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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Paraesthesia'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy partial responder'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Throat irritation'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombocytopenia'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tremor'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Urinary tract infection'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
What was the dosage of drug 'RITUXIMAB-ABBS'? | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 375 MG/M2 | DrugDosageText | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Ayurveda co-interventions have supported complete recovery in Severe COVID- 19 infection with a Chest Severity Score 18/25: A Case Report.
Severe COVID-19 infection requiring oxygen support is reported to have high mortality. Chest Severity Score evaluated through CT scan has a predictive value about future outcomes in such cases. Score value ∼18 is predicted to have poor outcomes. We are presenting here a case of severe COVID-19 with all predictors suggestive of a bad prognosis including IL-6, D-Dimer, Ferritin and CRP in addition to 18/25 Chest Severity Score. Initially treated under ICU care at a tertiary care COVID hospital for about 14days, the patient was intervened with Ayurveda on his own insistence seeing the unsatisfactory improvements. Ayurveda intervention for 19 days along with standard ICU care resulted in complete clinical recovery of the patient besides the correction of biomarker levels. Rapid clinical and biochemical correction in this severe COVID-19 case against all odds is highly significant and warrants an urgent search for possibility of instituting the integrative management strategies for all those treated in an allopathic facility. This case also advocates an early institution of Ayurveda interventions in COVID-19 in order to prevent deterioration leading to complications.
pmc1 Introduction
Ayurveda physicians often get the opportunities to intervene in cases where modern medicine had shown limitations owing to the bad prognosis or limited treatment options. If not all, at least some of these cases eventually benefit from such interventions. A very few among these successful interventions however are documented. This non documentation of meaningful interventions in intractable conditions is largely attributed to the unfamiliarity of Ayurveda physicians with scientific writing and meticulous record keeping. Such observations of benefits however have proven to be of immense value in the lives of the beneficiaries. From research perspectives, all these observations may have a potential to act as strong cues demanding further exploration for their possible generalisation.
COVID-19 pandemic has presented numerous such opportunities before Ayurveda physicians where novelty of the disease and absence of clear cure has come as a compulsion to many for the search of other pragmatic alternatives [1]. Ayurveda physicians invariably treated many of such cases in their individual capacities and met with success in terms of reduced complications, improved recovery rate and reduced hospital stay. Such cases are treated either in an integrative model using Ayurveda in an ‘add on’ mode upon the insistence of the patients or as the stand alone therapy where Ayurveda has been instituted as the sole intervention modality. A few of such cases having variable stages of COVID-19 related pathology and treated through Ayurveda are reported in literature [2,3]. As a response to the pandemic, Ayurvedic classical literature has been critically revisited in the context and many novel propositions including rephrasing the COVID-19 patho-physiology in terms of Ayurveda has been attempted [4,5]. Many clinical trials on Ayurvedic formulations and their role in SARS-CoV-2 infection are underway and their results are eagerly awaited [6]. In this background, we present here a case of 52 year old male having severe breathlessness with COVID related Chest Severity Score (CSS) 18/25 and CT scan showing intermediate phase changes in lungs (CORADS-6) due to COVID-19 infection, diagnosed as a RT-PCR positive case of severe COVID-19 and was admitted to Intensive Care Unit of a tertiary care hospital. He constantly required oxygen support as without oxygen his SPO2 was reported as low as 64%. On the basis of various biomarkers related to the prognosis of COVID-19 infection, he was identified as severe COVID-19 case with poor prognosis. In this condition, facing the state of hopelessness with on-going care, he sought Ayurveda opinion. Upon initiation of the Ayurveda therapy along with standard ICU care while the patient was still in ICU, in next three days, he was able to breath at his own without any supplemental oxygen need for as long as 45 min. On 6th day of initiation of Ayurveda medications, he was able to breathe without additional oxygen support. Subsequent blood and biochemical investigations have shown remarkable improvement on all parameters.
Although the case was on standard COVID care in a tertiary care hospital, the improvements were not satisfactory till 16th day of his admission in the ICU. The improvements were visible only after the initiation of Ayurveda therapy. After 26 days spending in the ICU, the patient was shifted to High Dependency Unit (HDU) and was finally discharged from the hospital on 33rd day of his admission.
Improvements seen in this case after the initiation of Ayurveda therapy were remarkable and worthy of getting noticed for two obvious reasons. One is that it highlights the potential of Ayurveda interventions in many intractable conditions even when the patients are receiving ICU care. This was argued earlier also that Ayurveda should be given an access to ICUs for active treatment at least in the conditions where standard care have not shown much to offer [7]. Second and even more important message is that such cases, for their novelty, unusualness and demonstrable clinical benefits should be taken as important cues of future research. Serious clinical trials therefor should be planned to establish the feasibility of such interventions in larger population. This inference has a high significance in current pandemic where the real cures proven through robust and generalizable evidence are still awaited. Our observations as a case report are placed on record in order to see the generalizability of such interventions proven through larger systematic studies. Till such cures are in sight, any proposition offering a reduction in the morbidity and improved survival in COVID-19 seems to have a great value.
2 Patient information
This case is about a 52 year old, resident of Delhi, average built, otherwise healthy (without any known co-morbidity relevant to COVID-19) and a non-smoker male who was infected with SARS-CoV-2 infection confirmed by RT-PCR test (11.11.2020).
3 Clinical Findings
Corresponding Coronavirus disease 2019 (COVID-19) Reporting and Data System (CO-RADS) score −6 on CT scan (18.11.2020). CO-RADS 6 is strongly suggestive of lung changes due to SARS-CoV-2 infection. Chest severity score (CSS) calculated on the basis of radiological findings was found to be 18/25 which was associated with a high risk of mortality (Table 1). Since the initial onset of fever and flu like symptoms (running nose, sore throat, cough, head ache 21.10.2020) till the diagnosis of SARS-CoV-2 infection by RT-PCR test, the patient was receiving home based care inclusive of hot water drinking and gargling, steam inhalation, analgesic, antipyretic and antihistamine. In addition to this, he has received AYUSH quath and Chyawanprash as per the recommendations of Ministry of Ayush. Additional antibiotic (Azithromycin), antiviral (Favipiravir) and antiplatelet (Low dose aspirin) was added upon the SARS-CoV-2 infection confirmation. Initially there was no breathlessness but the cough and breathless gradually set in requiring a shifting of patient to DRDO-COVID Hospital, New Delhi where he was admitted in ICU (18.11.2020). Since then he was continuously kept on Oxygen as he was not able to breathe on his own without additional oxygen support. Without oxygen support, his SPO2 was reported to be as low as 64%. Blood investigations carried out on 18.11.2020 were suggestive of bad prognostic values for all the severity predictors including D-Dimer, CRP, IL-6 and Ferritin (Table 2). A high total count (17,280) was reported on 1.12.2020 indicated steroids used in the case. Despite being under standard ICU care till 2.12.2020, his condition did not improve much.Table 1 CT scan lung findings and Chest Severity Score (18.11.2020).
Table 1Lobe score (0–5)
Right upper lobe 3
Right middle lobe 3
Right lower lobe 4
Left upper lobe 4
Left lower lobe 4
CT chest severity score 18/25
There is evidence of extensive large ill-defined confluent areas of ground glass attenuation in bilateral lungs involving all the lobes with peri-broncho-vascular and peripheral sub-pleural distribution pattern and few superimposed linear fibro-atelectatic densities. Findings are suggestive of early/intermediate phase changes of Covid 19 infection (CORADS-6).
Table 2 Blood Investigations before and after Ayurveda intervention.
Table 2Parameters Units Values on 18.11.2020 (before Ayurvedic Intervention) Values on 1.12.2020 (before Ayurvedic Intervention) Values on 12.12.2020 (after Ayurvedic Intervention)
Haemoglobin g/dL 14.9 14.8 12.7
Total Leucocyte Count Cumm 5300 17,280 7700
RBC Million/cumm 6.82 – –
Platelets Lacks/cumm 1.56 4.16 1.20
Neutrophils % 84 86 70
Lymphocytes % 07 11 28
Monocytes % 08 01
Eosinophil % 01 01
Basophils % 0 0
PCV % 47.5 39.8
MCV pl 69.6 70.4
MCH pg 21.8 22.5
MCHC % 31.4 31.9
RDW % 16.8 42.9
D-Dimer Ng/ml 973.90 225.0 76.88%↓
CRP Mg/l 87.90 14.70 83.28%↓
IL-6 Pg/ml 149.40 6.53 95.63%↓
Ferritin Ng/ml 339 353.4 4.1%↑
LDH U/L – 328.8
Urea Mg/dl – 30.5 17
Creatinine Mg% – 1.06 0.89
BUN Mg% 7.94
S. Bilirubin Mg/dL – 1.15
SGOT IU/L – 21.9
SGPT IU/L – 31.7
Alkaline Phosphatase U/L – 130.60
S Sodium Mmol/L – 133 137
S Potassium Mmol/L – 3.8 4.45
4 Ayurvedic Interventions
In the state of hopelessness, he sought Ayurveda intervention. After a tele-consultation he was recommended Chausath Prahari Pippali (CPP) 500 mg twice in a day, Shringarabhra rasa (SR) 125 mg twice in a day and Amrit Bhallataka (AB) 2.5 g twice in a day. CPP and SR were started from 3.12.2020 whereas AB was started only from 6.12.2020. He continued to be in standard ICU care as usual with oxygen support. The patient reported to feel positive from the very first day of start of Ayurveda intervention. His dependency upon oxygen started reducing on the following days. From 9.12.2020 he reported to sustain without oxygen support for ∼45 min. He continued with Ayurvedic intervention along with ICU standard care. On 11.12.2020 his RT-PCR became negative. He still required oxygen support but his dependency on it continued to reduce as he was able to sustain for longer periods without additional oxygen support. On 12.12.2020 his blood investigations were carried out and most prognosis indicators of SARS-CoV-2 infection were found to be in normal range (Table 2). From 12.12.2020 he did not require any oxygen support. On 14.12.2020 he was shifted from ICU to HDU. He continued the standard care and also the Ayurveda medications. He continued to improve on following days and finally discharged from the hospital on 21.12.2020.
5 Followup and outcomes
Although, the patient was on simultaneous standard ICU and HDU care for ∼ 1 month, he largely attributed his improvements to Ayurveda interventions which were started from 2.12.2020 and continued till his discharge (19 days). A narrative of patient’s perspective of the case is appended at the end of this case report. A time line of major events in the course of illness is appended as Fig. 1.Fig. 1 Major events and their time line.
Fig. 1
6 Discussion
There has been a recent report on outcomes of Ayurvedic care in a COVID-19 patient with severe hypoxia [2]. The case presented here although observes similar outcomes, is noteworthy for two important reasons. One is that the patient here was receiving the ICU care in a tertiary care hospital for over 2 weeks and decided to add on Ayurveda interventions only when there was unsatisfactory improvement in the condition. He further had all biomarkers indicative of severity of the disease and bad prognosis. On the coronavirus disease 2019 (COVID-19) Reporting and Data System (CO-RADS) which is developed as a categorical system to assess suspicion of lung involvement by COVID-19 on chest CT scans he was found CO-RADS 6, a condition with positive RT-PCR and bilateral Ground Glass Opacity (GGO) and halo sign [8]. Chest Severity Score (CSS) which is a rapid identifier of patients with severe forms of coronavirus disease 2019 was found 18/25 in this case. A CT score of ≥18 is reported to be associated with an increased mortality risk and is found to be predictive of death both in univariate and multivariate analysis [9]. In this condition, a complete clinical recovery along with reversal of most biomarkers related to the disease severity within 19 days of initiation of Ayurveda intervention along with standard ICU and HDU care is remarkable and needs the utmost attention.
This case was treated through a vyadhipratyanik approach of Ayurveda where the disease complex is targeted in toto through specific interventions. Three medicines (CPP, SR and AB) which have been given to the case were mainly vata-kapha shamak in nature which is presumed to be the principal pathology in SARS-CoV-2 infection [4]. From Ayurveda perspectives, lungs are invariably the seat of vata and kapha. Pippali (Piper longum) as the sole ingredient in the CPP is recommended as rasayana to pranavaha srotus which is rooted in lungs [10]. SR is a highly praised drug in respiratory conditions dominated by vata –kapha pathology [11]. AB where Bhallataka (Semicarpus anacardium) is the principal component is a highly praised kapha shamak drug [12]. All these drugs recommended in the case are used in ayurvedic clinical practice since long and have not been reported with any adversity during their monitored use. Failure of standard recommendation of Ayurveda immune enhancive therapy in preventing the disease and its complications as is noted in the case is another important observation. This is observed that such recommendations in general reduce the intensity of the disease and hence promote its benign course but do not prevent the disease from occurrence in every individual [13]. Much research is still required to understand the preventive and disease modifying potential of standard Ayurveda recommendations in COVID-19.
Although vyadhi bala, rogi bala and dosha avastha should have been examined before prescribing a drug from Ayurvedic perspective, we see that in COVID-19 where consultations are largely offered in a tele-consultation mode [14] a knowledge about the roga and rogi bala is largely procured through telephonic enquiry. We adopted the similar method of disease assessment and in our case the roga and rogi both were found to be of pravara bala.
Ayurvedic physicians are often approached when the conventional health care fails to deliver what is actually desired. This is done often in the intractable cases with poor prognosis or in the conditions where the conventional approach is rejected by the patient. In many instances, such alternative interventions have resulted in improvements and cures which were not deliverable through conventional care despite of standard care approaches. Such observations have been noticed in variety of conditions including traumatic brain injury [15], Spinal cord injury [16], atonic bladder [17], Hepatic encephalopathy [7], metastatic liver disease [18] and achalasia [19].
A disease condition which was novel and was available in a pandemic proportion has given the health care systems an unprecedented opportunity to learn, to reinvent and to repurpose every bit of knowledge which could have been of help to mitigate the disease [20,21]. In the absence of a definitive cure anywhere in sight, this is natural for the people to look at alternative health care solutions. Although not utilised to the full of its potential, Ayurveda continued to show the evidence of its effectiveness in various stages of SARS-CoV-2 infection. Ayurveda responded to the pandemic initially by exploring its textual wisdom to find the clues for the disease management and subsequently it offered care to many cases who demanded individualised Ayurveda care. More clinical trials are underway and are expected to generate dependable evidences about possible role of Ayurveda in COVID-19. The observations made through such single case reports however are also significant for their possibility of getting converted into robust evidences following the systematic clinical trials. Ayurvedic case reports and clinical trials in the context of COVID-19 are also meaningful from an entirely different perspective. This is observed that the cases are treated differently following different protocols based on the individual logics and judgments. This variability of protocols reaching to successful outcomes is a clear example of versatility of Ayurveda interventions and its treatment personalisation approach.
Although valuable, such case reports in Ayurveda are inherently deficient in precise details of the disease process and changes in response to the given interventions. Being retrospective in nature, such cases in Ayurveda are largely reported only when the outcome of interest has already arrived. This implies for two important limitations of such reporting. One is that the cases where the desired outcomes are not achieved are never reported and hence the limitations of Ayurvedic interventions in unsuccessful cases do not see the light of the day. Second limitation is that a clear reasoning of intervention and its effects is always difficult to interpret in the presence of other variables and confounding factors including any on-going therapy. This case report should essentially be viewed in light of these limitations related with retrospective case reporting in Ayurveda.
7 Conclusion
Severe COVID-19 associated with respiratory distress corresponding to the high chest severity score and raised specific biomarkers like IL-6, CRP, Ferritin and D-Dimer has invariably been associated with poor outcomes. Studies have revealed that the mortality rate for Covid-19 positive critically ill patients receiving ICU care can be very high [22,23] In India although the mortality among critically ill COVID-19 patients with respiratory failure is reported to be slightly lower [24], it is expected to be of much higher value if reported correctly [25].
In this background, improved outcome in such critically ill patients, reducing complications, reduced stay in hospitals, and recovery, should be the main points of focus. An integrative strategy for hospitalised patients which uses Ayurvedic management strategies is expected to improve the outcome and minimise risk. This case report highlights that despite prolonged hospitalisation in an ICU, Ayurvedic intervention can prevent deterioration leading to complications, and enable complete recovery.
8 Patient Perspectives
Patient’s Perspectives (Excerpts from the whatsapp messages received from the patient).
I have been discharged and am finally home now after 33 days. Fresh air and evening sun reminded me that I am alive!! I have no words to express my deep gratitude to Ayurveda and to you for your kind concern, support, medical advice, motivation, wishes and prayers. I’m deeply indebted to you for this new lease of life.
I am still unable to believe that I have returned home alive. I was admitted on Nov 18, 2020 when my condition had gone worst. My SpO 2 level dipped to 64 that evening. Right from the morning I was unable to breathe. While I was in ICU-- during the first five days, I prayed to God and to doctors to allow me go home only for a day … excluding night, so that I can tell my wife about my bank account and give her legal authorisation to withdraw money from my salary account which is not a joint account. Just wanted to have last glimpse of my son and wife!! Because I started realising that my days were numbered. And on any day I would be off, especially after I was declared of having Pneumonia.
Facing death so close was rarest of experience. I virtually saw death in front of me but also felt the presence of super consciousness, or Supreme power which we call God … who pulled me out of that. So today being at home, I have no words to express myself.
Inner strength genuinely came, once I became assured that the 3 Ayurvedic medicines you gave me would actually heal my lungs infection and strengthen it. Prior to that even after taking allopathic medicines I wasn’t getting that confidence. My father in law proved it as he didn’t take any allopathic medicine as he took only Ayurvedic medicines for 7 days. I am also indebted to you for boosting my morale and your kind support, to the extent of sending me medicines from Lucknow.
9 Informed Consent
Informed Consent has been obtained from the patient regarding the initiation of Ayurveda intervention in his case. Consent has also been obtained for publication of his case report for the purpose of dissemination of knowledge among medical fraternity.
Source(s) of funding
None.
Conflict of interest
None.
Peer review under responsibility of Transdisciplinary University, Bangalore. | ASPIRIN, AZITHROMYCIN, FAVIPIRAVIR | DrugsGivenReaction | CC BY-NC-ND | 33727768 | 20,805,418 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Ayurveda co-interventions have supported complete recovery in Severe COVID- 19 infection with a Chest Severity Score 18/25: A Case Report.
Severe COVID-19 infection requiring oxygen support is reported to have high mortality. Chest Severity Score evaluated through CT scan has a predictive value about future outcomes in such cases. Score value ∼18 is predicted to have poor outcomes. We are presenting here a case of severe COVID-19 with all predictors suggestive of a bad prognosis including IL-6, D-Dimer, Ferritin and CRP in addition to 18/25 Chest Severity Score. Initially treated under ICU care at a tertiary care COVID hospital for about 14days, the patient was intervened with Ayurveda on his own insistence seeing the unsatisfactory improvements. Ayurveda intervention for 19 days along with standard ICU care resulted in complete clinical recovery of the patient besides the correction of biomarker levels. Rapid clinical and biochemical correction in this severe COVID-19 case against all odds is highly significant and warrants an urgent search for possibility of instituting the integrative management strategies for all those treated in an allopathic facility. This case also advocates an early institution of Ayurveda interventions in COVID-19 in order to prevent deterioration leading to complications.
pmc1 Introduction
Ayurveda physicians often get the opportunities to intervene in cases where modern medicine had shown limitations owing to the bad prognosis or limited treatment options. If not all, at least some of these cases eventually benefit from such interventions. A very few among these successful interventions however are documented. This non documentation of meaningful interventions in intractable conditions is largely attributed to the unfamiliarity of Ayurveda physicians with scientific writing and meticulous record keeping. Such observations of benefits however have proven to be of immense value in the lives of the beneficiaries. From research perspectives, all these observations may have a potential to act as strong cues demanding further exploration for their possible generalisation.
COVID-19 pandemic has presented numerous such opportunities before Ayurveda physicians where novelty of the disease and absence of clear cure has come as a compulsion to many for the search of other pragmatic alternatives [1]. Ayurveda physicians invariably treated many of such cases in their individual capacities and met with success in terms of reduced complications, improved recovery rate and reduced hospital stay. Such cases are treated either in an integrative model using Ayurveda in an ‘add on’ mode upon the insistence of the patients or as the stand alone therapy where Ayurveda has been instituted as the sole intervention modality. A few of such cases having variable stages of COVID-19 related pathology and treated through Ayurveda are reported in literature [2,3]. As a response to the pandemic, Ayurvedic classical literature has been critically revisited in the context and many novel propositions including rephrasing the COVID-19 patho-physiology in terms of Ayurveda has been attempted [4,5]. Many clinical trials on Ayurvedic formulations and their role in SARS-CoV-2 infection are underway and their results are eagerly awaited [6]. In this background, we present here a case of 52 year old male having severe breathlessness with COVID related Chest Severity Score (CSS) 18/25 and CT scan showing intermediate phase changes in lungs (CORADS-6) due to COVID-19 infection, diagnosed as a RT-PCR positive case of severe COVID-19 and was admitted to Intensive Care Unit of a tertiary care hospital. He constantly required oxygen support as without oxygen his SPO2 was reported as low as 64%. On the basis of various biomarkers related to the prognosis of COVID-19 infection, he was identified as severe COVID-19 case with poor prognosis. In this condition, facing the state of hopelessness with on-going care, he sought Ayurveda opinion. Upon initiation of the Ayurveda therapy along with standard ICU care while the patient was still in ICU, in next three days, he was able to breath at his own without any supplemental oxygen need for as long as 45 min. On 6th day of initiation of Ayurveda medications, he was able to breathe without additional oxygen support. Subsequent blood and biochemical investigations have shown remarkable improvement on all parameters.
Although the case was on standard COVID care in a tertiary care hospital, the improvements were not satisfactory till 16th day of his admission in the ICU. The improvements were visible only after the initiation of Ayurveda therapy. After 26 days spending in the ICU, the patient was shifted to High Dependency Unit (HDU) and was finally discharged from the hospital on 33rd day of his admission.
Improvements seen in this case after the initiation of Ayurveda therapy were remarkable and worthy of getting noticed for two obvious reasons. One is that it highlights the potential of Ayurveda interventions in many intractable conditions even when the patients are receiving ICU care. This was argued earlier also that Ayurveda should be given an access to ICUs for active treatment at least in the conditions where standard care have not shown much to offer [7]. Second and even more important message is that such cases, for their novelty, unusualness and demonstrable clinical benefits should be taken as important cues of future research. Serious clinical trials therefor should be planned to establish the feasibility of such interventions in larger population. This inference has a high significance in current pandemic where the real cures proven through robust and generalizable evidence are still awaited. Our observations as a case report are placed on record in order to see the generalizability of such interventions proven through larger systematic studies. Till such cures are in sight, any proposition offering a reduction in the morbidity and improved survival in COVID-19 seems to have a great value.
