment of patients with hyperthyroid GD with β-adrenergic antagonist drugs was followed by remission of hyperthyroidism in 30.8% of cases. Their patients showed a homogeneous thyroid 99mTc uptake and 62% of them were positive for TSAb at the diagnosis of GD. In contrast, our reported cases showed an extremely diminished thyroid 99mTc uptake, although the dark structures were visible in the salivary gland. These finding were consistent with PT, that occurred in Hashimoto's thyroiditis patients.
In our experience, 99mTc uptake was not significantly different between PT occurring in GD remission (n=163) and KI-induced PT (n=11) (0.38±0.19% vs 0.34±0.15%; p=0.4785). However, Hays and Wesselossky (10) reported that Lugol's solution induced the suppression of the 99mTc thyroid uptake. In fact, Hamada et al. (11) reported two patients with mild GD who were misdiagnosed as PT because of low 99mTc uptake during KI therapy. However, they also emphasized that, aside from two cases, the 99mTc uptake could be used to differentiate PT from GD in most of patients with GD receiving KI therapy. Further studies will be needed to establish the effect of iodine on the 99mTc uptake.
In our study, only 1 patient showed relapse of GD 49 days after PT, and another patient underwent a total thyroidectomy with recovery of euthyroidism as previously decided because she was planning a pregnancy. The mechanism underlying the high remission rates of GD after KI-induced PT remained unclear. However, there was a case report of spontaneous remission of GD preceded by PT (12), suggesting that PT might have some effect on the prognosis of GD.
Physiologically, iodine is an indispensable constituent of thyroid hormones, and the recommended daily adult iodine intake is 150 μg. The thyroid gland has intrinsic regulatory mechanisms that maintain normal thyroid function even in the presence of iodine excess (13). Wolff and Chaikoff (14) reported that the organic binding of iodide in the rat thyroid is blocked when the plasma iodide level reaches a critical threshold. This acute inhibitory effect of iodide on thyroid hormone synthesis is called the acute Wolf-Chaikoff effect and is due to increased intrathyroid iodine concentration. They next demonstrated that this inhibitory effect of excess iodide is transient, lasting approximately 48 hours, which was known as escape from the acute Wolff-Chaikoff effect. Eng et al. demonstrated the escape from it was caused by a decrease in Na+/I- symporter mRNA with a resultant decreased iodide transport into the thyroid (15).
In addition to this physiological action of iodide, the administration of stable iodine to hyperthyroid patients produces clinical benefits by inhibiting the release of thyroid hormone (16) and its synthesis due to a decrease in TPO mRNA (12). Historically, iodine was used to treat toxic goiter as early as 1840 by von Basedow, who reported an improvement in all clinical symptoms by iodine administration in one woman (17). From Japan, Okamura et al. (4) reported that KI therapy was effective in two-thirds of patients who discontinued ATD because of side effects, and about 40% of patients experienced remission after KI therapy alone.
In the present study, we prescribed KI for the treatment of GD patients who discontinued ATD because of adverse effects. Unexpectedly, we found that 11 patients developed PT during KI therapy.
Amiodarone is a benzofuranic derivative that contains approximately 37% iodine by weight. The amount of iodine released is approximately 6 mg/day for each 200-mg tablet. Interestingly, amiodarone also leads to destructive thyrotoxicosis, known as Type 2 amiodarone-induced thyrotoxicosis in the normal thyroid (18). Chiovato et al. (19) demonstrated in an in vitro study that amiodarone has a cytotoxic effect on FRTL-5 cells, CHO cells, and human thyroid follicles obtained from nontoxic goiters at surgery.
In contrast, KI has a cytotoxic effect on only human thyroid follicles that is abolished by MMI. Furthermore, Xu et al. (20) showed a cytotoxic effect due to KI by demonstrating that excess iodine contributes to autophagy suppression and apoptosis of thyroid follicular cells using a cell line of human thyroid follicular epithelial cells. The pathogenesis of KI-induced PT is unclear but may be related to this cytotoxic effect of KI. In addition, because 10 of the 11 patients in our current study with KI-induced PT were positive for TgAb and/or TPOAb, an autoimmune mechanism may be involved in this process.
Finally, we emphasize that clinicians who manage GD patients who received KI after discontinuing ATD due to side effects., should be alert for KI-induce PT.
Study limitations
The present study was limited by the fact that only patients treated for KI for GD after discontinuing ATD due to side effects were evaluated. Future studies should confirm whether or not untreated patients with GD who received initial therapy of KI similarly develop PT.
Conclusion
We herein report for the first time that 11 patients with GD developed PT during treatment with KI following ATD treatment cessation due to side effects.
The author states that he has no Conflict of Interest (COI). | POTASSIUM | DrugsGivenReaction | CC BY-NC-ND | 33431733 | 19,763,417 | 2021-06-01 |
What was the outcome of reaction 'Thyroiditis'? | Clinical Studies on Potassium Iodide-induced Painless Thyroiditis in 11 Graves' Disease Patients.
Objective Painless thyroiditis (PT) is characterized by transient hyperthyroidism with a low 99mTc uptake. We herein describe 11 cases of PT that occurred during treatment with potassium iodide (KI) for Graves' disease (GD). Methods From August 2016 to December 2018, 11 women with GD who developed PT during treatment with KI were enrolled. Of these patients, 10 discontinued antithyroid drug (ATD) because of side effects and began KI, and 1 patient switched from thiamazole to KI because she was planning a pregnancy. The mean patient age was 40.1 years old. Thyroid function tests, thyroid autoantibodies including anti thyroglobulin antibody (TgAb), anti-thyroperoxidase antibody (TPOAb), and M22-TRAb, and the 99mTc uptake were evaluated at the time of PT. Results All 11 women patients presented with transient thyrotoxicosis in which 99mTc scans revealed a low uptake of 0.34±0.15% (normal 0.70-1.02%). M22-TRAb was absent in all cases except for one (2.4 IU/L), whereas TgAb and TPOAb were present in 10 and 6 cases, respectively. Ten patients returned to a euthyroid status without passing through the post-hypothyroid phase, and one patient underwent total thyroidectomy during the euthyroid phase of PT. Only four patients require beta-blocker therapy. All patients with KI-induced PT except 1 displayed GD remission during a mean observation period of 23.3 months, and 1 patient had recurrence of GD after PT. Conclusion We encountered 11 GD patients who developed PT during treatment with KI, which was initiated after ATD had been discontinued due to side effects.
Introduction
The administration of stable iodine to hyperthyroid patients provides a clinical benefit (1-3). In Japan, where the iodine intake is sufficient, among hyperthyroid patients with antithyroid drug (ATD)-associated side effects, potassium iodide (KI) therapy is effective in two-thirds of cases, and about 40% of patients experience remission after KI therapy alone (4). In patients with mild Graves' disease (GD), KI is a possible alternative initial treatment for this condition (5).
Painless thyroiditis (PT also called silent thyroiditis) can be subclassified into the sporadic type (unrelated to pregnancy), postpartum thyroiditis, gestational PT (6), exogenous PT, and others.
We herein report cases of KI-induced PT that occurred during treatment for GD, mostly after the cessation of ATD due to side effects.
Materials and Methods
From August 2016 to December 2018, 11 patients who met the eligibility criteria and gave their written informed consent were enrolled in the study. The study cohort comprised 11 women who developed PT during treatment with KI at 50 mg or 100 mg daily (50 mg KI is equivalent to 38.2 mg inorganic iodide; Nichiiko, Tokyo, Japan) for GD. These patients were outpatients of the Kamijo Thyroid Clinic, and the median age at the diagnosis was 40 years old (range, 21-56 years old). Ten GD patients discontinued thionamide due to side effects and began to take KI. The remaining patient discontinued methylmercaptoimidazole (MMI) and switched to KI because she was planning a pregnancy.
Tests (normal ranges in parentheses) were performed with an electrochemiluminescence immunoassay (Roche Diagnostics, Mannheim, Germany) for free thyroxine (FT4) (0.80 to 1.90 ng/dL), free triiodothyronine (FT3) (2.00-4.40 pg/mL), and thyrotropin (TSH) (0.45-4.50 μU/mL). The thyroid weight was estimated by the previously reported method (7). The normal range of female thyroid weight is 15 to 25 g. The cut-off values of anti-thyroperoxidase antibody (TPOAb) and anti-thyroglobulin antibody (TgAb) were 30 and 40 IU/L, respectively, and the values were calculated by a receiver operating characteristic (ROC) analysis based on patients with Hashimoto's disease and normal controls pathologically diagnosed according to resected tissue (data not shown). The M22-TRAb levels were measured with the inhibition assay kit Elecsys anti-TSH receptor assay (Roche Diagnostic) according to the manufacturer's instructions (8). This assay detects M22-TRAb via the inhibition of a monoclonal antibody (M22), which binds to the extracellular domain of porcine TSH receptor. M22-TRAb was considered present when the value exceeded 2.0 IU/L (8). The intra- and inter-assay coefficients of variation for M22-TRAb in 4 different serum samples ranged from 0.8-9.4% and 1.3-22.0%, respectively. The 20-minute uptake of 99mTc pertechnetate was assessed immediately after thyrotoxicosis was diagnosed. According to the ROC analysis with untreated GD (n=1,234) and PT (n=679), the 99mTc uptake cut-off value was to be 1.02%. The sensitivity and specificity of the optimal cut-off value were 99.8% and 100%, respectively. When the 99mTc uptake is <0.70%, all thyrotoxic patients are considered to have PT. Thus, the reference range is 0.70% to 1.02%.
The diagnosis of PT was based on 1) a transient increase in FT3 and FT4 with suppressed TSH (<0.01 μU/mL), 2) a painless thyroid gland, and 3) a marked decrease in the thyroid 99mTc uptake. In all cases, PT occurred during treatment with KI. None of the 11 patients were using levothyroxine or amiodarone at the time of the diagnosis.
Results
Enrollment and characteristics of patients with KI-induced PT
Table 1 summarizes the clinical and laboratory findings of the 11 patients. The dose of KI at the diagnosis of PT was 52.1±19.3 (mean±standard deviation) mg daily (range, 38.2-76.4). Routine blood work detected evidence of thyrotoxicosis approximately 18.5±14.5 months (range, 2.0-45.0) after the initiation of KI therapy.
Table 1. Summary of the Clinical and Laboratory Findings and Thyroid Tests at the Diagnosis of PT in 11 Patients with KI-induced PT.
Case No. Age (years) Reason for use of KI KI dose (mg) FT4 levels (N: 0.80-1.90 ng/dL) FT3 levels (N: 2.00-4.40 pg/mL) TSH levels (N: 0.45-4.50 μU/mL) Thyroid weight (10-25 g) 99mTc uptake (N: 0.70-1.02%) M22-TRAb (N: ≤2.0 IU/L) TPOAb (N: <30 IU/mL) TgAb (N:<40 IU/mL)
1 29 Side effect of PTU 38.2 2.74 6.51 <0.01 26 0.59 0.3 597.1 775
2 21 Side effect of MMI 76.4 3.81 10.34 <0.01 43 0.27 0.5 92.2 72.7
3 38 Side effect of MMI 38.2 3.06 8.53 <0.01 36 0.21 2.4 17.4 2,023
4 55 Side effect of MMI 76.4 2.04 6.67 <0.01 25 0.30 0.3 <5.0 301.4
5 56 Side effect of MMI 38.2 2.34 4.5 <0.01 23 0.33 0.7 126.2 1,035
6 53 Side effect of MMI 38.2 4.74 14.77 <0.01 35 0.65 0.3 600 496.3
7 37 Side effect of MMI and PTU 38.2 4.64 10.63 <0.01 34 0.26 1.3 14.6 68.3
8 38 Planning a pregnancy 38.2 2.34 5.73 <0.01 33 0.29 0.3 <5.0 301.4
9 34 Side effect of MMI 76.4 2.77 6.55 <0.01 36 0.21 0.6 536.3 684.4
10 52 Side effect of MMI 38.2 2.51 5.51 <0.01 34 0.39 0.3 119.7 4,000
11 28 Side effect of MMI 76.4 2.01 5.05 <0.01 50 0.20 1.9 12.8 19.5
Mean±standard deviation 52.1±19.3 3.00±0.98 7.71±3.10 34.1±7.0 0.34±0.15
Range 38.2-76.4 2.01-4.74 4.50-14.77 23-50 0.20-0.65
PT: painless thyroiditis, KI: potassium iodide, PTU: propylthiouracil, MMI: methylmercaptoimidazole, TPOAb: anti-thyroperoxidase antibody, TgAb: anti-thyroglobulin antibody
Blood tests revealed suppressed TSH (<0.01 μU/mL) along with elevated FT4 (3.00±0.98 ng/dL (mean±standard deviation) (normal, 0.80-1.90 ng/dL) and FT3 (7.71±3.10 pg/mL (normal, 2.00-4.40 pg/mL). During the thyrotoxic phase, serologic tests and a thyroid scan with 99mTc were performed in all 11 patients. M22-TRAb was negative except in 1 patient whose value (2.4 IU/L) was just above the reference range (normal: <2.0 IU/L). Six patients (54.5%) had elevated TPOAb (>30 IU/mL), and 10 (90.9%) had elevated TgAb (>40 IU/mL). The thyroid weights were mildly enlarged [34.1±7.0 g (normal, 15-25g)]. A thyroid scan with 99mTc revealed a decreased uptake at 0.34±0.15% (reference range, 0.80-1.20%). The thyroid images obtained by 99mTc scan in all patients with KI-induced PT showed an extremely diminished uptake by the thyroid, although a dark structure was visible in the salivary glands, consistent with PT, as shown in Fig. 1.
Figure 1. 99mTc thyroid scan showing an extremely diminished uptake by the thyroid, although a dark structure is visible in the salivary glands.
KI treatment was promptly discontinued after the diagnosis of PT in all patients. During the thyrotoxic phase, 8 patients (73%) were symptomatic, with palpitations being the most common symptom, followed by shortness of breath, tremors, perspiration, heat intolerance, and fatigue. Four patients required temporary β-blocker therapy. No specific therapeutic intervention was required for these patients because their thyroid dysfunction resolved spontaneously.
Timeline of PT
The details of the clinical course and prognosis of the 11 patients are shown in Table 2. The mean period from thyrotoxicosis to euthyroidism was 72.7±45.9 days (range, 34-174 days). The FT4 levels at 100.4±30.0 days prior to PT were normal at 1.43±0.22 ng/dL (range, 1.00-1.70 ng/dL). The euthyroid condition remained in 9 patients for 315.2±44.1 days (range, 84-558 days) after PT. No hypothyroidism following thyrotoxicosis was observed.
Table 2. The Clinical Course and Prognosis of KI-induced PT.
Case No. FT4 value (months: mos) prior to PT Months to PT from KI initiation FT4 values at PT β-blocker Days to spontaneous normalization FT4 values at normalization Hypothyroid phase Prognosis after PT
1 1.56 (2 mos) 2 2.74 Not 54 0.98 no Total thyroidectomy immediately after recovery from PT
2 1.53 (2 mos) 24 3.81 Pr 132 1.51 no GD remission for 14 mos
3 1.53 (2 mos) 6 3.06 Not 41 1.49 no GD remission for 24 mos
4 1.06 (2 mos) 36 2.04 Not 34 1.00 no GD remission for 24 mos
5 1.58 (4 mos) 12 2.34 Not 41 1.30 no GD recurred 49 days after recovery from PT
6 1.23 (3 mos) 10 4.74 Not 48 0.81 no GD remission for 26 mos
7 1.29 (3 mos) 45 4.64 Not 45 1.67 no GD remission for 34 mos
8 1.31 (4 mos) 36 6.89 Pr 84 1.22 no GD remission for 22 mos
9 1.78 (4 mos) 16 2.77 Not 108 1.53 no GD remission for 22 mos
10 1.26 (4 mos) 9 2.51 Pr 44 1.31 no GD remission for 36 mos
11 1.70 (2 mos) 12 2.01 Pr 174 0.94 no GD remission for 8 mos
Mean± standard deviation 1.44±0.22 (2.9±0.9) 18.9±14.0 3.41±1.49 73.2±46.1 1.25±0.29
Range 1.06-1.78 (2.0-4.0) 2.0-45.0 (2.01-6.89) (34-174) (0.81-1.67)
KI: potassium iodide, PT: painless thyroiditis, Pr: prescribed, Not: not prescribed, GD: Graves’ disease
In case 5 only, GD recurred 49 days after PT, as shown in Table 2. Case 1 who was planning a pregnancy underwent total thyroidectomy immediately after recovery from PT, as described in detail below.
Pathological findings
Case 1 stopped propylthiouracil (PTU) because of myeloperoxidase-anti-neutrophil cytoplasmic antibody [MPO-ANCA: 14.3 IU/mL (normal, <3.5)]-associated general arthralgia and started KI (50 mg daily). Seventy-seven days after the initiation of KI, she developed PT. The patient received no therapy, and 54 days later she was clinically euthyroid with FT3 2.31 pg/mL, FT4 0.98 ng/dL, and TSH <0.01 μU/mL. She therefore underwent total thyroidectomy 71 days later, as previously decided. The histology of the resected thyroid showed cells in the papillary folds that extended into the lumen of the follicles (Fig. 2a), consistent with GD and disrupted thyroid follicles (Fig. 2b). No oxyphilia or evidence of granulomatous thyroiditis was seen.
Figure 2. Pathology of the resected thyroid gland in a 29-year-old female Graves’ disease patient with KI-induced painless thyroiditis. The cells are present in the papillary folds and extend into the lumen of the follicles [arrow in (a)] and (b) disrupted follicles [arrowhead in (b)] (Hematoxylin and Eosin staining, ×20).
Discussion
To our knowledge, the present study is the first case study of patients who developed PT during treatment with KI for GD. Ten patients started KI because of discontinuation of ATD due to side effects. At the diagnosis of the thyrotoxic phase of PT, the mean 99mTc scintigram was 0.34% (range 0.20-0.60%), and all patients spontaneously achieved clinical and biochemical euthyroidism, consistent with PT. In this study, no hypothyroidism following thyrotoxicosis was observed. More recently in 2020, outside of our observation period, two patients with KI-induced PT showed spontaneous resolution with subsequent hypothyroidism. One of these two patients is currently receiving levothyroxine (data unshown).
Interestingly, 60.7% of cases of PT that occurred in GD patients, directly recovered to a euthyroid status without passing through the hypothyroid phase, in contrast with 40% of cases of PT in Hashimoto's thyroiditis patients (6). Regarding the spontaneous remission of GD, Codaccioni et al. (9) reported that treatment of patients with hyperthyroid GD with β-adrenergic antagonist drugs was followed by remission of hyperthyroidism in 30.8% of cases. Their patients showed a homogeneous thyroid 99mTc uptake and 62% of them were positive for TSAb at the diagnosis of GD. In contrast, our reported cases showed an extremely diminished thyroid 99mTc uptake, although the dark structures were visible in the salivary gland. These finding were consistent with PT, that occurred in Hashimoto's thyroiditis patients.
In our experience, 99mTc uptake was not significantly different between PT occurring in GD remission (n=163) and KI-induced PT (n=11) (0.38±0.19% vs 0.34±0.15%; p=0.4785). However, Hays and Wesselossky (10) reported that Lugol's solution induced the suppression of the 99mTc thyroid uptake. In fact, Hamada et al. (11) reported two patients with mild GD who were misdiagnosed as PT because of low 99mTc uptake during KI therapy. However, they also emphasized that, aside from two cases, the 99mTc uptake could be used to differentiate PT from GD in most of patients with GD receiving KI therapy. Further studies will be needed to establish the effect of iodine on the 99mTc uptake.
In our study, only 1 patient showed relapse of GD 49 days after PT, and another patient underwent a total thyroidectomy with recovery of euthyroidism as previously decided because she was planning a pregnancy. The mechanism underlying the high remission rates of GD after KI-induced PT remained unclear. However, there was a case report of spontaneous remission of GD preceded by PT (12), suggesting that PT might have some effect on the prognosis of GD.
Physiologically, iodine is an indispensable constituent of thyroid hormones, and the recommended daily adult iodine intake is 150 μg. The thyroid gland has intrinsic regulatory mechanisms that maintain normal thyroid function even in the presence of iodine excess (13). Wolff and Chaikoff (14) reported that the organic binding of iodide in the rat thyroid is blocked when the plasma iodide level reaches a critical threshold. This acute inhibitory effect of iodide on thyroid hormone synthesis is called the acute Wolf-Chaikoff effect and is due to increased intrathyroid iodine concentration. They next demonstrated that this inhibitory effect of excess iodide is transient, lasting approximately 48 hours, which was known as escape from the acute Wolff-Chaikoff effect. Eng et al. demonstrated the escape from it was caused by a decrease in Na+/I- symporter mRNA with a resultant decreased iodide transport into the thyroid (15).
In addition to this physiological action of iodide, the administration of stable iodine to hyperthyroid patients produces clinical benefits by inhibiting the release of thyroid hormone (16) and its synthesis due to a decrease in TPO mRNA (12). Historically, iodine was used to treat toxic goiter as early as 1840 by von Basedow, who reported an improvement in all clinical symptoms by iodine administration in one woman (17). From Japan, Okamura et al. (4) reported that KI therapy was effective in two-thirds of patients who discontinued ATD because of side effects, and about 40% of patients experienced remission after KI therapy alone.
In the present study, we prescribed KI for the treatment of GD patients who discontinued ATD because of adverse effects. Unexpectedly, we found that 11 patients developed PT during KI therapy.
Amiodarone is a benzofuranic derivative that contains approximately 37% iodine by weight. The amount of iodine released is approximately 6 mg/day for each 200-mg tablet. Interestingly, amiodarone also leads to destructive thyrotoxicosis, known as Type 2 amiodarone-induced thyrotoxicosis in the normal thyroid (18). Chiovato et al. (19) demonstrated in an in vitro study that amiodarone has a cytotoxic effect on FRTL-5 cells, CHO cells, and human thyroid follicles obtained from nontoxic goiters at surgery.
In contrast, KI has a cytotoxic effect on only human thyroid follicles that is abolished by MMI. Furthermore, Xu et al. (20) showed a cytotoxic effect due to KI by demonstrating that excess iodine contributes to autophagy suppression and apoptosis of thyroid follicular cells using a cell line of human thyroid follicular epithelial cells. The pathogenesis of KI-induced PT is unclear but may be related to this cytotoxic effect of KI. In addition, because 10 of the 11 patients in our current study with KI-induced PT were positive for TgAb and/or TPOAb, an autoimmune mechanism may be involved in this process.
Finally, we emphasize that clinicians who manage GD patients who received KI after discontinuing ATD due to side effects., should be alert for KI-induce PT.
Study limitations
The present study was limited by the fact that only patients treated for KI for GD after discontinuing ATD due to side effects were evaluated. Future studies should confirm whether or not untreated patients with GD who received initial therapy of KI similarly develop PT.
Conclusion
We herein report for the first time that 11 patients with GD developed PT during treatment with KI following ATD treatment cessation due to side effects.
The author states that he has no Conflict of Interest (COI). | Recovered | ReactionOutcome | CC BY-NC-ND | 33431733 | 19,763,417 | 2021-06-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Atelectasis'. | Transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced tumor flare reaction.
Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as rapid enlargement of the tumor, which mimics disease progression, developing in the early stage of treatment using immunomodulatory drugs or immune checkpoint inhibitors. A 59-year-old man with follicular lymphoma had residual tumor burden in the left hilar lymph nodes after R-CHOP therapy, and received lenalidomide and rituximab (R2) therapy. He developed respiratory distress on day 11 of R2 therapy. Chest X-ray and CT demonstrated left lung atelectasis due to left hilar lymph node swelling. We performed transbronchial lung biopsy on day 20 of R2 therapy. The biopsied left bronchus tissue exhibited extensive necrosis, which had a B-cell phenotype consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. It was unclear whether the immune effector cells disappeared at the time of transbronchial lung biopsy. Atelectasis in our patient improved by continuing R2 therapy beyond TFR.
INTRODUCTION
Lenalidomide, an immunomodulatory drug, was reported to reactivate dysfunctional T and natural killer (NK) cells ex vivo by increasing their proliferative capacity and T-helper cell type 1 (Th1) cytokine release.1 Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as an increase in tumor burden, low-grade fever and rash. Lenalidomide-induced TFR involves the activation of NK cells and T cells, and their infiltration into the tumor sites.2
TFR was originally described in patients with chronic lymphocytic leukemia (CLL) treated using immunomodulatory drugs (IMiDs) (thalidomide and lenalidomide)3,4 TFR was also observed in mantle cell lymphoma, indolent non-Hodgkin lymphoma (NHL), aggressive NHL and Hodgkin lymphoma treated by lenalidomide.5
TFR mimics disease progression on imaging before an effective anti-tumor response occurs. A similar phenomenon, ‘pseudo-progression’, was also reported in multiple solid tumor types treated using immune checkpoint inhibitors (ICIs) resulting from T cells infiltrating the tumor site.6
We report a patient with refractory follicular lymphoma who exhibited transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced TFR.
CASE REPORT
A 58-year-old man visited a hospital in October 2019 for lymph node swelling and the left inguinal lymph node was biopsied. He was diagnosed with follicular lymphoma grade 3a (Figure 1 A–B) and referred to our hospital. We diagnosed his lymphoma as follicular lymphoma grade 3a, stage IV and FLIPI: high. We administered bendamustine, but it was ineffective. He then received R-CHOP therapy and had a partial response. After 5 courses of R-CHOP therapy, left hilar lymph node swelling remained on PET/CT with a SUV of 20.5 as the main lesion (Figure 2).
Fig. 1 Pathological findings: The inguinal lymph node at onset (A x 40, B x 400); The neoplastic follicles show a vaguely nodular pattern (A). Both centrocytes and centroblasts were present (B).