2 Patient information
This case is about a 52 year old, resident of Delhi, average built, otherwise healthy (without any known co-morbidity relevant to COVID-19) and a non-smoker male who was infected with SARS-CoV-2 infection confirmed by RT-PCR test (11.11.2020).
3 Clinical Findings
Corresponding Coronavirus disease 2019 (COVID-19) Reporting and Data System (CO-RADS) score −6 on CT scan (18.11.2020). CO-RADS 6 is strongly suggestive of lung changes due to SARS-CoV-2 infection. Chest severity score (CSS) calculated on the basis of radiological findings was found to be 18/25 which was associated with a high risk of mortality (Table 1). Since the initial onset of fever and flu like symptoms (running nose, sore throat, cough, head ache 21.10.2020) till the diagnosis of SARS-CoV-2 infection by RT-PCR test, the patient was receiving home based care inclusive of hot water drinking and gargling, steam inhalation, analgesic, antipyretic and antihistamine. In addition to this, he has received AYUSH quath and Chyawanprash as per the recommendations of Ministry of Ayush. Additional antibiotic (Azithromycin), antiviral (Favipiravir) and antiplatelet (Low dose aspirin) was added upon the SARS-CoV-2 infection confirmation. Initially there was no breathlessness but the cough and breathless gradually set in requiring a shifting of patient to DRDO-COVID Hospital, New Delhi where he was admitted in ICU (18.11.2020). Since then he was continuously kept on Oxygen as he was not able to breathe on his own without additional oxygen support. Without oxygen support, his SPO2 was reported to be as low as 64%. Blood investigations carried out on 18.11.2020 were suggestive of bad prognostic values for all the severity predictors including D-Dimer, CRP, IL-6 and Ferritin (Table 2). A high total count (17,280) was reported on 1.12.2020 indicated steroids used in the case. Despite being under standard ICU care till 2.12.2020, his condition did not improve much.Table 1 CT scan lung findings and Chest Severity Score (18.11.2020).
Table 1Lobe score (0–5)
Right upper lobe 3
Right middle lobe 3
Right lower lobe 4
Left upper lobe 4
Left lower lobe 4
CT chest severity score 18/25
There is evidence of extensive large ill-defined confluent areas of ground glass attenuation in bilateral lungs involving all the lobes with peri-broncho-vascular and peripheral sub-pleural distribution pattern and few superimposed linear fibro-atelectatic densities. Findings are suggestive of early/intermediate phase changes of Covid 19 infection (CORADS-6).
Table 2 Blood Investigations before and after Ayurveda intervention.
Table 2Parameters Units Values on 18.11.2020 (before Ayurvedic Intervention) Values on 1.12.2020 (before Ayurvedic Intervention) Values on 12.12.2020 (after Ayurvedic Intervention)
Haemoglobin g/dL 14.9 14.8 12.7
Total Leucocyte Count Cumm 5300 17,280 7700
RBC Million/cumm 6.82 – –
Platelets Lacks/cumm 1.56 4.16 1.20
Neutrophils % 84 86 70
Lymphocytes % 07 11 28
Monocytes % 08 01
Eosinophil % 01 01
Basophils % 0 0
PCV % 47.5 39.8
MCV pl 69.6 70.4
MCH pg 21.8 22.5
MCHC % 31.4 31.9
RDW % 16.8 42.9
D-Dimer Ng/ml 973.90 225.0 76.88%↓
CRP Mg/l 87.90 14.70 83.28%↓
IL-6 Pg/ml 149.40 6.53 95.63%↓
Ferritin Ng/ml 339 353.4 4.1%↑
LDH U/L – 328.8
Urea Mg/dl – 30.5 17
Creatinine Mg% – 1.06 0.89
BUN Mg% 7.94
S. Bilirubin Mg/dL – 1.15
SGOT IU/L – 21.9
SGPT IU/L – 31.7
Alkaline Phosphatase U/L – 130.60
S Sodium Mmol/L – 133 137
S Potassium Mmol/L – 3.8 4.45
4 Ayurvedic Interventions
In the state of hopelessness, he sought Ayurveda intervention. After a tele-consultation he was recommended Chausath Prahari Pippali (CPP) 500 mg twice in a day, Shringarabhra rasa (SR) 125 mg twice in a day and Amrit Bhallataka (AB) 2.5 g twice in a day. CPP and SR were started from 3.12.2020 whereas AB was started only from 6.12.2020. He continued to be in standard ICU care as usual with oxygen support. The patient reported to feel positive from the very first day of start of Ayurveda intervention. His dependency upon oxygen started reducing on the following days. From 9.12.2020 he reported to sustain without oxygen support for ∼45 min. He continued with Ayurvedic intervention along with ICU standard care. On 11.12.2020 his RT-PCR became negative. He still required oxygen support but his dependency on it continued to reduce as he was able to sustain for longer periods without additional oxygen support. On 12.12.2020 his blood investigations were carried out and most prognosis indicators of SARS-CoV-2 infection were found to be in normal range (Table 2). From 12.12.2020 he did not require any oxygen support. On 14.12.2020 he was shifted from ICU to HDU. He continued the standard care and also the Ayurveda medications. He continued to improve on following days and finally discharged from the hospital on 21.12.2020.
5 Followup and outcomes
Although, the patient was on simultaneous standard ICU and HDU care for ∼ 1 month, he largely attributed his improvements to Ayurveda interventions which were started from 2.12.2020 and continued till his discharge (19 days). A narrative of patient’s perspective of the case is appended at the end of this case report. A time line of major events in the course of illness is appended as Fig. 1.Fig. 1 Major events and their time line.
Fig. 1
6 Discussion
There has been a recent report on outcomes of Ayurvedic care in a COVID-19 patient with severe hypoxia [2]. The case presented here although observes similar outcomes, is noteworthy for two important reasons. One is that the patient here was receiving the ICU care in a tertiary care hospital for over 2 weeks and decided to add on Ayurveda interventions only when there was unsatisfactory improvement in the condition. He further had all biomarkers indicative of severity of the disease and bad prognosis. On the coronavirus disease 2019 (COVID-19) Reporting and Data System (CO-RADS) which is developed as a categorical system to assess suspicion of lung involvement by COVID-19 on chest CT scans he was found CO-RADS 6, a condition with positive RT-PCR and bilateral Ground Glass Opacity (GGO) and halo sign [8]. Chest Severity Score (CSS) which is a rapid identifier of patients with severe forms of coronavirus disease 2019 was found 18/25 in this case. A CT score of ≥18 is reported to be associated with an increased mortality risk and is found to be predictive of death both in univariate and multivariate analysis [9]. In this condition, a complete clinical recovery along with reversal of most biomarkers related to the disease severity within 19 days of initiation of Ayurveda intervention along with standard ICU and HDU care is remarkable and needs the utmost attention.
This case was treated through a vyadhipratyanik approach of Ayurveda where the disease complex is targeted in toto through specific interventions. Three medicines (CPP, SR and AB) which have been given to the case were mainly vata-kapha shamak in nature which is presumed to be the principal pathology in SARS-CoV-2 infection [4]. From Ayurveda perspectives, lungs are invariably the seat of vata and kapha. Pippali (Piper longum) as the sole ingredient in the CPP is recommended as rasayana to pranavaha srotus which is rooted in lungs [10]. SR is a highly praised drug in respiratory conditions dominated by vata –kapha pathology [11]. AB where Bhallataka (Semicarpus anacardium) is the principal component is a highly praised kapha shamak drug [12]. All these drugs recommended in the case are used in ayurvedic clinical practice since long and have not been reported with any adversity during their monitored use. Failure of standard recommendation of Ayurveda immune enhancive therapy in preventing the disease and its complications as is noted in the case is another important observation. This is observed that such recommendations in general reduce the intensity of the disease and hence promote its benign course but do not prevent the disease from occurrence in every individual [13]. Much research is still required to understand the preventive and disease modifying potential of standard Ayurveda recommendations in COVID-19.
Although vyadhi bala, rogi bala and dosha avastha should have been examined before prescribing a drug from Ayurvedic perspective, we see that in COVID-19 where consultations are largely offered in a tele-consultation mode [14] a knowledge about the roga and rogi bala is largely procured through telephonic enquiry. We adopted the similar method of disease assessment and in our case the roga and rogi both were found to be of pravara bala.
Ayurvedic physicians are often approached when the conventional health care fails to deliver what is actually desired. This is done often in the intractable cases with poor prognosis or in the conditions where the conventional approach is rejected by the patient. In many instances, such alternative interventions have resulted in improvements and cures which were not deliverable through conventional care despite of standard care approaches. Such observations have been noticed in variety of conditions including traumatic brain injury [15], Spinal cord injury [16], atonic bladder [17], Hepatic encephalopathy [7], metastatic liver disease [18] and achalasia [19].
A disease condition which was novel and was available in a pandemic proportion has given the health care systems an unprecedented opportunity to learn, to reinvent and to repurpose every bit of knowledge which could have been of help to mitigate the disease [20,21]. In the absence of a definitive cure anywhere in sight, this is natural for the people to look at alternative health care solutions. Although not utilised to the full of its potential, Ayurveda continued to show the evidence of its effectiveness in various stages of SARS-CoV-2 infection. Ayurveda responded to the pandemic initially by exploring its textual wisdom to find the clues for the disease management and subsequently it offered care to many cases who demanded individualised Ayurveda care. More clinical trials are underway and are expected to generate dependable evidences about possible role of Ayurveda in COVID-19. The observations made through such single case reports however are also significant for their possibility of getting converted into robust evidences following the systematic clinical trials. Ayurvedic case reports and clinical trials in the context of COVID-19 are also meaningful from an entirely different perspective. This is observed that the cases are treated differently following different protocols based on the individual logics and judgments. This variability of protocols reaching to successful outcomes is a clear example of versatility of Ayurveda interventions and its treatment personalisation approach.
Although valuable, such case reports in Ayurveda are inherently deficient in precise details of the disease process and changes in response to the given interventions. Being retrospective in nature, such cases in Ayurveda are largely reported only when the outcome of interest has already arrived. This implies for two important limitations of such reporting. One is that the cases where the desired outcomes are not achieved are never reported and hence the limitations of Ayurvedic interventions in unsuccessful cases do not see the light of the day. Second limitation is that a clear reasoning of intervention and its effects is always difficult to interpret in the presence of other variables and confounding factors including any on-going therapy. This case report should essentially be viewed in light of these limitations related with retrospective case reporting in Ayurveda.
7 Conclusion
Severe COVID-19 associated with respiratory distress corresponding to the high chest severity score and raised specific biomarkers like IL-6, CRP, Ferritin and D-Dimer has invariably been associated with poor outcomes. Studies have revealed that the mortality rate for Covid-19 positive critically ill patients receiving ICU care can be very high [22,23] In India although the mortality among critically ill COVID-19 patients with respiratory failure is reported to be slightly lower [24], it is expected to be of much higher value if reported correctly [25].
In this background, improved outcome in such critically ill patients, reducing complications, reduced stay in hospitals, and recovery, should be the main points of focus. An integrative strategy for hospitalised patients which uses Ayurvedic management strategies is expected to improve the outcome and minimise risk. This case report highlights that despite prolonged hospitalisation in an ICU, Ayurvedic intervention can prevent deterioration leading to complications, and enable complete recovery.
8 Patient Perspectives
Patient’s Perspectives (Excerpts from the whatsapp messages received from the patient).
I have been discharged and am finally home now after 33 days. Fresh air and evening sun reminded me that I am alive!! I have no words to express my deep gratitude to Ayurveda and to you for your kind concern, support, medical advice, motivation, wishes and prayers. I’m deeply indebted to you for this new lease of life.
I am still unable to believe that I have returned home alive. I was admitted on Nov 18, 2020 when my condition had gone worst. My SpO 2 level dipped to 64 that evening. Right from the morning I was unable to breathe. While I was in ICU-- during the first five days, I prayed to God and to doctors to allow me go home only for a day … excluding night, so that I can tell my wife about my bank account and give her legal authorisation to withdraw money from my salary account which is not a joint account. Just wanted to have last glimpse of my son and wife!! Because I started realising that my days were numbered. And on any day I would be off, especially after I was declared of having Pneumonia.
Facing death so close was rarest of experience. I virtually saw death in front of me but also felt the presence of super consciousness, or Supreme power which we call God … who pulled me out of that. So today being at home, I have no words to express myself.
Inner strength genuinely came, once I became assured that the 3 Ayurvedic medicines you gave me would actually heal my lungs infection and strengthen it. Prior to that even after taking allopathic medicines I wasn’t getting that confidence. My father in law proved it as he didn’t take any allopathic medicine as he took only Ayurvedic medicines for 7 days. I am also indebted to you for boosting my morale and your kind support, to the extent of sending me medicines from Lucknow.
9 Informed Consent
Informed Consent has been obtained from the patient regarding the initiation of Ayurveda intervention in his case. Consent has also been obtained for publication of his case report for the purpose of dissemination of knowledge among medical fraternity.
Source(s) of funding
None.
Conflict of interest
None.
Peer review under responsibility of Transdisciplinary University, Bangalore. | ASPIRIN, AZITHROMYCIN, BLACK PEPPER, FAVIPIRAVIR | DrugsGivenReaction | CC BY-NC-ND | 33727768 | 20,802,296 | 2021-03-12 |
What was the dosage of drug 'ASPIRIN'? | Ayurveda co-interventions have supported complete recovery in Severe COVID- 19 infection with a Chest Severity Score 18/25: A Case Report.
Severe COVID-19 infection requiring oxygen support is reported to have high mortality. Chest Severity Score evaluated through CT scan has a predictive value about future outcomes in such cases. Score value ∼18 is predicted to have poor outcomes. We are presenting here a case of severe COVID-19 with all predictors suggestive of a bad prognosis including IL-6, D-Dimer, Ferritin and CRP in addition to 18/25 Chest Severity Score. Initially treated under ICU care at a tertiary care COVID hospital for about 14days, the patient was intervened with Ayurveda on his own insistence seeing the unsatisfactory improvements. Ayurveda intervention for 19 days along with standard ICU care resulted in complete clinical recovery of the patient besides the correction of biomarker levels. Rapid clinical and biochemical correction in this severe COVID-19 case against all odds is highly significant and warrants an urgent search for possibility of instituting the integrative management strategies for all those treated in an allopathic facility. This case also advocates an early institution of Ayurveda interventions in COVID-19 in order to prevent deterioration leading to complications.
pmc1 Introduction
Ayurveda physicians often get the opportunities to intervene in cases where modern medicine had shown limitations owing to the bad prognosis or limited treatment options. If not all, at least some of these cases eventually benefit from such interventions. A very few among these successful interventions however are documented. This non documentation of meaningful interventions in intractable conditions is largely attributed to the unfamiliarity of Ayurveda physicians with scientific writing and meticulous record keeping. Such observations of benefits however have proven to be of immense value in the lives of the beneficiaries. From research perspectives, all these observations may have a potential to act as strong cues demanding further exploration for their possible generalisation.
COVID-19 pandemic has presented numerous such opportunities before Ayurveda physicians where novelty of the disease and absence of clear cure has come as a compulsion to many for the search of other pragmatic alternatives [1]. Ayurveda physicians invariably treated many of such cases in their individual capacities and met with success in terms of reduced complications, improved recovery rate and reduced hospital stay. Such cases are treated either in an integrative model using Ayurveda in an ‘add on’ mode upon the insistence of the patients or as the stand alone therapy where Ayurveda has been instituted as the sole intervention modality. A few of such cases having variable stages of COVID-19 related pathology and treated through Ayurveda are reported in literature [2,3]. As a response to the pandemic, Ayurvedic classical literature has been critically revisited in the context and many novel propositions including rephrasing the COVID-19 patho-physiology in terms of Ayurveda has been attempted [4,5]. Many clinical trials on Ayurvedic formulations and their role in SARS-CoV-2 infection are underway and their results are eagerly awaited [6]. In this background, we present here a case of 52 year old male having severe breathlessness with COVID related Chest Severity Score (CSS) 18/25 and CT scan showing intermediate phase changes in lungs (CORADS-6) due to COVID-19 infection, diagnosed as a RT-PCR positive case of severe COVID-19 and was admitted to Intensive Care Unit of a tertiary care hospital. He constantly required oxygen support as without oxygen his SPO2 was reported as low as 64%. On the basis of various biomarkers related to the prognosis of COVID-19 infection, he was identified as severe COVID-19 case with poor prognosis. In this condition, facing the state of hopelessness with on-going care, he sought Ayurveda opinion. Upon initiation of the Ayurveda therapy along with standard ICU care while the patient was still in ICU, in next three days, he was able to breath at his own without any supplemental oxygen need for as long as 45 min. On 6th day of initiation of Ayurveda medications, he was able to breathe without additional oxygen support. Subsequent blood and biochemical investigations have shown remarkable improvement on all parameters.
Although the case was on standard COVID care in a tertiary care hospital, the improvements were not satisfactory till 16th day of his admission in the ICU. The improvements were visible only after the initiation of Ayurveda therapy. After 26 days spending in the ICU, the patient was shifted to High Dependency Unit (HDU) and was finally discharged from the hospital on 33rd day of his admission.
Improvements seen in this case after the initiation of Ayurveda therapy were remarkable and worthy of getting noticed for two obvious reasons. One is that it highlights the potential of Ayurveda interventions in many intractable conditions even when the patients are receiving ICU care. This was argued earlier also that Ayurveda should be given an access to ICUs for active treatment at least in the conditions where standard care have not shown much to offer [7]. Second and even more important message is that such cases, for their novelty, unusualness and demonstrable clinical benefits should be taken as important cues of future research. Serious clinical trials therefor should be planned to establish the feasibility of such interventions in larger population. This inference has a high significance in current pandemic where the real cures proven through robust and generalizable evidence are still awaited. Our observations as a case report are placed on record in order to see the generalizability of such interventions proven through larger systematic studies. Till such cures are in sight, any proposition offering a reduction in the morbidity and improved survival in COVID-19 seems to have a great value.
2 Patient information
This case is about a 52 year old, resident of Delhi, average built, otherwise healthy (without any known co-morbidity relevant to COVID-19) and a non-smoker male who was infected with SARS-CoV-2 infection confirmed by RT-PCR test (11.11.2020).
3 Clinical Findings
Corresponding Coronavirus disease 2019 (COVID-19) Reporting and Data System (CO-RADS) score −6 on CT scan (18.11.2020). CO-RADS 6 is strongly suggestive of lung changes due to SARS-CoV-2 infection. Chest severity score (CSS) calculated on the basis of radiological findings was found to be 18/25 which was associated with a high risk of mortality (Table 1). Since the initial onset of fever and flu like symptoms (running nose, sore throat, cough, head ache 21.10.2020) till the diagnosis of SARS-CoV-2 infection by RT-PCR test, the patient was receiving home based care inclusive of hot water drinking and gargling, steam inhalation, analgesic, antipyretic and antihistamine. In addition to this, he has received AYUSH quath and Chyawanprash as per the recommendations of Ministry of Ayush. Additional antibiotic (Azithromycin), antiviral (Favipiravir) and antiplatelet (Low dose aspirin) was added upon the SARS-CoV-2 infection confirmation. Initially there was no breathlessness but the cough and breathless gradually set in requiring a shifting of patient to DRDO-COVID Hospital, New Delhi where he was admitted in ICU (18.11.2020). Since then he was continuously kept on Oxygen as he was not able to breathe on his own without additional oxygen support. Without oxygen support, his SPO2 was reported to be as low as 64%. Blood investigations carried out on 18.11.2020 were suggestive of bad prognostic values for all the severity predictors including D-Dimer, CRP, IL-6 and Ferritin (Table 2). A high total count (17,280) was reported on 1.12.2020 indicated steroids used in the case. Despite being under standard ICU care till 2.12.2020, his condition did not improve much.Table 1 CT scan lung findings and Chest Severity Score (18.11.2020).
Table 1Lobe score (0–5)
Right upper lobe 3
Right middle lobe 3
Right lower lobe 4
Left upper lobe 4
Left lower lobe 4
CT chest severity score 18/25
There is evidence of extensive large ill-defined confluent areas of ground glass attenuation in bilateral lungs involving all the lobes with peri-broncho-vascular and peripheral sub-pleural distribution pattern and few superimposed linear fibro-atelectatic densities. Findings are suggestive of early/intermediate phase changes of Covid 19 infection (CORADS-6).
Table 2 Blood Investigations before and after Ayurveda intervention.
Table 2Parameters Units Values on 18.11.2020 (before Ayurvedic Intervention) Values on 1.12.2020 (before Ayurvedic Intervention) Values on 12.12.2020 (after Ayurvedic Intervention)
Haemoglobin g/dL 14.9 14.8 12.7
Total Leucocyte Count Cumm 5300 17,280 7700
RBC Million/cumm 6.82 – –
Platelets Lacks/cumm 1.56 4.16 1.20
Neutrophils % 84 86 70
Lymphocytes % 07 11 28
Monocytes % 08 01
Eosinophil % 01 01
Basophils % 0 0
PCV % 47.5 39.8
MCV pl 69.6 70.4
MCH pg 21.8 22.5
MCHC % 31.4 31.9
RDW % 16.8 42.9
D-Dimer Ng/ml 973.90 225.0 76.88%↓
CRP Mg/l 87.90 14.70 83.28%↓
IL-6 Pg/ml 149.40 6.53 95.63%↓
Ferritin Ng/ml 339 353.4 4.1%↑
LDH U/L – 328.8
Urea Mg/dl – 30.5 17
Creatinine Mg% – 1.06 0.89
BUN Mg% 7.94
S. Bilirubin Mg/dL – 1.15
SGOT IU/L – 21.9
SGPT IU/L – 31.7
Alkaline Phosphatase U/L – 130.60
S Sodium Mmol/L – 133 137
S Potassium Mmol/L – 3.8 4.45
4 Ayurvedic Interventions
In the state of hopelessness, he sought Ayurveda intervention. After a tele-consultation he was recommended Chausath Prahari Pippali (CPP) 500 mg twice in a day, Shringarabhra rasa (SR) 125 mg twice in a day and Amrit Bhallataka (AB) 2.5 g twice in a day. CPP and SR were started from 3.12.2020 whereas AB was started only from 6.12.2020. He continued to be in standard ICU care as usual with oxygen support. The patient reported to feel positive from the very first day of start of Ayurveda intervention. His dependency upon oxygen started reducing on the following days. From 9.12.2020 he reported to sustain without oxygen support for ∼45 min. He continued with Ayurvedic intervention along with ICU standard care. On 11.12.2020 his RT-PCR became negative. He still required oxygen support but his dependency on it continued to reduce as he was able to sustain for longer periods without additional oxygen support. On 12.12.2020 his blood investigations were carried out and most prognosis indicators of SARS-CoV-2 infection were found to be in normal range (Table 2). From 12.12.2020 he did not require any oxygen support. On 14.12.2020 he was shifted from ICU to HDU. He continued the standard care and also the Ayurveda medications. He continued to improve on following days and finally discharged from the hospital on 21.12.2020.
5 Followup and outcomes
Although, the patient was on simultaneous standard ICU and HDU care for ∼ 1 month, he largely attributed his improvements to Ayurveda interventions which were started from 2.12.2020 and continued till his discharge (19 days). A narrative of patient’s perspective of the case is appended at the end of this case report. A time line of major events in the course of illness is appended as Fig. 1.Fig. 1 Major events and their time line.
Fig. 1
6 Discussion
There has been a recent report on outcomes of Ayurvedic care in a COVID-19 patient with severe hypoxia [2]. The case presented here although observes similar outcomes, is noteworthy for two important reasons. One is that the patient here was receiving the ICU care in a tertiary care hospital for over 2 weeks and decided to add on Ayurveda interventions only when there was unsatisfactory improvement in the condition. He further had all biomarkers indicative of severity of the disease and bad prognosis. On the coronavirus disease 2019 (COVID-19) Reporting and Data System (CO-RADS) which is developed as a categorical system to assess suspicion of lung involvement by COVID-19 on chest CT scans he was found CO-RADS 6, a condition with positive RT-PCR and bilateral Ground Glass Opacity (GGO) and halo sign [8]. Chest Severity Score (CSS) which is a rapid identifier of patients with severe forms of coronavirus disease 2019 was found 18/25 in this case. A CT score of ≥18 is reported to be associated with an increased mortality risk and is found to be predictive of death both in univariate and multivariate analysis [9]. In this condition, a complete clinical recovery along with reversal of most biomarkers related to the disease severity within 19 days of initiation of Ayurveda intervention along with standard ICU and HDU care is remarkable and needs the utmost attention.
This case was treated through a vyadhipratyanik approach of Ayurveda where the disease complex is targeted in toto through specific interventions. Three medicines (CPP, SR and AB) which have been given to the case were mainly vata-kapha shamak in nature which is presumed to be the principal pathology in SARS-CoV-2 infection [4]. From Ayurveda perspectives, lungs are invariably the seat of vata and kapha. Pippali (Piper longum) as the sole ingredient in the CPP is recommended as rasayana to pranavaha srotus which is rooted in lungs [10]. SR is a highly praised drug in respiratory conditions dominated by vata –kapha pathology [11]. AB where Bhallataka (Semicarpus anacardium) is the principal component is a highly praised kapha shamak drug [12]. All these drugs recommended in the case are used in ayurvedic clinical practice since long and have not been reported with any adversity during their monitored use. Failure of standard recommendation of Ayurveda immune enhancive therapy in preventing the disease and its complications as is noted in the case is another important observation. This is observed that such recommendations in general reduce the intensity of the disease and hence promote its benign course but do not prevent the disease from occurrence in every individual [13]. Much research is still required to understand the preventive and disease modifying potential of standard Ayurveda recommendations in COVID-19.
Although vyadhi bala, rogi bala and dosha avastha should have been examined before prescribing a drug from Ayurvedic perspective, we see that in COVID-19 where consultations are largely offered in a tele-consultation mode [14] a knowledge about the roga and rogi bala is largely procured through telephonic enquiry. We adopted the similar method of disease assessment and in our case the roga and rogi both were found to be of pravara bala.
Ayurvedic physicians are often approached when the conventional health care fails to deliver what is actually desired. This is done often in the intractable cases with poor prognosis or in the conditions where the conventional approach is rejected by the patient. In many instances, such alternative interventions have resulted in improvements and cures which were not deliverable through conventional care despite of standard care approaches. Such observations have been noticed in variety of conditions including traumatic brain injury [15], Spinal cord injury [16], atonic bladder [17], Hepatic encephalopathy [7], metastatic liver disease [18] and achalasia [19].
A disease condition which was novel and was available in a pandemic proportion has given the health care systems an unprecedented opportunity to learn, to reinvent and to repurpose every bit of knowledge which could have been of help to mitigate the disease [20,21]. In the absence of a definitive cure anywhere in sight, this is natural for the people to look at alternative health care solutions. Although not utilised to the full of its potential, Ayurveda continued to show the evidence of its effectiveness in various stages of SARS-CoV-2 infection. Ayurveda responded to the pandemic initially by exploring its textual wisdom to find the clues for the disease management and subsequently it offered care to many cases who demanded individualised Ayurveda care. More clinical trials are underway and are expected to generate dependable evidences about possible role of Ayurveda in COVID-19. The observations made through such single case reports however are also significant for their possibility of getting converted into robust evidences following the systematic clinical trials. Ayurvedic case reports and clinical trials in the context of COVID-19 are also meaningful from an entirely different perspective. This is observed that the cases are treated differently following different protocols based on the individual logics and judgments. This variability of protocols reaching to successful outcomes is a clear example of versatility of Ayurveda interventions and its treatment personalisation approach.
Although valuable, such case reports in Ayurveda are inherently deficient in precise details of the disease process and changes in response to the given interventions. Being retrospective in nature, such cases in Ayurveda are largely reported only when the outcome of interest has already arrived. This implies for two important limitations of such reporting. One is that the cases where the desired outcomes are not achieved are never reported and hence the limitations of Ayurvedic interventions in unsuccessful cases do not see the light of the day. Second limitation is that a clear reasoning of intervention and its effects is always difficult to interpret in the presence of other variables and confounding factors including any on-going therapy. This case report should essentially be viewed in light of these limitations related with retrospective case reporting in Ayurveda.
7 Conclusion
Severe COVID-19 associated with respiratory distress corresponding to the high chest severity score and raised specific biomarkers like IL-6, CRP, Ferritin and D-Dimer has invariably been associated with poor outcomes. Studies have revealed that the mortality rate for Covid-19 positive critically ill patients receiving ICU care can be very high [22,23] In India although the mortality among critically ill COVID-19 patients with respiratory failure is reported to be slightly lower [24], it is expected to be of much higher value if reported correctly [25].
In this background, improved outcome in such critically ill patients, reducing complications, reduced stay in hospitals, and recovery, should be the main points of focus. An integrative strategy for hospitalised patients which uses Ayurvedic management strategies is expected to improve the outcome and minimise risk. This case report highlights that despite prolonged hospitalisation in an ICU, Ayurvedic intervention can prevent deterioration leading to complications, and enable complete recovery.
8 Patient Perspectives
Patient’s Perspectives (Excerpts from the whatsapp messages received from the patient).
I have been discharged and am finally home now after 33 days. Fresh air and evening sun reminded me that I am alive!! I have no words to express my deep gratitude to Ayurveda and to you for your kind concern, support, medical advice, motivation, wishes and prayers. I’m deeply indebted to you for this new lease of life.
I am still unable to believe that I have returned home alive. I was admitted on Nov 18, 2020 when my condition had gone worst. My SpO 2 level dipped to 64 that evening. Right from the morning I was unable to breathe. While I was in ICU-- during the first five days, I prayed to God and to doctors to allow me go home only for a day … excluding night, so that I can tell my wife about my bank account and give her legal authorisation to withdraw money from my salary account which is not a joint account. Just wanted to have last glimpse of my son and wife!! Because I started realising that my days were numbered. And on any day I would be off, especially after I was declared of having Pneumonia.
Facing death so close was rarest of experience. I virtually saw death in front of me but also felt the presence of super consciousness, or Supreme power which we call God … who pulled me out of that. So today being at home, I have no words to express myself.
Inner strength genuinely came, once I became assured that the 3 Ayurvedic medicines you gave me would actually heal my lungs infection and strengthen it. Prior to that even after taking allopathic medicines I wasn’t getting that confidence. My father in law proved it as he didn’t take any allopathic medicine as he took only Ayurvedic medicines for 7 days. I am also indebted to you for boosting my morale and your kind support, to the extent of sending me medicines from Lucknow.
9 Informed Consent
Informed Consent has been obtained from the patient regarding the initiation of Ayurveda intervention in his case. Consent has also been obtained for publication of his case report for the purpose of dissemination of knowledge among medical fraternity.
Source(s) of funding
None.
Conflict of interest
None.
Peer review under responsibility of Transdisciplinary University, Bangalore. | UNK (LOW DOSE) | DrugDosageText | CC BY-NC-ND | 33727768 | 20,802,296 | 2021-03-12 |
What was the dosage of drug 'BLACK PEPPER'? | Ayurveda co-interventions have supported complete recovery in Severe COVID- 19 infection with a Chest Severity Score 18/25: A Case Report.
Severe COVID-19 infection requiring oxygen support is reported to have high mortality. Chest Severity Score evaluated through CT scan has a predictive value about future outcomes in such cases. Score value ∼18 is predicted to have poor outcomes. We are presenting here a case of severe COVID-19 with all predictors suggestive of a bad prognosis including IL-6, D-Dimer, Ferritin and CRP in addition to 18/25 Chest Severity Score. Initially treated under ICU care at a tertiary care COVID hospital for about 14days, the patient was intervened with Ayurveda on his own insistence seeing the unsatisfactory improvements. Ayurveda intervention for 19 days along with standard ICU care resulted in complete clinical recovery of the patient besides the correction of biomarker levels. Rapid clinical and biochemical correction in this severe COVID-19 case against all odds is highly significant and warrants an urgent search for possibility of instituting the integrative management strategies for all those treated in an allopathic facility. This case also advocates an early institution of Ayurveda interventions in COVID-19 in order to prevent deterioration leading to complications.
pmc1 Introduction
Ayurveda physicians often get the opportunities to intervene in cases where modern medicine had shown limitations owing to the bad prognosis or limited treatment options. If not all, at least some of these cases eventually benefit from such interventions. A very few among these successful interventions however are documented. This non documentation of meaningful interventions in intractable conditions is largely attributed to the unfamiliarity of Ayurveda physicians with scientific writing and meticulous record keeping. Such observations of benefits however have proven to be of immense value in the lives of the beneficiaries. From research perspectives, all these observations may have a potential to act as strong cues demanding further exploration for their possible generalisation.
COVID-19 pandemic has presented numerous such opportunities before Ayurveda physicians where novelty of the disease and absence of clear cure has come as a compulsion to many for the search of other pragmatic alternatives [1]. Ayurveda physicians invariably treated many of such cases in their individual capacities and met with success in terms of reduced complications, improved recovery rate and reduced hospital stay. Such cases are treated either in an integrative model using Ayurveda in an ‘add on’ mode upon the insistence of the patients or as the stand alone therapy where Ayurveda has been instituted as the sole intervention modality. A few of such cases having variable stages of COVID-19 related pathology and treated through Ayurveda are reported in literature [2,3]. As a response to the pandemic, Ayurvedic classical literature has been critically revisited in the context and many novel propositions including rephrasing the COVID-19 patho-physiology in terms of Ayurveda has been attempted [4,5]. Many clinical trials on Ayurvedic formulations and their role in SARS-CoV-2 infection are underway and their results are eagerly awaited [6]. In this background, we present here a case of 52 year old male having severe breathlessness with COVID related Chest Severity Score (CSS) 18/25 and CT scan showing intermediate phase changes in lungs (CORADS-6) due to COVID-19 infection, diagnosed as a RT-PCR positive case of severe COVID-19 and was admitted to Intensive Care Unit of a tertiary care hospital. He constantly required oxygen support as without oxygen his SPO2 was reported as low as 64%. On the basis of various biomarkers related to the prognosis of COVID-19 infection, he was identified as severe COVID-19 case with poor prognosis. In this condition, facing the state of hopelessness with on-going care, he sought Ayurveda opinion. Upon initiation of the Ayurveda therapy along with standard ICU care while the patient was still in ICU, in next three days, he was able to breath at his own without any supplemental oxygen need for as long as 45 min. On 6th day of initiation of Ayurveda medications, he was able to breathe without additional oxygen support. Subsequent blood and biochemical investigations have shown remarkable improvement on all parameters.
Although the case was on standard COVID care in a tertiary care hospital, the improvements were not satisfactory till 16th day of his admission in the ICU. The improvements were visible only after the initiation of Ayurveda therapy. After 26 days spending in the ICU, the patient was shifted to High Dependency Unit (HDU) and was finally discharged from the hospital on 33rd day of his admission.
Improvements seen in this case after the initiation of Ayurveda therapy were remarkable and worthy of getting noticed for two obvious reasons. One is that it highlights the potential of Ayurveda interventions in many intractable conditions even when the patients are receiving ICU care. This was argued earlier also that Ayurveda should be given an access to ICUs for active treatment at least in the conditions where standard care have not shown much to offer [7]. Second and even more important message is that such cases, for their novelty, unusualness and demonstrable clinical benefits should be taken as important cues of future research. Serious clinical trials therefor should be planned to establish the feasibility of such interventions in larger population. This inference has a high significance in current pandemic where the real cures proven through robust and generalizable evidence are still awaited. Our observations as a case report are placed on record in order to see the generalizability of such interventions proven through larger systematic studies. Till such cures are in sight, any proposition offering a reduction in the morbidity and improved survival in COVID-19 seems to have a great value.
2 Patient information
This case is about a 52 year old, resident of Delhi, average built, otherwise healthy (without any known co-morbidity relevant to COVID-19) and a non-smoker male who was infected with SARS-CoV-2 infection confirmed by RT-PCR test (11.11.2020).
3 Clinical Findings
Corresponding Coronavirus disease 2019 (COVID-19) Reporting and Data System (CO-RADS) score −6 on CT scan (18.11.2020). CO-RADS 6 is strongly suggestive of lung changes due to SARS-CoV-2 infection. Chest severity score (CSS) calculated on the basis of radiological findings was found to be 18/25 which was associated with a high risk of mortality (Table 1). Since the initial onset of fever and flu like symptoms (running nose, sore throat, cough, head ache 21.10.2020) till the diagnosis of SARS-CoV-2 infection by RT-PCR test, the patient was receiving home based care inclusive of hot water drinking and gargling, steam inhalation, analgesic, antipyretic and antihistamine. In addition to this, he has received AYUSH quath and Chyawanprash as per the recommendations of Ministry of Ayush. Additional antibiotic (Azithromycin), antiviral (Favipiravir) and antiplatelet (Low dose aspirin) was added upon the SARS-CoV-2 infection confirmation. Initially there was no breathlessness but the cough and breathless gradually set in requiring a shifting of patient to DRDO-COVID Hospital, New Delhi where he was admitted in ICU (18.11.2020). Since then he was continuously kept on Oxygen as he was not able to breathe on his own without additional oxygen support. Without oxygen support, his SPO2 was reported to be as low as 64%. Blood investigations carried out on 18.11.2020 were suggestive of bad prognostic values for all the severity predictors including D-Dimer, CRP, IL-6 and Ferritin (Table 2). A high total count (17,280) was reported on 1.12.2020 indicated steroids used in the case. Despite being under standard ICU care till 2.12.2020, his condition did not improve much.Table 1 CT scan lung findings and Chest Severity Score (18.11.2020).
Table 1Lobe score (0–5)
Right upper lobe 3
Right middle lobe 3
Right lower lobe 4
Left upper lobe 4
Left lower lobe 4
CT chest severity score 18/25
There is evidence of extensive large ill-defined confluent areas of ground glass attenuation in bilateral lungs involving all the lobes with peri-broncho-vascular and peripheral sub-pleural distribution pattern and few superimposed linear fibro-atelectatic densities. Findings are suggestive of early/intermediate phase changes of Covid 19 infection (CORADS-6).
Table 2 Blood Investigations before and after Ayurveda intervention.
Table 2Parameters Units Values on 18.11.2020 (before Ayurvedic Intervention) Values on 1.12.2020 (before Ayurvedic Intervention) Values on 12.12.2020 (after Ayurvedic Intervention)
Haemoglobin g/dL 14.9 14.8 12.7
Total Leucocyte Count Cumm 5300 17,280 7700
RBC Million/cumm 6.82 – –
Platelets Lacks/cumm 1.56 4.16 1.20
Neutrophils % 84 86 70
Lymphocytes % 07 11 28
Monocytes % 08 01
Eosinophil % 01 01
Basophils % 0 0
PCV % 47.5 39.8
MCV pl 69.6 70.4
MCH pg 21.8 22.5
MCHC % 31.4 31.9
RDW % 16.8 42.9
D-Dimer Ng/ml 973.90 225.0 76.88%↓
CRP Mg/l 87.90 14.70 83.28%↓
IL-6 Pg/ml 149.40 6.53 95.63%↓
Ferritin Ng/ml 339 353.4 4.1%↑
LDH U/L – 328.8
Urea Mg/dl – 30.5 17
Creatinine Mg% – 1.06 0.89
BUN Mg% 7.94
S. Bilirubin Mg/dL – 1.15
SGOT IU/L – 21.9
SGPT IU/L – 31.7
Alkaline Phosphatase U/L – 130.60
S Sodium Mmol/L – 133 137
S Potassium Mmol/L – 3.8 4.45
4 Ayurvedic Interventions
In the state of hopelessness, he sought Ayurveda intervention. After a tele-consultation he was recommended Chausath Prahari Pippali (CPP) 500 mg twice in a day, Shringarabhra rasa (SR) 125 mg twice in a day and Amrit Bhallataka (AB) 2.5 g twice in a day. CPP and SR were started from 3.12.2020 whereas AB was started only from 6.12.2020. He continued to be in standard ICU care as usual with oxygen support. The patient reported to feel positive from the very first day of start of Ayurveda intervention. His dependency upon oxygen started reducing on the following days. From 9.12.2020 he reported to sustain without oxygen support for ∼45 min. He continued with Ayurvedic intervention along with ICU standard care. On 11.12.2020 his RT-PCR became negative. He still required oxygen support but his dependency on it continued to reduce as he was able to sustain for longer periods without additional oxygen support. On 12.12.2020 his blood investigations were carried out and most prognosis indicators of SARS-CoV-2 infection were found to be in normal range (Table 2). From 12.12.2020 he did not require any oxygen support. On 14.12.2020 he was shifted from ICU to HDU. He continued the standard care and also the Ayurveda medications. He continued to improve on following days and finally discharged from the hospital on 21.12.2020.
5 Followup and outcomes
Although, the patient was on simultaneous standard ICU and HDU care for ∼ 1 month, he largely attributed his improvements to Ayurveda interventions which were started from 2.12.2020 and continued till his discharge (19 days). A narrative of patient’s perspective of the case is appended at the end of this case report. A time line of major events in the course of illness is appended as Fig. 1.Fig. 1 Major events and their time line.
Fig. 1
6 Discussion
There has been a recent report on outcomes of Ayurvedic care in a COVID-19 patient with severe hypoxia [2]. The case presented here although observes similar outcomes, is noteworthy for two important reasons. One is that the patient here was receiving the ICU care in a tertiary care hospital for over 2 weeks and decided to add on Ayurveda interventions only when there was unsatisfactory improvement in the condition. He further had all biomarkers indicative of severity of the disease and bad prognosis. On the coronavirus disease 2019 (COVID-19) Reporting and Data System (CO-RADS) which is developed as a categorical system to assess suspicion of lung involvement by COVID-19 on chest CT scans he was found CO-RADS 6, a condition with positive RT-PCR and bilateral Ground Glass Opacity (GGO) and halo sign [8]. Chest Severity Score (CSS) which is a rapid identifier of patients with severe forms of coronavirus disease 2019 was found 18/25 in this case. A CT score of ≥18 is reported to be associated with an increased mortality risk and is found to be predictive of death both in univariate and multivariate analysis [9]. In this condition, a complete clinical recovery along with reversal of most biomarkers related to the disease severity within 19 days of initiation of Ayurveda intervention along with standard ICU and HDU care is remarkable and needs the utmost attention.
This case was treated through a vyadhipratyanik approach of Ayurveda where the disease complex is targeted in toto through specific interventions. Three medicines (CPP, SR and AB) which have been given to the case were mainly vata-kapha shamak in nature which is presumed to be the principal pathology in SARS-CoV-2 infection [4]. From Ayurveda perspectives, lungs are invariably the seat of vata and kapha. Pippali (Piper longum) as the sole ingredient in the CPP is recommended as rasayana to pranavaha srotus which is rooted in lungs [10]. SR is a highly praised drug in respiratory conditions dominated by vata –kapha pathology [11]. AB where Bhallataka (Semicarpus anacardium) is the principal component is a highly praised kapha shamak drug [12]. All these drugs recommended in the case are used in ayurvedic clinical practice since long and have not been reported with any adversity during their monitored use. Failure of standard recommendation of Ayurveda immune enhancive therapy in preventing the disease and its complications as is noted in the case is another important observation. This is observed that such recommendations in general reduce the intensity of the disease and hence promote its benign course but do not prevent the disease from occurrence in every individual [13]. Much research is still required to understand the preventive and disease modifying potential of standard Ayurveda recommendations in COVID-19.
Although vyadhi bala, rogi bala and dosha avastha should have been examined before prescribing a drug from Ayurvedic perspective, we see that in COVID-19 where consultations are largely offered in a tele-consultation mode [14] a knowledge about the roga and rogi bala is largely procured through telephonic enquiry. We adopted the similar method of disease assessment and in our case the roga and rogi both were found to be of pravara bala.
Ayurvedic physicians are often approached when the conventional health care fails to deliver what is actually desired. This is done often in the intractable cases with poor prognosis or in the conditions where the conventional approach is rejected by the patient. In many instances, such alternative interventions have resulted in improvements and cures which were not deliverable through conventional care despite of standard care approaches. Such observations have been noticed in variety of conditions including traumatic brain injury [15], Spinal cord injury [16], atonic bladder [17], Hepatic encephalopathy [7], metastatic liver disease [18] and achalasia [19].
A disease condition which was novel and was available in a pandemic proportion has given the health care systems an unprecedented opportunity to learn, to reinvent and to repurpose every bit of knowledge which could have been of help to mitigate the disease [20,21]. In the absence of a definitive cure anywhere in sight, this is natural for the people to look at alternative health care solutions. Although not utilised to the full of its potential, Ayurveda continued to show the evidence of its effectiveness in various stages of SARS-CoV-2 infection. Ayurveda responded to the pandemic initially by exploring its textual wisdom to find the clues for the disease management and subsequently it offered care to many cases who demanded individualised Ayurveda care. More clinical trials are underway and are expected to generate dependable evidences about possible role of Ayurveda in COVID-19. The observations made through such single case reports however are also significant for their possibility of getting converted into robust evidences following the systematic clinical trials. Ayurvedic case reports and clinical trials in the context of COVID-19 are also meaningful from an entirely different perspective. This is observed that the cases are treated differently following different protocols based on the individual logics and judgments. This variability of protocols reaching to successful outcomes is a clear example of versatility of Ayurveda interventions and its treatment personalisation approach.