The biopsied left bronchus tissue (C–J x 200); On hematoxylin and eosin staining, dense infiltration of lymphocytes, which were almost all necrotic, was observed under the bronchial epithelium (C). Although they had necrotic change, they were CD10-positive (D), CD20-positive (E), PAX-5-positive (not shown) and bcl-2-posistive cells (F), which is consistent with the phenotype of follicular lymphoma. There were few CD3-positive cells (G), which were negative for granzyme B (H), i.e., not cytotoxic T cells. CD56-positive cells, i.e. NK cells, were not detected (I). CD68-positive cells considered to be macrophages were well noted (J).
Fig. 2 ?Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right). Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right).
We started R2 (lenalidomide at 20 mg/day, days 1-21 and rituximab at 375 mg/m2, day 1) therapy in June 2020 (day 1). At that time, the WBC count was 3,870/μl (3,500-8,500), containing 2,593/μl of neutrophils and 368/μl of monocytes. Hb was 12.4 g/dl (11.5-17.0), platelet count was 25.4 × 104/μl (15.0-35.0), LDH was 387 U/L (120-200) and CRP was 0.57 mg/dl (≤ 0.30). He was in a good condition on day 4 of R2 therapy. Eleven days after starting R2 therapy, he visited our hospital for respiratory discomfort. His body temperature was 36.5˚C, blood pressure was 129/62 mmHg and SpO2 (room air) was 89-90%. He exhibited grade 1 rash, but had no pain. The WBC count was 2,120/μl, containing 922/μl of neutrophils and 424/μl of monocytes. The monocyte count was relatively high at 20% of the WBC. Hb was 13.6 g/dl, platelet count was 29.3 × 104/μl, LDH was 264 U/L and CRP was 0.99 mg/dl. Chest X-ray revealed a left lung severe shadow (Figure 3). CT demonstrated left lung atelectasis due to left hilar obstruction by lymph node swelling (Figure 2).
Fig. 3 Clinical course of R2 therapy: Chest X-ray on days 11, 18, 28, 42 and 54. Chest imaging on day 0 was by CT because we did not perform chest X-ray at the start of R2 therapy.
After emergency hospitalization on day 11 of R2 treatment, he was stable on oxygen inhalation of 0.5 L/min at rest and 2 L/min when walking. Antihistamine was prescribed for rash. We continued the combination lenalidomide-rituximab (R2) immunotherapy. Although rituximab was administered 6 times through 5 courses of R-CHOP therapy and on day 1 of this course, it was added on day 13. The left hilar lymph node swelling and atelectasis did not improve on chest X-ray on day 18 (Figure 3). If the obstruction of the left bronchus was not due to TFR but to true progression, radiation therapy was considered necessary. We thus carried out transbronchial lung biopsy on day 20 of R2 treatment. The biopsied left bronchus tissue exhibited dense infiltration of lymphocytes, which were almost all necrotic. Although they had necrotic change, their phenotype was consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. Macrophages were well noted. (Figure 1 C–J).
Rituximab was added just after transbronchial lung biopsy on day 20. From around this time, his respiratory state improved. Chest X-ray on day 25 revealed a decrease in left hilar lymph node swelling and improvement of atelectasis. He no longer needed oxygen inhalation and was discharged. As chest X-ray on day 28 (Figure 3) revealed left lung expansion, he received a second cycle of R2 therapy from day 29. The left lung atelectasis expanded through the second cycle of R2 therapy (Figure 3). Central nervous system involvement developed thereafter and we changed R2 therapy to R-CHASE therapy, which contains high-dose cytarabine, and intrathecal administration of methotrexate, cytarabine and prednisolone.
DISCUSSION
TFR is acutely dependent on NK cell function, and is then maintained by the rapid recruitment and proliferation of T cells.2 Andritsos et al. reported increased CD3-positive, CD4-positive, CD8-positive and granzyme B-positive T-cells in an excised swollen tonsil after lenalidomide treatment.7 In the present case, the biopsied left bronchus tissue on day 20 of R2 therapy did not contain NK cells or cytotoxic T cells. Macrophages were relatively conspicuous. It is unclear whether NK cells and cytotoxic T cells disappeared at the time of transbronchial lung biopsy when the respiratory state began improving. Although it is possible that the left hilar lymph nodes swelled due to tumor progression without TFR, rapid enlargement just after the start of R2 therapy may have been related to TFR.
R2 therapy was reported to have favorable activity in patients with relapsed/refractory follicular lymphoma.8 Wang et al. found that lenalidomide with rituximab is effective even for transformed large cell lymphoma originating from follicular lymphoma.9 In a randomized study for relapsed/refractory diffuse large B-cell lymphoma, patients treated using lenalidomide had a longer progression-free survival than those treated at the investigator’s discretion (gemcitabine, rituximab, etoposide or oxaliplatin).10 Based on the resistance to chemotherapy in the present case, we expected complete remission via a unique mechanism of action from the combination of lenalidomide and rituximab rather than the intensity of salvage chemotherapy. Therefore, we selected R2 therapy even if transformation was possible.
Immunotherapy, such as IMiDs and ICIs, works differently from chemotherapy and takes more time to exhibit effects than cytotoxic drugs. Chanan-Khan et al. reported that TFR induced by immunomodulatory drugs, such as lenalidomide, develops in >90% of patients during the first treatment cycle and the median time to onset is 6 days.11 Goy et al. also found that TFR generally developed during the first cycle of lenalidomide, with few events during later cycles.12 Our patient exhibited a typical clinical course regarding the time of TFR. Steroids are used for the management of severe cases of TFR and prophylaxis. Chong et al. reported that patients who received once weekly low-dose (10 mg) dexamethasone had fewer dose interruptions for TFR during the first 8 weeks of lenalidomide.13 Our patient did not receive dexamethasone, but he was administered 100 mg of hydrocortisone once just before the start of rituximab on day 1, day 13 and day 20. Hydrocortisone acts for a short time, unlike dexamethasone. The present patient did not receive any steroids after hydrocortisone on day 1, until he received hydrocortisone on day 13. If dexamethasone had been administered weekly in the first course, TFR may have been less severe.
It is difficult to differentiate pseudo-progression due to TFR from true progression only by imaging, which largely relies on the tumor size.5 The identification of TFR is important to avoid the premature discontinuation of effective therapy because the intensity of TFR is correlated with the probability of achieving a complete response.11 TFR should be paid attention to in the early stage of treatment using immunomodulatory drugs.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest. | HYDROCORTISONE, LENALIDOMIDE, RITUXIMAB | DrugsGivenReaction | CC BY-NC-SA | 33431741 | 18,434,257 | 2021-03-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced tumor flare reaction.
Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as rapid enlargement of the tumor, which mimics disease progression, developing in the early stage of treatment using immunomodulatory drugs or immune checkpoint inhibitors. A 59-year-old man with follicular lymphoma had residual tumor burden in the left hilar lymph nodes after R-CHOP therapy, and received lenalidomide and rituximab (R2) therapy. He developed respiratory distress on day 11 of R2 therapy. Chest X-ray and CT demonstrated left lung atelectasis due to left hilar lymph node swelling. We performed transbronchial lung biopsy on day 20 of R2 therapy. The biopsied left bronchus tissue exhibited extensive necrosis, which had a B-cell phenotype consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. It was unclear whether the immune effector cells disappeared at the time of transbronchial lung biopsy. Atelectasis in our patient improved by continuing R2 therapy beyond TFR.
INTRODUCTION
Lenalidomide, an immunomodulatory drug, was reported to reactivate dysfunctional T and natural killer (NK) cells ex vivo by increasing their proliferative capacity and T-helper cell type 1 (Th1) cytokine release.1 Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as an increase in tumor burden, low-grade fever and rash. Lenalidomide-induced TFR involves the activation of NK cells and T cells, and their infiltration into the tumor sites.2
TFR was originally described in patients with chronic lymphocytic leukemia (CLL) treated using immunomodulatory drugs (IMiDs) (thalidomide and lenalidomide)3,4 TFR was also observed in mantle cell lymphoma, indolent non-Hodgkin lymphoma (NHL), aggressive NHL and Hodgkin lymphoma treated by lenalidomide.5
TFR mimics disease progression on imaging before an effective anti-tumor response occurs. A similar phenomenon, ‘pseudo-progression’, was also reported in multiple solid tumor types treated using immune checkpoint inhibitors (ICIs) resulting from T cells infiltrating the tumor site.6
We report a patient with refractory follicular lymphoma who exhibited transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced TFR.
CASE REPORT
A 58-year-old man visited a hospital in October 2019 for lymph node swelling and the left inguinal lymph node was biopsied. He was diagnosed with follicular lymphoma grade 3a (Figure 1 A–B) and referred to our hospital. We diagnosed his lymphoma as follicular lymphoma grade 3a, stage IV and FLIPI: high. We administered bendamustine, but it was ineffective. He then received R-CHOP therapy and had a partial response. After 5 courses of R-CHOP therapy, left hilar lymph node swelling remained on PET/CT with a SUV of 20.5 as the main lesion (Figure 2).
Fig. 1 Pathological findings: The inguinal lymph node at onset (A x 40, B x 400); The neoplastic follicles show a vaguely nodular pattern (A). Both centrocytes and centroblasts were present (B).
The biopsied left bronchus tissue (C–J x 200); On hematoxylin and eosin staining, dense infiltration of lymphocytes, which were almost all necrotic, was observed under the bronchial epithelium (C). Although they had necrotic change, they were CD10-positive (D), CD20-positive (E), PAX-5-positive (not shown) and bcl-2-posistive cells (F), which is consistent with the phenotype of follicular lymphoma. There were few CD3-positive cells (G), which were negative for granzyme B (H), i.e., not cytotoxic T cells. CD56-positive cells, i.e. NK cells, were not detected (I). CD68-positive cells considered to be macrophages were well noted (J).
Fig. 2 ?Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right). Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right).
We started R2 (lenalidomide at 20 mg/day, days 1-21 and rituximab at 375 mg/m2, day 1) therapy in June 2020 (day 1). At that time, the WBC count was 3,870/μl (3,500-8,500), containing 2,593/μl of neutrophils and 368/μl of monocytes. Hb was 12.4 g/dl (11.5-17.0), platelet count was 25.4 × 104/μl (15.0-35.0), LDH was 387 U/L (120-200) and CRP was 0.57 mg/dl (≤ 0.30). He was in a good condition on day 4 of R2 therapy. Eleven days after starting R2 therapy, he visited our hospital for respiratory discomfort. His body temperature was 36.5˚C, blood pressure was 129/62 mmHg and SpO2 (room air) was 89-90%. He exhibited grade 1 rash, but had no pain. The WBC count was 2,120/μl, containing 922/μl of neutrophils and 424/μl of monocytes. The monocyte count was relatively high at 20% of the WBC. Hb was 13.6 g/dl, platelet count was 29.3 × 104/μl, LDH was 264 U/L and CRP was 0.99 mg/dl. Chest X-ray revealed a left lung severe shadow (Figure 3). CT demonstrated left lung atelectasis due to left hilar obstruction by lymph node swelling (Figure 2).
Fig. 3 Clinical course of R2 therapy: Chest X-ray on days 11, 18, 28, 42 and 54. Chest imaging on day 0 was by CT because we did not perform chest X-ray at the start of R2 therapy.
After emergency hospitalization on day 11 of R2 treatment, he was stable on oxygen inhalation of 0.5 L/min at rest and 2 L/min when walking. Antihistamine was prescribed for rash. We continued the combination lenalidomide-rituximab (R2) immunotherapy. Although rituximab was administered 6 times through 5 courses of R-CHOP therapy and on day 1 of this course, it was added on day 13. The left hilar lymph node swelling and atelectasis did not improve on chest X-ray on day 18 (Figure 3). If the obstruction of the left bronchus was not due to TFR but to true progression, radiation therapy was considered necessary. We thus carried out transbronchial lung biopsy on day 20 of R2 treatment. The biopsied left bronchus tissue exhibited dense infiltration of lymphocytes, which were almost all necrotic. Although they had necrotic change, their phenotype was consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. Macrophages were well noted. (Figure 1 C–J).
Rituximab was added just after transbronchial lung biopsy on day 20. From around this time, his respiratory state improved. Chest X-ray on day 25 revealed a decrease in left hilar lymph node swelling and improvement of atelectasis. He no longer needed oxygen inhalation and was discharged. As chest X-ray on day 28 (Figure 3) revealed left lung expansion, he received a second cycle of R2 therapy from day 29. The left lung atelectasis expanded through the second cycle of R2 therapy (Figure 3). Central nervous system involvement developed thereafter and we changed R2 therapy to R-CHASE therapy, which contains high-dose cytarabine, and intrathecal administration of methotrexate, cytarabine and prednisolone.
DISCUSSION
TFR is acutely dependent on NK cell function, and is then maintained by the rapid recruitment and proliferation of T cells.2 Andritsos et al. reported increased CD3-positive, CD4-positive, CD8-positive and granzyme B-positive T-cells in an excised swollen tonsil after lenalidomide treatment.7 In the present case, the biopsied left bronchus tissue on day 20 of R2 therapy did not contain NK cells or cytotoxic T cells. Macrophages were relatively conspicuous. It is unclear whether NK cells and cytotoxic T cells disappeared at the time of transbronchial lung biopsy when the respiratory state began improving. Although it is possible that the left hilar lymph nodes swelled due to tumor progression without TFR, rapid enlargement just after the start of R2 therapy may have been related to TFR.
R2 therapy was reported to have favorable activity in patients with relapsed/refractory follicular lymphoma.8 Wang et al. found that lenalidomide with rituximab is effective even for transformed large cell lymphoma originating from follicular lymphoma.9 In a randomized study for relapsed/refractory diffuse large B-cell lymphoma, patients treated using lenalidomide had a longer progression-free survival than those treated at the investigator’s discretion (gemcitabine, rituximab, etoposide or oxaliplatin).10 Based on the resistance to chemotherapy in the present case, we expected complete remission via a unique mechanism of action from the combination of lenalidomide and rituximab rather than the intensity of salvage chemotherapy. Therefore, we selected R2 therapy even if transformation was possible.
Immunotherapy, such as IMiDs and ICIs, works differently from chemotherapy and takes more time to exhibit effects than cytotoxic drugs. Chanan-Khan et al. reported that TFR induced by immunomodulatory drugs, such as lenalidomide, develops in >90% of patients during the first treatment cycle and the median time to onset is 6 days.11 Goy et al. also found that TFR generally developed during the first cycle of lenalidomide, with few events during later cycles.12 Our patient exhibited a typical clinical course regarding the time of TFR. Steroids are used for the management of severe cases of TFR and prophylaxis. Chong et al. reported that patients who received once weekly low-dose (10 mg) dexamethasone had fewer dose interruptions for TFR during the first 8 weeks of lenalidomide.13 Our patient did not receive dexamethasone, but he was administered 100 mg of hydrocortisone once just before the start of rituximab on day 1, day 13 and day 20. Hydrocortisone acts for a short time, unlike dexamethasone. The present patient did not receive any steroids after hydrocortisone on day 1, until he received hydrocortisone on day 13. If dexamethasone had been administered weekly in the first course, TFR may have been less severe.
It is difficult to differentiate pseudo-progression due to TFR from true progression only by imaging, which largely relies on the tumor size.5 The identification of TFR is important to avoid the premature discontinuation of effective therapy because the intensity of TFR is correlated with the probability of achieving a complete response.11 TFR should be paid attention to in the early stage of treatment using immunomodulatory drugs.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest. | BENDAMUSTINE, CYCLOPHOSPHAMIDE, DOXORUBICIN, LENALIDOMIDE, PREDNISOLONE, RITUXIMAB, VINCRISTINE | DrugsGivenReaction | CC BY-NC-SA | 33431741 | 19,426,874 | 2021-03-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hilar lymphadenopathy'. | Transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced tumor flare reaction.
Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as rapid enlargement of the tumor, which mimics disease progression, developing in the early stage of treatment using immunomodulatory drugs or immune checkpoint inhibitors. A 59-year-old man with follicular lymphoma had residual tumor burden in the left hilar lymph nodes after R-CHOP therapy, and received lenalidomide and rituximab (R2) therapy. He developed respiratory distress on day 11 of R2 therapy. Chest X-ray and CT demonstrated left lung atelectasis due to left hilar lymph node swelling. We performed transbronchial lung biopsy on day 20 of R2 therapy. The biopsied left bronchus tissue exhibited extensive necrosis, which had a B-cell phenotype consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. It was unclear whether the immune effector cells disappeared at the time of transbronchial lung biopsy. Atelectasis in our patient improved by continuing R2 therapy beyond TFR.
INTRODUCTION
Lenalidomide, an immunomodulatory drug, was reported to reactivate dysfunctional T and natural killer (NK) cells ex vivo by increasing their proliferative capacity and T-helper cell type 1 (Th1) cytokine release.1 Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as an increase in tumor burden, low-grade fever and rash. Lenalidomide-induced TFR involves the activation of NK cells and T cells, and their infiltration into the tumor sites.2
TFR was originally described in patients with chronic lymphocytic leukemia (CLL) treated using immunomodulatory drugs (IMiDs) (thalidomide and lenalidomide)3,4 TFR was also observed in mantle cell lymphoma, indolent non-Hodgkin lymphoma (NHL), aggressive NHL and Hodgkin lymphoma treated by lenalidomide.5
TFR mimics disease progression on imaging before an effective anti-tumor response occurs. A similar phenomenon, ‘pseudo-progression’, was also reported in multiple solid tumor types treated using immune checkpoint inhibitors (ICIs) resulting from T cells infiltrating the tumor site.6
We report a patient with refractory follicular lymphoma who exhibited transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced TFR.
CASE REPORT
A 58-year-old man visited a hospital in October 2019 for lymph node swelling and the left inguinal lymph node was biopsied. He was diagnosed with follicular lymphoma grade 3a (Figure 1 A–B) and referred to our hospital. We diagnosed his lymphoma as follicular lymphoma grade 3a, stage IV and FLIPI: high. We administered bendamustine, but it was ineffective. He then received R-CHOP therapy and had a partial response. After 5 courses of R-CHOP therapy, left hilar lymph node swelling remained on PET/CT with a SUV of 20.5 as the main lesion (Figure 2).
Fig. 1 Pathological findings: The inguinal lymph node at onset (A x 40, B x 400); The neoplastic follicles show a vaguely nodular pattern (A). Both centrocytes and centroblasts were present (B).
The biopsied left bronchus tissue (C–J x 200); On hematoxylin and eosin staining, dense infiltration of lymphocytes, which were almost all necrotic, was observed under the bronchial epithelium (C). Although they had necrotic change, they were CD10-positive (D), CD20-positive (E), PAX-5-positive (not shown) and bcl-2-posistive cells (F), which is consistent with the phenotype of follicular lymphoma. There were few CD3-positive cells (G), which were negative for granzyme B (H), i.e., not cytotoxic T cells. CD56-positive cells, i.e. NK cells, were not detected (I). CD68-positive cells considered to be macrophages were well noted (J).
Fig. 2 ?Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right). Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right).
We started R2 (lenalidomide at 20 mg/day, days 1-21 and rituximab at 375 mg/m2, day 1) therapy in June 2020 (day 1). At that time, the WBC count was 3,870/μl (3,500-8,500), containing 2,593/μl of neutrophils and 368/μl of monocytes. Hb was 12.4 g/dl (11.5-17.0), platelet count was 25.4 × 104/μl (15.0-35.0), LDH was 387 U/L (120-200) and CRP was 0.57 mg/dl (≤ 0.30). He was in a good condition on day 4 of R2 therapy. Eleven days after starting R2 therapy, he visited our hospital for respiratory discomfort. His body temperature was 36.5˚C, blood pressure was 129/62 mmHg and SpO2 (room air) was 89-90%. He exhibited grade 1 rash, but had no pain. The WBC count was 2,120/μl, containing 922/μl of neutrophils and 424/μl of monocytes. The monocyte count was relatively high at 20% of the WBC. Hb was 13.6 g/dl, platelet count was 29.3 × 104/μl, LDH was 264 U/L and CRP was 0.99 mg/dl. Chest X-ray revealed a left lung severe shadow (Figure 3). CT demonstrated left lung atelectasis due to left hilar obstruction by lymph node swelling (Figure 2).
Fig. 3 Clinical course of R2 therapy: Chest X-ray on days 11, 18, 28, 42 and 54. Chest imaging on day 0 was by CT because we did not perform chest X-ray at the start of R2 therapy.
After emergency hospitalization on day 11 of R2 treatment, he was stable on oxygen inhalation of 0.5 L/min at rest and 2 L/min when walking. Antihistamine was prescribed for rash. We continued the combination lenalidomide-rituximab (R2) immunotherapy. Although rituximab was administered 6 times through 5 courses of R-CHOP therapy and on day 1 of this course, it was added on day 13. The left hilar lymph node swelling and atelectasis did not improve on chest X-ray on day 18 (Figure 3). If the obstruction of the left bronchus was not due to TFR but to true progression, radiation therapy was considered necessary. We thus carried out transbronchial lung biopsy on day 20 of R2 treatment. The biopsied left bronchus tissue exhibited dense infiltration of lymphocytes, which were almost all necrotic. Although they had necrotic change, their phenotype was consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. Macrophages were well noted. (Figure 1 C–J).
Rituximab was added just after transbronchial lung biopsy on day 20. From around this time, his respiratory state improved. Chest X-ray on day 25 revealed a decrease in left hilar lymph node swelling and improvement of atelectasis. He no longer needed oxygen inhalation and was discharged. As chest X-ray on day 28 (Figure 3) revealed left lung expansion, he received a second cycle of R2 therapy from day 29. The left lung atelectasis expanded through the second cycle of R2 therapy (Figure 3). Central nervous system involvement developed thereafter and we changed R2 therapy to R-CHASE therapy, which contains high-dose cytarabine, and intrathecal administration of methotrexate, cytarabine and prednisolone.
DISCUSSION
TFR is acutely dependent on NK cell function, and is then maintained by the rapid recruitment and proliferation of T cells.2 Andritsos et al. reported increased CD3-positive, CD4-positive, CD8-positive and granzyme B-positive T-cells in an excised swollen tonsil after lenalidomide treatment.7 In the present case, the biopsied left bronchus tissue on day 20 of R2 therapy did not contain NK cells or cytotoxic T cells. Macrophages were relatively conspicuous. It is unclear whether NK cells and cytotoxic T cells disappeared at the time of transbronchial lung biopsy when the respiratory state began improving. Although it is possible that the left hilar lymph nodes swelled due to tumor progression without TFR, rapid enlargement just after the start of R2 therapy may have been related to TFR.
R2 therapy was reported to have favorable activity in patients with relapsed/refractory follicular lymphoma.8 Wang et al. found that lenalidomide with rituximab is effective even for transformed large cell lymphoma originating from follicular lymphoma.9 In a randomized study for relapsed/refractory diffuse large B-cell lymphoma, patients treated using lenalidomide had a longer progression-free survival than those treated at the investigator’s discretion (gemcitabine, rituximab, etoposide or oxaliplatin).10 Based on the resistance to chemotherapy in the present case, we expected complete remission via a unique mechanism of action from the combination of lenalidomide and rituximab rather than the intensity of salvage chemotherapy. Therefore, we selected R2 therapy even if transformation was possible.
Immunotherapy, such as IMiDs and ICIs, works differently from chemotherapy and takes more time to exhibit effects than cytotoxic drugs. Chanan-Khan et al. reported that TFR induced by immunomodulatory drugs, such as lenalidomide, develops in >90% of patients during the first treatment cycle and the median time to onset is 6 days.11 Goy et al. also found that TFR generally developed during the first cycle of lenalidomide, with few events during later cycles.12 Our patient exhibited a typical clinical course regarding the time of TFR. Steroids are used for the management of severe cases of TFR and prophylaxis. Chong et al. reported that patients who received once weekly low-dose (10 mg) dexamethasone had fewer dose interruptions for TFR during the first 8 weeks of lenalidomide.13 Our patient did not receive dexamethasone, but he was administered 100 mg of hydrocortisone once just before the start of rituximab on day 1, day 13 and day 20. Hydrocortisone acts for a short time, unlike dexamethasone. The present patient did not receive any steroids after hydrocortisone on day 1, until he received hydrocortisone on day 13. If dexamethasone had been administered weekly in the first course, TFR may have been less severe.
It is difficult to differentiate pseudo-progression due to TFR from true progression only by imaging, which largely relies on the tumor size.5 The identification of TFR is important to avoid the premature discontinuation of effective therapy because the intensity of TFR is correlated with the probability of achieving a complete response.11 TFR should be paid attention to in the early stage of treatment using immunomodulatory drugs.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest. | HYDROCORTISONE, LENALIDOMIDE, RITUXIMAB | DrugsGivenReaction | CC BY-NC-SA | 33431741 | 18,434,257 | 2021-03-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash'. | Transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced tumor flare reaction.
Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as rapid enlargement of the tumor, which mimics disease progression, developing in the early stage of treatment using immunomodulatory drugs or immune checkpoint inhibitors. A 59-year-old man with follicular lymphoma had residual tumor burden in the left hilar lymph nodes after R-CHOP therapy, and received lenalidomide and rituximab (R2) therapy. He developed respiratory distress on day 11 of R2 therapy. Chest X-ray and CT demonstrated left lung atelectasis due to left hilar lymph node swelling. We performed transbronchial lung biopsy on day 20 of R2 therapy. The biopsied left bronchus tissue exhibited extensive necrosis, which had a B-cell phenotype consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. It was unclear whether the immune effector cells disappeared at the time of transbronchial lung biopsy. Atelectasis in our patient improved by continuing R2 therapy beyond TFR.
INTRODUCTION
Lenalidomide, an immunomodulatory drug, was reported to reactivate dysfunctional T and natural killer (NK) cells ex vivo by increasing their proliferative capacity and T-helper cell type 1 (Th1) cytokine release.1 Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as an increase in tumor burden, low-grade fever and rash. Lenalidomide-induced TFR involves the activation of NK cells and T cells, and their infiltration into the tumor sites.2
TFR was originally described in patients with chronic lymphocytic leukemia (CLL) treated using immunomodulatory drugs (IMiDs) (thalidomide and lenalidomide)3,4 TFR was also observed in mantle cell lymphoma, indolent non-Hodgkin lymphoma (NHL), aggressive NHL and Hodgkin lymphoma treated by lenalidomide.5
TFR mimics disease progression on imaging before an effective anti-tumor response occurs. A similar phenomenon, ‘pseudo-progression’, was also reported in multiple solid tumor types treated using immune checkpoint inhibitors (ICIs) resulting from T cells infiltrating the tumor site.6
We report a patient with refractory follicular lymphoma who exhibited transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced TFR.
CASE REPORT
A 58-year-old man visited a hospital in October 2019 for lymph node swelling and the left inguinal lymph node was biopsied. He was diagnosed with follicular lymphoma grade 3a (Figure 1 A–B) and referred to our hospital. We diagnosed his lymphoma as follicular lymphoma grade 3a, stage IV and FLIPI: high. We administered bendamustine, but it was ineffective. He then received R-CHOP therapy and had a partial response. After 5 courses of R-CHOP therapy, left hilar lymph node swelling remained on PET/CT with a SUV of 20.5 as the main lesion (Figure 2).
Fig. 1 Pathological findings: The inguinal lymph node at onset (A x 40, B x 400); The neoplastic follicles show a vaguely nodular pattern (A). Both centrocytes and centroblasts were present (B).
The biopsied left bronchus tissue (C–J x 200); On hematoxylin and eosin staining, dense infiltration of lymphocytes, which were almost all necrotic, was observed under the bronchial epithelium (C). Although they had necrotic change, they were CD10-positive (D), CD20-positive (E), PAX-5-positive (not shown) and bcl-2-posistive cells (F), which is consistent with the phenotype of follicular lymphoma. There were few CD3-positive cells (G), which were negative for granzyme B (H), i.e., not cytotoxic T cells. CD56-positive cells, i.e. NK cells, were not detected (I). CD68-positive cells considered to be macrophages were well noted (J).
Fig. 2 ?Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right). Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right).
We started R2 (lenalidomide at 20 mg/day, days 1-21 and rituximab at 375 mg/m2, day 1) therapy in June 2020 (day 1). At that time, the WBC count was 3,870/μl (3,500-8,500), containing 2,593/μl of neutrophils and 368/μl of monocytes. Hb was 12.4 g/dl (11.5-17.0), platelet count was 25.4 × 104/μl (15.0-35.0), LDH was 387 U/L (120-200) and CRP was 0.57 mg/dl (≤ 0.30). He was in a good condition on day 4 of R2 therapy. Eleven days after starting R2 therapy, he visited our hospital for respiratory discomfort. His body temperature was 36.5˚C, blood pressure was 129/62 mmHg and SpO2 (room air) was 89-90%. He exhibited grade 1 rash, but had no pain. The WBC count was 2,120/μl, containing 922/μl of neutrophils and 424/μl of monocytes. The monocyte count was relatively high at 20% of the WBC. Hb was 13.6 g/dl, platelet count was 29.3 × 104/μl, LDH was 264 U/L and CRP was 0.99 mg/dl. Chest X-ray revealed a left lung severe shadow (Figure 3). CT demonstrated left lung atelectasis due to left hilar obstruction by lymph node swelling (Figure 2).
Fig. 3 Clinical course of R2 therapy: Chest X-ray on days 11, 18, 28, 42 and 54. Chest imaging on day 0 was by CT because we did not perform chest X-ray at the start of R2 therapy.
After emergency hospitalization on day 11 of R2 treatment, he was stable on oxygen inhalation of 0.5 L/min at rest and 2 L/min when walking. Antihistamine was prescribed for rash. We continued the combination lenalidomide-rituximab (R2) immunotherapy. Although rituximab was administered 6 times through 5 courses of R-CHOP therapy and on day 1 of this course, it was added on day 13. The left hilar lymph node swelling and atelectasis did not improve on chest X-ray on day 18 (Figure 3). If the obstruction of the left bronchus was not due to TFR but to true progression, radiation therapy was considered necessary. We thus carried out transbronchial lung biopsy on day 20 of R2 treatment. The biopsied left bronchus tissue exhibited dense infiltration of lymphocytes, which were almost all necrotic. Although they had necrotic change, their phenotype was consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. Macrophages were well noted. (Figure 1 C–J).
Rituximab was added just after transbronchial lung biopsy on day 20. From around this time, his respiratory state improved. Chest X-ray on day 25 revealed a decrease in left hilar lymph node swelling and improvement of atelectasis. He no longer needed oxygen inhalation and was discharged. As chest X-ray on day 28 (Figure 3) revealed left lung expansion, he received a second cycle of R2 therapy from day 29. The left lung atelectasis expanded through the second cycle of R2 therapy (Figure 3). Central nervous system involvement developed thereafter and we changed R2 therapy to R-CHASE therapy, which contains high-dose cytarabine, and intrathecal administration of methotrexate, cytarabine and prednisolone.
DISCUSSION
TFR is acutely dependent on NK cell function, and is then maintained by the rapid recruitment and proliferation of T cells.2 Andritsos et al. reported increased CD3-positive, CD4-positive, CD8-positive and granzyme B-positive T-cells in an excised swollen tonsil after lenalidomide treatment.7 In the present case, the biopsied left bronchus tissue on day 20 of R2 therapy did not contain NK cells or cytotoxic T cells. Macrophages were relatively conspicuous. It is unclear whether NK cells and cytotoxic T cells disappeared at the time of transbronchial lung biopsy when the respiratory state began improving. Although it is possible that the left hilar lymph nodes swelled due to tumor progression without TFR, rapid enlargement just after the start of R2 therapy may have been related to TFR.
R2 therapy was reported to have favorable activity in patients with relapsed/refractory follicular lymphoma.8 Wang et al. found that lenalidomide with rituximab is effective even for transformed large cell lymphoma originating from follicular lymphoma.9 In a randomized study for relapsed/refractory diffuse large B-cell lymphoma, patients treated using lenalidomide had a longer progression-free survival than those treated at the investigator’s discretion (gemcitabine, rituximab, etoposide or oxaliplatin).10 Based on the resistance to chemotherapy in the present case, we expected complete remission via a unique mechanism of action from the combination of lenalidomide and rituximab rather than the intensity of salvage chemotherapy. Therefore, we selected R2 therapy even if transformation was possible.
Immunotherapy, such as IMiDs and ICIs, works differently from chemotherapy and takes more time to exhibit effects than cytotoxic drugs. Chanan-Khan et al. reported that TFR induced by immunomodulatory drugs, such as lenalidomide, develops in >90% of patients during the first treatment cycle and the median time to onset is 6 days.11 Goy et al. also found that TFR generally developed during the first cycle of lenalidomide, with few events during later cycles.12 Our patient exhibited a typical clinical course regarding the time of TFR. Steroids are used for the management of severe cases of TFR and prophylaxis. Chong et al. reported that patients who received once weekly low-dose (10 mg) dexamethasone had fewer dose interruptions for TFR during the first 8 weeks of lenalidomide.13 Our patient did not receive dexamethasone, but he was administered 100 mg of hydrocortisone once just before the start of rituximab on day 1, day 13 and day 20. Hydrocortisone acts for a short time, unlike dexamethasone. The present patient did not receive any steroids after hydrocortisone on day 1, until he received hydrocortisone on day 13. If dexamethasone had been administered weekly in the first course, TFR may have been less severe.
It is difficult to differentiate pseudo-progression due to TFR from true progression only by imaging, which largely relies on the tumor size.5 The identification of TFR is important to avoid the premature discontinuation of effective therapy because the intensity of TFR is correlated with the probability of achieving a complete response.11 TFR should be paid attention to in the early stage of treatment using immunomodulatory drugs.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest. | BENDAMUSTINE, CYCLOPHOSPHAMIDE, DOXORUBICIN, LENALIDOMIDE, PREDNISOLONE, RITUXIMAB, VINCRISTINE | DrugsGivenReaction | CC BY-NC-SA | 33431741 | 19,426,874 | 2021-03-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced tumor flare reaction.
Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as rapid enlargement of the tumor, which mimics disease progression, developing in the early stage of treatment using immunomodulatory drugs or immune checkpoint inhibitors. A 59-year-old man with follicular lymphoma had residual tumor burden in the left hilar lymph nodes after R-CHOP therapy, and received lenalidomide and rituximab (R2) therapy. He developed respiratory distress on day 11 of R2 therapy. Chest X-ray and CT demonstrated left lung atelectasis due to left hilar lymph node swelling. We performed transbronchial lung biopsy on day 20 of R2 therapy. The biopsied left bronchus tissue exhibited extensive necrosis, which had a B-cell phenotype consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. It was unclear whether the immune effector cells disappeared at the time of transbronchial lung biopsy. Atelectasis in our patient improved by continuing R2 therapy beyond TFR.
INTRODUCTION
Lenalidomide, an immunomodulatory drug, was reported to reactivate dysfunctional T and natural killer (NK) cells ex vivo by increasing their proliferative capacity and T-helper cell type 1 (Th1) cytokine release.1 Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as an increase in tumor burden, low-grade fever and rash. Lenalidomide-induced TFR involves the activation of NK cells and T cells, and their infiltration into the tumor sites.2
TFR was originally described in patients with chronic lymphocytic leukemia (CLL) treated using immunomodulatory drugs (IMiDs) (thalidomide and lenalidomide)3,4 TFR was also observed in mantle cell lymphoma, indolent non-Hodgkin lymphoma (NHL), aggressive NHL and Hodgkin lymphoma treated by lenalidomide.5
TFR mimics disease progression on imaging before an effective anti-tumor response occurs. A similar phenomenon, ‘pseudo-progression’, was also reported in multiple solid tumor types treated using immune checkpoint inhibitors (ICIs) resulting from T cells infiltrating the tumor site.6
We report a patient with refractory follicular lymphoma who exhibited transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced TFR.
CASE REPORT
A 58-year-old man visited a hospital in October 2019 for lymph node swelling and the left inguinal lymph node was biopsied. He was diagnosed with follicular lymphoma grade 3a (Figure 1 A–B) and referred to our hospital. We diagnosed his lymphoma as follicular lymphoma grade 3a, stage IV and FLIPI: high. We administered bendamustine, but it was ineffective. He then received R-CHOP therapy and had a partial response. After 5 courses of R-CHOP therapy, left hilar lymph node swelling remained on PET/CT with a SUV of 20.5 as the main lesion (Figure 2).
Fig. 1 Pathological findings: The inguinal lymph node at onset (A x 40, B x 400); The neoplastic follicles show a vaguely nodular pattern (A). Both centrocytes and centroblasts were present (B).
The biopsied left bronchus tissue (C–J x 200); On hematoxylin and eosin staining, dense infiltration of lymphocytes, which were almost all necrotic, was observed under the bronchial epithelium (C). Although they had necrotic change, they were CD10-positive (D), CD20-positive (E), PAX-5-positive (not shown) and bcl-2-posistive cells (F), which is consistent with the phenotype of follicular lymphoma. There were few CD3-positive cells (G), which were negative for granzyme B (H), i.e., not cytotoxic T cells. CD56-positive cells, i.e. NK cells, were not detected (I). CD68-positive cells considered to be macrophages were well noted (J).
Fig. 2 ?Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right). Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right).
We started R2 (lenalidomide at 20 mg/day, days 1-21 and rituximab at 375 mg/m2, day 1) therapy in June 2020 (day 1). At that time, the WBC count was 3,870/μl (3,500-8,500), containing 2,593/μl of neutrophils and 368/μl of monocytes. Hb was 12.4 g/dl (11.5-17.0), platelet count was 25.4 × 104/μl (15.0-35.0), LDH was 387 U/L (120-200) and CRP was 0.57 mg/dl (≤ 0.30). He was in a good condition on day 4 of R2 therapy. Eleven days after starting R2 therapy, he visited our hospital for respiratory discomfort. His body temperature was 36.5˚C, blood pressure was 129/62 mmHg and SpO2 (room air) was 89-90%. He exhibited grade 1 rash, but had no pain. The WBC count was 2,120/μl, containing 922/μl of neutrophils and 424/μl of monocytes. The monocyte count was relatively high at 20% of the WBC. Hb was 13.6 g/dl, platelet count was 29.3 × 104/μl, LDH was 264 U/L and CRP was 0.99 mg/dl. Chest X-ray revealed a left lung severe shadow (Figure 3). CT demonstrated left lung atelectasis due to left hilar obstruction by lymph node swelling (Figure 2).
Fig. 3 Clinical course of R2 therapy: Chest X-ray on days 11, 18, 28, 42 and 54. Chest imaging on day 0 was by CT because we did not perform chest X-ray at the start of R2 therapy.
After emergency hospitalization on day 11 of R2 treatment, he was stable on oxygen inhalation of 0.5 L/min at rest and 2 L/min when walking. Antihistamine was prescribed for rash. We continued the combination lenalidomide-rituximab (R2) immunotherapy. Although rituximab was administered 6 times through 5 courses of R-CHOP therapy and on day 1 of this course, it was added on day 13. The left hilar lymph node swelling and atelectasis did not improve on chest X-ray on day 18 (Figure 3). If the obstruction of the left bronchus was not due to TFR but to true progression, radiation therapy was considered necessary. We thus carried out transbronchial lung biopsy on day 20 of R2 treatment. The biopsied left bronchus tissue exhibited dense infiltration of lymphocytes, which were almost all necrotic. Although they had necrotic change, their phenotype was consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. Macrophages were well noted. (Figure 1 C–J).
Rituximab was added just after transbronchial lung biopsy on day 20. From around this time, his respiratory state improved. Chest X-ray on day 25 revealed a decrease in left hilar lymph node swelling and improvement of atelectasis. He no longer needed oxygen inhalation and was discharged. As chest X-ray on day 28 (Figure 3) revealed left lung expansion, he received a second cycle of R2 therapy from day 29. The left lung atelectasis expanded through the second cycle of R2 therapy (Figure 3). Central nervous system involvement developed thereafter and we changed R2 therapy to R-CHASE therapy, which contains high-dose cytarabine, and intrathecal administration of methotrexate, cytarabine and prednisolone.
DISCUSSION
TFR is acutely dependent on NK cell function, and is then maintained by the rapid recruitment and proliferation of T cells.2 Andritsos et al. reported increased CD3-positive, CD4-positive, CD8-positive and granzyme B-positive T-cells in an excised swollen tonsil after lenalidomide treatment.7 In the present case, the biopsied left bronchus tissue on day 20 of R2 therapy did not contain NK cells or cytotoxic T cells. Macrophages were relatively conspicuous. It is unclear whether NK cells and cytotoxic T cells disappeared at the time of transbronchial lung biopsy when the respiratory state began improving. Although it is possible that the left hilar lymph nodes swelled due to tumor progression without TFR, rapid enlargement just after the start of R2 therapy may have been related to TFR.
R2 therapy was reported to have favorable activity in patients with relapsed/refractory follicular lymphoma.8 Wang et al. found that lenalidomide with rituximab is effective even for transformed large cell lymphoma originating from follicular lymphoma.9 In a randomized study for relapsed/refractory diffuse large B-cell lymphoma, patients treated using lenalidomide had a longer progression-free survival than those treated at the investigator’s discretion (gemcitabine, rituximab, etoposide or oxaliplatin).10 Based on the resistance to chemotherapy in the present case, we expected complete remission via a unique mechanism of action from the combination of lenalidomide and rituximab rather than the intensity of salvage chemotherapy. Therefore, we selected R2 therapy even if transformation was possible.
Immunotherapy, such as IMiDs and ICIs, works differently from chemotherapy and takes more time to exhibit effects than cytotoxic drugs. Chanan-Khan et al. reported that TFR induced by immunomodulatory drugs, such as lenalidomide, develops in >90% of patients during the first treatment cycle and the median time to onset is 6 days.11 Goy et al. also found that TFR generally developed during the first cycle of lenalidomide, with few events during later cycles.12 Our patient exhibited a typical clinical course regarding the time of TFR. Steroids are used for the management of severe cases of TFR and prophylaxis. Chong et al. reported that patients who received once weekly low-dose (10 mg) dexamethasone had fewer dose interruptions for TFR during the first 8 weeks of lenalidomide.13 Our patient did not receive dexamethasone, but he was administered 100 mg of hydrocortisone once just before the start of rituximab on day 1, day 13 and day 20. Hydrocortisone acts for a short time, unlike dexamethasone. The present patient did not receive any steroids after hydrocortisone on day 1, until he received hydrocortisone on day 13. If dexamethasone had been administered weekly in the first course, TFR may have been less severe.
It is difficult to differentiate pseudo-progression due to TFR from true progression only by imaging, which largely relies on the tumor size.5 The identification of TFR is important to avoid the premature discontinuation of effective therapy because the intensity of TFR is correlated with the probability of achieving a complete response.11 TFR should be paid attention to in the early stage of treatment using immunomodulatory drugs.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest. | BENDAMUSTINE, CYCLOPHOSPHAMIDE, DOXORUBICIN, LENALIDOMIDE, PREDNISOLONE, RITUXIMAB, VINCRISTINE | DrugsGivenReaction | CC BY-NC-SA | 33431741 | 19,426,874 | 2021-03-18 |
What was the administration route of drug 'LENALIDOMIDE'? | Transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced tumor flare reaction.
Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as rapid enlargement of the tumor, which mimics disease progression, developing in the early stage of treatment using immunomodulatory drugs or immune checkpoint inhibitors. A 59-year-old man with follicular lymphoma had residual tumor burden in the left hilar lymph nodes after R-CHOP therapy, and received lenalidomide and rituximab (R2) therapy. He developed respiratory distress on day 11 of R2 therapy. Chest X-ray and CT demonstrated left lung atelectasis due to left hilar lymph node swelling. We performed transbronchial lung biopsy on day 20 of R2 therapy. The biopsied left bronchus tissue exhibited extensive necrosis, which had a B-cell phenotype consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. It was unclear whether the immune effector cells disappeared at the time of transbronchial lung biopsy. Atelectasis in our patient improved by continuing R2 therapy beyond TFR.
INTRODUCTION
Lenalidomide, an immunomodulatory drug, was reported to reactivate dysfunctional T and natural killer (NK) cells ex vivo by increasing their proliferative capacity and T-helper cell type 1 (Th1) cytokine release.1 Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as an increase in tumor burden, low-grade fever and rash. Lenalidomide-induced TFR involves the activation of NK cells and T cells, and their infiltration into the tumor sites.2
TFR was originally described in patients with chronic lymphocytic leukemia (CLL) treated using immunomodulatory drugs (IMiDs) (thalidomide and lenalidomide)3,4 TFR was also observed in mantle cell lymphoma, indolent non-Hodgkin lymphoma (NHL), aggressive NHL and Hodgkin lymphoma treated by lenalidomide.5
TFR mimics disease progression on imaging before an effective anti-tumor response occurs. A similar phenomenon, ‘pseudo-progression’, was also reported in multiple solid tumor types treated using immune checkpoint inhibitors (ICIs) resulting from T cells infiltrating the tumor site.6
We report a patient with refractory follicular lymphoma who exhibited transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced TFR.
CASE REPORT
A 58-year-old man visited a hospital in October 2019 for lymph node swelling and the left inguinal lymph node was biopsied. He was diagnosed with follicular lymphoma grade 3a (Figure 1 A–B) and referred to our hospital. We diagnosed his lymphoma as follicular lymphoma grade 3a, stage IV and FLIPI: high. We administered bendamustine, but it was ineffective. He then received R-CHOP therapy and had a partial response. After 5 courses of R-CHOP therapy, left hilar lymph node swelling remained on PET/CT with a SUV of 20.5 as the main lesion (Figure 2).
Fig. 1 Pathological findings: The inguinal lymph node at onset (A x 40, B x 400); The neoplastic follicles show a vaguely nodular pattern (A). Both centrocytes and centroblasts were present (B).
The biopsied left bronchus tissue (C–J x 200); On hematoxylin and eosin staining, dense infiltration of lymphocytes, which were almost all necrotic, was observed under the bronchial epithelium (C). Although they had necrotic change, they were CD10-positive (D), CD20-positive (E), PAX-5-positive (not shown) and bcl-2-posistive cells (F), which is consistent with the phenotype of follicular lymphoma. There were few CD3-positive cells (G), which were negative for granzyme B (H), i.e., not cytotoxic T cells. CD56-positive cells, i.e. NK cells, were not detected (I). CD68-positive cells considered to be macrophages were well noted (J).
Fig. 2 ?Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right). Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right).
We started R2 (lenalidomide at 20 mg/day, days 1-21 and rituximab at 375 mg/m2, day 1) therapy in June 2020 (day 1). At that time, the WBC count was 3,870/μl (3,500-8,500), containing 2,593/μl of neutrophils and 368/μl of monocytes. Hb was 12.4 g/dl (11.5-17.0), platelet count was 25.4 × 104/μl (15.0-35.0), LDH was 387 U/L (120-200) and CRP was 0.57 mg/dl (≤ 0.30). He was in a good condition on day 4 of R2 therapy. Eleven days after starting R2 therapy, he visited our hospital for respiratory discomfort. His body temperature was 36.5˚C, blood pressure was 129/62 mmHg and SpO2 (room air) was 89-90%. He exhibited grade 1 rash, but had no pain. The WBC count was 2,120/μl, containing 922/μl of neutrophils and 424/μl of monocytes. The monocyte count was relatively high at 20% of the WBC. Hb was 13.6 g/dl, platelet count was 29.3 × 104/μl, LDH was 264 U/L and CRP was 0.99 mg/dl. Chest X-ray revealed a left lung severe shadow (Figure 3). CT demonstrated left lung atelectasis due to left hilar obstruction by lymph node swelling (Figure 2).
Fig. 3 Clinical course of R2 therapy: Chest X-ray on days 11, 18, 28, 42 and 54. Chest imaging on day 0 was by CT because we did not perform chest X-ray at the start of R2 therapy.
After emergency hospitalization on day 11 of R2 treatment, he was stable on oxygen inhalation of 0.5 L/min at rest and 2 L/min when walking. Antihistamine was prescribed for rash. We continued the combination lenalidomide-rituximab (R2) immunotherapy. Although rituximab was administered 6 times through 5 courses of R-CHOP therapy and on day 1 of this course, it was added on day 13. The left hilar lymph node swelling and atelectasis did not improve on chest X-ray on day 18 (Figure 3). If the obstruction of the left bronchus was not due to TFR but to true progression, radiation therapy was considered necessary. We thus carried out transbronchial lung biopsy on day 20 of R2 treatment. The biopsied left bronchus tissue exhibited dense infiltration of lymphocytes, which were almost all necrotic. Although they had necrotic change, their phenotype was consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. Macrophages were well noted. (Figure 1 C–J).
Rituximab was added just after transbronchial lung biopsy on day 20. From around this time, his respiratory state improved. Chest X-ray on day 25 revealed a decrease in left hilar lymph node swelling and improvement of atelectasis. He no longer needed oxygen inhalation and was discharged. As chest X-ray on day 28 (Figure 3) revealed left lung expansion, he received a second cycle of R2 therapy from day 29. The left lung atelectasis expanded through the second cycle of R2 therapy (Figure 3). Central nervous system involvement developed thereafter and we changed R2 therapy to R-CHASE therapy, which contains high-dose cytarabine, and intrathecal administration of methotrexate, cytarabine and prednisolone.
DISCUSSION
TFR is acutely dependent on NK cell function, and is then maintained by the rapid recruitment and proliferation of T cells.2 Andritsos et al. reported increased CD3-positive, CD4-positive, CD8-positive and granzyme B-positive T-cells in an excised swollen tonsil after lenalidomide treatment.7 In the present case, the biopsied left bronchus tissue on day 20 of R2 therapy did not contain NK cells or cytotoxic T cells. Macrophages were relatively conspicuous. It is unclear whether NK cells and cytotoxic T cells disappeared at the time of transbronchial lung biopsy when the respiratory state began improving. Although it is possible that the left hilar lymph nodes swelled due to tumor progression without TFR, rapid enlargement just after the start of R2 therapy may have been related to TFR.
R2 therapy was reported to have favorable activity in patients with relapsed/refractory follicular lymphoma.8 Wang et al. found that lenalidomide with rituximab is effective even for transformed large cell lymphoma originating from follicular lymphoma.9 In a randomized study for relapsed/refractory diffuse large B-cell lymphoma, patients treated using lenalidomide had a longer progression-free survival than those treated at the investigator’s discretion (gemcitabine, rituximab, etoposide or oxaliplatin).10 Based on the resistance to chemotherapy in the present case, we expected complete remission via a unique mechanism of action from the combination of lenalidomide and rituximab rather than the intensity of salvage chemotherapy. Therefore, we selected R2 therapy even if transformation was possible.
Immunotherapy, such as IMiDs and ICIs, works differently from chemotherapy and takes more time to exhibit effects than cytotoxic drugs. Chanan-Khan et al. reported that TFR induced by immunomodulatory drugs, such as lenalidomide, develops in >90% of patients during the first treatment cycle and the median time to onset is 6 days.11 Goy et al. also found that TFR generally developed during the first cycle of lenalidomide, with few events during later cycles.12 Our patient exhibited a typical clinical course regarding the time of TFR. Steroids are used for the management of severe cases of TFR and prophylaxis. Chong et al. reported that patients who received once weekly low-dose (10 mg) dexamethasone had fewer dose interruptions for TFR during the first 8 weeks of lenalidomide.13 Our patient did not receive dexamethasone, but he was administered 100 mg of hydrocortisone once just before the start of rituximab on day 1, day 13 and day 20. Hydrocortisone acts for a short time, unlike dexamethasone. The present patient did not receive any steroids after hydrocortisone on day 1, until he received hydrocortisone on day 13. If dexamethasone had been administered weekly in the first course, TFR may have been less severe.