Although valuable, such case reports in Ayurveda are inherently deficient in precise details of the disease process and changes in response to the given interventions. Being retrospective in nature, such cases in Ayurveda are largely reported only when the outcome of interest has already arrived. This implies for two important limitations of such reporting. One is that the cases where the desired outcomes are not achieved are never reported and hence the limitations of Ayurvedic interventions in unsuccessful cases do not see the light of the day. Second limitation is that a clear reasoning of intervention and its effects is always difficult to interpret in the presence of other variables and confounding factors including any on-going therapy. This case report should essentially be viewed in light of these limitations related with retrospective case reporting in Ayurveda.
7 Conclusion
Severe COVID-19 associated with respiratory distress corresponding to the high chest severity score and raised specific biomarkers like IL-6, CRP, Ferritin and D-Dimer has invariably been associated with poor outcomes. Studies have revealed that the mortality rate for Covid-19 positive critically ill patients receiving ICU care can be very high [22,23] In India although the mortality among critically ill COVID-19 patients with respiratory failure is reported to be slightly lower [24], it is expected to be of much higher value if reported correctly [25].
In this background, improved outcome in such critically ill patients, reducing complications, reduced stay in hospitals, and recovery, should be the main points of focus. An integrative strategy for hospitalised patients which uses Ayurvedic management strategies is expected to improve the outcome and minimise risk. This case report highlights that despite prolonged hospitalisation in an ICU, Ayurvedic intervention can prevent deterioration leading to complications, and enable complete recovery.
8 Patient Perspectives
Patient’s Perspectives (Excerpts from the whatsapp messages received from the patient).
I have been discharged and am finally home now after 33 days. Fresh air and evening sun reminded me that I am alive!! I have no words to express my deep gratitude to Ayurveda and to you for your kind concern, support, medical advice, motivation, wishes and prayers. I’m deeply indebted to you for this new lease of life.
I am still unable to believe that I have returned home alive. I was admitted on Nov 18, 2020 when my condition had gone worst. My SpO 2 level dipped to 64 that evening. Right from the morning I was unable to breathe. While I was in ICU-- during the first five days, I prayed to God and to doctors to allow me go home only for a day … excluding night, so that I can tell my wife about my bank account and give her legal authorisation to withdraw money from my salary account which is not a joint account. Just wanted to have last glimpse of my son and wife!! Because I started realising that my days were numbered. And on any day I would be off, especially after I was declared of having Pneumonia.
Facing death so close was rarest of experience. I virtually saw death in front of me but also felt the presence of super consciousness, or Supreme power which we call God … who pulled me out of that. So today being at home, I have no words to express myself.
Inner strength genuinely came, once I became assured that the 3 Ayurvedic medicines you gave me would actually heal my lungs infection and strengthen it. Prior to that even after taking allopathic medicines I wasn’t getting that confidence. My father in law proved it as he didn’t take any allopathic medicine as he took only Ayurvedic medicines for 7 days. I am also indebted to you for boosting my morale and your kind support, to the extent of sending me medicines from Lucknow.
9 Informed Consent
Informed Consent has been obtained from the patient regarding the initiation of Ayurveda intervention in his case. Consent has also been obtained for publication of his case report for the purpose of dissemination of knowledge among medical fraternity.
Source(s) of funding
None.
Conflict of interest
None.
Peer review under responsibility of Transdisciplinary University, Bangalore. | 500 MG | DrugDosageText | CC BY-NC-ND | 33727768 | 20,802,296 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac dysfunction'. | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | CEPHALEXIN, FUROSEMIDE, METHYLPREDNISOLONE, NIVOLUMAB, OMEPRAZOLE, PREDNISONE | DrugsGivenReaction | CC BY | 33728076 | 19,201,282 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | FUROSEMIDE | DrugsGivenReaction | CC BY | 33728076 | 19,187,754 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug dependence'. | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | FUROSEMIDE, METHYLPREDNISOLONE SODIUM SUCCINATE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33728076 | 19,158,756 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | CEPHALEXIN, FUROSEMIDE, METHYLPREDNISOLONE, NIVOLUMAB, OMEPRAZOLE, PREDNISONE | DrugsGivenReaction | CC BY | 33728076 | 19,201,282 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrocardiogram T wave peaked'. | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | CEPHALEXIN, FUROSEMIDE, METHYLPREDNISOLONE, NIVOLUMAB, OMEPRAZOLE, PREDNISONE | DrugsGivenReaction | CC BY | 33728076 | 19,201,282 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperkalaemia'. | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | CEPHALEXIN, FUROSEMIDE, METHYLPREDNISOLONE, NIVOLUMAB, OMEPRAZOLE, PREDNISONE | DrugsGivenReaction | CC BY | 33728076 | 19,201,282 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metabolic acidosis'. | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | CEPHALEXIN, FUROSEMIDE, METHYLPREDNISOLONE, NIVOLUMAB, OMEPRAZOLE, PREDNISONE | DrugsGivenReaction | CC BY | 33728076 | 19,201,282 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pleural effusion'. | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | CEPHALEXIN, FUROSEMIDE, METHYLPREDNISOLONE, NIVOLUMAB, OMEPRAZOLE, PREDNISONE | DrugsGivenReaction | CC BY | 33728076 | 19,201,282 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary congestion'. | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | CEPHALEXIN, FUROSEMIDE, METHYLPREDNISOLONE, NIVOLUMAB, OMEPRAZOLE, PREDNISONE | DrugsGivenReaction | CC BY | 33728076 | 19,201,282 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal tubular injury'. | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | CEPHALEXIN, FUROSEMIDE, METHYLPREDNISOLONE, NIVOLUMAB, OMEPRAZOLE, PREDNISONE | DrugsGivenReaction | CC BY | 33728076 | 19,201,282 | 2021 |
What was the administration route of drug 'METHYLPREDNISOLONE SODIUM SUCCINATE'? | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33728076 | 19,158,756 | 2021 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33728076 | 19,201,282 | 2021 |
What was the administration route of drug 'PREDNISONE'? | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | Oral | DrugAdministrationRoute | CC BY | 33728076 | 19,158,756 | 2021 |
What was the dosage of drug 'FUROSEMIDE'? | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | UNKNOWN | DrugDosageText | CC BY | 33728076 | 19,232,099 | 2021 |
What was the outcome of reaction 'Cardiac dysfunction'? | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | Recovered | ReactionOutcome | CC BY | 33728076 | 19,201,282 | 2021 |
What was the outcome of reaction 'Electrocardiogram T wave peaked'? | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | Recovered | ReactionOutcome | CC BY | 33728076 | 19,201,282 | 2021 |
What was the outcome of reaction 'Hyperkalaemia'? | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | Recovered | ReactionOutcome | CC BY | 33728076 | 19,201,282 | 2021 |
What was the outcome of reaction 'Metabolic acidosis'? | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | Recovered | ReactionOutcome | CC BY | 33728076 | 19,201,282 | 2021 |
What was the outcome of reaction 'Pleural effusion'? | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | Recovered | ReactionOutcome | CC BY | 33728076 | 19,201,282 | 2021 |
What was the outcome of reaction 'Pulmonary congestion'? | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | Recovered | ReactionOutcome | CC BY | 33728076 | 19,201,282 | 2021 |
What was the outcome of reaction 'Renal tubular injury'? | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | Recovered | ReactionOutcome | CC BY | 33728076 | 19,201,282 | 2021 |
What was the outcome of reaction 'Steroid dependence'? | Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy.
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
1. Introduction
A 65-year-old male with a past medical history of essential hypertension, type 2 diabetes mellitus, obesity with a BMI of 31.65 kg/m2, stage 2 chronic kidney disease (CKD), COPD, paroxysmal atrial fibrillation, dyslipidemia, and history of urinary retention secondary to benign prostate hyperplasia was found to have a 9.5 × 6 × 7.1 cm enhancing mass in the left kidney after an abdominal CT scan with intravenous contrast done for an R renal cyst follow-up. A high-resolution CT scan of the chest (HRCT) revealed numerous nodules suspicious for metastases. A CT scan-directed lung biopsy revealed metastatic clear cell renal cell carcinoma (CCRCC). One month later, the patient underwent a left nephrectomy and lymphectomy followed by sequential therapy with sunitinib, everolimus, and bevacizumab, which overall controlled the disease for a total period of 31 months. However, his disease eventually progressed, and new brain metastasis was found. The patient underwent gamma knife radiosurgery and was started on nivolumab, a checkpoint inhibitor (CPI). Two months later, around his fourth cycle of nivolumab, the patient's creatinine was found to be 1.6 mg/dl, from his baseline of 1.0–1.2 mg/dl. Four months after nivolumab was started, following his 8th cycle of nivolumab, the patient was admitted to the hospital because a creatinine level of 4 mg/dl was noted. The patient had recently completed a course of cephalexin for a throat infection and was on omeprazole, but not NSAIDs or ACEi. On admission, creatinine was 6.09 mg/dl and BUN was 68 mg/dl, and there were metabolic acidosis and hyperkalemia. There was evidence of urinary retention on kidney and bladder ultrasound based on a PVR of 450 cc. Urinalysis revealed few eosinophils, 3–10 leukocytes, and subnephrotic range proteinuria. Complement levels were normal. The patient was started on intravenous hydration, omeprazole was discontinued, and a Foley catheter was placed. However, his renal function did not improve. The patient was subsequently started on 45 mg of prednisone orally twice daily for presumptive acute interstitial nephritis (AIN) secondary to nivolumab. He was discharged on a prednisone taper and his renal function continued to improve.
Two months later, close after ending his prednisone taper, the patient presented to the ER complaining of 2 weeks of worsening shortness of breath and 20-pound weight gain. On admission, physical examination revealed jugular venous distension and 4+ lower extremity pitting edema up to the knee, but no lung rales. Creatinine was 7.79 mg/dL, BUN 81 mg/dL, and potassium 6.4 mg/dL. Urinalysis revealed eosinophiluria, subnephrotic range proteinuria, and leukocyturia >50. Urinary retention was ruled out. Urine cultured grew 100,000 CFU of E. coli. Chest X-rays revealed signs of lung congestion and new small bilateral pleural effusions. A transthoracic echo demonstrated severely enlarged left atrium, mild to moderate tricuspid regurgitation, evidence of mildly elevated right ventricular systolic pressure, and trace pulmonary regurgitation that were not present on a TTE done 2 years prior. Left ventricular chamber size was normal, there were no distinct wall motion abnormalities, and a visually estimated ejection fraction was 55%. He was started on furosemide and antibiotics, but his renal function continued to worsen. The presumptive diagnosis of recurrent AIN secondary to nivolumab was made, and the patient was started on a pulse IV methylprednisolone followed by oral prednisone. After creatinine peaked to 8.29 mg/dL, the patient was discharged one week later with a creatinine level of 3.74 mg/dL on a prednisone taper and his creatinine continued to improve weeks later.
Few weeks after ending his second steroid taper, the patient was hospitalized for the third time because of a creatinine level of 8.27 mg/dL. There were eosinophiluria, proteinuria, significant leukocyturia, metabolic acidosis, and hyperkalemia with peak T waves on EKG. The patient was deemed to be steroid-dependent, and consideration to a steroid-sparing drug was given. The patient was started once again on pulse 500 mg IV methylprednisolone and 1 gram of mofetil mycophenolate (MM) twice daily. Renal biopsy was finally done and showed moderate interstitial inflammation mainly composed of lymphocytes along with secondary acute tubular injury. In addition, trichrome staining revealed a moderate amount of interstitial fibrosis and tubular atrophy. No evidence of glomerulonephritis or crescent formation was present. On immunofluorescence, glomeruli were negative for IgG, IgA, IgM, C3, kappa, lambda, and C1q. Renal function improved, and the patient was discharged on a prednisone taper and mofetil mycophenolate. In the following months, the patient was able to complete his prednisone taper and his creatinine remained stable on his new baseline, 2 mg/dL, and proteinuria, leukocyturia, and proteinuria resolved. The entire course of his acute kidney injury and response to treatment is depicted in Figure 1. His dose of mofetil was eventually weaned to 250 mg twice daily which he is presently on. Overall, the patient only received 8 cycles of nivolumab. PET CT after 3 years off nivolumab and while receiving MM revealed no new or progressive lesion, decreased avidity in the only avid lesion in a subcarinal lymph node, and stable brain lesion. The patient is currently doing well.
2. Discussion
Nivolumab, a checkpoint inhibitor, is a human IgG4 anti-PD-1 antibody that selectively blocks the interaction between PD-1 expressed in activated Th lymphocytes and its ligands, PD-L1 and PD-L2, expressed in tissues and cancer cells [1]. PD-L1 and PD-L2 expressions in tissues are one of the major determinants of peripheral immune tolerance. PD-L1 is overexpressed in tissues via lymphokines during states of T-cell activation as a means to safeguard themselves from being “attacked.” Furthermore, some tumors constitutively express PD-L1 which dampens the activation of tumor-infiltrating lymphocytes. By blocking the interaction between PD-1 and PD-L1, the T-cell response is unleashed against the tumor. CCRCC expresses PD-L1 and there lies the rationale for nivolumab use. Nivolumab was approved by the FDA for its use in metastatic CCRCC in 2015 after demonstrating a significantly superior objective response rate and overall survival compared to everolimus in patients previously treated with bevacizumab [2].
Sometimes, T cells turn against a person's own tissues due to loss of peripheral tolerance induced by CPIs, resulting in immune-related adverse events (irAEs). Overall, irAEs are common in patients on CPIs and can affect almost any organ. CPIs are indicated for the treatment of several metastatic cancers. As cancer is more common with increasing age, the typical patient receiving CPIs is in the elderly age group and has numerous comorbidities and thus limited organ reserve, as the patient in this case vignette. IrAEs' timing of presentation and severity are vastly heterogeneous but more frequently occur between 21 and 245 days after they are initiated [3]. Commonly, irAEs present grade 1-2 events (at most requiring only symptomatic management), but grade 3 or 4 events (organ- or life-threatening) can occur in up to 15% of the patients that merits discontinuation of CPIs [4]. However, there are not practical ways for clinicians to predict the degree of an irAE's severity and refractoriness early on its course, when the affected organ is at its best chance of recovery. In addition, most of the irAEs are reversible with treatment.
Renal irAEs can occur with CPIs. The patient can present with variable elevation in creatinine, leukocyturia, and subnephrotic range proteinuria [5, 6]. Case reports and series of renal irAEs, including this case vignette, patients commonly had numerous risk factors for and/or an already established CKD. Furthermore, they were frequently receiving medications typically associated with drug-related AIN, such as proton pump inhibitors or first-generation cephalosporins. CKIN recommends monitoring creatinine frequently early in the initiation of CPIs as irAEs tend to occur more frequently during this period [7]. AIN is the most common renal irAE [6]. However, pathologic specimens have shown that renal irAEs are histologically heterogeneous and may inform about renal outcomes and treatment response. A higher degree of interstitial lymphocytic infiltrate and acute tubular damage may predict loss of renal function while a higher degree of granulomatous necrotizing vasculitis and glomerulonephritis (GN) seems to portend better renal outcomes [3, 6]. Furthermore, in a case series of 16 patients with renal irAEs, who were treated initially with a course of steroids and CPI discontinuation, none of the 5 AIN cases had complete renal function recovery and 2 of them ended up in permanent hemodialysis. Those with GN had a variable response to treatment depending on the type of GN. Those with granulomatous GN had complete recovery while IgA GN did not respond to steroids or MM [6]. Because of the severe renal irAEs' rareness, there are no guidelines for their management. Most of the information about the management of renal irAEs comes from case reports and series in which glucocorticoids were favored as front-line therapy [3, 6, 8, 9]. Overall, it seems that patients who were older, who developed AIN close to the start of CPIs, who had a high creatinine elevation peak, had metastatic disease, and those undergoing concurrent treatment with nivolumab and ipilimumab, present with more aggressive AIN phenotype characterized by severe lymphocytic AIN and tubular injury that may benefit from early and prolonged steroid-sparing immunosuppression. In addition, long-term use of immunosuppressive medication to treat CPI high-grade adverse effects has not been associated with worse prognosis or overall survival [5]. On the other hand, the prognosis of a patient with CKD stage 2 that progresses to stage 4 (our patient) after an irAE may potentially be worse. Thus, early biopsy and immunosuppression may decrease the risk of irreversible kidney damage, particularly in patients with grade 3-4 renal irAEs and those with low physiological reserve such as the elderly or patients with comorbidities. It is important to notice that, in this case, biopsy was delayed under the presumption of nivolumab-induced interstitial nephritis which missed the severity of the histologic phenotype and other potential differential diagnoses. The duration of immunosuppression is unknown, but our patient did well 3 years on MM and off nivolumab.
Also, it is unknown whether immunosuppressive medication can be used concomitantly with CPIs to control irAEs. Interestingly, a report of an elderly patient with metastatic anal melanoma was treated with a sequential use of ipilimumab followed by nivolumab after which she developed severe steroid-dependent AIN. This patient was kept on nivolumab concurrently with maintenance prednisone at a dose of 10 mg, and her renal function improved and stabilized. When prednisone was stopped, she developed a recurrence of AIN and nivolumab had to be discontinued. Of note, most of her metastatic lesions demonstrated ongoing regression except for new brain lesions treated with stereotaxic radiation after nivolumab was discontinued [9]. Some patients will only need a course of steroids and discontinuation of CPIs to treat their AIN [10]. In a series of 13 cases of AKI secondary to CPIs, AIN was the most common histological finding; the most common cancer treated was metastatic melanoma; AIN was more common in patients treated with nivolumab alone, ipilimumab alone, and twice as common with nivolumab and ipilimumab combination compared to pembrolizumab; half of the patients partially recovered their renal function with steroids, less than a quarter had a complete response, and one patient showed TMA and did not respond to steroids [3]. In this case series, those patients treated conservatively did not have an improvement in renal function. One patient required mofetil mycophenolate because of worsening renal function on methylprednisolone.
CPIs have proven to be effective in the management of some advanced cancer, so their use is expected to increase as well as the incidence of irAEs and physicians will have a major role in diagnosing and treating them with the goal of preventing irreversible organ damage that can increase morbidity and affect prognosis. This case is relevant because it presents a patient with a refractory grade 3 renal irAEs that was effectively controlled with long-term use of mofetil mycophenolate with ongoing regression of his metastases. Finally, to change the current steroid-centered paradigm, there is a need for randomized trials that compare initial treatment with long-term treatment with steroid-sparing immunosuppressants with tapering courses of steroids in a patient with grade 3-4 irAEs and high comorbidity burden.
Data Availability
No data were used to support the findings of this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Patient's acute kidney injury course. The first 2 creatinine peaks represent acute kidney injury during steroid tapering. Note that when mofetil mycophenolate was initiated, the patient's renal function improved and eventually stabilized, and complete steroid weaning was possible. | Recovering | ReactionOutcome | CC BY | 33728076 | 19,232,099 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Basal cell carcinoma'. | Development of Two Types of Skin Cancer in a Patient with Systemic Sclerosis: a Case Report and Overview of the Literature.
Systemic sclerosis (SSc) is an uncommon rheumatic disease in which the underlying main histopathologic feature is a thickening of the skin due to excessive accumulation of collagen in the extracellular tissue. Fibrogenesis, chronic inflammation, and ulceration may eventually promote skin neoplasms. Although nonmelanoma skin cancer (NMSC) is the most frequent type, there have been restricted case reports and case series with skin cancers in SSc patients in the literature. Herein, we describe a 78-year-old woman diagnosed with diffuse cutaneous systemic sclerosis thirteen years ago and associated nonspecific interstitial pneumonia that was successfully treated with high cumulative doses of cyclophosphamide. She developed basal cell carcinoma and squamous cell carcinoma of the skin in the follow-up. She is still on rituximab treatment with stable interstitial lung disease as indicated by pulmonary function tests and high-resolution chest computed tomography. To our knowledge and a literature search, this is the first reported patient with SSc with two types of skin cancer. In this review, we also aimed to emphasize the relationship between SSc and skin cancer, and possible risk factors for SSc-related skin cancer.
1. Introduction
Systemic sclerosis (SSc), also called scleroderma, is an uncommon rheumatic disease. It is a slowly progressive disease that is symbolized by vasculopathy, fibrosis of the skin and visceral organs, immune rearrangement, and B-cell activation with characteristic autoantibodies [1]. Although evidence for high risk of having malignancy is suggestive, the types of malignancies and the importance of the total risk are quite variable in each patient with SSc [2]. The lung and skin are the frequently seen specific tumor sites in patients with SSc, which are commonly affected by both fibrosis and underlying immune dysfunction [3]. Interstitial lung disease (ILD) is also a serious complication of SSc, which leads to significant morbidity and lung cancer [4]. Autoantibodies to topoisomerase I (also referred to as anti-Scl70), smoking, and some immunosuppressive drugs may also lead to a higher frequency of lung cancer among SSc patients [5]. On the other hand, skin cancers are also seen in SSc patients. Although nonmelanoma skin cancer (NMSC) is the most frequent subtype, there have been restricted case reports and case series with skin cancers in SSc patients. Although underlying pathogenetic mechanisms are not yet clear, a shred of evidence is present related to few immunosuppressive drugs. Cyclophosphamide (CyP) is one of them and nonselectively inhibits the whole immune system, and malignancy may develop by suppressing immune surveillance [6]. Today, the use of CyP for the treatment of ILD in connective tissue disorders has growing evidence for optimization of lung functions [7]. Immunosuppression with methotrexate use alone and/or combined with antitumor necrosis factor agents (anti-TNF) is also related to high risk of second nonmelanoma skin cancers (NMSC) in rheumatoid arthritis (RA) patients [8].
Herein, we report an older SSc patient who was treated with highly toxic cumulative doses of CyP due to progressive ILD and who subsequently developed two types of skin cancer simultaneously. Managing treatment of individuals with SSc-ILD is difficult due to balancing the need for therapy in severely progressive patients against the potential for adverse effects. Clinicians should identify patients who will develop the progressive disease with the lowest level of unexpected side effects before planning treatment. In addition to treatment modalities, underlying inflammatory diseases, prolonged life span and family histories, occupations, and sun exposure of patients should be examined. Written informed consent was obtained from our patient for publication.