It is difficult to differentiate pseudo-progression due to TFR from true progression only by imaging, which largely relies on the tumor size.5 The identification of TFR is important to avoid the premature discontinuation of effective therapy because the intensity of TFR is correlated with the probability of achieving a complete response.11 TFR should be paid attention to in the early stage of treatment using immunomodulatory drugs.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest. | Oral | DrugAdministrationRoute | CC BY-NC-SA | 33431741 | 18,434,257 | 2021-03-18 |
What was the outcome of reaction 'Atelectasis'? | Transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced tumor flare reaction.
Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as rapid enlargement of the tumor, which mimics disease progression, developing in the early stage of treatment using immunomodulatory drugs or immune checkpoint inhibitors. A 59-year-old man with follicular lymphoma had residual tumor burden in the left hilar lymph nodes after R-CHOP therapy, and received lenalidomide and rituximab (R2) therapy. He developed respiratory distress on day 11 of R2 therapy. Chest X-ray and CT demonstrated left lung atelectasis due to left hilar lymph node swelling. We performed transbronchial lung biopsy on day 20 of R2 therapy. The biopsied left bronchus tissue exhibited extensive necrosis, which had a B-cell phenotype consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. It was unclear whether the immune effector cells disappeared at the time of transbronchial lung biopsy. Atelectasis in our patient improved by continuing R2 therapy beyond TFR.
INTRODUCTION
Lenalidomide, an immunomodulatory drug, was reported to reactivate dysfunctional T and natural killer (NK) cells ex vivo by increasing their proliferative capacity and T-helper cell type 1 (Th1) cytokine release.1 Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as an increase in tumor burden, low-grade fever and rash. Lenalidomide-induced TFR involves the activation of NK cells and T cells, and their infiltration into the tumor sites.2
TFR was originally described in patients with chronic lymphocytic leukemia (CLL) treated using immunomodulatory drugs (IMiDs) (thalidomide and lenalidomide)3,4 TFR was also observed in mantle cell lymphoma, indolent non-Hodgkin lymphoma (NHL), aggressive NHL and Hodgkin lymphoma treated by lenalidomide.5
TFR mimics disease progression on imaging before an effective anti-tumor response occurs. A similar phenomenon, ‘pseudo-progression’, was also reported in multiple solid tumor types treated using immune checkpoint inhibitors (ICIs) resulting from T cells infiltrating the tumor site.6
We report a patient with refractory follicular lymphoma who exhibited transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced TFR.
CASE REPORT
A 58-year-old man visited a hospital in October 2019 for lymph node swelling and the left inguinal lymph node was biopsied. He was diagnosed with follicular lymphoma grade 3a (Figure 1 A–B) and referred to our hospital. We diagnosed his lymphoma as follicular lymphoma grade 3a, stage IV and FLIPI: high. We administered bendamustine, but it was ineffective. He then received R-CHOP therapy and had a partial response. After 5 courses of R-CHOP therapy, left hilar lymph node swelling remained on PET/CT with a SUV of 20.5 as the main lesion (Figure 2).
Fig. 1 Pathological findings: The inguinal lymph node at onset (A x 40, B x 400); The neoplastic follicles show a vaguely nodular pattern (A). Both centrocytes and centroblasts were present (B).
The biopsied left bronchus tissue (C–J x 200); On hematoxylin and eosin staining, dense infiltration of lymphocytes, which were almost all necrotic, was observed under the bronchial epithelium (C). Although they had necrotic change, they were CD10-positive (D), CD20-positive (E), PAX-5-positive (not shown) and bcl-2-posistive cells (F), which is consistent with the phenotype of follicular lymphoma. There were few CD3-positive cells (G), which were negative for granzyme B (H), i.e., not cytotoxic T cells. CD56-positive cells, i.e. NK cells, were not detected (I). CD68-positive cells considered to be macrophages were well noted (J).
Fig. 2 ?Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right). Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right).
We started R2 (lenalidomide at 20 mg/day, days 1-21 and rituximab at 375 mg/m2, day 1) therapy in June 2020 (day 1). At that time, the WBC count was 3,870/μl (3,500-8,500), containing 2,593/μl of neutrophils and 368/μl of monocytes. Hb was 12.4 g/dl (11.5-17.0), platelet count was 25.4 × 104/μl (15.0-35.0), LDH was 387 U/L (120-200) and CRP was 0.57 mg/dl (≤ 0.30). He was in a good condition on day 4 of R2 therapy. Eleven days after starting R2 therapy, he visited our hospital for respiratory discomfort. His body temperature was 36.5˚C, blood pressure was 129/62 mmHg and SpO2 (room air) was 89-90%. He exhibited grade 1 rash, but had no pain. The WBC count was 2,120/μl, containing 922/μl of neutrophils and 424/μl of monocytes. The monocyte count was relatively high at 20% of the WBC. Hb was 13.6 g/dl, platelet count was 29.3 × 104/μl, LDH was 264 U/L and CRP was 0.99 mg/dl. Chest X-ray revealed a left lung severe shadow (Figure 3). CT demonstrated left lung atelectasis due to left hilar obstruction by lymph node swelling (Figure 2).
Fig. 3 Clinical course of R2 therapy: Chest X-ray on days 11, 18, 28, 42 and 54. Chest imaging on day 0 was by CT because we did not perform chest X-ray at the start of R2 therapy.
After emergency hospitalization on day 11 of R2 treatment, he was stable on oxygen inhalation of 0.5 L/min at rest and 2 L/min when walking. Antihistamine was prescribed for rash. We continued the combination lenalidomide-rituximab (R2) immunotherapy. Although rituximab was administered 6 times through 5 courses of R-CHOP therapy and on day 1 of this course, it was added on day 13. The left hilar lymph node swelling and atelectasis did not improve on chest X-ray on day 18 (Figure 3). If the obstruction of the left bronchus was not due to TFR but to true progression, radiation therapy was considered necessary. We thus carried out transbronchial lung biopsy on day 20 of R2 treatment. The biopsied left bronchus tissue exhibited dense infiltration of lymphocytes, which were almost all necrotic. Although they had necrotic change, their phenotype was consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. Macrophages were well noted. (Figure 1 C–J).
Rituximab was added just after transbronchial lung biopsy on day 20. From around this time, his respiratory state improved. Chest X-ray on day 25 revealed a decrease in left hilar lymph node swelling and improvement of atelectasis. He no longer needed oxygen inhalation and was discharged. As chest X-ray on day 28 (Figure 3) revealed left lung expansion, he received a second cycle of R2 therapy from day 29. The left lung atelectasis expanded through the second cycle of R2 therapy (Figure 3). Central nervous system involvement developed thereafter and we changed R2 therapy to R-CHASE therapy, which contains high-dose cytarabine, and intrathecal administration of methotrexate, cytarabine and prednisolone.
DISCUSSION
TFR is acutely dependent on NK cell function, and is then maintained by the rapid recruitment and proliferation of T cells.2 Andritsos et al. reported increased CD3-positive, CD4-positive, CD8-positive and granzyme B-positive T-cells in an excised swollen tonsil after lenalidomide treatment.7 In the present case, the biopsied left bronchus tissue on day 20 of R2 therapy did not contain NK cells or cytotoxic T cells. Macrophages were relatively conspicuous. It is unclear whether NK cells and cytotoxic T cells disappeared at the time of transbronchial lung biopsy when the respiratory state began improving. Although it is possible that the left hilar lymph nodes swelled due to tumor progression without TFR, rapid enlargement just after the start of R2 therapy may have been related to TFR.
R2 therapy was reported to have favorable activity in patients with relapsed/refractory follicular lymphoma.8 Wang et al. found that lenalidomide with rituximab is effective even for transformed large cell lymphoma originating from follicular lymphoma.9 In a randomized study for relapsed/refractory diffuse large B-cell lymphoma, patients treated using lenalidomide had a longer progression-free survival than those treated at the investigator’s discretion (gemcitabine, rituximab, etoposide or oxaliplatin).10 Based on the resistance to chemotherapy in the present case, we expected complete remission via a unique mechanism of action from the combination of lenalidomide and rituximab rather than the intensity of salvage chemotherapy. Therefore, we selected R2 therapy even if transformation was possible.
Immunotherapy, such as IMiDs and ICIs, works differently from chemotherapy and takes more time to exhibit effects than cytotoxic drugs. Chanan-Khan et al. reported that TFR induced by immunomodulatory drugs, such as lenalidomide, develops in >90% of patients during the first treatment cycle and the median time to onset is 6 days.11 Goy et al. also found that TFR generally developed during the first cycle of lenalidomide, with few events during later cycles.12 Our patient exhibited a typical clinical course regarding the time of TFR. Steroids are used for the management of severe cases of TFR and prophylaxis. Chong et al. reported that patients who received once weekly low-dose (10 mg) dexamethasone had fewer dose interruptions for TFR during the first 8 weeks of lenalidomide.13 Our patient did not receive dexamethasone, but he was administered 100 mg of hydrocortisone once just before the start of rituximab on day 1, day 13 and day 20. Hydrocortisone acts for a short time, unlike dexamethasone. The present patient did not receive any steroids after hydrocortisone on day 1, until he received hydrocortisone on day 13. If dexamethasone had been administered weekly in the first course, TFR may have been less severe.
It is difficult to differentiate pseudo-progression due to TFR from true progression only by imaging, which largely relies on the tumor size.5 The identification of TFR is important to avoid the premature discontinuation of effective therapy because the intensity of TFR is correlated with the probability of achieving a complete response.11 TFR should be paid attention to in the early stage of treatment using immunomodulatory drugs.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest. | Recovering | ReactionOutcome | CC BY-NC-SA | 33431741 | 18,434,257 | 2021-03-18 |
What was the outcome of reaction 'Hilar lymphadenopathy'? | Transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced tumor flare reaction.
Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as rapid enlargement of the tumor, which mimics disease progression, developing in the early stage of treatment using immunomodulatory drugs or immune checkpoint inhibitors. A 59-year-old man with follicular lymphoma had residual tumor burden in the left hilar lymph nodes after R-CHOP therapy, and received lenalidomide and rituximab (R2) therapy. He developed respiratory distress on day 11 of R2 therapy. Chest X-ray and CT demonstrated left lung atelectasis due to left hilar lymph node swelling. We performed transbronchial lung biopsy on day 20 of R2 therapy. The biopsied left bronchus tissue exhibited extensive necrosis, which had a B-cell phenotype consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. It was unclear whether the immune effector cells disappeared at the time of transbronchial lung biopsy. Atelectasis in our patient improved by continuing R2 therapy beyond TFR.
INTRODUCTION
Lenalidomide, an immunomodulatory drug, was reported to reactivate dysfunctional T and natural killer (NK) cells ex vivo by increasing their proliferative capacity and T-helper cell type 1 (Th1) cytokine release.1 Tumor flare reaction (TFR) is a unique immune-mediated tumor recognition phenomenon presenting as an increase in tumor burden, low-grade fever and rash. Lenalidomide-induced TFR involves the activation of NK cells and T cells, and their infiltration into the tumor sites.2
TFR was originally described in patients with chronic lymphocytic leukemia (CLL) treated using immunomodulatory drugs (IMiDs) (thalidomide and lenalidomide)3,4 TFR was also observed in mantle cell lymphoma, indolent non-Hodgkin lymphoma (NHL), aggressive NHL and Hodgkin lymphoma treated by lenalidomide.5
TFR mimics disease progression on imaging before an effective anti-tumor response occurs. A similar phenomenon, ‘pseudo-progression’, was also reported in multiple solid tumor types treated using immune checkpoint inhibitors (ICIs) resulting from T cells infiltrating the tumor site.6
We report a patient with refractory follicular lymphoma who exhibited transient atelectasis due to hilar lymph node swelling affected by lenalidomide-induced TFR.
CASE REPORT
A 58-year-old man visited a hospital in October 2019 for lymph node swelling and the left inguinal lymph node was biopsied. He was diagnosed with follicular lymphoma grade 3a (Figure 1 A–B) and referred to our hospital. We diagnosed his lymphoma as follicular lymphoma grade 3a, stage IV and FLIPI: high. We administered bendamustine, but it was ineffective. He then received R-CHOP therapy and had a partial response. After 5 courses of R-CHOP therapy, left hilar lymph node swelling remained on PET/CT with a SUV of 20.5 as the main lesion (Figure 2).
Fig. 1 Pathological findings: The inguinal lymph node at onset (A x 40, B x 400); The neoplastic follicles show a vaguely nodular pattern (A). Both centrocytes and centroblasts were present (B).
The biopsied left bronchus tissue (C–J x 200); On hematoxylin and eosin staining, dense infiltration of lymphocytes, which were almost all necrotic, was observed under the bronchial epithelium (C). Although they had necrotic change, they were CD10-positive (D), CD20-positive (E), PAX-5-positive (not shown) and bcl-2-posistive cells (F), which is consistent with the phenotype of follicular lymphoma. There were few CD3-positive cells (G), which were negative for granzyme B (H), i.e., not cytotoxic T cells. CD56-positive cells, i.e. NK cells, were not detected (I). CD68-positive cells considered to be macrophages were well noted (J).
Fig. 2 ?Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right). Radiographic findings: PET/CT at onset showed abnormal uptake in the extensive lymph nodes (left). Residual abnormal uptake in the left hilar lymph node was noted after 5 courses of R-CHOP therapy (middle). CT on day 0 showed enlargement of the left hilar lymph node (upper right). Further enlargement, obstructive atelectasis of the left lung and mediastinal shift to the left were observed on CT on day 11 (lower right).
We started R2 (lenalidomide at 20 mg/day, days 1-21 and rituximab at 375 mg/m2, day 1) therapy in June 2020 (day 1). At that time, the WBC count was 3,870/μl (3,500-8,500), containing 2,593/μl of neutrophils and 368/μl of monocytes. Hb was 12.4 g/dl (11.5-17.0), platelet count was 25.4 × 104/μl (15.0-35.0), LDH was 387 U/L (120-200) and CRP was 0.57 mg/dl (≤ 0.30). He was in a good condition on day 4 of R2 therapy. Eleven days after starting R2 therapy, he visited our hospital for respiratory discomfort. His body temperature was 36.5˚C, blood pressure was 129/62 mmHg and SpO2 (room air) was 89-90%. He exhibited grade 1 rash, but had no pain. The WBC count was 2,120/μl, containing 922/μl of neutrophils and 424/μl of monocytes. The monocyte count was relatively high at 20% of the WBC. Hb was 13.6 g/dl, platelet count was 29.3 × 104/μl, LDH was 264 U/L and CRP was 0.99 mg/dl. Chest X-ray revealed a left lung severe shadow (Figure 3). CT demonstrated left lung atelectasis due to left hilar obstruction by lymph node swelling (Figure 2).
Fig. 3 Clinical course of R2 therapy: Chest X-ray on days 11, 18, 28, 42 and 54. Chest imaging on day 0 was by CT because we did not perform chest X-ray at the start of R2 therapy.
After emergency hospitalization on day 11 of R2 treatment, he was stable on oxygen inhalation of 0.5 L/min at rest and 2 L/min when walking. Antihistamine was prescribed for rash. We continued the combination lenalidomide-rituximab (R2) immunotherapy. Although rituximab was administered 6 times through 5 courses of R-CHOP therapy and on day 1 of this course, it was added on day 13. The left hilar lymph node swelling and atelectasis did not improve on chest X-ray on day 18 (Figure 3). If the obstruction of the left bronchus was not due to TFR but to true progression, radiation therapy was considered necessary. We thus carried out transbronchial lung biopsy on day 20 of R2 treatment. The biopsied left bronchus tissue exhibited dense infiltration of lymphocytes, which were almost all necrotic. Although they had necrotic change, their phenotype was consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. Macrophages were well noted. (Figure 1 C–J).
Rituximab was added just after transbronchial lung biopsy on day 20. From around this time, his respiratory state improved. Chest X-ray on day 25 revealed a decrease in left hilar lymph node swelling and improvement of atelectasis. He no longer needed oxygen inhalation and was discharged. As chest X-ray on day 28 (Figure 3) revealed left lung expansion, he received a second cycle of R2 therapy from day 29. The left lung atelectasis expanded through the second cycle of R2 therapy (Figure 3). Central nervous system involvement developed thereafter and we changed R2 therapy to R-CHASE therapy, which contains high-dose cytarabine, and intrathecal administration of methotrexate, cytarabine and prednisolone.
DISCUSSION
TFR is acutely dependent on NK cell function, and is then maintained by the rapid recruitment and proliferation of T cells.2 Andritsos et al. reported increased CD3-positive, CD4-positive, CD8-positive and granzyme B-positive T-cells in an excised swollen tonsil after lenalidomide treatment.7 In the present case, the biopsied left bronchus tissue on day 20 of R2 therapy did not contain NK cells or cytotoxic T cells. Macrophages were relatively conspicuous. It is unclear whether NK cells and cytotoxic T cells disappeared at the time of transbronchial lung biopsy when the respiratory state began improving. Although it is possible that the left hilar lymph nodes swelled due to tumor progression without TFR, rapid enlargement just after the start of R2 therapy may have been related to TFR.
R2 therapy was reported to have favorable activity in patients with relapsed/refractory follicular lymphoma.8 Wang et al. found that lenalidomide with rituximab is effective even for transformed large cell lymphoma originating from follicular lymphoma.9 In a randomized study for relapsed/refractory diffuse large B-cell lymphoma, patients treated using lenalidomide had a longer progression-free survival than those treated at the investigator’s discretion (gemcitabine, rituximab, etoposide or oxaliplatin).10 Based on the resistance to chemotherapy in the present case, we expected complete remission via a unique mechanism of action from the combination of lenalidomide and rituximab rather than the intensity of salvage chemotherapy. Therefore, we selected R2 therapy even if transformation was possible.
Immunotherapy, such as IMiDs and ICIs, works differently from chemotherapy and takes more time to exhibit effects than cytotoxic drugs. Chanan-Khan et al. reported that TFR induced by immunomodulatory drugs, such as lenalidomide, develops in >90% of patients during the first treatment cycle and the median time to onset is 6 days.11 Goy et al. also found that TFR generally developed during the first cycle of lenalidomide, with few events during later cycles.12 Our patient exhibited a typical clinical course regarding the time of TFR. Steroids are used for the management of severe cases of TFR and prophylaxis. Chong et al. reported that patients who received once weekly low-dose (10 mg) dexamethasone had fewer dose interruptions for TFR during the first 8 weeks of lenalidomide.13 Our patient did not receive dexamethasone, but he was administered 100 mg of hydrocortisone once just before the start of rituximab on day 1, day 13 and day 20. Hydrocortisone acts for a short time, unlike dexamethasone. The present patient did not receive any steroids after hydrocortisone on day 1, until he received hydrocortisone on day 13. If dexamethasone had been administered weekly in the first course, TFR may have been less severe.
It is difficult to differentiate pseudo-progression due to TFR from true progression only by imaging, which largely relies on the tumor size.5 The identification of TFR is important to avoid the premature discontinuation of effective therapy because the intensity of TFR is correlated with the probability of achieving a complete response.11 TFR should be paid attention to in the early stage of treatment using immunomodulatory drugs.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest. | Recovering | ReactionOutcome | CC BY-NC-SA | 33431741 | 18,434,257 | 2021-03-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arterial occlusive disease'. | Opioid use may be associated with postoperative complications in myotonic dystrophy type 1 with high-grade muscular impairment.
Individuals with myotonic dystrophy type 1 (DM1) reportedly have a higher risk of postoperative complications than those without DM1; however, factors related to perioperative complications in DM1 patients remain unclear. We aimed to identify the risk factors that may be associated with postoperative complications in DM1 patients. We reviewed medical records of 256 patients with DM1 from 1998 to 2018, among whom 42 (16.4%) had previously undergone 51 surgeries under general and regional anaesthesia. Among the 42 patients, 11 (21.5%) had 13 postoperative complications including respiratory complications, sustained hypotension, wound infection and dehiscence, artery thrombosis and occlusion, and delayed recovery from anaesthesia. There were significant inter-group differences between the non-complicated and complicated groups considering the following parameters: high-grade (≥ 3) muscular impairment rating scale (MIRS), extubation time, postoperative opioid use, and hospital length of stay. Furthermore, univariate analysis revealed that an MIRS score ≥ 3 (odds ratio [OR] 9.346, confidence interval [CI] 1.761-49.595, p = 0.009) and postoperative opioid use (OR 8.000, CI 1.772-36.127, p = 0.007) were the only statistically significant factors. Therefore, clinicians should be cautious in administering opioids, particularly in patients with a high-grade MIRS score during the perioperative period.
Introduction
Myotonic dystrophy type 1 (dystrophia myotonica; DM1) is a genetic neuromuscular disorder with an estimated global prevalence of 1:20,000. It is primarily caused by the expansion of cytosine–thymine–guanine (CTG) trinucleotide repeat located in the non-coding region of the dystrophia myotonica protein kinase (DMPK) gene1. Although, it is clinically characterized by myotonia along with facial and distal dominant weakness, it is now categorized as a multisystemic disease involving cataract, diabetes, and arrhythmia, along with diseases of the central nervous system. Patients with neuromuscular diseases such as DM1 reportedly have a higher risk of postoperative complications than those without, this may be attributed to the presence of underlying muscle weakness, scoliosis, and cardiac abnormalities2. Additionally, involvement of multiple organ systems and increased sensitivity to anaesthetic medications further increase high risk of postoperative complications3. A recent meta-analysis described a predominantly restrictive ventilator pattern observed in DM1, with a significant emphasis on alveolar hypoventilation and chronic hypercapnia4. The advent of novel therapeutic strategies targeting DM1 has highlighted the need for a greater understanding of the respiratory decline while focusing primarily on the use of appropriate anaesthetic agents and respiratory management strategies. However, factors related to perioperative complications in patients with DM1 require further elucidation. Therefore, we aimed to address the possible risk factors that may be associated with postoperative complications in DM1 patients who had undergone surgical interventions under general or regional anaesthesia.
Results
We enrolled 256 patients with DM1, among whom 42 (16.4%) had previously undergone 51 surgeries under general or regional anaesthesia. The patients were divided into surgical and nonsurgical group as presented in Table 1 and there were no statistically significant inter-differences in the baseline clinical characteristics with regard to their age, body mass index (BMI), CTG repeats, and other comorbid diseases except cataract. However, gender and muscular impairment rating scale (MIRS) score demonstrated statistically significance differences in the baselines for each group. Among the 42 patients, 11 presented with postoperative complications (Fig. 1). Characteristics of the patients with postoperative complications, along with their perioperative parameters, are presented in Supplementary Table S1, S2, and S3.Table 1 Clinical characteristics of the patients with a myotonic dystrophy type 1.
Non-surgical group (n = 214) Surgical group (n = 42) p value
Age (year) 37.0 (28.0–48.0) 36.5 (18.0–43.0) 0.083
Body mass index (kg/m2) 21.5 ± 4.3 19.8 ± 3.9 0.016
Gender (male/female) 125 (58.4)/89 (41.6) 13 (31.0)/29 (69.0) 0.002
MIRS 0.001
1 2 (1.0) 5 (11.9)
2 72 (33.6) 16 (38.1)
3 81 (37.9) 15 (35.7)
4 51 (23.8) 4 (9.5)
5 8 (3.7) 2 (4.8)
FSRS 0.361
1 145 (67.8) 31 (73.8)
2 54 (25.2) 7 (16.7)
3 11 (5.1) 4 (9.5)
4 4 (1.9) 0 (0.0)
CTG repeat size 390 (165–550) 400 (220–540) 0.446
Serum creatinine kinase 293 (166–472) 261 (143–366) 0.153
Comorbidity
Cataract 14 (6.5) 8 (19.0) 0.019
Elevated liver enzymes 29 (13.6) 5 (11.9) 0.969
Autoimmune disease 8 (3.7) 2 (4.8) > 0.999
Baldness 23 (10.7) 3 (7.1) 0.669
Cardiovascular diseases 5 (2.3) 1 (2.4) > 0.999
Arrythmia 23 (10.7) 4 (9.5) > 0.999
Diabetes mellitus 40 (18.7) 3 (7.1) 0.109
Other diseases 11 (5.1) 11 (26.2) < 0.001
Data are expressed as mean (standard deviation), number (%), or median (interquartile range).
MIRS muscular impairment rating scale, FSRS functional status rating scale, CTG cytosine-thymine-guanine, Other diseases Bronchiectasis, myoma, biliary atresia, cryptorchism, hydrocephalus, neurofibroma, and vocal cord palsy.
Figure 1 Detailed postoperative complications in patients with myotonic dystrophy type 1.
Opioid administration for postoperative pain control was restricted to almost on the day of surgery (postoperative day 0); additionally, they were treated with nonsteroidal anti-inflammatory drugs or acetaminophen to ameliorate the mild to moderate postoperative pain. However, opioids were administered either in cases of moderate to severe pain associated with orthopaedic or abdominal surgery, or in cases of insufficient analgesia despite the administration of non-opioid analgesics. Eight patients in the complicated group received opioid analgesics on the day of surgery, with the average dosage ranging from 0.3 to 1.9 μg/kg.