2. Methods
A literature search was performed in PubMed using these terms: “scleroderma,” “systemic sclerosis,” “skin cancer,” “squamous cell carcinoma,” and “basal cell carcinoma.” An English language filter was activated. All case reports published before November 2020 were examined.
3. Case Report
A 78-year-old woman diagnosed with diffuse cutaneous systemic sclerosis (dcSSc) thirteen years ago is on regular follow-up in the tertiary health center, in Denizli. She is of Turkish origin and works as a farmer for a long time. She reports no use of tobacco and has no known allergic diseases. Her past medical history included idiopathic venous thromboembolism in 2016 without an identifiable cause. She was diagnosed with dcSSc based on the presence of Raynaud's phenomenon, digital pitting scars, sclerodactyly, and diffuse skin sclerosis extending proximal to the metacarpophalangeal joints on both hands. An indirect immunofluorescence test for antinuclear antibodies (ANA) was positive (titer ≥ 1 : 1280), and anti-Scl-70 was also positive. In the first year of diagnosis, she worsened and complained of dyspnea occurring with minimal exertion, along with chronic, persistent cough. Transthoracic echocardiogram revealed no findings suggestive of pulmonary arterial hypertension. After spirometry tests (forced vital capacity of 1.79 L (40% of the predicted)), high-resolution chest computed tomography (nonspecific interstitial pneumonia (NSIP)), and a 6-minute walk test (developing desaturation at 424 m), she was accepted as having SSc-related NSIP. CyP was administered at a dose of 1000 mg/m2 of body surface area per month for six months in an outpatient clinic, followed by 500 mg/m2 of body surface area every two months for one year. After two years of clinical stability, the same treatment regimen was repeated due to signs of lung exacerbation (total cumulative dose has exceeded 15 g). After three years of completed treatment, a 1-2 cm nonhealing ulcer on her right forearm and a pigmented mass at the tip of the nose appeared and were excised surgically. Histopathological examinations revealed squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), respectively (Figures 1 and 2). Surgical borders were intact without tumor cells. Additional scanning methods showed no local or distant metastases. She is still on rituximab treatment with stable interstitial lung disease as indicated by pulmonary function tests and high-resolution chest computed tomography.
4. Discussion
Skin cancers, covering SCC, BCC, and malignant melanoma were found as SSc-related tumors in a literature search. Although a malignant turn of localized scleroderma is rarely seen, Durcanska et al. concluded that a young 26-year-old woman who was diagnosed with localized scleroderma (morphea) ultimately developed SCC camouflaged by osteomyelitis on the lower extremities after a long course of the disease [9]. An 18-year-old woman with progressive SSc developed SCC of the skin. Despite resection, the tumor recurred and was resistant to local radiotherapy [10]. Song et al. reported a 46-year-old man with systemic sclerosis and BCC on his face that was successfully removed by surgical excision [11]. Sargın et al. reported variable cancers in 7 cases among 153 systemic sclerosis patients. Two of all the cancers were malignant melanoma in the eyes and skin, in Aydın, neighboring to Denizli [12]. Koksal et al. investigated the distribution of cancer cases in Denizli between 2000 and 2004. 10.9% of 2185 cancer cases were skin cancers. They emphasized a significant increase in skin cancers over the years [13]. Ceylan et al. investigated features of NMSCs in Izmir where high ultraviolet light exposure was present such as Denizli. Tumors were commonly seen in elderly men and were also related to sun exposure and older age. Among 3,186 NMSC lesions, 71 patients had both BCC and SCC, and BCC was the most common type among the whole group, and mostly located on the face [14]. Nose and lip were the most common locations on the face with high recurrence rates for NMSC [15]. Our patient also had SCC and BCC on the tip of her nose and on her right forearm which may be related to sun exposure.
The main histopathologic feature of scleroderma is a thickening of the skin due to excessive accumulation of collagen in the extracellular tissue. Fibrogenesis, chronic inflammation, and ulceration may eventually promote skin neoplasms [16]. SCC has been the most frequently reported skin cancer in association with chronic tissue inflammation [17]. Also, Magro et al. stated that not only malignancies but also atypical lymphoid aggregates are seen in cutaneous specimens of connective tissue disease (CTD) related to B-cell or T-cell phenotypes [18]. Numerous theories and pathophysiological mechanisms have been emphasized to explain this clinical association. One of the highlights is a significantly reduced percentage of CD4(+) Foxp3(+) T(reg) in the skin of patients with SSc or limited scleroderma [19]. Dysregulation of the endocannabinoid system (ECS) is also related to skin cancer in scleroderma [20]. Recent extensive research points to the renin-angiotensin-aldosterone system- (RAAS-) modulating drugs in the impaired regulatory function of local RAAS to be related to cancer development and scleroderma-like skin changes [21]. Recent literature revealed that the prevalence of all epithelial skin neoplasms, involving melanoma, SCC, and BCC, was significantly higher in patients with morphea compared with the healthy subjects [22]. Besides, a study in which malignancies were analyzed in SSc patients and were compared with the general population revealed 11 new cases of variable malignancies in 10 SSc patients (4.6%) more commonly seen than the general population. Only one of them had skin cancer [23]. Although there is no comprehensive analysis of the prevalence of skin cancers and other malignancies among SSc in our health center, we can report that she is the first case with two concurrent types of skin cancer.
SSc-specific autoantibodies may identify patients at high risk and play a role in the prognosis and triaging of patients who may require further cancer screening [24]. However, the best-known autoantibodies such as antitopoisomerase I and anticentromere are inconsistent in predicting risk for developing malignancy. In a comprehensive review, increased age, diffuse SSc, and female gender were well-known risk factors for the development of malignancy in patients with SSc [25]. In another large cohort including 2177 patients with SSc, the presence of anti-RNA polymerase III (anti-RNAPIII) was the most associated antibody for the development of malignancies [26]. Female gender, older age, and having antitopoisomerase I antibody were personal, unchangeable risk factors in our patient.
Also, immunosuppressants used in major organ involvements of scleroderma may encourage tumor formation. CyP is a very efficient immunosuppressant drug in autoimmune and inflammatory illnesses with possible major side effects [27]. Hematological adverse events, bone marrow suppression, hematuria, bladder cancer, and gonadal damage have been demonstrated and are the most feared side effects [28]. Increased risk of hematological and solid organ malignancies in patients treated with CyP suggests carcinogenic activity and should be kept in mind [29]. However, in addition to immunosuppressive drugs, some immunosuppressive conditions such as HIV, chronic lymphocytic leukemia, and/or transplant recipients have also a higher risk for developing any skin cancer than the general population [30].
Other important points are sun exposure and advanced age in the pathogenesis of NMSC. The most common cancer in the world, NMSC, was developed more commonly in outdoor workers including different job groups than indoor workers due to sun exposure in a recently published paper [31]. Although it is difficult to clearly distinguish the causative etiopathogenic mechanism, our patient had apparent multiple risk factors for developing skin cancer, including high sun exposure due to her occupation, exposure to high cumulative toxic doses of CyP, long-term immunosuppression with CyP and rituximab, the underlying chronic inflammatory disease, systemic sclerosis, and the advanced age. We think the unfortunate outcome in this patient is the cumulative result of all these risk factors.
5. Conclusion
We reported a rare case of BCC and SCC in a SSc patient along with a review of the literature. To our knowledge and the literature search, this is the first reported SSc patient with two types of skin cancer. With this review, we aimed to improve our knowledge of SSc-related skin cancers. Clinicians should always keep in mind the patient's risk of developing toxicity based on a risk-benefit analysis. These patients are candidates for cancer development due to underlying immune dysregulation and immunosuppressive drugs, in addition to traditional risk factors.
Conflicts of Interest
All authors declare that they have no conflicts of interest.
Figure 1 Squamous cell carcinoma. Blunt-type intradermal invasion of well-differentiated tumor nests (H&E, ×40).
Figure 2 Basal cell carcinoma. Nests of basaloid cells project from the overlying epidermis (H&E, ×40). | CYCLOPHOSPHAMIDE, RITUXIMAB | DrugsGivenReaction | CC BY | 33728079 | 19,065,205 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Squamous cell carcinoma'. | Development of Two Types of Skin Cancer in a Patient with Systemic Sclerosis: a Case Report and Overview of the Literature.
Systemic sclerosis (SSc) is an uncommon rheumatic disease in which the underlying main histopathologic feature is a thickening of the skin due to excessive accumulation of collagen in the extracellular tissue. Fibrogenesis, chronic inflammation, and ulceration may eventually promote skin neoplasms. Although nonmelanoma skin cancer (NMSC) is the most frequent type, there have been restricted case reports and case series with skin cancers in SSc patients in the literature. Herein, we describe a 78-year-old woman diagnosed with diffuse cutaneous systemic sclerosis thirteen years ago and associated nonspecific interstitial pneumonia that was successfully treated with high cumulative doses of cyclophosphamide. She developed basal cell carcinoma and squamous cell carcinoma of the skin in the follow-up. She is still on rituximab treatment with stable interstitial lung disease as indicated by pulmonary function tests and high-resolution chest computed tomography. To our knowledge and a literature search, this is the first reported patient with SSc with two types of skin cancer. In this review, we also aimed to emphasize the relationship between SSc and skin cancer, and possible risk factors for SSc-related skin cancer.
1. Introduction
Systemic sclerosis (SSc), also called scleroderma, is an uncommon rheumatic disease. It is a slowly progressive disease that is symbolized by vasculopathy, fibrosis of the skin and visceral organs, immune rearrangement, and B-cell activation with characteristic autoantibodies [1]. Although evidence for high risk of having malignancy is suggestive, the types of malignancies and the importance of the total risk are quite variable in each patient with SSc [2]. The lung and skin are the frequently seen specific tumor sites in patients with SSc, which are commonly affected by both fibrosis and underlying immune dysfunction [3]. Interstitial lung disease (ILD) is also a serious complication of SSc, which leads to significant morbidity and lung cancer [4]. Autoantibodies to topoisomerase I (also referred to as anti-Scl70), smoking, and some immunosuppressive drugs may also lead to a higher frequency of lung cancer among SSc patients [5]. On the other hand, skin cancers are also seen in SSc patients. Although nonmelanoma skin cancer (NMSC) is the most frequent subtype, there have been restricted case reports and case series with skin cancers in SSc patients. Although underlying pathogenetic mechanisms are not yet clear, a shred of evidence is present related to few immunosuppressive drugs. Cyclophosphamide (CyP) is one of them and nonselectively inhibits the whole immune system, and malignancy may develop by suppressing immune surveillance [6]. Today, the use of CyP for the treatment of ILD in connective tissue disorders has growing evidence for optimization of lung functions [7]. Immunosuppression with methotrexate use alone and/or combined with antitumor necrosis factor agents (anti-TNF) is also related to high risk of second nonmelanoma skin cancers (NMSC) in rheumatoid arthritis (RA) patients [8].
Herein, we report an older SSc patient who was treated with highly toxic cumulative doses of CyP due to progressive ILD and who subsequently developed two types of skin cancer simultaneously. Managing treatment of individuals with SSc-ILD is difficult due to balancing the need for therapy in severely progressive patients against the potential for adverse effects. Clinicians should identify patients who will develop the progressive disease with the lowest level of unexpected side effects before planning treatment. In addition to treatment modalities, underlying inflammatory diseases, prolonged life span and family histories, occupations, and sun exposure of patients should be examined. Written informed consent was obtained from our patient for publication.
2. Methods
A literature search was performed in PubMed using these terms: “scleroderma,” “systemic sclerosis,” “skin cancer,” “squamous cell carcinoma,” and “basal cell carcinoma.” An English language filter was activated. All case reports published before November 2020 were examined.
3. Case Report
A 78-year-old woman diagnosed with diffuse cutaneous systemic sclerosis (dcSSc) thirteen years ago is on regular follow-up in the tertiary health center, in Denizli. She is of Turkish origin and works as a farmer for a long time. She reports no use of tobacco and has no known allergic diseases. Her past medical history included idiopathic venous thromboembolism in 2016 without an identifiable cause. She was diagnosed with dcSSc based on the presence of Raynaud's phenomenon, digital pitting scars, sclerodactyly, and diffuse skin sclerosis extending proximal to the metacarpophalangeal joints on both hands. An indirect immunofluorescence test for antinuclear antibodies (ANA) was positive (titer ≥ 1 : 1280), and anti-Scl-70 was also positive. In the first year of diagnosis, she worsened and complained of dyspnea occurring with minimal exertion, along with chronic, persistent cough. Transthoracic echocardiogram revealed no findings suggestive of pulmonary arterial hypertension. After spirometry tests (forced vital capacity of 1.79 L (40% of the predicted)), high-resolution chest computed tomography (nonspecific interstitial pneumonia (NSIP)), and a 6-minute walk test (developing desaturation at 424 m), she was accepted as having SSc-related NSIP. CyP was administered at a dose of 1000 mg/m2 of body surface area per month for six months in an outpatient clinic, followed by 500 mg/m2 of body surface area every two months for one year. After two years of clinical stability, the same treatment regimen was repeated due to signs of lung exacerbation (total cumulative dose has exceeded 15 g). After three years of completed treatment, a 1-2 cm nonhealing ulcer on her right forearm and a pigmented mass at the tip of the nose appeared and were excised surgically. Histopathological examinations revealed squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), respectively (Figures 1 and 2). Surgical borders were intact without tumor cells. Additional scanning methods showed no local or distant metastases. She is still on rituximab treatment with stable interstitial lung disease as indicated by pulmonary function tests and high-resolution chest computed tomography.
4. Discussion
Skin cancers, covering SCC, BCC, and malignant melanoma were found as SSc-related tumors in a literature search. Although a malignant turn of localized scleroderma is rarely seen, Durcanska et al. concluded that a young 26-year-old woman who was diagnosed with localized scleroderma (morphea) ultimately developed SCC camouflaged by osteomyelitis on the lower extremities after a long course of the disease [9]. An 18-year-old woman with progressive SSc developed SCC of the skin. Despite resection, the tumor recurred and was resistant to local radiotherapy [10]. Song et al. reported a 46-year-old man with systemic sclerosis and BCC on his face that was successfully removed by surgical excision [11]. Sargın et al. reported variable cancers in 7 cases among 153 systemic sclerosis patients. Two of all the cancers were malignant melanoma in the eyes and skin, in Aydın, neighboring to Denizli [12]. Koksal et al. investigated the distribution of cancer cases in Denizli between 2000 and 2004. 10.9% of 2185 cancer cases were skin cancers. They emphasized a significant increase in skin cancers over the years [13]. Ceylan et al. investigated features of NMSCs in Izmir where high ultraviolet light exposure was present such as Denizli. Tumors were commonly seen in elderly men and were also related to sun exposure and older age. Among 3,186 NMSC lesions, 71 patients had both BCC and SCC, and BCC was the most common type among the whole group, and mostly located on the face [14]. Nose and lip were the most common locations on the face with high recurrence rates for NMSC [15]. Our patient also had SCC and BCC on the tip of her nose and on her right forearm which may be related to sun exposure.
The main histopathologic feature of scleroderma is a thickening of the skin due to excessive accumulation of collagen in the extracellular tissue. Fibrogenesis, chronic inflammation, and ulceration may eventually promote skin neoplasms [16]. SCC has been the most frequently reported skin cancer in association with chronic tissue inflammation [17]. Also, Magro et al. stated that not only malignancies but also atypical lymphoid aggregates are seen in cutaneous specimens of connective tissue disease (CTD) related to B-cell or T-cell phenotypes [18]. Numerous theories and pathophysiological mechanisms have been emphasized to explain this clinical association. One of the highlights is a significantly reduced percentage of CD4(+) Foxp3(+) T(reg) in the skin of patients with SSc or limited scleroderma [19]. Dysregulation of the endocannabinoid system (ECS) is also related to skin cancer in scleroderma [20]. Recent extensive research points to the renin-angiotensin-aldosterone system- (RAAS-) modulating drugs in the impaired regulatory function of local RAAS to be related to cancer development and scleroderma-like skin changes [21]. Recent literature revealed that the prevalence of all epithelial skin neoplasms, involving melanoma, SCC, and BCC, was significantly higher in patients with morphea compared with the healthy subjects [22]. Besides, a study in which malignancies were analyzed in SSc patients and were compared with the general population revealed 11 new cases of variable malignancies in 10 SSc patients (4.6%) more commonly seen than the general population. Only one of them had skin cancer [23]. Although there is no comprehensive analysis of the prevalence of skin cancers and other malignancies among SSc in our health center, we can report that she is the first case with two concurrent types of skin cancer.
SSc-specific autoantibodies may identify patients at high risk and play a role in the prognosis and triaging of patients who may require further cancer screening [24]. However, the best-known autoantibodies such as antitopoisomerase I and anticentromere are inconsistent in predicting risk for developing malignancy. In a comprehensive review, increased age, diffuse SSc, and female gender were well-known risk factors for the development of malignancy in patients with SSc [25]. In another large cohort including 2177 patients with SSc, the presence of anti-RNA polymerase III (anti-RNAPIII) was the most associated antibody for the development of malignancies [26]. Female gender, older age, and having antitopoisomerase I antibody were personal, unchangeable risk factors in our patient.
Also, immunosuppressants used in major organ involvements of scleroderma may encourage tumor formation. CyP is a very efficient immunosuppressant drug in autoimmune and inflammatory illnesses with possible major side effects [27]. Hematological adverse events, bone marrow suppression, hematuria, bladder cancer, and gonadal damage have been demonstrated and are the most feared side effects [28]. Increased risk of hematological and solid organ malignancies in patients treated with CyP suggests carcinogenic activity and should be kept in mind [29]. However, in addition to immunosuppressive drugs, some immunosuppressive conditions such as HIV, chronic lymphocytic leukemia, and/or transplant recipients have also a higher risk for developing any skin cancer than the general population [30].
Other important points are sun exposure and advanced age in the pathogenesis of NMSC. The most common cancer in the world, NMSC, was developed more commonly in outdoor workers including different job groups than indoor workers due to sun exposure in a recently published paper [31]. Although it is difficult to clearly distinguish the causative etiopathogenic mechanism, our patient had apparent multiple risk factors for developing skin cancer, including high sun exposure due to her occupation, exposure to high cumulative toxic doses of CyP, long-term immunosuppression with CyP and rituximab, the underlying chronic inflammatory disease, systemic sclerosis, and the advanced age. We think the unfortunate outcome in this patient is the cumulative result of all these risk factors.
5. Conclusion
We reported a rare case of BCC and SCC in a SSc patient along with a review of the literature. To our knowledge and the literature search, this is the first reported SSc patient with two types of skin cancer. With this review, we aimed to improve our knowledge of SSc-related skin cancers. Clinicians should always keep in mind the patient's risk of developing toxicity based on a risk-benefit analysis. These patients are candidates for cancer development due to underlying immune dysregulation and immunosuppressive drugs, in addition to traditional risk factors.
Conflicts of Interest
All authors declare that they have no conflicts of interest.
Figure 1 Squamous cell carcinoma. Blunt-type intradermal invasion of well-differentiated tumor nests (H&E, ×40).
Figure 2 Basal cell carcinoma. Nests of basaloid cells project from the overlying epidermis (H&E, ×40). | CYCLOPHOSPHAMIDE, RITUXIMAB | DrugsGivenReaction | CC BY | 33728079 | 19,065,205 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease recurrence'. | Early Gastrointestinal Progression to Immunotherapy in Lung Cancer: A Report of Two Cases.
Intestinal and pancreatic metastases are rare and often challenging to recognize and manage. Lung cancer patients with enteric involvement usually display poor outcomes. Hyperprogression to immunotherapy represents a concern, even though there is currently no agreement on its exact definition. Gastrointestinal hyperprogression to immune checkpoint inhibitors has not been described so far. In these cases, distinguishing disease-related symptoms from immune-related adverse events may represent a diagnostic conundrum. Here, we report two cases of non-small-cell lung cancer experiencing a rapid pancreatic and colic progression to immunotherapy, respectively. While further investigations to identify biomarkers associated with hyperprogression are warranted, clinicians should be aware of the potential unusual clinical presentations of this phenomenon.
1. Introduction
Lung cancer commonly metastasizes to the bone, contralateral lung, liver, adrenal glands, brain, and lymph nodes, but less frequently it spreads to other anatomic sites, including the gastrointestinal system [1, 2]. Indeed, enteric metastases have been infrequently described in patients with non-small-cell lung cancer (NSCLC). Clinical presentation can be either abrupt with bleeding, bowel obstruction, or perforation, requiring intensive care in a hospital setting, or subacute, with abdominal pain, progressive anaemia, or jaundice. Unfortunately, patients with gastrointestinal metastases display a dismal prognosis regardless of their clinical presentation [3–5]. While immunotherapy has significantly improved the outcomes of stage IV NSCLC, a subset of patients receiving immune checkpoint inhibitors experience rapid disease evolution during treatment, a phenomenon known as hyperprogression (HP) [6, 7]. To the best of our knowledge, no data are available about the occurrence of gastrointestinal HP to immunotherapy in lung cancer.
Here, we report two cases of NSCLC with a rapid and unusual pancreatic and intestinal progression during treatment with the anti-Programmed Death-1 (PD-1) monoclonal antibody nivolumab.
2. Cases Presentation
2.1. Case#1
In December 2015, a 68-year-old Caucasian man with a 55 pack-years smoking history, chronic obstructive pulmonary disease, type 2 diabetes, hypercholesterolemia, and hypertension presented to the Emergency Room because of persistent cough and haemoptysis. A whole body Computed Tomography (CT) scan revealed a 60 mm mass in the left lung along with several satellite nodules in the same lobe. Both the CT and an ensuing Positron Emission Tomography (PET) scan excluded the presence of distant metastases. Thus, in February 2016, he underwent a left pneumonectomy with lymph nodal dissection. The pathology report indicated the presence of a poorly differentiated squamous cell carcinoma, pT3 (main diameter 60 mm) N0 (0 out of 24) M0 (stage II according to the UICC/AJCC TNM 7th edition). From March to July 2016, he received four cycles of adjuvant cisplatin plus vinorelbine, but one month after completing the last chemotherapy infusion, both CT and PET scans showed hepatic and para-aortic nodal relapse that were confirmed by a liver biopsy. Programmed Death-Ligand 1 (PD-L1) immunohistochemical expression, assessed on the metastatic tissue, was below 1%. Given the short interval between the end of adjuvant chemotherapy and the disease relapse, in September 2016 the patient started a second line treatment with nivolumab 3 mg/kg every two weeks. After the third administration of immunotherapy, he developed progressive jaundice, fever, nausea, and vomiting along with a rise in bilirubin, alkaline phosphatase, and glutamyl-transpeptidase. Because of these symptoms, initially attributed to an immune-related adverse events, the patient was admitted to the oncology ward where he received high-dose corticosteroids (prednisone 1 mg/kg intravenously). However, in the absence of any meaningful clinical benefit after 48 hours, he performed a Magnetic Resonance Imaging (MRI) of the abdomen that showed a bulky lesion of the pancreatic head, partially infiltrating the duodenal wall and causing visible distension of both the Wirsung and the intrahepatic biliary ducts. Moreover, multiple hepatic and nodal metastases emerged (Figure 1). Given these findings, the patient underwent percutaneous trans-hepatic cholangiography with biliary drainage, stenting, and cytological sampling, the latter consistent with lung cancer metastasis. Once bilirubin levels normalized, he began third line chemotherapy with weekly paclitaxel. However, in the following six months his clinical conditions progressively deteriorated, and in June 2017, he developed persistent fever, abdominal pain, anorexia, and weight loss. He therefore suspended active treatment and eventually died in August 2017.