We comprehensively compared 42 surgical cases and categorized them into the non-complicated and complicated groups (Table 2). The non-complicated group (n = 31) and complicated group (n = 11) were compared considering their clinical, genetic, laboratory, anaesthesia, and postoperative parameters (Supplementary Table S2). There were no significant differences in their demographic parameters such as age at the time of the procedure operation, BMI, gender, and American Society of Anesthesiologists (ASA) physical status class. The complicated group showed significantly higher occurrences of high MIRS scores (≥ 3) than the non-complicated group, while both groups had similar functional status rating scale (FSRS) scores, CTG repeat lengths, and serum creatinine kinase levels. Both groups showed statistically significant differences in the anaesthesia-related parameters with regard to the extubation time and postoperative opioid use (5.0 min [5.0–13.0] vs. 638.0 min [22.5–1200.0], p = 0.003; 7 [22.6] vs. 8 [72.7], p = 0.009, respectively). The hospital length of stay (LOS) for the patients in the complicated group was longer than for those in the non-complicated group (5.0 [3.0–8.5] vs. 8.0 [6.5–78.0], p = 0.015).Table 2 Comparison of non-complicated group and complicated group during perioperative period.
Non-complicated group (n = 31) Complicated group (n = 11) p value
Age (year) 26.0 (5.5–38.0) 25.0 (15.0–39.5) 0.330
Body mass index (kg/m2) 19.5 ± 3.6 18.2 ± 4.4 0.356
Gender (male/female) 8 (25.8)/23 (74.2) 4 (36.4)/7 (63.6) 0.781
ASA class 0.214
1 17 (54.8) 4 (36.4)
2 8 (25.8) 6 (54.5)
3 6 (19.4) 1 (9.1)
MIRS 0.022
< 3 20 (64.5) 2 (18.2)
≥ 3 11 (35.5) 9 (81.8)
FSRS 0.560
1 21 (87.5) 8 (72.7)
2 2 (8.3) 2 (18.2)
3 1 (4.2) 1 (9.1)
4 0 (0.0) 0 (0.0)
CTG repeat size 400 (220–545) 530 (300–550) 0.336
Serum creatinine kinase 264.9 ± 148.9 306.8 ± 157.6 0.434
Type of anesthesia > 0.999
General 28 (90.3) 10 (90.9)
Regional 3 (9.7) 1 (9.1)
Type of surgery 0.540
Dental 1 (3.2) 0 (0)
Ears, nose, throat 3 (9.7) 0 (0)
General 5 (16.1) 4 (36.4)
Neurology 2 (6.5) 1 (9.1)
Obstetrics and gynecology 10 (32.3) 5 (45.4)
Ophthalmology 3 (9.7) 0 (0)
Orthopedic 5 (16.1) 1 (9.1)
Urology 2 (6.5) 0 (0.0)
Muscle relaxants use 25 (80.6) 10 (90.9) 0.754
Type of anesthetics 0.994
Inhalation 22 (71.0) 8 (72.7)
TIVA 6 (19.4) 2 (18.2)
Intraoperative opioid use 12 (38.7) 5 (45.5) 0.973
Reversal agents use 23 (74.2) 7 (63.6) 0.781
Sugammadex use 3 (9.7) 0 (0.0) 0.697
Airway device 24 (77.4) 10 (90.9) 0.448
ETT 4 (12.9) 0 (0.0)
LMA
Surgical time (min) 60.0 (40.0–87.5) 85.0 (52.5–155.0) 0.197
Anesthetic time (min) 155.0 (118.5–219.0) 220.0 (164.0–350.0) 0.247
Extubation time (min) 5.0 (5.0–13.0) 638.0 (22.5–1200.0) 0.003
Postoperative analgesics 0.009
Others 24 (77.4) 3 (27.3)
Opioid 7 (22.6) 8 (72.7)
PACU LOS (day) 50.0 (45.0–58.0) 77.5 (47.5–92.5) 0.227
ICU LOS (day) 2.0 (2.0–2.0) 3.0 (2.5–3.5) 0.081
Hospital LOS (day) 5.0 (3.0–8.5) 8.0 (6.5–78.0) 0.015
Readmission 1 (3.2) 1 (9.1) > 0.999
Data are expressed as mean (standard deviation), number (%), or median (interquartile range).
MIRS muscular impairment rating scale, FSRS functional status rating scale, CTG cytosine-thymine-guanine, TIVA total intravenous anesthesia, ETT endotracheal tube, LMA laryngeal mask airway, Others nonsteroidal anti-inflammatory drugs, acetaminophen, nefopam, and no analgesics, PACU Post Anesthetic Care Unit, LOS length of stay, ICU Intensive Care Unit.
Among 11 patients (complicated group), seven patients had respiratory complications including desaturation [oxygen partial pressure (PaO2) < 60 mmHg on room air] and dyspnoea and received prolonged ventilator care for > 1 postoperative day. Three patients presented with wound infection or dehiscence and one with arterial thrombotic occlusion (Supplementary Table S3). One patient who showed delayed recovery, had to recover for three days after the surgery to regain consciousness. One patient had postoperative hypotension. Summarily, there were 13 postoperative complications.
We used univariate regression analysis to identify the factors associated with the postoperative complications in DM1 patients (Table 3). We consequently selected the following parameters for univariate regression analysis considering their clinical importance and statistical significance: age, gender, BMI, MIRS score, hospital LOS, and postoperative use of opioids. MIRS score ≥ 3 and postoperative opioid use were the only statistically significant risk factors with a relatively higher odds ratio (OR), 95% confidence interval (CI), and p value (OR 8.182, 95% CI 1.495–44.772, p = 0.015; OR: 9.143, CI 1.899–44.011, p = 0.006) (Table 3).Table 3 Univariate regression analysis associated with postoperative complications in patients with a myotonic dystrophy type 1.
Variables Univariate analysis
OR (95% CI) p value
Age 1.024 (0.980–1.069) 0.286
Gender 0.508
Male 1.000
Female 0.609 (0.140–2.643)
Body mass index (kg/m2) 0.914 (0.757–1.103) 0.348
MIRS 0.015
< 3 1.000
≥ 3 8.182 (1.495–44.772)
Hospital LOS 1.004 (0.995–1.014) 0.376
Postoperative analgesics
Others 1.000 0.006
Opioid 9.143 (1.899–44.011)
Data are expressed as odds ratio (95% confidence interval).
MIRS muscular impairment rating scale, LOS length of stay, Others nonsteroidal anti-inflammatory drugs, acetaminophen, nefopam, and no analgesics.
Discussion
DM1 is clinically characterized by the presence of myotonia, which is an impairment of muscle relaxation following contraction. Electrophysiologically, it can be characterized by the presence of involuntary repetitive action potentials of the muscle membrane that is perpetually in its hyper-excitable state due to a persistent sodium influx or reduced chloride channel conductance5. Due to the high prevalence of DM1 in adults, there is an established anaesthesia management guideline based on the recommendations of several experts6, which elaborates on the importance of preoperative evaluations of the pulmonary, cardiac, and gastrointestinal symptoms in DM1 patients. It also highlights the need for caution when using anaesthetic and analgesic medications, and the necessity of oxygen saturation and electrocardiography monitoring during the perioperative period. However, these recommendations were based on a limited number of studies, possibly due to the rarity of the disease. Therefore, we aimed to evaluate the possible risk factors influencing DM1 postoperative complications, to consolidate the evidence for the current recommendations suggested by the Myotonic Dystrophy Foundation.
Patients with neuromuscular diseases demonstrate an increased risk of surgical complications when under general anaesthesia due to respiratory muscle weakness, musculoskeletal abnormalities, and cardiac involvement7–9. However, only a small number of studies have elaborated on the anaesthesia-related complications in DM110,11. These studies reported that the frequency of postoperative complications in DM1 patients typically ranges from 8.2 to 42.9%12,13, which was similar to our study (21.5%) and previous literatures on the subject.
Among the 11 DM1 patients who underwent anaesthesia-related adverse events, 7 (64%) demonstrated respiratory complications and 4 (36.3%) received ventilatory support. A retrospective study that reviewed 219 cases of DM1 reported an 89% prevalence of respiratory complications and 31% required ventilatory support10. Another study showed a rate of 10% with regard to postoperative respiratory complications. Discrepancies in the complication rate may be attributable to the severity of the patient’s condition, types of the disease or type of a surgery. It is noteworthy to state that compared to other muscular dystrophies, DM1 appeared to have a significantly high rate of respiratory complications with significantly low cardiac complications. We observed that DM1 patients showed a relatively high complication rate (81.8%) with an MIRS score ≥ 3 and showed an increased odds ratio of 9.346; similarly, Mathieu et al. reported an odds ratio of 14.110. This can be partly explained by the fact that general anaesthesia may have decreased lung compliance and functional residual capacity, leading to alveolar hypoventilation and atelectasis. There is substantial evidence to prove that DM1 patients show abnormalities with regard to the ventilator control mechanisms, and their conditions became more critical when exposed to anaesthetic agents, resulting in a low central respiratory drive14,15. Furthermore, this hypothesis can be consolidated by our result in which 9 of 11 patients received abdominal surgery, which is an important risk factor of hypoventilation16.
The concerns regarding increase in the risk of defects in the cardiac rhythm conduction and potential progression of known conduction delays in patients with DM1 during the perioperative period are evident17. Considering the presence of progressive deterioration of atrioventricular and intraventricular conduction, they can further be exacerbated by anaesthetic drugs, airway manipulation, changes in sympathetic and parasympathetic tone, or hypoxia2,18. Although one patient in the complicated group had atrial fibrillation, the risk of cardiac rhythm conduction or aggravated conduction delay remained the same throughout the study. Studies have previously reported that complications associated with perioperative cardiac conduction were absent or were present in only one case10,11, which was further validated by our results.
A previous study with 27 juvenile-onset DM1 patients, who had undergone 78 surgeries11, Reported that a higher MIRS score, CTG repeat lengths, longer duration of surgery, use of muscle relaxants, and perioperative opioid use were risk factors of perioperative adverse events. However, multivariate regression analysis revealed that a higher MIRS score and use of muscle relaxants were independent risk factors. Interestingly, our result showed that postoperative opioid use and a higher MIRS score were independent risk factors. Although the length of CTG repeats typically correlates with the severity of DM1, we noted no such relationship between the two. The novelty of our study was that we recruited a large number of patients and identified a statistically significant risk factor of postoperative opioid use that influenced the increased possibility of postoperative adverse events in DM1 with an odds ratio of 8.0. Although Sinclair et al. found perioperative opioid use as a risk factor, it could not be considered independent after undergoing regression analysis. The discrepancy may also be explained by differences in mean age of the participants in our study as opposed to that of Sinclair et al. (36.8 years vs 8 years, respectively).
Recent studies have reported the role of central nervous system abnormality in DM1 in the aspects of neurodegeneration19,20. Opioid receptors are widely present in brainstem, carotid bodies, the vagus nerve, and airway walls21. Opioids upregulate the activity of inhibitory neurons in the brainstem and decrease the rate of respiration and tidal volume22; Furthermore, a study has recently reported that administering opioids reduced the ventilator response to hypoxemia and hypercapnia23. These mechanisms may have aggravated the overall central nervous system depression to induce greater postoperative complications. However, further investigation is needed to understand the mechanism of high prevalence of respiratory complications in relation to opioids in DM1.
There are a few limitations that need to be addressed. First, the present study was based on a small retrospective analysis, it could limit and compromise its results. However, DM1 is an uncommon genetic neuromuscular disorder, the investigative studies on perioperative outcomes in patients with DM1 are limited. Therefore, we believed that this study further consolidated the known evidence related to the risk factors of perioperative outcomes. Second, this was a retrospective study based on medical and anaesthesia-related records of the patients and therefore selection of analgesics and protocol for analgesic management may be inaccurate, influenced by the preference of individual surgeons and anaesthesiologists. Third, the present study was conducted in only one tertiary hospital and most of the procedures were elective; therefore, the risk of the adverse events might be over- or under-estimated. Lastly, our results do not represent all clinical stages of DM1.
Conclusions
This is possibly the first study on DM1 patients of Asian ethnicities and our data was in accordance to other Caucasian studies that showed a high prevalence of pulmonary complications after the surgery. Higher MIRS scores positively correlated with a higher prevalence of adverse events. Moreover, postoperative opioid use was also an independent risk factor of accentuated complication rates. Further research on respiratory complications and opioid usage may reduce the rate of onset of surgical complications in DM1.
Methods
Patients
The medical records of the patients who visited Asan medical center between January 1998 and June 2018 were reviewed and 256 cases were retrieved. This study was approved by the institutional review board and registered at the University of Ulsan, Seoul, Republic of Korea (2018–0876). We searched information technology of service management of our institution using the terms “myotonic disorders”, “dystrophia myotonica”, and “myotonia congenita”. DM1 diagnosis was based on a genetic study that showed an abnormal increase in the length of untranslated CTG repeat in the DMPK gene on19q13. We included DM1 patients who underwent confirmatory genetic examinations; furthermore, DM1 patients who underwent surgery with general or regional anaesthesia were included in the surgical group. We excluded the patients whose diagnosis was not confirmed genetically, along with those who were diagnosed with drug-induced myotonia, pseudomyotonia, and non-drodystrophic myotonia after reviewing their medical data. Patients who had received local anaesthesia during the surgery were also excluded in the surgical group.
Outcome assessment and factors associated with postoperative complications
The clinical and laboratory parameters of the patients including gender, age at surgery, gender, ASA physical status class, type of surgery, type of anaesthesia, BMI, CTG repeat length, serum creatine kinase, and comorbid diseases including autoimmune disease, cardiovascular disease, arrhythmia, and diabetes, among other parameters were retrieved from their medical records. A functional muscular involvement was evaluated using the MIRS and the FSRS10. MIRS is a 5-point scale ranging from 1 to 5, with a higher numerical value reflecting a more severe muscle weakness, with grade 1 = no muscular impairment, grade 2 = minimal signs such as myotonia or facial weakness, grade 3 = distal weakness, grade 4 = mild to moderate proximal weakness, and grade 5 = severe proximal limb weakness. FSRS is a 4-point scale ranging from 1 to 4, in which 1 = mild and 4 = bedridden.
Records related to the type of anaesthesia, hypnotics used for induction, neuromuscular blockers, anaesthetic agents for maintenance, opioid usage, body temperature, reversal agent, airway device, need for extubation, extubation time (minutes) (from the end of surgery to extubation), surgical time (minutes), postoperative analgesics, hospital wards occupied by the patients and duration of hospitalization (post anaesthetic care unit, intensive care unit), hospital LOS (day), re-admission, postoperative complications were retrieved from the medical records. Doses of all opioids administered to patients were converted to intravenous fentanyl equianalgesic doses according to published conversion factors (intravenous fentanyl 100 μg = meperidine 100 mg = tramadol 100 mg)23.
24Surgery and anaesthesia-associated complications, and any adverse events during the postoperative period (up to seven days after the surgery) were defined as postoperative complications in the study. They may or may not be related to the disease for which the surgery was performed or be the direct results of the surgery24. We defined respiratory complications as follows: postoperative PaO2 < 60 mmHg on room air, a PaO2: fraction of inspired oxygen of ratio < 300 mmHg, arterial oxyhaemoglobin saturation measured with pulse oximetry < 90% and requiring oxygen therapy, or ventilator dependence for > postoperative one day or re-intubation25–27. Delayed recovery from anaesthesia was defined as a state of unresponsiveness from which the patient could not be aroused for more than 90 min after being administered with general anaesthesia. We defined sustained hypotension by introducing minor modifications to a definition used in a previous study: systolic blood pressure < 90 mmHg for > 30 min that required the usage of vasopressors25.
Statistical analysis
The data were analysed by using the Statistical Package for the Social Sciences Version 21.0 (SPSS, IBM SPSS Statistics, IBM Corporation, Armonk, NY, USA). Data are expressed as mean (standard deviation), median (interquartile range), number (proportion), or odds ratio (OR) and 95% confidence interval (95% CI). Normal distribution of data was assessed using the Kolmogorov–Smirnov test. Normally distributed continuous demographic data such as body mass index were compared using the Student’s t test; however, non-normally distributed continuous data such as age, CTG repeat size, serum creatinine kinase, and surgical time, among other parameters, were compared using the Mann–Whitney U test. Categorical demographic data were compared using the chi-square test or Fisher’s exact test, as appropriate. By using univariate logistic regression, the factors associated with postoperative complications in patients with DM1 were analysed. A value of p < 0.05 was considered statistically significant.
Ethics
This study was performed according to the Declaration of Helsinki. The current study protocol was approved by the institutional review board of Asan Medical Center, Seoul, Korea (approval number: 2018-0876). Due to the retrospective nature of the study, informed consent was waived.
Supplementary information
Supplementary Information.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Chan-Sik Kim and Jin -Mo Park.
Supplementary information
is available for this paper at 10.1038/s41598-020-76217-9.
Acknowledgements
This work was supported by a Grant from the National Research Foundation of Korea, which is funded by the Korean Government, Ministry of Science and ICT (NRF-2017R1C1B5076264 and NRF-2018R1C1B5045675).
Author contributions
C.-S.K., J.-M.P. and J.-S.P. were involved in study conception and wrote the manuscript. D.P. and D.-H.K. were involved in study deign and revised the manuscript. C.-S.K. and D.-H.K. were involved in data acquisition. D.P. and D.-H.K. were involved in analysis and interpretation of the data. J.-M.P. and J.-S.P. were involved in study design and critical revision of manuscript. All the authors approve the final version of manuscript.
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests. | ETOMIDATE, FENTANYL, PYRIDOSTIGMINE, SEVOFLURANE, VECURONIUM BROMIDE | DrugsGivenReaction | CC BY | 33431966 | 19,815,553 | 2021-01-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombosis'. | Opioid use may be associated with postoperative complications in myotonic dystrophy type 1 with high-grade muscular impairment.
Individuals with myotonic dystrophy type 1 (DM1) reportedly have a higher risk of postoperative complications than those without DM1; however, factors related to perioperative complications in DM1 patients remain unclear. We aimed to identify the risk factors that may be associated with postoperative complications in DM1 patients. We reviewed medical records of 256 patients with DM1 from 1998 to 2018, among whom 42 (16.4%) had previously undergone 51 surgeries under general and regional anaesthesia. Among the 42 patients, 11 (21.5%) had 13 postoperative complications including respiratory complications, sustained hypotension, wound infection and dehiscence, artery thrombosis and occlusion, and delayed recovery from anaesthesia. There were significant inter-group differences between the non-complicated and complicated groups considering the following parameters: high-grade (≥ 3) muscular impairment rating scale (MIRS), extubation time, postoperative opioid use, and hospital length of stay. Furthermore, univariate analysis revealed that an MIRS score ≥ 3 (odds ratio [OR] 9.346, confidence interval [CI] 1.761-49.595, p = 0.009) and postoperative opioid use (OR 8.000, CI 1.772-36.127, p = 0.007) were the only statistically significant factors. Therefore, clinicians should be cautious in administering opioids, particularly in patients with a high-grade MIRS score during the perioperative period.
Introduction
Myotonic dystrophy type 1 (dystrophia myotonica; DM1) is a genetic neuromuscular disorder with an estimated global prevalence of 1:20,000. It is primarily caused by the expansion of cytosine–thymine–guanine (CTG) trinucleotide repeat located in the non-coding region of the dystrophia myotonica protein kinase (DMPK) gene1. Although, it is clinically characterized by myotonia along with facial and distal dominant weakness, it is now categorized as a multisystemic disease involving cataract, diabetes, and arrhythmia, along with diseases of the central nervous system. Patients with neuromuscular diseases such as DM1 reportedly have a higher risk of postoperative complications than those without, this may be attributed to the presence of underlying muscle weakness, scoliosis, and cardiac abnormalities2. Additionally, involvement of multiple organ systems and increased sensitivity to anaesthetic medications further increase high risk of postoperative complications3. A recent meta-analysis described a predominantly restrictive ventilator pattern observed in DM1, with a significant emphasis on alveolar hypoventilation and chronic hypercapnia4. The advent of novel therapeutic strategies targeting DM1 has highlighted the need for a greater understanding of the respiratory decline while focusing primarily on the use of appropriate anaesthetic agents and respiratory management strategies. However, factors related to perioperative complications in patients with DM1 require further elucidation. Therefore, we aimed to address the possible risk factors that may be associated with postoperative complications in DM1 patients who had undergone surgical interventions under general or regional anaesthesia.
Results
We enrolled 256 patients with DM1, among whom 42 (16.4%) had previously undergone 51 surgeries under general or regional anaesthesia. The patients were divided into surgical and nonsurgical group as presented in Table 1 and there were no statistically significant inter-differences in the baseline clinical characteristics with regard to their age, body mass index (BMI), CTG repeats, and other comorbid diseases except cataract. However, gender and muscular impairment rating scale (MIRS) score demonstrated statistically significance differences in the baselines for each group. Among the 42 patients, 11 presented with postoperative complications (Fig. 1). Characteristics of the patients with postoperative complications, along with their perioperative parameters, are presented in Supplementary Table S1, S2, and S3.Table 1 Clinical characteristics of the patients with a myotonic dystrophy type 1.
Non-surgical group (n = 214) Surgical group (n = 42) p value
Age (year) 37.0 (28.0–48.0) 36.5 (18.0–43.0) 0.083
Body mass index (kg/m2) 21.5 ± 4.3 19.8 ± 3.9 0.016
Gender (male/female) 125 (58.4)/89 (41.6) 13 (31.0)/29 (69.0) 0.002
MIRS 0.001
1 2 (1.0) 5 (11.9)
2 72 (33.6) 16 (38.1)
3 81 (37.9) 15 (35.7)
4 51 (23.8) 4 (9.5)
5 8 (3.7) 2 (4.8)
FSRS 0.361
1 145 (67.8) 31 (73.8)
2 54 (25.2) 7 (16.7)
3 11 (5.1) 4 (9.5)
4 4 (1.9) 0 (0.0)
CTG repeat size 390 (165–550) 400 (220–540) 0.446
Serum creatinine kinase 293 (166–472) 261 (143–366) 0.153
Comorbidity
Cataract 14 (6.5) 8 (19.0) 0.019
Elevated liver enzymes 29 (13.6) 5 (11.9) 0.969
Autoimmune disease 8 (3.7) 2 (4.8) > 0.999
Baldness 23 (10.7) 3 (7.1) 0.669
Cardiovascular diseases 5 (2.3) 1 (2.4) > 0.999
Arrythmia 23 (10.7) 4 (9.5) > 0.999
Diabetes mellitus 40 (18.7) 3 (7.1) 0.109
Other diseases 11 (5.1) 11 (26.2) < 0.001
Data are expressed as mean (standard deviation), number (%), or median (interquartile range).
MIRS muscular impairment rating scale, FSRS functional status rating scale, CTG cytosine-thymine-guanine, Other diseases Bronchiectasis, myoma, biliary atresia, cryptorchism, hydrocephalus, neurofibroma, and vocal cord palsy.
Figure 1 Detailed postoperative complications in patients with myotonic dystrophy type 1.
Opioid administration for postoperative pain control was restricted to almost on the day of surgery (postoperative day 0); additionally, they were treated with nonsteroidal anti-inflammatory drugs or acetaminophen to ameliorate the mild to moderate postoperative pain. However, opioids were administered either in cases of moderate to severe pain associated with orthopaedic or abdominal surgery, or in cases of insufficient analgesia despite the administration of non-opioid analgesics. Eight patients in the complicated group received opioid analgesics on the day of surgery, with the average dosage ranging from 0.3 to 1.9 μg/kg.
We comprehensively compared 42 surgical cases and categorized them into the non-complicated and complicated groups (Table 2). The non-complicated group (n = 31) and complicated group (n = 11) were compared considering their clinical, genetic, laboratory, anaesthesia, and postoperative parameters (Supplementary Table S2). There were no significant differences in their demographic parameters such as age at the time of the procedure operation, BMI, gender, and American Society of Anesthesiologists (ASA) physical status class. The complicated group showed significantly higher occurrences of high MIRS scores (≥ 3) than the non-complicated group, while both groups had similar functional status rating scale (FSRS) scores, CTG repeat lengths, and serum creatinine kinase levels. Both groups showed statistically significant differences in the anaesthesia-related parameters with regard to the extubation time and postoperative opioid use (5.0 min [5.0–13.0] vs. 638.0 min [22.5–1200.0], p = 0.003; 7 [22.6] vs. 8 [72.7], p = 0.009, respectively). The hospital length of stay (LOS) for the patients in the complicated group was longer than for those in the non-complicated group (5.0 [3.0–8.5] vs. 8.0 [6.5–78.0], p = 0.015).Table 2 Comparison of non-complicated group and complicated group during perioperative period.