2.2. Case#2
In November 2016, a 69-year-old Caucasian male came to our attention because of the acute onset of dyspnoea and haemoptysis. He was a 35-pack-year former smoker since 2010, and his previous medical history was notable for myocardial infarction, diabetes mellitus, bilateral glaucoma, and benign prostatic hyperplasia. A CT scan showed a 40 × 33 mm mass in the right lung invading the main bronchus, with increased metabolic activity (Standardized Uptake Value (SUV) 41) at the PET scan. An ensuing bronchoscopy indicated the presence of a poorly differentiated lung adenocarcinoma for which he received four cycles of neo-adjuvant chemotherapy with cisplatin and vinorelbine, achieving a satisfactory dimensional and metabolic response. Thus, in April 2017, he underwent a right upper lobectomy with mediastinal node dissection. The pathologist's assessment revealed a 30 mm poorly differentiated adenocarcinoma of the lung, Cytokeratin 7, and Thyroid Transcription Factor 1 (TTF1) positive, with involvement of the main bronchus (pT2b) and no nodal metastases (0 out of 21; stage IIB according to the UICC/AJCC TNM 7th edition). Five months after surgery the patient noticed a rapidly growing subcutaneous lump in his right thigh and another one in his left axilla, both excised and histologically proven to be lung adenocarcinoma metastases. No Epidermal Growth Factor Receptor (EGFR) mutations or Anaplastic Lymphoma Kinase (ALK) translocations were detected, and immunohistochemical staining for PD-L1 was below 1%. Hence, in December 2017, he began first line chemotherapy with carboplatin and pemetrexed, experiencing disease stabilization, followed by pemetrexed maintenance until April 2018, when a CT scan showed an abdominal nodal progression. At this time, the patient received second line treatment with nivolumab 240 mg every two weeks, from May to August 2018. However, throughout these months, he experienced progressively worsening fatigue and developed G1 anaemia. After the 6th nivolumab cycle, a CT scan revealed a new cerebellar lesion, confirmed by MRI and treated with stereotactic radiation therapy. The CT exam also documented extensive nodal progression and a left colonic wall thickening, further investigated with a colonoscopy which revealed an ulcerated lesion in the splenic flexure histologically consistent with a lung adenocarcinoma metastasis (Figures 2 and 3). Thus, in September 2018, he underwent palliative segmental resection of the left colon, which confirmed the diagnosis of intestinal metastasis of lung adenocarcinoma (Figure 4). Upon recovery, he began third line chemotherapy with weekly paclitaxel of which he received only two cycles, as he developed both G2 anaemia and melena. A new colonoscopy showed cancer relapse at the site of the previous surgery, whereas a CT scan performed in January 2019 revealed nodal and hepatic progression, along with a femoral vein thrombosis. Because of the latter finding, interventional radiologists positioned an inferior vena cava filter. The patient continued best supportive care and died in August 2019.
3. Discussion
We describe here two cases of metastatic NSCLC with unusual early gastrointestinal progression to the immune checkpoint inhibitor nivolumab. Both patients were heavy smokers (i.e., >30 pack-years) presenting with a squamous cell carcinoma or an adenocarcinoma, the histological variants most frequently associated with pancreatic and intestinal involvement, respectively [3, 4, 8]. However, no data are currently available concerning the EGFR, ALK, and PD-L1 status of these tumours. Consistent with preexisting evidence, clinical manifestations of gastrointestinal metastases were severe and led to treatment discontinuation, heavily worsening the patients' quality of life [5]. Moreover, symptoms were difficult to recognize, and even after radiological diagnosis, a biopsy was mandatory to rule out a second synchronous cancer. Although our patients received additional chemotherapy after discontinuing nivolumab, they lacked any consistent benefit from the subsequent treatment (weekly paclitaxel). However, our patients experienced a 9-month and a 12-month survival from the detection of the enteric lesions, respectively. Hence, their survival is significantly longer than the one reported in the literature (2.8 months) [4, 5].
To the best of our knowledge, this is the first report of gastrointestinal hyperprogression to immunotherapy in lung cancer. Of note, Miyazawa and colleagues reported two cases of metastatic melanoma spreading to the small bowel and the colon during nivolumab treatment [9]. Due to the rapid and extensive disease progression that our patients experienced, we deemed them “hyper-progressors.” Although several studies recently provided an overview about HP, this phenomenon is still matter of debate [10–12]. However, preliminary evidences are emerging about potential molecular biomarkers useful in the timely identification of hyperprogressing patients [11, 13–15]. It is crucial to promptly and correctly recognize NSCLC gastrointestinal progression as this atypical metastatic spread, usually associated with subtle and equivocal symptoms, may result in diagnostic delay. In addition, if an intestinal progression occurs during immunotherapy, its clinical identification can be extremely challenging as it may be potentially mistaken for an immune-related complication. The present report emphasizes the possibility of an unusual enteric metastatic disease in patients affected by NSCLC treated with immune checkpoint inhibitors. As an increasing number of patients will receive anti-PD-1 or anti-PD-L1 antibodies, a concerted effort is needed in order to identify biomarkers predictive of HP.
Data Availability
The underlying data supporting the results of the study can be found in the manuscript.
Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
Authors' Contributions
FM, KL, GP, LM, GM, NI, RC, HSP, AZ, and PV participated in the patient's treatment. GMV and GAM reviewed the histological samples. FM and LM did the literature search. PV, FM, KL, GP, and LM drafted the manuscript. All authors read and approved the final manuscript.
Figure 1 MR imaging of the pancreatic head mass (a) of the larger liver metastasis (b) and of the biliary dilatation (c). CT imaging of the biliary drainage (d).
Figure 2 Endoscopic imaging of lung adenocarcinoma metastasis in the splenic flexure and (a) CT imaging of left colonic wall thickening (b).
Figure 3 Intestinal biopsy: normal colonic mucosa infiltrated by solid-pseudoglandolar carcinoma, positive for CK7 and negative for intestinal differentiation markers, such as CK20 and CDX2 (arrows). Lung adenocarcinomas with prevalent solid pattern may be negative for TTF-1 but often positive for CK7. On the basis of the morpho-immunohistochemical data and clinical history, the diagnosis of intestinal metastasis of lung adenocarcinoma was made.
Figure 4 Surgical findings: the diagnosis of lung adenocarcinoma metastasis was confirmed after surgical resection. The figure shows intramural CK7 positive neoplasia, with a normal underlying colonic mucosa. | CARBOPLATIN, CISPLATIN, PACLITAXEL, PEMETREXED, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY | 33728080 | 19,198,284 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to lung'. | Early Gastrointestinal Progression to Immunotherapy in Lung Cancer: A Report of Two Cases.
Intestinal and pancreatic metastases are rare and often challenging to recognize and manage. Lung cancer patients with enteric involvement usually display poor outcomes. Hyperprogression to immunotherapy represents a concern, even though there is currently no agreement on its exact definition. Gastrointestinal hyperprogression to immune checkpoint inhibitors has not been described so far. In these cases, distinguishing disease-related symptoms from immune-related adverse events may represent a diagnostic conundrum. Here, we report two cases of non-small-cell lung cancer experiencing a rapid pancreatic and colic progression to immunotherapy, respectively. While further investigations to identify biomarkers associated with hyperprogression are warranted, clinicians should be aware of the potential unusual clinical presentations of this phenomenon.
1. Introduction
Lung cancer commonly metastasizes to the bone, contralateral lung, liver, adrenal glands, brain, and lymph nodes, but less frequently it spreads to other anatomic sites, including the gastrointestinal system [1, 2]. Indeed, enteric metastases have been infrequently described in patients with non-small-cell lung cancer (NSCLC). Clinical presentation can be either abrupt with bleeding, bowel obstruction, or perforation, requiring intensive care in a hospital setting, or subacute, with abdominal pain, progressive anaemia, or jaundice. Unfortunately, patients with gastrointestinal metastases display a dismal prognosis regardless of their clinical presentation [3–5]. While immunotherapy has significantly improved the outcomes of stage IV NSCLC, a subset of patients receiving immune checkpoint inhibitors experience rapid disease evolution during treatment, a phenomenon known as hyperprogression (HP) [6, 7]. To the best of our knowledge, no data are available about the occurrence of gastrointestinal HP to immunotherapy in lung cancer.
Here, we report two cases of NSCLC with a rapid and unusual pancreatic and intestinal progression during treatment with the anti-Programmed Death-1 (PD-1) monoclonal antibody nivolumab.
2. Cases Presentation
2.1. Case#1
In December 2015, a 68-year-old Caucasian man with a 55 pack-years smoking history, chronic obstructive pulmonary disease, type 2 diabetes, hypercholesterolemia, and hypertension presented to the Emergency Room because of persistent cough and haemoptysis. A whole body Computed Tomography (CT) scan revealed a 60 mm mass in the left lung along with several satellite nodules in the same lobe. Both the CT and an ensuing Positron Emission Tomography (PET) scan excluded the presence of distant metastases. Thus, in February 2016, he underwent a left pneumonectomy with lymph nodal dissection. The pathology report indicated the presence of a poorly differentiated squamous cell carcinoma, pT3 (main diameter 60 mm) N0 (0 out of 24) M0 (stage II according to the UICC/AJCC TNM 7th edition). From March to July 2016, he received four cycles of adjuvant cisplatin plus vinorelbine, but one month after completing the last chemotherapy infusion, both CT and PET scans showed hepatic and para-aortic nodal relapse that were confirmed by a liver biopsy. Programmed Death-Ligand 1 (PD-L1) immunohistochemical expression, assessed on the metastatic tissue, was below 1%. Given the short interval between the end of adjuvant chemotherapy and the disease relapse, in September 2016 the patient started a second line treatment with nivolumab 3 mg/kg every two weeks. After the third administration of immunotherapy, he developed progressive jaundice, fever, nausea, and vomiting along with a rise in bilirubin, alkaline phosphatase, and glutamyl-transpeptidase. Because of these symptoms, initially attributed to an immune-related adverse events, the patient was admitted to the oncology ward where he received high-dose corticosteroids (prednisone 1 mg/kg intravenously). However, in the absence of any meaningful clinical benefit after 48 hours, he performed a Magnetic Resonance Imaging (MRI) of the abdomen that showed a bulky lesion of the pancreatic head, partially infiltrating the duodenal wall and causing visible distension of both the Wirsung and the intrahepatic biliary ducts. Moreover, multiple hepatic and nodal metastases emerged (Figure 1). Given these findings, the patient underwent percutaneous trans-hepatic cholangiography with biliary drainage, stenting, and cytological sampling, the latter consistent with lung cancer metastasis. Once bilirubin levels normalized, he began third line chemotherapy with weekly paclitaxel. However, in the following six months his clinical conditions progressively deteriorated, and in June 2017, he developed persistent fever, abdominal pain, anorexia, and weight loss. He therefore suspended active treatment and eventually died in August 2017.
2.2. Case#2
In November 2016, a 69-year-old Caucasian male came to our attention because of the acute onset of dyspnoea and haemoptysis. He was a 35-pack-year former smoker since 2010, and his previous medical history was notable for myocardial infarction, diabetes mellitus, bilateral glaucoma, and benign prostatic hyperplasia. A CT scan showed a 40 × 33 mm mass in the right lung invading the main bronchus, with increased metabolic activity (Standardized Uptake Value (SUV) 41) at the PET scan. An ensuing bronchoscopy indicated the presence of a poorly differentiated lung adenocarcinoma for which he received four cycles of neo-adjuvant chemotherapy with cisplatin and vinorelbine, achieving a satisfactory dimensional and metabolic response. Thus, in April 2017, he underwent a right upper lobectomy with mediastinal node dissection. The pathologist's assessment revealed a 30 mm poorly differentiated adenocarcinoma of the lung, Cytokeratin 7, and Thyroid Transcription Factor 1 (TTF1) positive, with involvement of the main bronchus (pT2b) and no nodal metastases (0 out of 21; stage IIB according to the UICC/AJCC TNM 7th edition). Five months after surgery the patient noticed a rapidly growing subcutaneous lump in his right thigh and another one in his left axilla, both excised and histologically proven to be lung adenocarcinoma metastases. No Epidermal Growth Factor Receptor (EGFR) mutations or Anaplastic Lymphoma Kinase (ALK) translocations were detected, and immunohistochemical staining for PD-L1 was below 1%. Hence, in December 2017, he began first line chemotherapy with carboplatin and pemetrexed, experiencing disease stabilization, followed by pemetrexed maintenance until April 2018, when a CT scan showed an abdominal nodal progression. At this time, the patient received second line treatment with nivolumab 240 mg every two weeks, from May to August 2018. However, throughout these months, he experienced progressively worsening fatigue and developed G1 anaemia. After the 6th nivolumab cycle, a CT scan revealed a new cerebellar lesion, confirmed by MRI and treated with stereotactic radiation therapy. The CT exam also documented extensive nodal progression and a left colonic wall thickening, further investigated with a colonoscopy which revealed an ulcerated lesion in the splenic flexure histologically consistent with a lung adenocarcinoma metastasis (Figures 2 and 3). Thus, in September 2018, he underwent palliative segmental resection of the left colon, which confirmed the diagnosis of intestinal metastasis of lung adenocarcinoma (Figure 4). Upon recovery, he began third line chemotherapy with weekly paclitaxel of which he received only two cycles, as he developed both G2 anaemia and melena. A new colonoscopy showed cancer relapse at the site of the previous surgery, whereas a CT scan performed in January 2019 revealed nodal and hepatic progression, along with a femoral vein thrombosis. Because of the latter finding, interventional radiologists positioned an inferior vena cava filter. The patient continued best supportive care and died in August 2019.
3. Discussion
We describe here two cases of metastatic NSCLC with unusual early gastrointestinal progression to the immune checkpoint inhibitor nivolumab. Both patients were heavy smokers (i.e., >30 pack-years) presenting with a squamous cell carcinoma or an adenocarcinoma, the histological variants most frequently associated with pancreatic and intestinal involvement, respectively [3, 4, 8]. However, no data are currently available concerning the EGFR, ALK, and PD-L1 status of these tumours. Consistent with preexisting evidence, clinical manifestations of gastrointestinal metastases were severe and led to treatment discontinuation, heavily worsening the patients' quality of life [5]. Moreover, symptoms were difficult to recognize, and even after radiological diagnosis, a biopsy was mandatory to rule out a second synchronous cancer. Although our patients received additional chemotherapy after discontinuing nivolumab, they lacked any consistent benefit from the subsequent treatment (weekly paclitaxel). However, our patients experienced a 9-month and a 12-month survival from the detection of the enteric lesions, respectively. Hence, their survival is significantly longer than the one reported in the literature (2.8 months) [4, 5].
To the best of our knowledge, this is the first report of gastrointestinal hyperprogression to immunotherapy in lung cancer. Of note, Miyazawa and colleagues reported two cases of metastatic melanoma spreading to the small bowel and the colon during nivolumab treatment [9]. Due to the rapid and extensive disease progression that our patients experienced, we deemed them “hyper-progressors.” Although several studies recently provided an overview about HP, this phenomenon is still matter of debate [10–12]. However, preliminary evidences are emerging about potential molecular biomarkers useful in the timely identification of hyperprogressing patients [11, 13–15]. It is crucial to promptly and correctly recognize NSCLC gastrointestinal progression as this atypical metastatic spread, usually associated with subtle and equivocal symptoms, may result in diagnostic delay. In addition, if an intestinal progression occurs during immunotherapy, its clinical identification can be extremely challenging as it may be potentially mistaken for an immune-related complication. The present report emphasizes the possibility of an unusual enteric metastatic disease in patients affected by NSCLC treated with immune checkpoint inhibitors. As an increasing number of patients will receive anti-PD-1 or anti-PD-L1 antibodies, a concerted effort is needed in order to identify biomarkers predictive of HP.
Data Availability
The underlying data supporting the results of the study can be found in the manuscript.
Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
Authors' Contributions
FM, KL, GP, LM, GM, NI, RC, HSP, AZ, and PV participated in the patient's treatment. GMV and GAM reviewed the histological samples. FM and LM did the literature search. PV, FM, KL, GP, and LM drafted the manuscript. All authors read and approved the final manuscript.
Figure 1 MR imaging of the pancreatic head mass (a) of the larger liver metastasis (b) and of the biliary dilatation (c). CT imaging of the biliary drainage (d).
Figure 2 Endoscopic imaging of lung adenocarcinoma metastasis in the splenic flexure and (a) CT imaging of left colonic wall thickening (b).
Figure 3 Intestinal biopsy: normal colonic mucosa infiltrated by solid-pseudoglandolar carcinoma, positive for CK7 and negative for intestinal differentiation markers, such as CK20 and CDX2 (arrows). Lung adenocarcinomas with prevalent solid pattern may be negative for TTF-1 but often positive for CK7. On the basis of the morpho-immunohistochemical data and clinical history, the diagnosis of intestinal metastasis of lung adenocarcinoma was made.
Figure 4 Surgical findings: the diagnosis of lung adenocarcinoma metastasis was confirmed after surgical resection. The figure shows intramural CK7 positive neoplasia, with a normal underlying colonic mucosa. | CARBOPLATIN, CISPLATIN, PACLITAXEL, PEMETREXED, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY | 33728080 | 19,198,284 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Early Gastrointestinal Progression to Immunotherapy in Lung Cancer: A Report of Two Cases.
Intestinal and pancreatic metastases are rare and often challenging to recognize and manage. Lung cancer patients with enteric involvement usually display poor outcomes. Hyperprogression to immunotherapy represents a concern, even though there is currently no agreement on its exact definition. Gastrointestinal hyperprogression to immune checkpoint inhibitors has not been described so far. In these cases, distinguishing disease-related symptoms from immune-related adverse events may represent a diagnostic conundrum. Here, we report two cases of non-small-cell lung cancer experiencing a rapid pancreatic and colic progression to immunotherapy, respectively. While further investigations to identify biomarkers associated with hyperprogression are warranted, clinicians should be aware of the potential unusual clinical presentations of this phenomenon.
1. Introduction
Lung cancer commonly metastasizes to the bone, contralateral lung, liver, adrenal glands, brain, and lymph nodes, but less frequently it spreads to other anatomic sites, including the gastrointestinal system [1, 2]. Indeed, enteric metastases have been infrequently described in patients with non-small-cell lung cancer (NSCLC). Clinical presentation can be either abrupt with bleeding, bowel obstruction, or perforation, requiring intensive care in a hospital setting, or subacute, with abdominal pain, progressive anaemia, or jaundice. Unfortunately, patients with gastrointestinal metastases display a dismal prognosis regardless of their clinical presentation [3–5]. While immunotherapy has significantly improved the outcomes of stage IV NSCLC, a subset of patients receiving immune checkpoint inhibitors experience rapid disease evolution during treatment, a phenomenon known as hyperprogression (HP) [6, 7]. To the best of our knowledge, no data are available about the occurrence of gastrointestinal HP to immunotherapy in lung cancer.
Here, we report two cases of NSCLC with a rapid and unusual pancreatic and intestinal progression during treatment with the anti-Programmed Death-1 (PD-1) monoclonal antibody nivolumab.
2. Cases Presentation
2.1. Case#1
In December 2015, a 68-year-old Caucasian man with a 55 pack-years smoking history, chronic obstructive pulmonary disease, type 2 diabetes, hypercholesterolemia, and hypertension presented to the Emergency Room because of persistent cough and haemoptysis. A whole body Computed Tomography (CT) scan revealed a 60 mm mass in the left lung along with several satellite nodules in the same lobe. Both the CT and an ensuing Positron Emission Tomography (PET) scan excluded the presence of distant metastases. Thus, in February 2016, he underwent a left pneumonectomy with lymph nodal dissection. The pathology report indicated the presence of a poorly differentiated squamous cell carcinoma, pT3 (main diameter 60 mm) N0 (0 out of 24) M0 (stage II according to the UICC/AJCC TNM 7th edition). From March to July 2016, he received four cycles of adjuvant cisplatin plus vinorelbine, but one month after completing the last chemotherapy infusion, both CT and PET scans showed hepatic and para-aortic nodal relapse that were confirmed by a liver biopsy. Programmed Death-Ligand 1 (PD-L1) immunohistochemical expression, assessed on the metastatic tissue, was below 1%. Given the short interval between the end of adjuvant chemotherapy and the disease relapse, in September 2016 the patient started a second line treatment with nivolumab 3 mg/kg every two weeks. After the third administration of immunotherapy, he developed progressive jaundice, fever, nausea, and vomiting along with a rise in bilirubin, alkaline phosphatase, and glutamyl-transpeptidase. Because of these symptoms, initially attributed to an immune-related adverse events, the patient was admitted to the oncology ward where he received high-dose corticosteroids (prednisone 1 mg/kg intravenously). However, in the absence of any meaningful clinical benefit after 48 hours, he performed a Magnetic Resonance Imaging (MRI) of the abdomen that showed a bulky lesion of the pancreatic head, partially infiltrating the duodenal wall and causing visible distension of both the Wirsung and the intrahepatic biliary ducts. Moreover, multiple hepatic and nodal metastases emerged (Figure 1). Given these findings, the patient underwent percutaneous trans-hepatic cholangiography with biliary drainage, stenting, and cytological sampling, the latter consistent with lung cancer metastasis. Once bilirubin levels normalized, he began third line chemotherapy with weekly paclitaxel. However, in the following six months his clinical conditions progressively deteriorated, and in June 2017, he developed persistent fever, abdominal pain, anorexia, and weight loss. He therefore suspended active treatment and eventually died in August 2017.
2.2. Case#2
In November 2016, a 69-year-old Caucasian male came to our attention because of the acute onset of dyspnoea and haemoptysis. He was a 35-pack-year former smoker since 2010, and his previous medical history was notable for myocardial infarction, diabetes mellitus, bilateral glaucoma, and benign prostatic hyperplasia. A CT scan showed a 40 × 33 mm mass in the right lung invading the main bronchus, with increased metabolic activity (Standardized Uptake Value (SUV) 41) at the PET scan. An ensuing bronchoscopy indicated the presence of a poorly differentiated lung adenocarcinoma for which he received four cycles of neo-adjuvant chemotherapy with cisplatin and vinorelbine, achieving a satisfactory dimensional and metabolic response. Thus, in April 2017, he underwent a right upper lobectomy with mediastinal node dissection. The pathologist's assessment revealed a 30 mm poorly differentiated adenocarcinoma of the lung, Cytokeratin 7, and Thyroid Transcription Factor 1 (TTF1) positive, with involvement of the main bronchus (pT2b) and no nodal metastases (0 out of 21; stage IIB according to the UICC/AJCC TNM 7th edition). Five months after surgery the patient noticed a rapidly growing subcutaneous lump in his right thigh and another one in his left axilla, both excised and histologically proven to be lung adenocarcinoma metastases. No Epidermal Growth Factor Receptor (EGFR) mutations or Anaplastic Lymphoma Kinase (ALK) translocations were detected, and immunohistochemical staining for PD-L1 was below 1%. Hence, in December 2017, he began first line chemotherapy with carboplatin and pemetrexed, experiencing disease stabilization, followed by pemetrexed maintenance until April 2018, when a CT scan showed an abdominal nodal progression. At this time, the patient received second line treatment with nivolumab 240 mg every two weeks, from May to August 2018. However, throughout these months, he experienced progressively worsening fatigue and developed G1 anaemia. After the 6th nivolumab cycle, a CT scan revealed a new cerebellar lesion, confirmed by MRI and treated with stereotactic radiation therapy. The CT exam also documented extensive nodal progression and a left colonic wall thickening, further investigated with a colonoscopy which revealed an ulcerated lesion in the splenic flexure histologically consistent with a lung adenocarcinoma metastasis (Figures 2 and 3). Thus, in September 2018, he underwent palliative segmental resection of the left colon, which confirmed the diagnosis of intestinal metastasis of lung adenocarcinoma (Figure 4). Upon recovery, he began third line chemotherapy with weekly paclitaxel of which he received only two cycles, as he developed both G2 anaemia and melena. A new colonoscopy showed cancer relapse at the site of the previous surgery, whereas a CT scan performed in January 2019 revealed nodal and hepatic progression, along with a femoral vein thrombosis. Because of the latter finding, interventional radiologists positioned an inferior vena cava filter. The patient continued best supportive care and died in August 2019.
3. Discussion
We describe here two cases of metastatic NSCLC with unusual early gastrointestinal progression to the immune checkpoint inhibitor nivolumab. Both patients were heavy smokers (i.e., >30 pack-years) presenting with a squamous cell carcinoma or an adenocarcinoma, the histological variants most frequently associated with pancreatic and intestinal involvement, respectively [3, 4, 8]. However, no data are currently available concerning the EGFR, ALK, and PD-L1 status of these tumours. Consistent with preexisting evidence, clinical manifestations of gastrointestinal metastases were severe and led to treatment discontinuation, heavily worsening the patients' quality of life [5]. Moreover, symptoms were difficult to recognize, and even after radiological diagnosis, a biopsy was mandatory to rule out a second synchronous cancer. Although our patients received additional chemotherapy after discontinuing nivolumab, they lacked any consistent benefit from the subsequent treatment (weekly paclitaxel). However, our patients experienced a 9-month and a 12-month survival from the detection of the enteric lesions, respectively. Hence, their survival is significantly longer than the one reported in the literature (2.8 months) [4, 5].
To the best of our knowledge, this is the first report of gastrointestinal hyperprogression to immunotherapy in lung cancer. Of note, Miyazawa and colleagues reported two cases of metastatic melanoma spreading to the small bowel and the colon during nivolumab treatment [9]. Due to the rapid and extensive disease progression that our patients experienced, we deemed them “hyper-progressors.” Although several studies recently provided an overview about HP, this phenomenon is still matter of debate [10–12]. However, preliminary evidences are emerging about potential molecular biomarkers useful in the timely identification of hyperprogressing patients [11, 13–15]. It is crucial to promptly and correctly recognize NSCLC gastrointestinal progression as this atypical metastatic spread, usually associated with subtle and equivocal symptoms, may result in diagnostic delay. In addition, if an intestinal progression occurs during immunotherapy, its clinical identification can be extremely challenging as it may be potentially mistaken for an immune-related complication. The present report emphasizes the possibility of an unusual enteric metastatic disease in patients affected by NSCLC treated with immune checkpoint inhibitors. As an increasing number of patients will receive anti-PD-1 or anti-PD-L1 antibodies, a concerted effort is needed in order to identify biomarkers predictive of HP.
Data Availability
The underlying data supporting the results of the study can be found in the manuscript.
Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
Authors' Contributions
FM, KL, GP, LM, GM, NI, RC, HSP, AZ, and PV participated in the patient's treatment. GMV and GAM reviewed the histological samples. FM and LM did the literature search. PV, FM, KL, GP, and LM drafted the manuscript. All authors read and approved the final manuscript.
Figure 1 MR imaging of the pancreatic head mass (a) of the larger liver metastasis (b) and of the biliary dilatation (c). CT imaging of the biliary drainage (d).
Figure 2 Endoscopic imaging of lung adenocarcinoma metastasis in the splenic flexure and (a) CT imaging of left colonic wall thickening (b).
Figure 3 Intestinal biopsy: normal colonic mucosa infiltrated by solid-pseudoglandolar carcinoma, positive for CK7 and negative for intestinal differentiation markers, such as CK20 and CDX2 (arrows). Lung adenocarcinomas with prevalent solid pattern may be negative for TTF-1 but often positive for CK7. On the basis of the morpho-immunohistochemical data and clinical history, the diagnosis of intestinal metastasis of lung adenocarcinoma was made.
Figure 4 Surgical findings: the diagnosis of lung adenocarcinoma metastasis was confirmed after surgical resection. The figure shows intramural CK7 positive neoplasia, with a normal underlying colonic mucosa. | CARBOPLATIN, CISPLATIN, PACLITAXEL, PEMETREXED, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY | 33728080 | 19,198,284 | 2021 |
What was the administration route of drug 'PREDNISONE'? | Early Gastrointestinal Progression to Immunotherapy in Lung Cancer: A Report of Two Cases.
Intestinal and pancreatic metastases are rare and often challenging to recognize and manage. Lung cancer patients with enteric involvement usually display poor outcomes. Hyperprogression to immunotherapy represents a concern, even though there is currently no agreement on its exact definition. Gastrointestinal hyperprogression to immune checkpoint inhibitors has not been described so far. In these cases, distinguishing disease-related symptoms from immune-related adverse events may represent a diagnostic conundrum. Here, we report two cases of non-small-cell lung cancer experiencing a rapid pancreatic and colic progression to immunotherapy, respectively. While further investigations to identify biomarkers associated with hyperprogression are warranted, clinicians should be aware of the potential unusual clinical presentations of this phenomenon.
1. Introduction
Lung cancer commonly metastasizes to the bone, contralateral lung, liver, adrenal glands, brain, and lymph nodes, but less frequently it spreads to other anatomic sites, including the gastrointestinal system [1, 2]. Indeed, enteric metastases have been infrequently described in patients with non-small-cell lung cancer (NSCLC). Clinical presentation can be either abrupt with bleeding, bowel obstruction, or perforation, requiring intensive care in a hospital setting, or subacute, with abdominal pain, progressive anaemia, or jaundice. Unfortunately, patients with gastrointestinal metastases display a dismal prognosis regardless of their clinical presentation [3–5]. While immunotherapy has significantly improved the outcomes of stage IV NSCLC, a subset of patients receiving immune checkpoint inhibitors experience rapid disease evolution during treatment, a phenomenon known as hyperprogression (HP) [6, 7]. To the best of our knowledge, no data are available about the occurrence of gastrointestinal HP to immunotherapy in lung cancer.
Here, we report two cases of NSCLC with a rapid and unusual pancreatic and intestinal progression during treatment with the anti-Programmed Death-1 (PD-1) monoclonal antibody nivolumab.
2. Cases Presentation
2.1. Case#1
In December 2015, a 68-year-old Caucasian man with a 55 pack-years smoking history, chronic obstructive pulmonary disease, type 2 diabetes, hypercholesterolemia, and hypertension presented to the Emergency Room because of persistent cough and haemoptysis. A whole body Computed Tomography (CT) scan revealed a 60 mm mass in the left lung along with several satellite nodules in the same lobe. Both the CT and an ensuing Positron Emission Tomography (PET) scan excluded the presence of distant metastases. Thus, in February 2016, he underwent a left pneumonectomy with lymph nodal dissection. The pathology report indicated the presence of a poorly differentiated squamous cell carcinoma, pT3 (main diameter 60 mm) N0 (0 out of 24) M0 (stage II according to the UICC/AJCC TNM 7th edition). From March to July 2016, he received four cycles of adjuvant cisplatin plus vinorelbine, but one month after completing the last chemotherapy infusion, both CT and PET scans showed hepatic and para-aortic nodal relapse that were confirmed by a liver biopsy. Programmed Death-Ligand 1 (PD-L1) immunohistochemical expression, assessed on the metastatic tissue, was below 1%. Given the short interval between the end of adjuvant chemotherapy and the disease relapse, in September 2016 the patient started a second line treatment with nivolumab 3 mg/kg every two weeks. After the third administration of immunotherapy, he developed progressive jaundice, fever, nausea, and vomiting along with a rise in bilirubin, alkaline phosphatase, and glutamyl-transpeptidase. Because of these symptoms, initially attributed to an immune-related adverse events, the patient was admitted to the oncology ward where he received high-dose corticosteroids (prednisone 1 mg/kg intravenously). However, in the absence of any meaningful clinical benefit after 48 hours, he performed a Magnetic Resonance Imaging (MRI) of the abdomen that showed a bulky lesion of the pancreatic head, partially infiltrating the duodenal wall and causing visible distension of both the Wirsung and the intrahepatic biliary ducts. Moreover, multiple hepatic and nodal metastases emerged (Figure 1). Given these findings, the patient underwent percutaneous trans-hepatic cholangiography with biliary drainage, stenting, and cytological sampling, the latter consistent with lung cancer metastasis. Once bilirubin levels normalized, he began third line chemotherapy with weekly paclitaxel. However, in the following six months his clinical conditions progressively deteriorated, and in June 2017, he developed persistent fever, abdominal pain, anorexia, and weight loss. He therefore suspended active treatment and eventually died in August 2017.
2.2. Case#2
In November 2016, a 69-year-old Caucasian male came to our attention because of the acute onset of dyspnoea and haemoptysis. He was a 35-pack-year former smoker since 2010, and his previous medical history was notable for myocardial infarction, diabetes mellitus, bilateral glaucoma, and benign prostatic hyperplasia. A CT scan showed a 40 × 33 mm mass in the right lung invading the main bronchus, with increased metabolic activity (Standardized Uptake Value (SUV) 41) at the PET scan. An ensuing bronchoscopy indicated the presence of a poorly differentiated lung adenocarcinoma for which he received four cycles of neo-adjuvant chemotherapy with cisplatin and vinorelbine, achieving a satisfactory dimensional and metabolic response. Thus, in April 2017, he underwent a right upper lobectomy with mediastinal node dissection. The pathologist's assessment revealed a 30 mm poorly differentiated adenocarcinoma of the lung, Cytokeratin 7, and Thyroid Transcription Factor 1 (TTF1) positive, with involvement of the main bronchus (pT2b) and no nodal metastases (0 out of 21; stage IIB according to the UICC/AJCC TNM 7th edition). Five months after surgery the patient noticed a rapidly growing subcutaneous lump in his right thigh and another one in his left axilla, both excised and histologically proven to be lung adenocarcinoma metastases. No Epidermal Growth Factor Receptor (EGFR) mutations or Anaplastic Lymphoma Kinase (ALK) translocations were detected, and immunohistochemical staining for PD-L1 was below 1%. Hence, in December 2017, he began first line chemotherapy with carboplatin and pemetrexed, experiencing disease stabilization, followed by pemetrexed maintenance until April 2018, when a CT scan showed an abdominal nodal progression. At this time, the patient received second line treatment with nivolumab 240 mg every two weeks, from May to August 2018. However, throughout these months, he experienced progressively worsening fatigue and developed G1 anaemia. After the 6th nivolumab cycle, a CT scan revealed a new cerebellar lesion, confirmed by MRI and treated with stereotactic radiation therapy. The CT exam also documented extensive nodal progression and a left colonic wall thickening, further investigated with a colonoscopy which revealed an ulcerated lesion in the splenic flexure histologically consistent with a lung adenocarcinoma metastasis (Figures 2 and 3). Thus, in September 2018, he underwent palliative segmental resection of the left colon, which confirmed the diagnosis of intestinal metastasis of lung adenocarcinoma (Figure 4). Upon recovery, he began third line chemotherapy with weekly paclitaxel of which he received only two cycles, as he developed both G2 anaemia and melena. A new colonoscopy showed cancer relapse at the site of the previous surgery, whereas a CT scan performed in January 2019 revealed nodal and hepatic progression, along with a femoral vein thrombosis. Because of the latter finding, interventional radiologists positioned an inferior vena cava filter. The patient continued best supportive care and died in August 2019.
3. Discussion
We describe here two cases of metastatic NSCLC with unusual early gastrointestinal progression to the immune checkpoint inhibitor nivolumab. Both patients were heavy smokers (i.e., >30 pack-years) presenting with a squamous cell carcinoma or an adenocarcinoma, the histological variants most frequently associated with pancreatic and intestinal involvement, respectively [3, 4, 8]. However, no data are currently available concerning the EGFR, ALK, and PD-L1 status of these tumours. Consistent with preexisting evidence, clinical manifestations of gastrointestinal metastases were severe and led to treatment discontinuation, heavily worsening the patients' quality of life [5]. Moreover, symptoms were difficult to recognize, and even after radiological diagnosis, a biopsy was mandatory to rule out a second synchronous cancer. Although our patients received additional chemotherapy after discontinuing nivolumab, they lacked any consistent benefit from the subsequent treatment (weekly paclitaxel). However, our patients experienced a 9-month and a 12-month survival from the detection of the enteric lesions, respectively. Hence, their survival is significantly longer than the one reported in the literature (2.8 months) [4, 5].
To the best of our knowledge, this is the first report of gastrointestinal hyperprogression to immunotherapy in lung cancer. Of note, Miyazawa and colleagues reported two cases of metastatic melanoma spreading to the small bowel and the colon during nivolumab treatment [9]. Due to the rapid and extensive disease progression that our patients experienced, we deemed them “hyper-progressors.” Although several studies recently provided an overview about HP, this phenomenon is still matter of debate [10–12]. However, preliminary evidences are emerging about potential molecular biomarkers useful in the timely identification of hyperprogressing patients [11, 13–15]. It is crucial to promptly and correctly recognize NSCLC gastrointestinal progression as this atypical metastatic spread, usually associated with subtle and equivocal symptoms, may result in diagnostic delay. In addition, if an intestinal progression occurs during immunotherapy, its clinical identification can be extremely challenging as it may be potentially mistaken for an immune-related complication. The present report emphasizes the possibility of an unusual enteric metastatic disease in patients affected by NSCLC treated with immune checkpoint inhibitors. As an increasing number of patients will receive anti-PD-1 or anti-PD-L1 antibodies, a concerted effort is needed in order to identify biomarkers predictive of HP.
Data Availability
The underlying data supporting the results of the study can be found in the manuscript.
Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
Authors' Contributions
FM, KL, GP, LM, GM, NI, RC, HSP, AZ, and PV participated in the patient's treatment. GMV and GAM reviewed the histological samples. FM and LM did the literature search. PV, FM, KL, GP, and LM drafted the manuscript. All authors read and approved the final manuscript.
Figure 1 MR imaging of the pancreatic head mass (a) of the larger liver metastasis (b) and of the biliary dilatation (c). CT imaging of the biliary drainage (d).
Figure 2 Endoscopic imaging of lung adenocarcinoma metastasis in the splenic flexure and (a) CT imaging of left colonic wall thickening (b).
Figure 3 Intestinal biopsy: normal colonic mucosa infiltrated by solid-pseudoglandolar carcinoma, positive for CK7 and negative for intestinal differentiation markers, such as CK20 and CDX2 (arrows). Lung adenocarcinomas with prevalent solid pattern may be negative for TTF-1 but often positive for CK7. On the basis of the morpho-immunohistochemical data and clinical history, the diagnosis of intestinal metastasis of lung adenocarcinoma was made.
Figure 4 Surgical findings: the diagnosis of lung adenocarcinoma metastasis was confirmed after surgical resection. The figure shows intramural CK7 positive neoplasia, with a normal underlying colonic mucosa. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33728080 | 19,184,707 | 2021 |
What was the dosage of drug 'CISPLATIN'? | Early Gastrointestinal Progression to Immunotherapy in Lung Cancer: A Report of Two Cases.
Intestinal and pancreatic metastases are rare and often challenging to recognize and manage. Lung cancer patients with enteric involvement usually display poor outcomes. Hyperprogression to immunotherapy represents a concern, even though there is currently no agreement on its exact definition. Gastrointestinal hyperprogression to immune checkpoint inhibitors has not been described so far. In these cases, distinguishing disease-related symptoms from immune-related adverse events may represent a diagnostic conundrum. Here, we report two cases of non-small-cell lung cancer experiencing a rapid pancreatic and colic progression to immunotherapy, respectively. While further investigations to identify biomarkers associated with hyperprogression are warranted, clinicians should be aware of the potential unusual clinical presentations of this phenomenon.
1. Introduction
Lung cancer commonly metastasizes to the bone, contralateral lung, liver, adrenal glands, brain, and lymph nodes, but less frequently it spreads to other anatomic sites, including the gastrointestinal system [1, 2]. Indeed, enteric metastases have been infrequently described in patients with non-small-cell lung cancer (NSCLC). Clinical presentation can be either abrupt with bleeding, bowel obstruction, or perforation, requiring intensive care in a hospital setting, or subacute, with abdominal pain, progressive anaemia, or jaundice. Unfortunately, patients with gastrointestinal metastases display a dismal prognosis regardless of their clinical presentation [3–5]. While immunotherapy has significantly improved the outcomes of stage IV NSCLC, a subset of patients receiving immune checkpoint inhibitors experience rapid disease evolution during treatment, a phenomenon known as hyperprogression (HP) [6, 7]. To the best of our knowledge, no data are available about the occurrence of gastrointestinal HP to immunotherapy in lung cancer.
Here, we report two cases of NSCLC with a rapid and unusual pancreatic and intestinal progression during treatment with the anti-Programmed Death-1 (PD-1) monoclonal antibody nivolumab.
2. Cases Presentation
2.1. Case#1
In December 2015, a 68-year-old Caucasian man with a 55 pack-years smoking history, chronic obstructive pulmonary disease, type 2 diabetes, hypercholesterolemia, and hypertension presented to the Emergency Room because of persistent cough and haemoptysis. A whole body Computed Tomography (CT) scan revealed a 60 mm mass in the left lung along with several satellite nodules in the same lobe. Both the CT and an ensuing Positron Emission Tomography (PET) scan excluded the presence of distant metastases. Thus, in February 2016, he underwent a left pneumonectomy with lymph nodal dissection. The pathology report indicated the presence of a poorly differentiated squamous cell carcinoma, pT3 (main diameter 60 mm) N0 (0 out of 24) M0 (stage II according to the UICC/AJCC TNM 7th edition). From March to July 2016, he received four cycles of adjuvant cisplatin plus vinorelbine, but one month after completing the last chemotherapy infusion, both CT and PET scans showed hepatic and para-aortic nodal relapse that were confirmed by a liver biopsy. Programmed Death-Ligand 1 (PD-L1) immunohistochemical expression, assessed on the metastatic tissue, was below 1%. Given the short interval between the end of adjuvant chemotherapy and the disease relapse, in September 2016 the patient started a second line treatment with nivolumab 3 mg/kg every two weeks. After the third administration of immunotherapy, he developed progressive jaundice, fever, nausea, and vomiting along with a rise in bilirubin, alkaline phosphatase, and glutamyl-transpeptidase. Because of these symptoms, initially attributed to an immune-related adverse events, the patient was admitted to the oncology ward where he received high-dose corticosteroids (prednisone 1 mg/kg intravenously). However, in the absence of any meaningful clinical benefit after 48 hours, he performed a Magnetic Resonance Imaging (MRI) of the abdomen that showed a bulky lesion of the pancreatic head, partially infiltrating the duodenal wall and causing visible distension of both the Wirsung and the intrahepatic biliary ducts. Moreover, multiple hepatic and nodal metastases emerged (Figure 1). Given these findings, the patient underwent percutaneous trans-hepatic cholangiography with biliary drainage, stenting, and cytological sampling, the latter consistent with lung cancer metastasis. Once bilirubin levels normalized, he began third line chemotherapy with weekly paclitaxel. However, in the following six months his clinical conditions progressively deteriorated, and in June 2017, he developed persistent fever, abdominal pain, anorexia, and weight loss. He therefore suspended active treatment and eventually died in August 2017.