Non-complicated group (n = 31) Complicated group (n = 11) p value
Age (year) 26.0 (5.5–38.0) 25.0 (15.0–39.5) 0.330
Body mass index (kg/m2) 19.5 ± 3.6 18.2 ± 4.4 0.356
Gender (male/female) 8 (25.8)/23 (74.2) 4 (36.4)/7 (63.6) 0.781
ASA class 0.214
1 17 (54.8) 4 (36.4)
2 8 (25.8) 6 (54.5)
3 6 (19.4) 1 (9.1)
MIRS 0.022
< 3 20 (64.5) 2 (18.2)
≥ 3 11 (35.5) 9 (81.8)
FSRS 0.560
1 21 (87.5) 8 (72.7)
2 2 (8.3) 2 (18.2)
3 1 (4.2) 1 (9.1)
4 0 (0.0) 0 (0.0)
CTG repeat size 400 (220–545) 530 (300–550) 0.336
Serum creatinine kinase 264.9 ± 148.9 306.8 ± 157.6 0.434
Type of anesthesia > 0.999
General 28 (90.3) 10 (90.9)
Regional 3 (9.7) 1 (9.1)
Type of surgery 0.540
Dental 1 (3.2) 0 (0)
Ears, nose, throat 3 (9.7) 0 (0)
General 5 (16.1) 4 (36.4)
Neurology 2 (6.5) 1 (9.1)
Obstetrics and gynecology 10 (32.3) 5 (45.4)
Ophthalmology 3 (9.7) 0 (0)
Orthopedic 5 (16.1) 1 (9.1)
Urology 2 (6.5) 0 (0.0)
Muscle relaxants use 25 (80.6) 10 (90.9) 0.754
Type of anesthetics 0.994
Inhalation 22 (71.0) 8 (72.7)
TIVA 6 (19.4) 2 (18.2)
Intraoperative opioid use 12 (38.7) 5 (45.5) 0.973
Reversal agents use 23 (74.2) 7 (63.6) 0.781
Sugammadex use 3 (9.7) 0 (0.0) 0.697
Airway device 24 (77.4) 10 (90.9) 0.448
ETT 4 (12.9) 0 (0.0)
LMA
Surgical time (min) 60.0 (40.0–87.5) 85.0 (52.5–155.0) 0.197
Anesthetic time (min) 155.0 (118.5–219.0) 220.0 (164.0–350.0) 0.247
Extubation time (min) 5.0 (5.0–13.0) 638.0 (22.5–1200.0) 0.003
Postoperative analgesics 0.009
Others 24 (77.4) 3 (27.3)
Opioid 7 (22.6) 8 (72.7)
PACU LOS (day) 50.0 (45.0–58.0) 77.5 (47.5–92.5) 0.227
ICU LOS (day) 2.0 (2.0–2.0) 3.0 (2.5–3.5) 0.081
Hospital LOS (day) 5.0 (3.0–8.5) 8.0 (6.5–78.0) 0.015
Readmission 1 (3.2) 1 (9.1) > 0.999
Data are expressed as mean (standard deviation), number (%), or median (interquartile range).
MIRS muscular impairment rating scale, FSRS functional status rating scale, CTG cytosine-thymine-guanine, TIVA total intravenous anesthesia, ETT endotracheal tube, LMA laryngeal mask airway, Others nonsteroidal anti-inflammatory drugs, acetaminophen, nefopam, and no analgesics, PACU Post Anesthetic Care Unit, LOS length of stay, ICU Intensive Care Unit.
Among 11 patients (complicated group), seven patients had respiratory complications including desaturation [oxygen partial pressure (PaO2) < 60 mmHg on room air] and dyspnoea and received prolonged ventilator care for > 1 postoperative day. Three patients presented with wound infection or dehiscence and one with arterial thrombotic occlusion (Supplementary Table S3). One patient who showed delayed recovery, had to recover for three days after the surgery to regain consciousness. One patient had postoperative hypotension. Summarily, there were 13 postoperative complications.
We used univariate regression analysis to identify the factors associated with the postoperative complications in DM1 patients (Table 3). We consequently selected the following parameters for univariate regression analysis considering their clinical importance and statistical significance: age, gender, BMI, MIRS score, hospital LOS, and postoperative use of opioids. MIRS score ≥ 3 and postoperative opioid use were the only statistically significant risk factors with a relatively higher odds ratio (OR), 95% confidence interval (CI), and p value (OR 8.182, 95% CI 1.495–44.772, p = 0.015; OR: 9.143, CI 1.899–44.011, p = 0.006) (Table 3).Table 3 Univariate regression analysis associated with postoperative complications in patients with a myotonic dystrophy type 1.
Variables Univariate analysis
OR (95% CI) p value
Age 1.024 (0.980–1.069) 0.286
Gender 0.508
Male 1.000
Female 0.609 (0.140–2.643)
Body mass index (kg/m2) 0.914 (0.757–1.103) 0.348
MIRS 0.015
< 3 1.000
≥ 3 8.182 (1.495–44.772)
Hospital LOS 1.004 (0.995–1.014) 0.376
Postoperative analgesics
Others 1.000 0.006
Opioid 9.143 (1.899–44.011)
Data are expressed as odds ratio (95% confidence interval).
MIRS muscular impairment rating scale, LOS length of stay, Others nonsteroidal anti-inflammatory drugs, acetaminophen, nefopam, and no analgesics.
Discussion
DM1 is clinically characterized by the presence of myotonia, which is an impairment of muscle relaxation following contraction. Electrophysiologically, it can be characterized by the presence of involuntary repetitive action potentials of the muscle membrane that is perpetually in its hyper-excitable state due to a persistent sodium influx or reduced chloride channel conductance5. Due to the high prevalence of DM1 in adults, there is an established anaesthesia management guideline based on the recommendations of several experts6, which elaborates on the importance of preoperative evaluations of the pulmonary, cardiac, and gastrointestinal symptoms in DM1 patients. It also highlights the need for caution when using anaesthetic and analgesic medications, and the necessity of oxygen saturation and electrocardiography monitoring during the perioperative period. However, these recommendations were based on a limited number of studies, possibly due to the rarity of the disease. Therefore, we aimed to evaluate the possible risk factors influencing DM1 postoperative complications, to consolidate the evidence for the current recommendations suggested by the Myotonic Dystrophy Foundation.
Patients with neuromuscular diseases demonstrate an increased risk of surgical complications when under general anaesthesia due to respiratory muscle weakness, musculoskeletal abnormalities, and cardiac involvement7–9. However, only a small number of studies have elaborated on the anaesthesia-related complications in DM110,11. These studies reported that the frequency of postoperative complications in DM1 patients typically ranges from 8.2 to 42.9%12,13, which was similar to our study (21.5%) and previous literatures on the subject.
Among the 11 DM1 patients who underwent anaesthesia-related adverse events, 7 (64%) demonstrated respiratory complications and 4 (36.3%) received ventilatory support. A retrospective study that reviewed 219 cases of DM1 reported an 89% prevalence of respiratory complications and 31% required ventilatory support10. Another study showed a rate of 10% with regard to postoperative respiratory complications. Discrepancies in the complication rate may be attributable to the severity of the patient’s condition, types of the disease or type of a surgery. It is noteworthy to state that compared to other muscular dystrophies, DM1 appeared to have a significantly high rate of respiratory complications with significantly low cardiac complications. We observed that DM1 patients showed a relatively high complication rate (81.8%) with an MIRS score ≥ 3 and showed an increased odds ratio of 9.346; similarly, Mathieu et al. reported an odds ratio of 14.110. This can be partly explained by the fact that general anaesthesia may have decreased lung compliance and functional residual capacity, leading to alveolar hypoventilation and atelectasis. There is substantial evidence to prove that DM1 patients show abnormalities with regard to the ventilator control mechanisms, and their conditions became more critical when exposed to anaesthetic agents, resulting in a low central respiratory drive14,15. Furthermore, this hypothesis can be consolidated by our result in which 9 of 11 patients received abdominal surgery, which is an important risk factor of hypoventilation16.
The concerns regarding increase in the risk of defects in the cardiac rhythm conduction and potential progression of known conduction delays in patients with DM1 during the perioperative period are evident17. Considering the presence of progressive deterioration of atrioventricular and intraventricular conduction, they can further be exacerbated by anaesthetic drugs, airway manipulation, changes in sympathetic and parasympathetic tone, or hypoxia2,18. Although one patient in the complicated group had atrial fibrillation, the risk of cardiac rhythm conduction or aggravated conduction delay remained the same throughout the study. Studies have previously reported that complications associated with perioperative cardiac conduction were absent or were present in only one case10,11, which was further validated by our results.
A previous study with 27 juvenile-onset DM1 patients, who had undergone 78 surgeries11, Reported that a higher MIRS score, CTG repeat lengths, longer duration of surgery, use of muscle relaxants, and perioperative opioid use were risk factors of perioperative adverse events. However, multivariate regression analysis revealed that a higher MIRS score and use of muscle relaxants were independent risk factors. Interestingly, our result showed that postoperative opioid use and a higher MIRS score were independent risk factors. Although the length of CTG repeats typically correlates with the severity of DM1, we noted no such relationship between the two. The novelty of our study was that we recruited a large number of patients and identified a statistically significant risk factor of postoperative opioid use that influenced the increased possibility of postoperative adverse events in DM1 with an odds ratio of 8.0. Although Sinclair et al. found perioperative opioid use as a risk factor, it could not be considered independent after undergoing regression analysis. The discrepancy may also be explained by differences in mean age of the participants in our study as opposed to that of Sinclair et al. (36.8 years vs 8 years, respectively).
Recent studies have reported the role of central nervous system abnormality in DM1 in the aspects of neurodegeneration19,20. Opioid receptors are widely present in brainstem, carotid bodies, the vagus nerve, and airway walls21. Opioids upregulate the activity of inhibitory neurons in the brainstem and decrease the rate of respiration and tidal volume22; Furthermore, a study has recently reported that administering opioids reduced the ventilator response to hypoxemia and hypercapnia23. These mechanisms may have aggravated the overall central nervous system depression to induce greater postoperative complications. However, further investigation is needed to understand the mechanism of high prevalence of respiratory complications in relation to opioids in DM1.
There are a few limitations that need to be addressed. First, the present study was based on a small retrospective analysis, it could limit and compromise its results. However, DM1 is an uncommon genetic neuromuscular disorder, the investigative studies on perioperative outcomes in patients with DM1 are limited. Therefore, we believed that this study further consolidated the known evidence related to the risk factors of perioperative outcomes. Second, this was a retrospective study based on medical and anaesthesia-related records of the patients and therefore selection of analgesics and protocol for analgesic management may be inaccurate, influenced by the preference of individual surgeons and anaesthesiologists. Third, the present study was conducted in only one tertiary hospital and most of the procedures were elective; therefore, the risk of the adverse events might be over- or under-estimated. Lastly, our results do not represent all clinical stages of DM1.
Conclusions
This is possibly the first study on DM1 patients of Asian ethnicities and our data was in accordance to other Caucasian studies that showed a high prevalence of pulmonary complications after the surgery. Higher MIRS scores positively correlated with a higher prevalence of adverse events. Moreover, postoperative opioid use was also an independent risk factor of accentuated complication rates. Further research on respiratory complications and opioid usage may reduce the rate of onset of surgical complications in DM1.
Methods
Patients
The medical records of the patients who visited Asan medical center between January 1998 and June 2018 were reviewed and 256 cases were retrieved. This study was approved by the institutional review board and registered at the University of Ulsan, Seoul, Republic of Korea (2018–0876). We searched information technology of service management of our institution using the terms “myotonic disorders”, “dystrophia myotonica”, and “myotonia congenita”. DM1 diagnosis was based on a genetic study that showed an abnormal increase in the length of untranslated CTG repeat in the DMPK gene on19q13. We included DM1 patients who underwent confirmatory genetic examinations; furthermore, DM1 patients who underwent surgery with general or regional anaesthesia were included in the surgical group. We excluded the patients whose diagnosis was not confirmed genetically, along with those who were diagnosed with drug-induced myotonia, pseudomyotonia, and non-drodystrophic myotonia after reviewing their medical data. Patients who had received local anaesthesia during the surgery were also excluded in the surgical group.
Outcome assessment and factors associated with postoperative complications
The clinical and laboratory parameters of the patients including gender, age at surgery, gender, ASA physical status class, type of surgery, type of anaesthesia, BMI, CTG repeat length, serum creatine kinase, and comorbid diseases including autoimmune disease, cardiovascular disease, arrhythmia, and diabetes, among other parameters were retrieved from their medical records. A functional muscular involvement was evaluated using the MIRS and the FSRS10. MIRS is a 5-point scale ranging from 1 to 5, with a higher numerical value reflecting a more severe muscle weakness, with grade 1 = no muscular impairment, grade 2 = minimal signs such as myotonia or facial weakness, grade 3 = distal weakness, grade 4 = mild to moderate proximal weakness, and grade 5 = severe proximal limb weakness. FSRS is a 4-point scale ranging from 1 to 4, in which 1 = mild and 4 = bedridden.
Records related to the type of anaesthesia, hypnotics used for induction, neuromuscular blockers, anaesthetic agents for maintenance, opioid usage, body temperature, reversal agent, airway device, need for extubation, extubation time (minutes) (from the end of surgery to extubation), surgical time (minutes), postoperative analgesics, hospital wards occupied by the patients and duration of hospitalization (post anaesthetic care unit, intensive care unit), hospital LOS (day), re-admission, postoperative complications were retrieved from the medical records. Doses of all opioids administered to patients were converted to intravenous fentanyl equianalgesic doses according to published conversion factors (intravenous fentanyl 100 μg = meperidine 100 mg = tramadol 100 mg)23.
24Surgery and anaesthesia-associated complications, and any adverse events during the postoperative period (up to seven days after the surgery) were defined as postoperative complications in the study. They may or may not be related to the disease for which the surgery was performed or be the direct results of the surgery24. We defined respiratory complications as follows: postoperative PaO2 < 60 mmHg on room air, a PaO2: fraction of inspired oxygen of ratio < 300 mmHg, arterial oxyhaemoglobin saturation measured with pulse oximetry < 90% and requiring oxygen therapy, or ventilator dependence for > postoperative one day or re-intubation25–27. Delayed recovery from anaesthesia was defined as a state of unresponsiveness from which the patient could not be aroused for more than 90 min after being administered with general anaesthesia. We defined sustained hypotension by introducing minor modifications to a definition used in a previous study: systolic blood pressure < 90 mmHg for > 30 min that required the usage of vasopressors25.
Statistical analysis
The data were analysed by using the Statistical Package for the Social Sciences Version 21.0 (SPSS, IBM SPSS Statistics, IBM Corporation, Armonk, NY, USA). Data are expressed as mean (standard deviation), median (interquartile range), number (proportion), or odds ratio (OR) and 95% confidence interval (95% CI). Normal distribution of data was assessed using the Kolmogorov–Smirnov test. Normally distributed continuous demographic data such as body mass index were compared using the Student’s t test; however, non-normally distributed continuous data such as age, CTG repeat size, serum creatinine kinase, and surgical time, among other parameters, were compared using the Mann–Whitney U test. Categorical demographic data were compared using the chi-square test or Fisher’s exact test, as appropriate. By using univariate logistic regression, the factors associated with postoperative complications in patients with DM1 were analysed. A value of p < 0.05 was considered statistically significant.
Ethics
This study was performed according to the Declaration of Helsinki. The current study protocol was approved by the institutional review board of Asan Medical Center, Seoul, Korea (approval number: 2018-0876). Due to the retrospective nature of the study, informed consent was waived.
Supplementary information
Supplementary Information.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Chan-Sik Kim and Jin -Mo Park.
Supplementary information
is available for this paper at 10.1038/s41598-020-76217-9.
Acknowledgements
This work was supported by a Grant from the National Research Foundation of Korea, which is funded by the Korean Government, Ministry of Science and ICT (NRF-2017R1C1B5076264 and NRF-2018R1C1B5045675).
Author contributions
C.-S.K., J.-M.P. and J.-S.P. were involved in study conception and wrote the manuscript. D.P. and D.-H.K. were involved in study deign and revised the manuscript. C.-S.K. and D.-H.K. were involved in data acquisition. D.P. and D.-H.K. were involved in analysis and interpretation of the data. J.-M.P. and J.-S.P. were involved in study design and critical revision of manuscript. All the authors approve the final version of manuscript.
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests. | ETOMIDATE, FENTANYL, PYRIDOSTIGMINE, SEVOFLURANE, VECURONIUM BROMIDE | DrugsGivenReaction | CC BY | 33431966 | 19,815,553 | 2021-01-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Wound infection'. | Opioid use may be associated with postoperative complications in myotonic dystrophy type 1 with high-grade muscular impairment.
Individuals with myotonic dystrophy type 1 (DM1) reportedly have a higher risk of postoperative complications than those without DM1; however, factors related to perioperative complications in DM1 patients remain unclear. We aimed to identify the risk factors that may be associated with postoperative complications in DM1 patients. We reviewed medical records of 256 patients with DM1 from 1998 to 2018, among whom 42 (16.4%) had previously undergone 51 surgeries under general and regional anaesthesia. Among the 42 patients, 11 (21.5%) had 13 postoperative complications including respiratory complications, sustained hypotension, wound infection and dehiscence, artery thrombosis and occlusion, and delayed recovery from anaesthesia. There were significant inter-group differences between the non-complicated and complicated groups considering the following parameters: high-grade (≥ 3) muscular impairment rating scale (MIRS), extubation time, postoperative opioid use, and hospital length of stay. Furthermore, univariate analysis revealed that an MIRS score ≥ 3 (odds ratio [OR] 9.346, confidence interval [CI] 1.761-49.595, p = 0.009) and postoperative opioid use (OR 8.000, CI 1.772-36.127, p = 0.007) were the only statistically significant factors. Therefore, clinicians should be cautious in administering opioids, particularly in patients with a high-grade MIRS score during the perioperative period.
Introduction
Myotonic dystrophy type 1 (dystrophia myotonica; DM1) is a genetic neuromuscular disorder with an estimated global prevalence of 1:20,000. It is primarily caused by the expansion of cytosine–thymine–guanine (CTG) trinucleotide repeat located in the non-coding region of the dystrophia myotonica protein kinase (DMPK) gene1. Although, it is clinically characterized by myotonia along with facial and distal dominant weakness, it is now categorized as a multisystemic disease involving cataract, diabetes, and arrhythmia, along with diseases of the central nervous system. Patients with neuromuscular diseases such as DM1 reportedly have a higher risk of postoperative complications than those without, this may be attributed to the presence of underlying muscle weakness, scoliosis, and cardiac abnormalities2. Additionally, involvement of multiple organ systems and increased sensitivity to anaesthetic medications further increase high risk of postoperative complications3. A recent meta-analysis described a predominantly restrictive ventilator pattern observed in DM1, with a significant emphasis on alveolar hypoventilation and chronic hypercapnia4. The advent of novel therapeutic strategies targeting DM1 has highlighted the need for a greater understanding of the respiratory decline while focusing primarily on the use of appropriate anaesthetic agents and respiratory management strategies. However, factors related to perioperative complications in patients with DM1 require further elucidation. Therefore, we aimed to address the possible risk factors that may be associated with postoperative complications in DM1 patients who had undergone surgical interventions under general or regional anaesthesia.
Results
We enrolled 256 patients with DM1, among whom 42 (16.4%) had previously undergone 51 surgeries under general or regional anaesthesia. The patients were divided into surgical and nonsurgical group as presented in Table 1 and there were no statistically significant inter-differences in the baseline clinical characteristics with regard to their age, body mass index (BMI), CTG repeats, and other comorbid diseases except cataract. However, gender and muscular impairment rating scale (MIRS) score demonstrated statistically significance differences in the baselines for each group. Among the 42 patients, 11 presented with postoperative complications (Fig. 1). Characteristics of the patients with postoperative complications, along with their perioperative parameters, are presented in Supplementary Table S1, S2, and S3.Table 1 Clinical characteristics of the patients with a myotonic dystrophy type 1.
Non-surgical group (n = 214) Surgical group (n = 42) p value
Age (year) 37.0 (28.0–48.0) 36.5 (18.0–43.0) 0.083
Body mass index (kg/m2) 21.5 ± 4.3 19.8 ± 3.9 0.016
Gender (male/female) 125 (58.4)/89 (41.6) 13 (31.0)/29 (69.0) 0.002
MIRS 0.001
1 2 (1.0) 5 (11.9)
2 72 (33.6) 16 (38.1)
3 81 (37.9) 15 (35.7)
4 51 (23.8) 4 (9.5)
5 8 (3.7) 2 (4.8)
FSRS 0.361
1 145 (67.8) 31 (73.8)
2 54 (25.2) 7 (16.7)
3 11 (5.1) 4 (9.5)
4 4 (1.9) 0 (0.0)
CTG repeat size 390 (165–550) 400 (220–540) 0.446
Serum creatinine kinase 293 (166–472) 261 (143–366) 0.153
Comorbidity
Cataract 14 (6.5) 8 (19.0) 0.019
Elevated liver enzymes 29 (13.6) 5 (11.9) 0.969
Autoimmune disease 8 (3.7) 2 (4.8) > 0.999
Baldness 23 (10.7) 3 (7.1) 0.669
Cardiovascular diseases 5 (2.3) 1 (2.4) > 0.999
Arrythmia 23 (10.7) 4 (9.5) > 0.999
Diabetes mellitus 40 (18.7) 3 (7.1) 0.109
Other diseases 11 (5.1) 11 (26.2) < 0.001
Data are expressed as mean (standard deviation), number (%), or median (interquartile range).
MIRS muscular impairment rating scale, FSRS functional status rating scale, CTG cytosine-thymine-guanine, Other diseases Bronchiectasis, myoma, biliary atresia, cryptorchism, hydrocephalus, neurofibroma, and vocal cord palsy.
Figure 1 Detailed postoperative complications in patients with myotonic dystrophy type 1.
Opioid administration for postoperative pain control was restricted to almost on the day of surgery (postoperative day 0); additionally, they were treated with nonsteroidal anti-inflammatory drugs or acetaminophen to ameliorate the mild to moderate postoperative pain. However, opioids were administered either in cases of moderate to severe pain associated with orthopaedic or abdominal surgery, or in cases of insufficient analgesia despite the administration of non-opioid analgesics. Eight patients in the complicated group received opioid analgesics on the day of surgery, with the average dosage ranging from 0.3 to 1.9 μg/kg.
We comprehensively compared 42 surgical cases and categorized them into the non-complicated and complicated groups (Table 2). The non-complicated group (n = 31) and complicated group (n = 11) were compared considering their clinical, genetic, laboratory, anaesthesia, and postoperative parameters (Supplementary Table S2). There were no significant differences in their demographic parameters such as age at the time of the procedure operation, BMI, gender, and American Society of Anesthesiologists (ASA) physical status class. The complicated group showed significantly higher occurrences of high MIRS scores (≥ 3) than the non-complicated group, while both groups had similar functional status rating scale (FSRS) scores, CTG repeat lengths, and serum creatinine kinase levels. Both groups showed statistically significant differences in the anaesthesia-related parameters with regard to the extubation time and postoperative opioid use (5.0 min [5.0–13.0] vs. 638.0 min [22.5–1200.0], p = 0.003; 7 [22.6] vs. 8 [72.7], p = 0.009, respectively). The hospital length of stay (LOS) for the patients in the complicated group was longer than for those in the non-complicated group (5.0 [3.0–8.5] vs. 8.0 [6.5–78.0], p = 0.015).Table 2 Comparison of non-complicated group and complicated group during perioperative period.
Non-complicated group (n = 31) Complicated group (n = 11) p value
Age (year) 26.0 (5.5–38.0) 25.0 (15.0–39.5) 0.330
Body mass index (kg/m2) 19.5 ± 3.6 18.2 ± 4.4 0.356
Gender (male/female) 8 (25.8)/23 (74.2) 4 (36.4)/7 (63.6) 0.781
ASA class 0.214
1 17 (54.8) 4 (36.4)
2 8 (25.8) 6 (54.5)
3 6 (19.4) 1 (9.1)
MIRS 0.022
< 3 20 (64.5) 2 (18.2)
≥ 3 11 (35.5) 9 (81.8)
FSRS 0.560
1 21 (87.5) 8 (72.7)
2 2 (8.3) 2 (18.2)
3 1 (4.2) 1 (9.1)
4 0 (0.0) 0 (0.0)
CTG repeat size 400 (220–545) 530 (300–550) 0.336
Serum creatinine kinase 264.9 ± 148.9 306.8 ± 157.6 0.434
Type of anesthesia > 0.999
General 28 (90.3) 10 (90.9)
Regional 3 (9.7) 1 (9.1)
Type of surgery 0.540
Dental 1 (3.2) 0 (0)
Ears, nose, throat 3 (9.7) 0 (0)
General 5 (16.1) 4 (36.4)
Neurology 2 (6.5) 1 (9.1)
Obstetrics and gynecology 10 (32.3) 5 (45.4)
Ophthalmology 3 (9.7) 0 (0)
Orthopedic 5 (16.1) 1 (9.1)
Urology 2 (6.5) 0 (0.0)
Muscle relaxants use 25 (80.6) 10 (90.9) 0.754
Type of anesthetics 0.994
Inhalation 22 (71.0) 8 (72.7)
TIVA 6 (19.4) 2 (18.2)
Intraoperative opioid use 12 (38.7) 5 (45.5) 0.973
Reversal agents use 23 (74.2) 7 (63.6) 0.781
Sugammadex use 3 (9.7) 0 (0.0) 0.697
Airway device 24 (77.4) 10 (90.9) 0.448
ETT 4 (12.9) 0 (0.0)
LMA
Surgical time (min) 60.0 (40.0–87.5) 85.0 (52.5–155.0) 0.197
Anesthetic time (min) 155.0 (118.5–219.0) 220.0 (164.0–350.0) 0.247
Extubation time (min) 5.0 (5.0–13.0) 638.0 (22.5–1200.0) 0.003
Postoperative analgesics 0.009
Others 24 (77.4) 3 (27.3)
Opioid 7 (22.6) 8 (72.7)
PACU LOS (day) 50.0 (45.0–58.0) 77.5 (47.5–92.5) 0.227
ICU LOS (day) 2.0 (2.0–2.0) 3.0 (2.5–3.5) 0.081
Hospital LOS (day) 5.0 (3.0–8.5) 8.0 (6.5–78.0) 0.015
Readmission 1 (3.2) 1 (9.1) > 0.999
Data are expressed as mean (standard deviation), number (%), or median (interquartile range).
MIRS muscular impairment rating scale, FSRS functional status rating scale, CTG cytosine-thymine-guanine, TIVA total intravenous anesthesia, ETT endotracheal tube, LMA laryngeal mask airway, Others nonsteroidal anti-inflammatory drugs, acetaminophen, nefopam, and no analgesics, PACU Post Anesthetic Care Unit, LOS length of stay, ICU Intensive Care Unit.
Among 11 patients (complicated group), seven patients had respiratory complications including desaturation [oxygen partial pressure (PaO2) < 60 mmHg on room air] and dyspnoea and received prolonged ventilator care for > 1 postoperative day. Three patients presented with wound infection or dehiscence and one with arterial thrombotic occlusion (Supplementary Table S3). One patient who showed delayed recovery, had to recover for three days after the surgery to regain consciousness. One patient had postoperative hypotension. Summarily, there were 13 postoperative complications.
We used univariate regression analysis to identify the factors associated with the postoperative complications in DM1 patients (Table 3). We consequently selected the following parameters for univariate regression analysis considering their clinical importance and statistical significance: age, gender, BMI, MIRS score, hospital LOS, and postoperative use of opioids. MIRS score ≥ 3 and postoperative opioid use were the only statistically significant risk factors with a relatively higher odds ratio (OR), 95% confidence interval (CI), and p value (OR 8.182, 95% CI 1.495–44.772, p = 0.015; OR: 9.143, CI 1.899–44.011, p = 0.006) (Table 3).Table 3 Univariate regression analysis associated with postoperative complications in patients with a myotonic dystrophy type 1.
Variables Univariate analysis
OR (95% CI) p value
Age 1.024 (0.980–1.069) 0.286
Gender 0.508
Male 1.000
Female 0.609 (0.140–2.643)
Body mass index (kg/m2) 0.914 (0.757–1.103) 0.348
MIRS 0.015
< 3 1.000
≥ 3 8.182 (1.495–44.772)
Hospital LOS 1.004 (0.995–1.014) 0.376
Postoperative analgesics
Others 1.000 0.006
Opioid 9.143 (1.899–44.011)
Data are expressed as odds ratio (95% confidence interval).
MIRS muscular impairment rating scale, LOS length of stay, Others nonsteroidal anti-inflammatory drugs, acetaminophen, nefopam, and no analgesics.
Discussion
DM1 is clinically characterized by the presence of myotonia, which is an impairment of muscle relaxation following contraction. Electrophysiologically, it can be characterized by the presence of involuntary repetitive action potentials of the muscle membrane that is perpetually in its hyper-excitable state due to a persistent sodium influx or reduced chloride channel conductance5. Due to the high prevalence of DM1 in adults, there is an established anaesthesia management guideline based on the recommendations of several experts6, which elaborates on the importance of preoperative evaluations of the pulmonary, cardiac, and gastrointestinal symptoms in DM1 patients. It also highlights the need for caution when using anaesthetic and analgesic medications, and the necessity of oxygen saturation and electrocardiography monitoring during the perioperative period. However, these recommendations were based on a limited number of studies, possibly due to the rarity of the disease. Therefore, we aimed to evaluate the possible risk factors influencing DM1 postoperative complications, to consolidate the evidence for the current recommendations suggested by the Myotonic Dystrophy Foundation.
Patients with neuromuscular diseases demonstrate an increased risk of surgical complications when under general anaesthesia due to respiratory muscle weakness, musculoskeletal abnormalities, and cardiac involvement7–9. However, only a small number of studies have elaborated on the anaesthesia-related complications in DM110,11. These studies reported that the frequency of postoperative complications in DM1 patients typically ranges from 8.2 to 42.9%12,13, which was similar to our study (21.5%) and previous literatures on the subject.
Among the 11 DM1 patients who underwent anaesthesia-related adverse events, 7 (64%) demonstrated respiratory complications and 4 (36.3%) received ventilatory support. A retrospective study that reviewed 219 cases of DM1 reported an 89% prevalence of respiratory complications and 31% required ventilatory support10. Another study showed a rate of 10% with regard to postoperative respiratory complications. Discrepancies in the complication rate may be attributable to the severity of the patient’s condition, types of the disease or type of a surgery. It is noteworthy to state that compared to other muscular dystrophies, DM1 appeared to have a significantly high rate of respiratory complications with significantly low cardiac complications. We observed that DM1 patients showed a relatively high complication rate (81.8%) with an MIRS score ≥ 3 and showed an increased odds ratio of 9.346; similarly, Mathieu et al. reported an odds ratio of 14.110. This can be partly explained by the fact that general anaesthesia may have decreased lung compliance and functional residual capacity, leading to alveolar hypoventilation and atelectasis. There is substantial evidence to prove that DM1 patients show abnormalities with regard to the ventilator control mechanisms, and their conditions became more critical when exposed to anaesthetic agents, resulting in a low central respiratory drive14,15. Furthermore, this hypothesis can be consolidated by our result in which 9 of 11 patients received abdominal surgery, which is an important risk factor of hypoventilation16.
The concerns regarding increase in the risk of defects in the cardiac rhythm conduction and potential progression of known conduction delays in patients with DM1 during the perioperative period are evident17. Considering the presence of progressive deterioration of atrioventricular and intraventricular conduction, they can further be exacerbated by anaesthetic drugs, airway manipulation, changes in sympathetic and parasympathetic tone, or hypoxia2,18. Although one patient in the complicated group had atrial fibrillation, the risk of cardiac rhythm conduction or aggravated conduction delay remained the same throughout the study. Studies have previously reported that complications associated with perioperative cardiac conduction were absent or were present in only one case10,11, which was further validated by our results.
A previous study with 27 juvenile-onset DM1 patients, who had undergone 78 surgeries11, Reported that a higher MIRS score, CTG repeat lengths, longer duration of surgery, use of muscle relaxants, and perioperative opioid use were risk factors of perioperative adverse events. However, multivariate regression analysis revealed that a higher MIRS score and use of muscle relaxants were independent risk factors. Interestingly, our result showed that postoperative opioid use and a higher MIRS score were independent risk factors. Although the length of CTG repeats typically correlates with the severity of DM1, we noted no such relationship between the two. The novelty of our study was that we recruited a large number of patients and identified a statistically significant risk factor of postoperative opioid use that influenced the increased possibility of postoperative adverse events in DM1 with an odds ratio of 8.0. Although Sinclair et al. found perioperative opioid use as a risk factor, it could not be considered independent after undergoing regression analysis. The discrepancy may also be explained by differences in mean age of the participants in our study as opposed to that of Sinclair et al. (36.8 years vs 8 years, respectively).
Recent studies have reported the role of central nervous system abnormality in DM1 in the aspects of neurodegeneration19,20. Opioid receptors are widely present in brainstem, carotid bodies, the vagus nerve, and airway walls21. Opioids upregulate the activity of inhibitory neurons in the brainstem and decrease the rate of respiration and tidal volume22; Furthermore, a study has recently reported that administering opioids reduced the ventilator response to hypoxemia and hypercapnia23. These mechanisms may have aggravated the overall central nervous system depression to induce greater postoperative complications. However, further investigation is needed to understand the mechanism of high prevalence of respiratory complications in relation to opioids in DM1.
There are a few limitations that need to be addressed. First, the present study was based on a small retrospective analysis, it could limit and compromise its results. However, DM1 is an uncommon genetic neuromuscular disorder, the investigative studies on perioperative outcomes in patients with DM1 are limited. Therefore, we believed that this study further consolidated the known evidence related to the risk factors of perioperative outcomes. Second, this was a retrospective study based on medical and anaesthesia-related records of the patients and therefore selection of analgesics and protocol for analgesic management may be inaccurate, influenced by the preference of individual surgeons and anaesthesiologists. Third, the present study was conducted in only one tertiary hospital and most of the procedures were elective; therefore, the risk of the adverse events might be over- or under-estimated. Lastly, our results do not represent all clinical stages of DM1.
Conclusions
This is possibly the first study on DM1 patients of Asian ethnicities and our data was in accordance to other Caucasian studies that showed a high prevalence of pulmonary complications after the surgery. Higher MIRS scores positively correlated with a higher prevalence of adverse events. Moreover, postoperative opioid use was also an independent risk factor of accentuated complication rates. Further research on respiratory complications and opioid usage may reduce the rate of onset of surgical complications in DM1.
Methods
Patients
The medical records of the patients who visited Asan medical center between January 1998 and June 2018 were reviewed and 256 cases were retrieved. This study was approved by the institutional review board and registered at the University of Ulsan, Seoul, Republic of Korea (2018–0876). We searched information technology of service management of our institution using the terms “myotonic disorders”, “dystrophia myotonica”, and “myotonia congenita”. DM1 diagnosis was based on a genetic study that showed an abnormal increase in the length of untranslated CTG repeat in the DMPK gene on19q13. We included DM1 patients who underwent confirmatory genetic examinations; furthermore, DM1 patients who underwent surgery with general or regional anaesthesia were included in the surgical group. We excluded the patients whose diagnosis was not confirmed genetically, along with those who were diagnosed with drug-induced myotonia, pseudomyotonia, and non-drodystrophic myotonia after reviewing their medical data. Patients who had received local anaesthesia during the surgery were also excluded in the surgical group.
Outcome assessment and factors associated with postoperative complications
The clinical and laboratory parameters of the patients including gender, age at surgery, gender, ASA physical status class, type of surgery, type of anaesthesia, BMI, CTG repeat length, serum creatine kinase, and comorbid diseases including autoimmune disease, cardiovascular disease, arrhythmia, and diabetes, among other parameters were retrieved from their medical records. A functional muscular involvement was evaluated using the MIRS and the FSRS10. MIRS is a 5-point scale ranging from 1 to 5, with a higher numerical value reflecting a more severe muscle weakness, with grade 1 = no muscular impairment, grade 2 = minimal signs such as myotonia or facial weakness, grade 3 = distal weakness, grade 4 = mild to moderate proximal weakness, and grade 5 = severe proximal limb weakness. FSRS is a 4-point scale ranging from 1 to 4, in which 1 = mild and 4 = bedridden.
Records related to the type of anaesthesia, hypnotics used for induction, neuromuscular blockers, anaesthetic agents for maintenance, opioid usage, body temperature, reversal agent, airway device, need for extubation, extubation time (minutes) (from the end of surgery to extubation), surgical time (minutes), postoperative analgesics, hospital wards occupied by the patients and duration of hospitalization (post anaesthetic care unit, intensive care unit), hospital LOS (day), re-admission, postoperative complications were retrieved from the medical records. Doses of all opioids administered to patients were converted to intravenous fentanyl equianalgesic doses according to published conversion factors (intravenous fentanyl 100 μg = meperidine 100 mg = tramadol 100 mg)23.
24Surgery and anaesthesia-associated complications, and any adverse events during the postoperative period (up to seven days after the surgery) were defined as postoperative complications in the study. They may or may not be related to the disease for which the surgery was performed or be the direct results of the surgery24. We defined respiratory complications as follows: postoperative PaO2 < 60 mmHg on room air, a PaO2: fraction of inspired oxygen of ratio < 300 mmHg, arterial oxyhaemoglobin saturation measured with pulse oximetry < 90% and requiring oxygen therapy, or ventilator dependence for > postoperative one day or re-intubation25–27. Delayed recovery from anaesthesia was defined as a state of unresponsiveness from which the patient could not be aroused for more than 90 min after being administered with general anaesthesia. We defined sustained hypotension by introducing minor modifications to a definition used in a previous study: systolic blood pressure < 90 mmHg for > 30 min that required the usage of vasopressors25.
Statistical analysis
The data were analysed by using the Statistical Package for the Social Sciences Version 21.0 (SPSS, IBM SPSS Statistics, IBM Corporation, Armonk, NY, USA). Data are expressed as mean (standard deviation), median (interquartile range), number (proportion), or odds ratio (OR) and 95% confidence interval (95% CI). Normal distribution of data was assessed using the Kolmogorov–Smirnov test. Normally distributed continuous demographic data such as body mass index were compared using the Student’s t test; however, non-normally distributed continuous data such as age, CTG repeat size, serum creatinine kinase, and surgical time, among other parameters, were compared using the Mann–Whitney U test. Categorical demographic data were compared using the chi-square test or Fisher’s exact test, as appropriate. By using univariate logistic regression, the factors associated with postoperative complications in patients with DM1 were analysed. A value of p < 0.05 was considered statistically significant.
Ethics
This study was performed according to the Declaration of Helsinki. The current study protocol was approved by the institutional review board of Asan Medical Center, Seoul, Korea (approval number: 2018-0876). Due to the retrospective nature of the study, informed consent was waived.
Supplementary information
Supplementary Information.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Chan-Sik Kim and Jin -Mo Park.
Supplementary information
is available for this paper at 10.1038/s41598-020-76217-9.
Acknowledgements
This work was supported by a Grant from the National Research Foundation of Korea, which is funded by the Korean Government, Ministry of Science and ICT (NRF-2017R1C1B5076264 and NRF-2018R1C1B5045675).
Author contributions
C.-S.K., J.-M.P. and J.-S.P. were involved in study conception and wrote the manuscript. D.P. and D.-H.K. were involved in study deign and revised the manuscript. C.-S.K. and D.-H.K. were involved in data acquisition. D.P. and D.-H.K. were involved in analysis and interpretation of the data. J.-M.P. and J.-S.P. were involved in study design and critical revision of manuscript. All the authors approve the final version of manuscript.
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests. | FENTANYL, SEVOFLURANE, THIOPENTAL SODIUM, VECURONIUM BROMIDE | DrugsGivenReaction | CC BY | 33431966 | 19,815,562 | 2021-01-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrocardiogram QT prolonged'. | Effect of domperidone, ondansetron, olanzapine-containing antiemetic regimen on QTC interval in patients with malignancy: a prospective, observational, single-group, assessor-blinded study.
Domperidone, ondansetron and olanzapine can prolong the QT interval. The clinical use of combinations of these drugs is not uncommon. Our study aimed to determine the presence of any QTc prolonging effect of the combination when used as antiemetic in patients receiving cancer chemotherapy. We carried out a prospective, observational study of patients with malignancy who were to receive domperidone, ondansetron and olanzapine-containing antiemetic regimen. Electrocardiograms were recorded before and during the administration of antiemetics, for three consecutive days. A blinded assessor determined the QTc interval using Bazett and Fridericia formulae. Thirty-six patients completed the study; 23 (63.9%) were females. There was a statistically significant change in QTc with time (Fridericia, χ2(4) = 15.629, p = 0.004; Bazett, χ2(4) = 15.910, p = 0.003); QTc on Day 1 was more than that during baseline (p < 0.001); these differences were significant in females (Fridericia, χ2(4) = 13.753, p = 0.008; Bazett, χ2 (4) = 13.278, p = 0.010) but not in males (Fridericia, χ2 (4) = 4.419, p = 0.352; Bazett, χ2(4) = 4.280, p = 0.369). Two female patients had an absolute QTc prolongation (Bazett correction) of > 500 ms. However, no clinically significant adverse events occurred. The findings show that QTc prolongation is a concern with olanzapine alone and in combination with domperidone and ondansetron, and needs to be investigated further.
Introduction
The use of antiemetics is an integral part of cancer chemotherapy and radiotherapy. Not only do they significantly reduce the incidence of nausea and vomiting and, thereby, improve the quality of life but also enable the use of high-dose chemotherapy resulting in better treatment response1. Drugs such as dopamine D2 receptor antagonists, 5-HT3 antagonists, glucocorticoids and neurokinin receptor antagonists are used in various combinations, depending on the emetogenic risk of chemotherapy or the extent of irradiation. The combination of glucocorticoids with 5-HT3 antagonists is synergistic and is a commonly used combination to manage the acute phase of cancer-induced vomiting. Olanzapine and aprepitant can be added to this combination for highly-emetogenic chemotherapy1. Olanzapine is a potentially safer and cost-effective alternative to aprepitant to prevent nausea and vomiting2. Domperidone is a commonly used drug for the delayed phase of cancer chemotherapy-induced nausea and vomiting3. A combination of olanzapine and dexamethasone to prevent acute phase nausea and vomiting and short-term ondansetron and domperidone for the delayed phase is a cost-effective treatment approach compared with aprepitant-containing regimens in resource-poor settings2. An open-label interventional study comparing the combination of domperidone with ondansetron to ondansetron alone found that the former produced a more pronounced antiemetic effect without any significant adverse effects in breast cancer patients on moderately emetogenic chemotherapy4. The addition of domperidone to other antiemetic drug regimens in non-responsive cases and those receiving total body irradiation has also been described in some of the treatment guidelines5,6. However, one of the important drawbacks of domperidone is its tendency to cause QT prolongation, particularly in the presence of other drugs in the antiemetic regimen with QT-prolonging potential7. The extent to which such interactions are clinically relevant to the short-term use of domperidone at therapeutic doses is unclear. Studies of domperidone in healthy volunteers, as well as patients, have not shown any significant QT-prolonging effects in the recommended doses8,9. During a recent study to identify potentially interacting drug combinations using a proprietary drug interaction detection software in patients undergoing chemoradiation, a downgrading of the severity of drug-drug interaction for the combination of domperidone with ondansetron in the software database was noted10; the DDI was downgraded from category X, requiring the drug combination to be avoided, to category D, requiring modification of therapy. The combination of domperidone, ondansetron, and olanzapine is used at the study site in patients being treated with highly emetogenic chemotherapy and high-dose radiation. Considering the high risk of QT prolongation with the use of domperidone and moderate risk with ondansetron11,12 and olanzapine13–15, we aimed to determine the presence of any QT-prolonging effect of the combination (domperidone, ondansetron and olanzapine) when used for prevention of nausea and vomiting in patients on cancer chemotherapy.
Methods
A prospective, observational study was carried out at the Radiation Oncology department of Kasturba Medical College Hospital, Mangalore, a tertiary care teaching hospital in South India. Patients with malignancy aged 18 − 80 years, of either gender, Eastern Cooperative Oncology Group status ≤ 2, who were scheduled to receive domperidone, ondansetron and olanzapine-containing antiemetic regimen, and willing to provide written informed consent were included in the study. Patients with a baseline QTc interval > 450 ms, history of cardiac arrhythmias, history of additional risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome), use of concomitant medications that prolong the QT/QTc (other than the study drugs), unable to complete the study as per the opinion of the investigators were excluded from the study.
The study was initiated after receiving approval from Kasturba Medical College Institutional Ethics Committee (IEC KMC MLR 08–18/165) and registration of the study protocol in the Clinical Trial Registry of India (CTRI/2018/09/015676). The study was conducted in accordance with the Ethical Guidelines for Biomedical Research on Human Subjects (Indian Council of Medical Research) and the Declaration of Helsinki. After obtaining written informed consent from the participants, serial electrocardiograms (ECGs) were recorded at specific time points over three days; the antiemetic drugs used, their dose, and frequency of administration are shown in Table 1.Table 1 The antiemetic regimen used at the study site in patients with malignancy treated with highly emetogenic chemotherapy and/or high-dose radiation.
Antiemetic regimen Activity Number of ECGs recorded per day
Day 0
Baseline Two ECGs recorded at least 10 min apart within 24 h before the administration of the antiemetic on Day 1 2
Day 1
Injection Palonosetron 0.25 mg OD
Tablet Olanzapine 10 mg OD
One ECG recorded 6 h (± 30 min) after the antiemetic dose on Day 1 1
Day 2
Tablet Olanzapine 10 mg OD
Tablet Pantoprazole 40 mg OD
Tablet Domperidone 10 mg BID
Tablet Ondansetron 8 mg TID
1 h (± 15 min; Day 2_1) and 2 h (± 15 min; Day 2_2) after the first antiemetic dose on Day 2 2
Day 3
Tablet Olanzapine 10 mg OD
Tablet Pantoprazole 40 mg OD
Tablet Domperidone 10 mg BID
Tablet Ondansetron 8 mg TID
4 h (± 30 min) after the first antiemetic dose on Day 3 1
ECG, electrocardiogram; OD, once a day; BID, twice a day; TID, thrice a day.
The ECGs were recorded at the specified time points using Cardiart 9108 12-channel ECG machine (BPL Medical Technologies, India) with a paper speed of 25 mm/s, amplitude 1 mV/10 mm, high pass filter at 0.5 Hz and low pass filter at 40 Hz, with the time of administration of the first antiemetic on Day 1 determining the time to record the subsequent ECGs. The ECG recordings of all the patients were assessed by a cardiologist to manually determine the QT interval corrected for heart rate, who was blinded to the patient identity, the day and time point of the recording of the ECGs; the end of T-wave was determined using the tangent method. The QT correction was performed using Bazett and Fridericia formulae8. Intra-reader variability was determined by reassessment of the QTc for 10% of the recorded ECGs by the same evaluator on a different occasion.
Statistical analysis
The heart rate, QTc interval and change from baseline in heart rate and QTc for each time point of measurement are summarized using descriptive statistics. Intraclass correlation coefficient was measured to determine the intra-reader variability. The number of ECGs with an absolute QTc interval > 450, > 480 and > 500 ms was determined; also, an increase in QTc values from baseline by > 30 and > 60 ms was noted8; Chi-square test was used for group comparisons. Patients ≥ 50 years of age were considered elderly; this arbitrary cut-off limit was based on the age distribution of the study population. Since the data was not normally distributed (as determined using the Shapiro–Wilk test; p < 0.05), nonparametric repeated-measures analysis of variance (Freidman’s test) was used to determine the presence of any significant difference in the QTc interval before and after administration of the drugs. If a significant difference in the QTc interval was seen with time, Wilcoxon signed-rank test was used to identify the time points with a significant difference, using Bonferroni correction to adjust for multiple comparisons. A p value < 0.05 was considered statistically significant.
The sample size was calculated based on the assumption that, for a sample size of 36 patients, with a probability of 80% and a two-sided significance level of 0.05 and estimated standard deviation in the population of 10 ms9, the minimum effect size that can be detected is 5 ms (calculated using University of California San Francisco Online Sample Size Calculator). The sample size was determined to be 40 considering a screen failure rate of 10%.
Results
Forty patients were screened for the study. Four patients were excluded due to prolonged QTc (> 450 ms) at baseline. Of the 36 patients who completed the study, 23 (63.9%) were females; the median age of males was 55 years (interquartile range [IQR], 48–60) and females 45 (41–58) years (p = 0.202). There was no significant difference in gender distribution among young adults and the elderly (χ2(1) = 1.084, p = 0.298); 27.78% (10/36) had breast malignancy, 19.44% (7/36) oropharyngeal, 16.67% (6/36) ovarian and 11.11% (4/36) oesophageal malignancy. The intraclass correlation coefficient for QTc assessment using Fridericia formula was 0.928 (95% confidence interval, 0.842–0.968), suggesting good to excellent intra-reader measurement reliability.
We compared the median QTc values at different time points with that at baseline (Fig. 1, Table 2). There was a statistically significant change in the QTc with time (Fridericia, χ2(4) = 15.629, p = 0.004; Bazett, χ2(4) = 15.910, p = 0.003). Post hoc analysis with Wilcoxon signed-rank tests was conducted with a Bonferroni correction applied, resulting in a significance level set at p < 0.005. Compared with baseline QTc (median [IQR], 386.0 ms [373.3–399.5]), assessed using Fridericia formula, QTc on Day 1 (399.0 ms [388.3–420.3]; Z = − 3.784, p < 0.0001) and first time point of Day 2 (399.0 ms [380.0–421.8]; Z = − 3.080, p < 0.002) was significantly prolonged. Bazett’s correction showed a statistically significant increase in QTc on Day 1 (median [IQR], 424.5 ms [402.8–450.0]) compared with baseline (409.3 ms [394.1–423.1]; Z = − 3.865, p < 0.0001), second time point of Day 2 (Day 2_2; 406.5 ms [389.3–430.5]; Z = − 3.088, p = 0.002) and Day 3 (412.5 ms [392.0–435.3]; Z = − 3.172, p = 0.002). On analysis based on gender, these differences were significant in females (Fridericia, χ2(4) = 13.753, p = 0.008; Bazett, χ2(4) = 13.278, p = 0.010) but not in males (Fridericia, χ2(4) = 4.419, p = 0.352; Bazett, χ2(4) = 4.280, p = 0.369).Figure 1 Change in QTc (corrected using Bazett formula) with time. (a) The median QTc values with interquartile range (vertical bars) at different study time points in patients with malignancy receiving antiemetics with QT-prolonging potential are shown. *p < 0.01 for comparison with baseline, second timepoint on day 2 and day 3. (b) The median QTc values in male and female patients at different study time points are shown. The variation in QTc with time was statistically significant in females (p < 0.05). (c) The median QTc values in young adults and elderly patients (≥ 50 years) at different study time points are shown. The variation in QTc with time was statistically significant in the elderly (p < 0.05). Day 2_1, first time point on Day 2; Day 2_2, second time point on Day 2.
Table 2 Change in QTc (corrected using Fridericia formula) with time in patients with malignancy receiving antiemetic drugs with QT-prolonging potential.
Study time point QTc in milliseconds, Median (25th to 75th percentile)
Overall, N = 36 Males, N = 13 Females, N = 23 Young, N = 18 Elderly, N = 18
Baseline 386 (373–400) 379 (365–391) 388 (379–402) 385 (374–405) 387 (367–399)
Day 1 399 (388–420) 391 (380–399) 417 (395–433) 405 (388–434) 397 (387–419)
Day 2_1 399 (380–422) 405 (365–431) 398 (382–421) 400 (382–419) 397 (371–425)
Day 2_2 394 (379–410) 395 (375–414) 393 (379–410) 396 (379–412) 393 (375–410)
Day 3 396 (374–414) 379 (340–410) 403 (381–415) 395 (373–410) 404 (368–426)
QTc values have been rounded off to whole number.
Table 3 shows the number of patients with at least one of the electrocardiograms (ECGs) with QTc > 450 ms, > 480 ms or > 500 ms, after drug administration, based on gender. There was no statistically significant gender difference with regard to the occurrence of QTc prolongation (Fridericia, χ2(1) = 3.282, p = 0.070; Bazett, χ2(1) = 0.994, p = 0.319). However, two female patients had an absolute QTc prolongation (Bazett’s correction) of > 500 ms, which is considered a clinically significant threshold for the risk of serious arrhythmias.Table 3 Absolute increase in QTc interval in patients with malignancy receiving antiemetic drugs with QT-prolonging potential.
Variable QTc prolongation (N)
> 450–480 ms > 480–500 ms > 500 ms
Fridericia Bazett Fridericia Bazett Fridericia Bazett
Gender
Male (N = 13) 0 4 0 0 0 0
Female (N = 23) 2 8 2 1 1 2
Study time point (N = 36)
Day 1 2 7 0 0 0 0
Day 2_1 1 4 2 1 0 1
Day 2_2 0 0 0 0 1 1
Day 3 1 4 0 0 0 0
Day 2_1, first time point on Day 2; Day 2_2, second time point on Day 2.
Table 4 shows the number of patients with at least one of the ECGs with ∆QTc > 30 ms or > 60 ms, compared with the baseline value. Overall, no statistically significant gender difference was seen (Fridericia, χ2(1) = 0.890, p = 0.346; Bazett, χ2(1) = 0.358, p = 0.549), although, more female patients had QTc prolongation of more than 60 ms compared with males (Bazett’s correction, 13.04% versus 7.69%, respectively).Table 4 QTc interval increase from baseline (∆QTc) in patients with malignancy receiving antiemetic drugs with QT-prolonging potential.
Variable ∆QTc (N)
> 30 ms > 60 ms
Fridericia Bazett Fridericia Bazett
Gender
Male (N = 13) 7 5 0 1
Female (N = 23) 11 10 5 3
Study time point (N = 36)
Day 1 10 10 3 1
Day 2_1 8 3 2 3
Day 2_2 7 6 1 1
Day 3 6 6 0 0
Day 2_1, first time point on Day 2; Day 2_2, second time point on Day 2.
We compared the median heart rate (HR) at different time points with that at baseline (Fig. 2). There was a statistically significant change in the HR with time (χ2(4) = 29.787, p < 0.001). Post hoc analysis was conducted with a Bonferroni correction applied, resulting in a significance level set at p < 0.005. There was a statistically significant decrease in HR on first (Day 2_1; 77 beats per minute [bpm; 63–91]; Z = − 3.499, p < 0.001) and second time point of Day 2 (Day 2_2; 71 bpm [59–89]); Z = − 4.403, p < 0.001) compared with baseline (84 bpm [69–98]); on Day 2_2 (71 bpm [59–89]) compared with Day 1 (79 bpm [72–93]; Z = − 3.449, p = 0.001) and Day 2_1 (77 bpm [63–91]; Z = − 3.309, p = 0.001). On analysis based on gender, these differences were significant in females (χ2(4) = 27.483, p < 0.001) but not in males (χ2(4) = 9.150, p = 0.057).Figure 2 Change in heart rate with time. (a) The median heart rate and interquartile range (vertical bars) at different study time points in patients with malignancy receiving antiemetics with QT-prolonging potential are shown. *p < 0.01 for comparison with first and second time point on Day 2; # p < 0.01 for comparison with Day 1 and first timepoint of Day 2. (b) The median heart rate in male and female patients at different study time points are shown. The variation in heart rate with time was statistically significant in females (p < 0.001). (c) The median heart rate in young adults and elderly patients (≥ 50 years) at different study time points are shown. The variation in heart rate with time was statistically significant in both the groups (p < 0.05). Day 2_1, first time point on Day 2; Day 2_2, second time point on Day 2.
A similar trend of a significant decrease in HR with time was seen in young adults (χ2(4) = 19.921, p = 0.001) as well as elderly (χ2(4) = 12.596, p < 0.013). However, a significant change in the QTc with time was seen in the elderly (Fridericia, χ2(4) = 7.796, p = 0.099; Bazett, χ2(4) = 11.003, p = 0.027) but not young adults (Fridericia, χ2(4) = 8.858, p = 0.065; Bazett, χ2(4) = 5.732, p = 0.220) only when Bazett formula was applied.
Discussion
We studied the effects of the combination of domperidone, ondansetron and olanzapine, administered in patients receiving highly emetogenic chemotherapy and/or radiotherapy, on the QTc interval. Although palonosetron was also a part of the antiemetic regimen, it does not have any significant QT-prolonging potential, and in particular, has no pharmacologic interaction with domperidone13. Our study showed that there was a significant prolongation in the QTc following administration of olanzapine on Day 1; this was significantly more than the QTc at baseline. Administration of domperidone and ondansetron on Day 2, along with olanzapine, did not show further significant prolongation of QTc. However, elevations in absolute QTc > 480 ms occurred on Day 2, suggesting that the combination may produce clinically significant QTc prolongations in some individuals, and hence, is better avoided. In general, the maximum number of QTc prolongations occurred on Day 1, whereas more severe QTc prolongations occurred on Day 2. No participants, however, developed clinically identifiable arrhythmias. We used two formulae for QT correction; Bazett formula is widely used in clinical settings, and thorough QT/QTc study guidelines recommend Fridericia formula8. Bazett formula has been shown to overestimate the QTc prolongation and performs relatively poorly at higher heart rates16,17. While this was true even in the current study, there was an overall agreement in the study findings irrespective of the correction formula used. Analysis of the heart rate shows a fall in the heart rate compared with baseline and Day 1. However, the changes in the heart rate were not clinically significant because the interquartile ranges did not exceed the lower limit of 50 or upper limit of 100 beats/minute.
Although the antiemetic regimen used in our study may not be the standard practice at other sites, the findings provide clinically significant information regarding the safety of drug combinations with potential QT-prolonging effects. QTc changes with time were significant in females and elderly in our study; this is in agreement with the findings of a retrospective ECG review of hospitalized psychiatry patients on psychotropic drugs18. The gender difference is likely to be sex hormone-related19 whereas the age difference is likely to be due to the effect of ageing on the myocardium and autonomic tone20; interestingly, the latter study showed that in elderly, the QTc prolongation is more severe in males compared with females.
Our study shows that olanzapine has a QT-prolonging effect, particularly on the day of initiation. Studies, mainly case reports, have reported an increased risk of QT prolongation with atypical antipsychotics15; an increased risk of sudden cardiac death has also been shown for olanzapine14,21. However, the association between QT prolongation due to atypical antipsychotics and cardiac death has not been well established22. In fact, a study showed that despite the prolongation in QT interval with atypical antipsychotics, there was no increased risk of torsades de pointes23. Nonetheless, olanzapine has a low risk of QT prolongation24, and the risk increases with dose14. The dose used in our study was moderate, which has been shown to significantly increase the risk of cardiac death14. Guidelines recommend decreasing the dose or switching to safer alternatives when QTc is > 440 ms in males and > 470 ms in females, and stopping the drug when > 500 ms24.
Despite being a drug with a high risk of QT prolongation, domperidone did not produce a statistically significant increase in the QTc interval; in fact, using Bazett formula, the QTc on day 1 was significantly higher than on Day 2 when domperidone was introduced along with ondansetron. However, when the absolute and delta values are seen, severe increases in QTc interval, which are clinically important, occurred on Day 2. Like in the case of olanzapine, there are several case reports linking domperidone with life-threatening QT prolongation7. However, most of these have been with intravenous domperidone. A case–control study also showed an increased risk of sudden cardiac death25. A systematic review and meta-analysis also showed an increased risk of ventricular arrhythmias and sudden cardiac death by up to 70%26. However, some of the recent studies have failed to show an increased risk with domperidone, both at high antiemetic doses27 and low doses < 30 mg/day28. A similar risk profile is also present for ondansetron, where, despite its QT-prolonging potential, clinically significant arrhythmias are uncommon12. The lack of evidence of significant QT-prolonging risk in recent studies resulted in the downgrading of the risk category for the interaction between domperidone and ondansetron10.
Considering that prescription of a combination of QT-prolonging drugs, particularly those containing domperidone, is not uncommon10,29, the likely impact of such combinations on the risk of QT prolongation is important. An evaluation of such combinations in psychiatry patients showed that the risk class is more important rather than the number of coadministered QT-prolonging drugs30. The effect of the drugs did not seem to persist on Day 3, both in terms of change with time and absolute/delta values. One probable reason might be the different time points following the drug administration at which the ECGs were obtained. We used different time points to coincide with the peak drug concentrations (Day 1, peak concentration of olanzapine; Day 2_1, peak concentration of domperidone) as well as the non-peak effects (Day 2_2 and Day 3). It is also possible that the peak effect of olanzapine on QT interval occurs initially, coinciding with the autonomic effects of the drug, although there is no evidence to substantiate this. Moreover, contrary to the expected effect of the drug on heart rate31, a decrease in the heart rate was seen in our study. Notwithstanding the above observations, our study shows that QTc prolongation is a concern with olanzapine alone and in combination with domperidone and ondansetron. Whether this QT prolongation is adequate to cause clinical events is unclear, which is in line with the findings of earlier studies.
Our study has limitations. It was a single-centre study with small sample size. There was no control group; hence, it is not possible to definitely attribute the prolonged QTc observed in the study to be due to the study drugs. However, we intended to study the effects of the antiemetics in a real-world setting, and hence, including a control for each antiemetic studied was not feasible. Although the assessor (cardiologist) was blinded, having two persons read the ECG would have better eliminated reading errors. The time points were based on the time of administration of the first dose of the antiemetic combination; hence, the ECGs were recorded at different times of the day in the study participants. Although we have described significant differences in the measured parameters based on patient age and gender, the study was not primarily designed to evaluate these differences; the findings, therefore, need to be explored further in well-designed studies. We excluded patients receiving other QT-prolonging drugs (other than the study drugs); hence, the generalizability of our study findings is limited.
To conclude, our study showed that the combination of domperidone, ondansetron and olanzapine could cause potentially clinically significant QTc prolongation; caution needs to be exercised, particularly in females and elderly patients. Olanzapine alone can cause significant QTc prolongation. Targeted safety assessments in patients receiving these drugs with QT-prolonging potential in real-world settings are necessary to determine whether the QT-prolonging effects do translate into adverse clinical outcomes.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors thank all the study participants and the support staff of the Department of Radiation Oncology, Kasturba Medical College, Mangalore.
Author contributions
A.K. and P.P.S. conceived the study protocol with inputs from M.R. P.P.S., S.R. and S.B. collected the study data. A.K. and M.R. analysed the data. A.K. prepared the draft manuscript. P.P.S., M.R., S.R. and S.B. critically reviewed the manuscript. The final draft of the manuscript was prepared by A.K. and P.P.S. and approved by M.R., S.R. and S.B.
Funding
A.K. received funding for this research in the form of Seed Grant for Faculty Research from Manipal Academy of Higher Education, which partly covered the research expenses.
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests. | DOMPERIDONE, OLANZAPINE, ONDANSETRON | DrugsGivenReaction | CC BY | 33431995 | 19,992,269 | 2021-01-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Severe invasive Listeria monocytogenes rhombencephalitis mimicking facial neuritis in a healthy middle-aged man: a case report and literature review.
Neurolisteriosis is a foodborne infection of the central nervous system that is easily misdiagnosed, especially in healthy adults with atypical symptoms. A 50-year-old man presented with a 3-day history of distortion of the oral commissure. Facial neuritis was diagnosed and treated with intravenous dexamethasone. His condition deteriorated rapidly, and he presented with a slow pharyngeal reflex, stiff neck, and signs of peripheral facial paralysis. Brain magnetic resonance imaging revealed multiple ring-enhanced foci in the brainstem. Routine and biochemical cerebrospinal fluid (CSF) analyses showed increased white blood cells and microproteins. Blood culture and high-throughput genome sequencing revealed Listeria monocytogenes DNA in the CSF. Ampicillin, amikacin, and meropenem were administered, and the patient was transferred from the intensive care unit to a standard medical ward after 2 months. The patient could walk and eat normally; however, he required intermittent mechanical ventilation at 11 months after discharge. Although L. monocytogenes meningitis is rare in healthy immunocompetent adults, it must be considered as a differential diagnosis, especially in adults whose conditions do not improve with cephalosporin antibiotic administration. L. monocytogenes rhombencephalitis mimics facial neuritis and develops quickly. Prompt diagnosis is essential for rapid initiation of antibiotic therapy to achieve the best outcome.
Introduction
Listeriosis is a rare disease, with a reported annual incidence of 4.4 per 1 million individuals,1 and typical symptoms include fever, body aches, and gastrointestinal symptoms such as diarrhea. Immunocompromised, elderly, and pregnant individuals, as well as newborns, are most susceptible. Listeria monocytogenes is a Gram-positive facultative intracellular bacillus, and its transmission occurs mainly through the consumption of contaminated food. L. monocytogenes causes one of the most life-threatening bacterial infections of the central nervous system (CNS). Manifestations include meningitis, meningoencephalitis, and rhombencephalitis, and it is the third most common cause of bacterial meningitis.2
L. monocytogenes encephalitis has high mortality and neurological sequelae rates, at 20% and 68%, respectively.3 At present, reports of L. monocytogenes meningitis in immunocompetent and healthy adults with atypical initial symptoms (similar to facial neuritis) are limited. Such cases are easily misdiagnosed, and use of steroid therapy can endanger the patient’s life. Therefore, we report a case of severe, invasive L. monocytogenes rhombencephalitis mimicking facial neuritis in a healthy middle-aged man, and we present a comprehensive review of the literature to summarize similar reports.
Case report
In January 2018, a 50-year-old man was admitted to our hospital with a 3-day history of distortion of the oral commissure. He had dizziness, headache, malaise, and vomiting beginning 3 days before admission. A shallow nasolabial sulcus on the left side, distortion of the oral commissure, and weakness in closing the left eye subsequently appeared. The patient had no diplopia, dysdipsia, hemiplegia, or limb numbness, and he was lucid and alert. Diagnoses of acute upper respiratory tract infection and peripheral facial neuritis had been considered at another hospital. The patient was previously diagnosed with tuberculosis at 4 years old; he reported that the tuberculosis had long been cured, and he had no history of immunodeficiency. He had no history of major trauma, toxic exposure, smoking, alcoholism, drug abuse, or hereditary disease. His family denied any history of unpasteurized buttermilk consumption.
A physical examination on admission revealed a blood pressure of 135/85 mmHg, temperature of 36.5°C, and pulse rate of 85 bpm. He had no signs of meningismus or other neurological irregularities. The patient’s white blood cell count (10.61 × 109/L), fasting blood glucose level (6.3 mmol/L), and glycosylated hemoglobin level (6.1%) were slightly increased, whereas his serum creatinine, cholesterol, C-reactive protein, creatine kinase, and procalcitonin levels were normal. The blood coagulation parameters were within normal limits. Tests for antibodies to human immunodeficiency virus and Treponema pallidum were negative. Emergency head computed tomography (CT) showed no apparent abnormalities (Figure 1a). Chest CT showed chronic-appearing fibrotic streaks in both lungs. Peripheral facial neuritis was diagnosed; the patient was admitted, and dexamethasone (10 mg/day) was administered intravenously (iv) for 3 days.
Figure 1. Computed tomography (CT), magnetic resonance imaging (MRI), and blood culture results. (a) Head CT showing no apparent abnormality after admission. (b) The patient’s condition worsened; however, head CT re-examination showed no apparent abnormality on the third day after admission. (c) T1-weighted image (WI) showing low-signal midbrain lesions (arrow). (d) T2-WI showing a hyperintense dorsal pontine lesion (arrow). (e) Diffusion WI showing no abnormal signal in the midbrain. (f) A high apparent diffusion coefficient was observed in the midbrain lesions (arrow). (g) Fluid-attenuated inversion recovery sequence showing hyperintense lesions (arrow) in the dorsal lower pons. (h–k) Gadolinium-enhanced MRI showing multiple ring-enhanced lesions in the (h) left midbrain (arrow), (i) medulla oblongata, (j) dorsal upper medulla oblongata (arrow), and (k) dorsal lower pons (arrow). (l) Listeria monocytogenes was cultured from peripheral blood. The tryptone soy blood agar plate produced round bacterial colonies with neat edges and central uplifting; the surfaces were smooth and whitish gray.
The patient then developed a headache, dysdipsia, malaise, and fever (39.2°C) 3 days after hospitalization, and a physical examination at that time showed neck stiffness and slowness of the pharyngeal reflex, along with signs of peripheral facial paralysis. The facial nerve, glossopharyngeal nerve, and meninges were considered affected; however, the nature of the lesion was unknown. No apparent abnormality was found in a head CT re-examination (Figure 1b). The patient’s condition worsened rapidly, and he developed somnolence, aphagia, and slurred speech. Brain magnetic resonance imaging (MRI) (Figure 1c–k) performed 4 days after admission showed multiple abnormal foci in the brainstem. The cerebrospinal fluid (CSF) opening pressure was 245 mmH2O. Routine CSF testing showed a markedly increased white blood cell count (8.35 × 108/L). Biochemical CSF examination showed a potassium concentration of 2.5 mmol/L, chloride concentration of 144 mmol/L, glucose concentration of 3.0 mmol/L, and microprotein concentration of 2.19 g/L. No organisms were observed on Gram, India ink, or acid-fast staining.
The patient was considered to have a tuberculous or bacterial intracranial infection and was transferred to the intensive care unit (ICU). He underwent physical cooling using an ice blanket and ice cap and was given anti-infective and antiviral medications (ceftriaxone, 2 g iv every 12 hours; ganciclovir, 0.25 g iv every 12 hours). Furthermore, he underwent intracranial decompression using mannitol and symptomatic and supportive treatment in the ICU. Further examination revealed negative tests for influenza A and B viral antigens and anti-Toxoplasma antibodies. Two days later, L. monocytogenes (Figure 1l) was isolated from the blood culture and was identified by time-of-flight mass spectrometry, but no abnormality was found in the CSF culture. Genetic identification of CSF pathogens by high-throughput genome sequencing found only L. monocytogenes (sequence number 210).
The patient’s condition quickly progressed to respiratory failure; thus, mechanical ventilation was initiated. Based on the sequencing and antimicrobial susceptibility testing results, anti-infectives (ampicillin, 1 g iv every 8 hours; amikacin, 0.4 g iv every 12 hours; and later, meropenem, 2 g iv every 8 hours) were administered, and the patient was transferred from the ICU to a standard medical ward after 2 months. The patient could walk and eat normally; however, damage to the respiratory center resulted in central respiratory insufficiency, and he required intermittent mechanical ventilation at the 11-month post-discharge follow-up visit. He was satisfied with his treatment and recovery.
Discussion
This case of severe, invasive L. monocytogenes rhombencephalitis mimicking facial neuritis in a healthy middle-aged man showed that the disease can be easily misdiagnosed in this population. Moreover, this case showed that observation of ring-enhanced brainstem lesions on MRI and high-throughput genome sequencing results are important for accurate diagnosis. Furthermore, this case showed that the choice of proper antimicrobials is key to a successful therapy.
L. monocytogenes is routinely described as an opportunistic bacterium, and it typically infects pregnant women, newborns, the immunocompromised, and older adults. As in healthy adults, it is very rare in healthy children4 beyond the neonatal period. The cause of L. monocytogenes encephalitis in healthy adults may differ from that in patients with immunodeficiency.
The main transmission route of L. monocytogenes infection is the digestive tract, from which it is absorbed into the peripheral blood. From the peripheral blood, it can access the CNS by crossing the blood–brain barrier.5 Most patients have gastrointestinal symptoms (Table 1);6–10 however, as in this case, they often do not have a clear history of contaminated food ingestion.
Table 1. Clinical features of healthy and immunocompetent young and middle-aged individuals with Listeria meningitis.
Author, year of publication Age (years) and sex Consumption of unpasteurized buttermilk Symptoms and signs Brain CT/MRI CSF/CSF cultures for LM Blood/CSF cultures for LM Specific antibiotic treatment for LM and outcome
Zhang et al. [6], 2012 34, M Not mentioned Fever, headache, nausea, and vomiting for 3 days Not mentioned Leukocytosis and high protein levels –/+ Initial treatment with vancomycin (1 g iv q12h) and ceftriaxone (2 g iv q12h); however, his condition deteriorated
Altered consciousness for 1 day Consequently, the patient was given a combination of ampicillin (4 g iv q8h) and amikacin (0.4 g iv daily), to which he responded well
Meningeal irritation sign (+) The patient remained in good clinical condition on follow-up
Callaghan et al. [7], 2012 35, F Not mentioned Headaches, nausea, vomiting, and malaise for 4 days, followed by hemianesthesia, facial weakness, nystagmus, and ataxia MRI showed multiple ring-enhancing lesions in the brainstem Leukocytosis and high protein levels −/− Amoxicillin (2 g six times daily) and gentamicin (80 mg iv three times daily) for 2 weeks, to which the patient responded well
CSF PCR: + She had recovered well on follow-up
Vrbiü et al. [8], 2013 18, M Not mentioned Fever, severe headache, and vomiting for 3 days CT showed diffuse cerebral edema Leucocytes ↑ and high proteins levels –/+ Initial treatment with vancomycin and ceftriaxone, substituted with meropenem (2 g iv q8h), had no clinical effect
Meningeal irritation sign (+) Subsequently, ampicillin (2 g iv q4h) was administered after LM was isolated; the patient recovered completely.
Décard et al. [9], 2017 31, F Yes Isolated right facial numbness, followed by dysphagia, nystagmus, diplopia, peripheral facial palsy, and hemiparesis MRI showed multiple ring-enhancing lesions in the brainstem Lymphocytic pleocytosis and slightly elevated protein levels +/+ Ampicillin, ceftriaxone, and acyclovir were initiated and substituted with ampicillin and gentamicin after culturing of LM, followed by combination treatment with ampicillin, rifampicin, linezolid, and cotrimoxazole
The patient had severe sequelae
Li et al. [10], 2019 37, M Not mentioned Fever for 2 days, with dysphoria, followed by coma and respiratory and circulatory failure CT showed swelling of the brain and hydrocephalus High CSF pressure, increased leucocytes, and normal protein levels +/− Vancomycin (0.5 g iv q8h) and meropenem (0.5 g iv q8h)
The patient died 2 weeks after admission
CSF, cerebrospinal fluid; CT, computed tomography; F, female; iv, intravenously; LM, Listeria monocytogenes; MRI, magnetic resonance imaging; M, male; PCR, polymerase chain reaction; q4h, every 4 hours; q8h, every 8 hours; q12h, every 12 hours; −, negative; +, positive.
Some patients with L. monocytogenes encephalitis show mild symptoms and have a good treatment response.7 However, the disease can be aggressive, as in the case of our patient.
L. monocytogenes rhombencephalitis typically has a biphasic course, with non-specific prodromal symptoms such as fever, malaise, fatigue, headache, nausea, and vomiting, followed by any combination of cranial nerve palsies, ataxia, hemiparesis, hypesthesia,2 and altered consciousness. L. monocytogenes rhombencephalitis develops quickly and is often complicated by sepsis and respiratory failure.11 Common clinical findings include fever (57%), headache (57%), and focal neurological signs (64%).11
L. monocytogenes rhombencephalitis should be differentiated from tuberculous meningitis; both have similar CSF and brain MRI abnormalities, but L. monocytogenes rhombencephalitis often presents with high fever and progresses rapidly. Listeria may be identified in CSF cultures and much more rarely in blood cultures. L. monocytogenes rhombencephalitis should be distinguished from cryptococcal meningitis and other types of bacterial encephalitis. MRI usually shows multiple ring-enhanced lesions in the brainstem,7,9 as was observed in this case. With its high resolution, high-throughput genome sequencing is a promising technique for pathogen identification.
In general, penicillin, ampicillin,12 and amoxicillin are effective treatments for L. monocytogenes infection, but some strains are resistant. Thus, effective antibacterial agents, such as trimethoprim-sulfamethoxazole,13 meropenem, linezolid, and aminoglycosides,12 should be selected with the guidance of an antimicrobial sensitivity test. Guidelines recommend early steroid therapy for facial neuritis;14 however, patients with neurolisteriosis receiving adjunctive dexamethasone have higher mortality,15 and this treatment could aggravate conditions in patients without effective antibiotic treatment, as in this case. The treatment course with effective antibiotics should be at least 21 days. Because L. monocytogenes has a natural resistance to cephalosporin antibiotics, L. monocytogenes should be considered when third-generation cephalosporins are not effective against bacterial encephalitis. The empirical treatment of bacterial meningitis should include agents effective against listeriosis.16 The survival rate is greater than 70% when appropriate antibiotic therapy is initiated early.17 Younger, immunocompetent individuals with L. monocytogenes meningitis have favorable disease outcomes.8 However, approximately 60% of survivors develop neurological sequelae.17 Timely and effective antibacterial therapy is crucial to improving the prognosis.
We searched the PubMed database for the Medical Subject Heading terms “facial paralysis/cranial nerve injuries” and “Listeria monocytogenes/Listeria” in different combinations, but no case similar to ours was found. It is necessary to further study L. monocytogenes encephalitis with atypical initial symptoms to aid early identification.
In conclusion, although Listeria meningitis is rare in healthy, immunocompetent adults, it must be considered in the differential diagnosis, especially in those whose disease conditions do not improve with cephalosporin antibiotic treatment. L. monocytogenes rhombencephalitis develops quickly, and prompt diagnosis of L. monocytogenes encephalitis, which mimics facial neuritis, is essential so that adequate antibiotic treatment can be initiated and the best outcome is achieved.
Ethics Statement: The study design was approved by the ethics review board of the Third Affiliated Hospital of Shenzhen University (No. 2020-SZLH-LW-015). We obtained written consent for publication from the patient.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Liming Cao https://orcid.org/0000-0003-2836-9347 | DEXAMETHASONE | DrugsGivenReaction | CC BY-NC | 33435771 | 18,895,687 | 2021-01 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.