2.2. Case#2
In November 2016, a 69-year-old Caucasian male came to our attention because of the acute onset of dyspnoea and haemoptysis. He was a 35-pack-year former smoker since 2010, and his previous medical history was notable for myocardial infarction, diabetes mellitus, bilateral glaucoma, and benign prostatic hyperplasia. A CT scan showed a 40 × 33 mm mass in the right lung invading the main bronchus, with increased metabolic activity (Standardized Uptake Value (SUV) 41) at the PET scan. An ensuing bronchoscopy indicated the presence of a poorly differentiated lung adenocarcinoma for which he received four cycles of neo-adjuvant chemotherapy with cisplatin and vinorelbine, achieving a satisfactory dimensional and metabolic response. Thus, in April 2017, he underwent a right upper lobectomy with mediastinal node dissection. The pathologist's assessment revealed a 30 mm poorly differentiated adenocarcinoma of the lung, Cytokeratin 7, and Thyroid Transcription Factor 1 (TTF1) positive, with involvement of the main bronchus (pT2b) and no nodal metastases (0 out of 21; stage IIB according to the UICC/AJCC TNM 7th edition). Five months after surgery the patient noticed a rapidly growing subcutaneous lump in his right thigh and another one in his left axilla, both excised and histologically proven to be lung adenocarcinoma metastases. No Epidermal Growth Factor Receptor (EGFR) mutations or Anaplastic Lymphoma Kinase (ALK) translocations were detected, and immunohistochemical staining for PD-L1 was below 1%. Hence, in December 2017, he began first line chemotherapy with carboplatin and pemetrexed, experiencing disease stabilization, followed by pemetrexed maintenance until April 2018, when a CT scan showed an abdominal nodal progression. At this time, the patient received second line treatment with nivolumab 240 mg every two weeks, from May to August 2018. However, throughout these months, he experienced progressively worsening fatigue and developed G1 anaemia. After the 6th nivolumab cycle, a CT scan revealed a new cerebellar lesion, confirmed by MRI and treated with stereotactic radiation therapy. The CT exam also documented extensive nodal progression and a left colonic wall thickening, further investigated with a colonoscopy which revealed an ulcerated lesion in the splenic flexure histologically consistent with a lung adenocarcinoma metastasis (Figures 2 and 3). Thus, in September 2018, he underwent palliative segmental resection of the left colon, which confirmed the diagnosis of intestinal metastasis of lung adenocarcinoma (Figure 4). Upon recovery, he began third line chemotherapy with weekly paclitaxel of which he received only two cycles, as he developed both G2 anaemia and melena. A new colonoscopy showed cancer relapse at the site of the previous surgery, whereas a CT scan performed in January 2019 revealed nodal and hepatic progression, along with a femoral vein thrombosis. Because of the latter finding, interventional radiologists positioned an inferior vena cava filter. The patient continued best supportive care and died in August 2019.
3. Discussion
We describe here two cases of metastatic NSCLC with unusual early gastrointestinal progression to the immune checkpoint inhibitor nivolumab. Both patients were heavy smokers (i.e., >30 pack-years) presenting with a squamous cell carcinoma or an adenocarcinoma, the histological variants most frequently associated with pancreatic and intestinal involvement, respectively [3, 4, 8]. However, no data are currently available concerning the EGFR, ALK, and PD-L1 status of these tumours. Consistent with preexisting evidence, clinical manifestations of gastrointestinal metastases were severe and led to treatment discontinuation, heavily worsening the patients' quality of life [5]. Moreover, symptoms were difficult to recognize, and even after radiological diagnosis, a biopsy was mandatory to rule out a second synchronous cancer. Although our patients received additional chemotherapy after discontinuing nivolumab, they lacked any consistent benefit from the subsequent treatment (weekly paclitaxel). However, our patients experienced a 9-month and a 12-month survival from the detection of the enteric lesions, respectively. Hence, their survival is significantly longer than the one reported in the literature (2.8 months) [4, 5].
To the best of our knowledge, this is the first report of gastrointestinal hyperprogression to immunotherapy in lung cancer. Of note, Miyazawa and colleagues reported two cases of metastatic melanoma spreading to the small bowel and the colon during nivolumab treatment [9]. Due to the rapid and extensive disease progression that our patients experienced, we deemed them “hyper-progressors.” Although several studies recently provided an overview about HP, this phenomenon is still matter of debate [10–12]. However, preliminary evidences are emerging about potential molecular biomarkers useful in the timely identification of hyperprogressing patients [11, 13–15]. It is crucial to promptly and correctly recognize NSCLC gastrointestinal progression as this atypical metastatic spread, usually associated with subtle and equivocal symptoms, may result in diagnostic delay. In addition, if an intestinal progression occurs during immunotherapy, its clinical identification can be extremely challenging as it may be potentially mistaken for an immune-related complication. The present report emphasizes the possibility of an unusual enteric metastatic disease in patients affected by NSCLC treated with immune checkpoint inhibitors. As an increasing number of patients will receive anti-PD-1 or anti-PD-L1 antibodies, a concerted effort is needed in order to identify biomarkers predictive of HP.
Data Availability
The underlying data supporting the results of the study can be found in the manuscript.
Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
Authors' Contributions
FM, KL, GP, LM, GM, NI, RC, HSP, AZ, and PV participated in the patient's treatment. GMV and GAM reviewed the histological samples. FM and LM did the literature search. PV, FM, KL, GP, and LM drafted the manuscript. All authors read and approved the final manuscript.
Figure 1 MR imaging of the pancreatic head mass (a) of the larger liver metastasis (b) and of the biliary dilatation (c). CT imaging of the biliary drainage (d).
Figure 2 Endoscopic imaging of lung adenocarcinoma metastasis in the splenic flexure and (a) CT imaging of left colonic wall thickening (b).
Figure 3 Intestinal biopsy: normal colonic mucosa infiltrated by solid-pseudoglandolar carcinoma, positive for CK7 and negative for intestinal differentiation markers, such as CK20 and CDX2 (arrows). Lung adenocarcinomas with prevalent solid pattern may be negative for TTF-1 but often positive for CK7. On the basis of the morpho-immunohistochemical data and clinical history, the diagnosis of intestinal metastasis of lung adenocarcinoma was made.
Figure 4 Surgical findings: the diagnosis of lung adenocarcinoma metastasis was confirmed after surgical resection. The figure shows intramural CK7 positive neoplasia, with a normal underlying colonic mucosa. | FOUR CYCLES | DrugDosageText | CC BY | 33728080 | 19,198,284 | 2021 |
What was the dosage of drug 'PREDNISONE'? | Early Gastrointestinal Progression to Immunotherapy in Lung Cancer: A Report of Two Cases.
Intestinal and pancreatic metastases are rare and often challenging to recognize and manage. Lung cancer patients with enteric involvement usually display poor outcomes. Hyperprogression to immunotherapy represents a concern, even though there is currently no agreement on its exact definition. Gastrointestinal hyperprogression to immune checkpoint inhibitors has not been described so far. In these cases, distinguishing disease-related symptoms from immune-related adverse events may represent a diagnostic conundrum. Here, we report two cases of non-small-cell lung cancer experiencing a rapid pancreatic and colic progression to immunotherapy, respectively. While further investigations to identify biomarkers associated with hyperprogression are warranted, clinicians should be aware of the potential unusual clinical presentations of this phenomenon.
1. Introduction
Lung cancer commonly metastasizes to the bone, contralateral lung, liver, adrenal glands, brain, and lymph nodes, but less frequently it spreads to other anatomic sites, including the gastrointestinal system [1, 2]. Indeed, enteric metastases have been infrequently described in patients with non-small-cell lung cancer (NSCLC). Clinical presentation can be either abrupt with bleeding, bowel obstruction, or perforation, requiring intensive care in a hospital setting, or subacute, with abdominal pain, progressive anaemia, or jaundice. Unfortunately, patients with gastrointestinal metastases display a dismal prognosis regardless of their clinical presentation [3–5]. While immunotherapy has significantly improved the outcomes of stage IV NSCLC, a subset of patients receiving immune checkpoint inhibitors experience rapid disease evolution during treatment, a phenomenon known as hyperprogression (HP) [6, 7]. To the best of our knowledge, no data are available about the occurrence of gastrointestinal HP to immunotherapy in lung cancer.
Here, we report two cases of NSCLC with a rapid and unusual pancreatic and intestinal progression during treatment with the anti-Programmed Death-1 (PD-1) monoclonal antibody nivolumab.
2. Cases Presentation
2.1. Case#1
In December 2015, a 68-year-old Caucasian man with a 55 pack-years smoking history, chronic obstructive pulmonary disease, type 2 diabetes, hypercholesterolemia, and hypertension presented to the Emergency Room because of persistent cough and haemoptysis. A whole body Computed Tomography (CT) scan revealed a 60 mm mass in the left lung along with several satellite nodules in the same lobe. Both the CT and an ensuing Positron Emission Tomography (PET) scan excluded the presence of distant metastases. Thus, in February 2016, he underwent a left pneumonectomy with lymph nodal dissection. The pathology report indicated the presence of a poorly differentiated squamous cell carcinoma, pT3 (main diameter 60 mm) N0 (0 out of 24) M0 (stage II according to the UICC/AJCC TNM 7th edition). From March to July 2016, he received four cycles of adjuvant cisplatin plus vinorelbine, but one month after completing the last chemotherapy infusion, both CT and PET scans showed hepatic and para-aortic nodal relapse that were confirmed by a liver biopsy. Programmed Death-Ligand 1 (PD-L1) immunohistochemical expression, assessed on the metastatic tissue, was below 1%. Given the short interval between the end of adjuvant chemotherapy and the disease relapse, in September 2016 the patient started a second line treatment with nivolumab 3 mg/kg every two weeks. After the third administration of immunotherapy, he developed progressive jaundice, fever, nausea, and vomiting along with a rise in bilirubin, alkaline phosphatase, and glutamyl-transpeptidase. Because of these symptoms, initially attributed to an immune-related adverse events, the patient was admitted to the oncology ward where he received high-dose corticosteroids (prednisone 1 mg/kg intravenously). However, in the absence of any meaningful clinical benefit after 48 hours, he performed a Magnetic Resonance Imaging (MRI) of the abdomen that showed a bulky lesion of the pancreatic head, partially infiltrating the duodenal wall and causing visible distension of both the Wirsung and the intrahepatic biliary ducts. Moreover, multiple hepatic and nodal metastases emerged (Figure 1). Given these findings, the patient underwent percutaneous trans-hepatic cholangiography with biliary drainage, stenting, and cytological sampling, the latter consistent with lung cancer metastasis. Once bilirubin levels normalized, he began third line chemotherapy with weekly paclitaxel. However, in the following six months his clinical conditions progressively deteriorated, and in June 2017, he developed persistent fever, abdominal pain, anorexia, and weight loss. He therefore suspended active treatment and eventually died in August 2017.
2.2. Case#2
In November 2016, a 69-year-old Caucasian male came to our attention because of the acute onset of dyspnoea and haemoptysis. He was a 35-pack-year former smoker since 2010, and his previous medical history was notable for myocardial infarction, diabetes mellitus, bilateral glaucoma, and benign prostatic hyperplasia. A CT scan showed a 40 × 33 mm mass in the right lung invading the main bronchus, with increased metabolic activity (Standardized Uptake Value (SUV) 41) at the PET scan. An ensuing bronchoscopy indicated the presence of a poorly differentiated lung adenocarcinoma for which he received four cycles of neo-adjuvant chemotherapy with cisplatin and vinorelbine, achieving a satisfactory dimensional and metabolic response. Thus, in April 2017, he underwent a right upper lobectomy with mediastinal node dissection. The pathologist's assessment revealed a 30 mm poorly differentiated adenocarcinoma of the lung, Cytokeratin 7, and Thyroid Transcription Factor 1 (TTF1) positive, with involvement of the main bronchus (pT2b) and no nodal metastases (0 out of 21; stage IIB according to the UICC/AJCC TNM 7th edition). Five months after surgery the patient noticed a rapidly growing subcutaneous lump in his right thigh and another one in his left axilla, both excised and histologically proven to be lung adenocarcinoma metastases. No Epidermal Growth Factor Receptor (EGFR) mutations or Anaplastic Lymphoma Kinase (ALK) translocations were detected, and immunohistochemical staining for PD-L1 was below 1%. Hence, in December 2017, he began first line chemotherapy with carboplatin and pemetrexed, experiencing disease stabilization, followed by pemetrexed maintenance until April 2018, when a CT scan showed an abdominal nodal progression. At this time, the patient received second line treatment with nivolumab 240 mg every two weeks, from May to August 2018. However, throughout these months, he experienced progressively worsening fatigue and developed G1 anaemia. After the 6th nivolumab cycle, a CT scan revealed a new cerebellar lesion, confirmed by MRI and treated with stereotactic radiation therapy. The CT exam also documented extensive nodal progression and a left colonic wall thickening, further investigated with a colonoscopy which revealed an ulcerated lesion in the splenic flexure histologically consistent with a lung adenocarcinoma metastasis (Figures 2 and 3). Thus, in September 2018, he underwent palliative segmental resection of the left colon, which confirmed the diagnosis of intestinal metastasis of lung adenocarcinoma (Figure 4). Upon recovery, he began third line chemotherapy with weekly paclitaxel of which he received only two cycles, as he developed both G2 anaemia and melena. A new colonoscopy showed cancer relapse at the site of the previous surgery, whereas a CT scan performed in January 2019 revealed nodal and hepatic progression, along with a femoral vein thrombosis. Because of the latter finding, interventional radiologists positioned an inferior vena cava filter. The patient continued best supportive care and died in August 2019.
3. Discussion
We describe here two cases of metastatic NSCLC with unusual early gastrointestinal progression to the immune checkpoint inhibitor nivolumab. Both patients were heavy smokers (i.e., >30 pack-years) presenting with a squamous cell carcinoma or an adenocarcinoma, the histological variants most frequently associated with pancreatic and intestinal involvement, respectively [3, 4, 8]. However, no data are currently available concerning the EGFR, ALK, and PD-L1 status of these tumours. Consistent with preexisting evidence, clinical manifestations of gastrointestinal metastases were severe and led to treatment discontinuation, heavily worsening the patients' quality of life [5]. Moreover, symptoms were difficult to recognize, and even after radiological diagnosis, a biopsy was mandatory to rule out a second synchronous cancer. Although our patients received additional chemotherapy after discontinuing nivolumab, they lacked any consistent benefit from the subsequent treatment (weekly paclitaxel). However, our patients experienced a 9-month and a 12-month survival from the detection of the enteric lesions, respectively. Hence, their survival is significantly longer than the one reported in the literature (2.8 months) [4, 5].
To the best of our knowledge, this is the first report of gastrointestinal hyperprogression to immunotherapy in lung cancer. Of note, Miyazawa and colleagues reported two cases of metastatic melanoma spreading to the small bowel and the colon during nivolumab treatment [9]. Due to the rapid and extensive disease progression that our patients experienced, we deemed them “hyper-progressors.” Although several studies recently provided an overview about HP, this phenomenon is still matter of debate [10–12]. However, preliminary evidences are emerging about potential molecular biomarkers useful in the timely identification of hyperprogressing patients [11, 13–15]. It is crucial to promptly and correctly recognize NSCLC gastrointestinal progression as this atypical metastatic spread, usually associated with subtle and equivocal symptoms, may result in diagnostic delay. In addition, if an intestinal progression occurs during immunotherapy, its clinical identification can be extremely challenging as it may be potentially mistaken for an immune-related complication. The present report emphasizes the possibility of an unusual enteric metastatic disease in patients affected by NSCLC treated with immune checkpoint inhibitors. As an increasing number of patients will receive anti-PD-1 or anti-PD-L1 antibodies, a concerted effort is needed in order to identify biomarkers predictive of HP.
Data Availability
The underlying data supporting the results of the study can be found in the manuscript.
Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
Authors' Contributions
FM, KL, GP, LM, GM, NI, RC, HSP, AZ, and PV participated in the patient's treatment. GMV and GAM reviewed the histological samples. FM and LM did the literature search. PV, FM, KL, GP, and LM drafted the manuscript. All authors read and approved the final manuscript.
Figure 1 MR imaging of the pancreatic head mass (a) of the larger liver metastasis (b) and of the biliary dilatation (c). CT imaging of the biliary drainage (d).
Figure 2 Endoscopic imaging of lung adenocarcinoma metastasis in the splenic flexure and (a) CT imaging of left colonic wall thickening (b).
Figure 3 Intestinal biopsy: normal colonic mucosa infiltrated by solid-pseudoglandolar carcinoma, positive for CK7 and negative for intestinal differentiation markers, such as CK20 and CDX2 (arrows). Lung adenocarcinomas with prevalent solid pattern may be negative for TTF-1 but often positive for CK7. On the basis of the morpho-immunohistochemical data and clinical history, the diagnosis of intestinal metastasis of lung adenocarcinoma was made.
Figure 4 Surgical findings: the diagnosis of lung adenocarcinoma metastasis was confirmed after surgical resection. The figure shows intramural CK7 positive neoplasia, with a normal underlying colonic mucosa. | 1 MILLIGRAM/KILOGRAM | DrugDosageText | CC BY | 33728080 | 19,184,707 | 2021 |
What was the dosage of drug 'VINORELBINE TARTRATE'? | Early Gastrointestinal Progression to Immunotherapy in Lung Cancer: A Report of Two Cases.
Intestinal and pancreatic metastases are rare and often challenging to recognize and manage. Lung cancer patients with enteric involvement usually display poor outcomes. Hyperprogression to immunotherapy represents a concern, even though there is currently no agreement on its exact definition. Gastrointestinal hyperprogression to immune checkpoint inhibitors has not been described so far. In these cases, distinguishing disease-related symptoms from immune-related adverse events may represent a diagnostic conundrum. Here, we report two cases of non-small-cell lung cancer experiencing a rapid pancreatic and colic progression to immunotherapy, respectively. While further investigations to identify biomarkers associated with hyperprogression are warranted, clinicians should be aware of the potential unusual clinical presentations of this phenomenon.
1. Introduction
Lung cancer commonly metastasizes to the bone, contralateral lung, liver, adrenal glands, brain, and lymph nodes, but less frequently it spreads to other anatomic sites, including the gastrointestinal system [1, 2]. Indeed, enteric metastases have been infrequently described in patients with non-small-cell lung cancer (NSCLC). Clinical presentation can be either abrupt with bleeding, bowel obstruction, or perforation, requiring intensive care in a hospital setting, or subacute, with abdominal pain, progressive anaemia, or jaundice. Unfortunately, patients with gastrointestinal metastases display a dismal prognosis regardless of their clinical presentation [3–5]. While immunotherapy has significantly improved the outcomes of stage IV NSCLC, a subset of patients receiving immune checkpoint inhibitors experience rapid disease evolution during treatment, a phenomenon known as hyperprogression (HP) [6, 7]. To the best of our knowledge, no data are available about the occurrence of gastrointestinal HP to immunotherapy in lung cancer.
Here, we report two cases of NSCLC with a rapid and unusual pancreatic and intestinal progression during treatment with the anti-Programmed Death-1 (PD-1) monoclonal antibody nivolumab.
2. Cases Presentation
2.1. Case#1
In December 2015, a 68-year-old Caucasian man with a 55 pack-years smoking history, chronic obstructive pulmonary disease, type 2 diabetes, hypercholesterolemia, and hypertension presented to the Emergency Room because of persistent cough and haemoptysis. A whole body Computed Tomography (CT) scan revealed a 60 mm mass in the left lung along with several satellite nodules in the same lobe. Both the CT and an ensuing Positron Emission Tomography (PET) scan excluded the presence of distant metastases. Thus, in February 2016, he underwent a left pneumonectomy with lymph nodal dissection. The pathology report indicated the presence of a poorly differentiated squamous cell carcinoma, pT3 (main diameter 60 mm) N0 (0 out of 24) M0 (stage II according to the UICC/AJCC TNM 7th edition). From March to July 2016, he received four cycles of adjuvant cisplatin plus vinorelbine, but one month after completing the last chemotherapy infusion, both CT and PET scans showed hepatic and para-aortic nodal relapse that were confirmed by a liver biopsy. Programmed Death-Ligand 1 (PD-L1) immunohistochemical expression, assessed on the metastatic tissue, was below 1%. Given the short interval between the end of adjuvant chemotherapy and the disease relapse, in September 2016 the patient started a second line treatment with nivolumab 3 mg/kg every two weeks. After the third administration of immunotherapy, he developed progressive jaundice, fever, nausea, and vomiting along with a rise in bilirubin, alkaline phosphatase, and glutamyl-transpeptidase. Because of these symptoms, initially attributed to an immune-related adverse events, the patient was admitted to the oncology ward where he received high-dose corticosteroids (prednisone 1 mg/kg intravenously). However, in the absence of any meaningful clinical benefit after 48 hours, he performed a Magnetic Resonance Imaging (MRI) of the abdomen that showed a bulky lesion of the pancreatic head, partially infiltrating the duodenal wall and causing visible distension of both the Wirsung and the intrahepatic biliary ducts. Moreover, multiple hepatic and nodal metastases emerged (Figure 1). Given these findings, the patient underwent percutaneous trans-hepatic cholangiography with biliary drainage, stenting, and cytological sampling, the latter consistent with lung cancer metastasis. Once bilirubin levels normalized, he began third line chemotherapy with weekly paclitaxel. However, in the following six months his clinical conditions progressively deteriorated, and in June 2017, he developed persistent fever, abdominal pain, anorexia, and weight loss. He therefore suspended active treatment and eventually died in August 2017.
2.2. Case#2
In November 2016, a 69-year-old Caucasian male came to our attention because of the acute onset of dyspnoea and haemoptysis. He was a 35-pack-year former smoker since 2010, and his previous medical history was notable for myocardial infarction, diabetes mellitus, bilateral glaucoma, and benign prostatic hyperplasia. A CT scan showed a 40 × 33 mm mass in the right lung invading the main bronchus, with increased metabolic activity (Standardized Uptake Value (SUV) 41) at the PET scan. An ensuing bronchoscopy indicated the presence of a poorly differentiated lung adenocarcinoma for which he received four cycles of neo-adjuvant chemotherapy with cisplatin and vinorelbine, achieving a satisfactory dimensional and metabolic response. Thus, in April 2017, he underwent a right upper lobectomy with mediastinal node dissection. The pathologist's assessment revealed a 30 mm poorly differentiated adenocarcinoma of the lung, Cytokeratin 7, and Thyroid Transcription Factor 1 (TTF1) positive, with involvement of the main bronchus (pT2b) and no nodal metastases (0 out of 21; stage IIB according to the UICC/AJCC TNM 7th edition). Five months after surgery the patient noticed a rapidly growing subcutaneous lump in his right thigh and another one in his left axilla, both excised and histologically proven to be lung adenocarcinoma metastases. No Epidermal Growth Factor Receptor (EGFR) mutations or Anaplastic Lymphoma Kinase (ALK) translocations were detected, and immunohistochemical staining for PD-L1 was below 1%. Hence, in December 2017, he began first line chemotherapy with carboplatin and pemetrexed, experiencing disease stabilization, followed by pemetrexed maintenance until April 2018, when a CT scan showed an abdominal nodal progression. At this time, the patient received second line treatment with nivolumab 240 mg every two weeks, from May to August 2018. However, throughout these months, he experienced progressively worsening fatigue and developed G1 anaemia. After the 6th nivolumab cycle, a CT scan revealed a new cerebellar lesion, confirmed by MRI and treated with stereotactic radiation therapy. The CT exam also documented extensive nodal progression and a left colonic wall thickening, further investigated with a colonoscopy which revealed an ulcerated lesion in the splenic flexure histologically consistent with a lung adenocarcinoma metastasis (Figures 2 and 3). Thus, in September 2018, he underwent palliative segmental resection of the left colon, which confirmed the diagnosis of intestinal metastasis of lung adenocarcinoma (Figure 4). Upon recovery, he began third line chemotherapy with weekly paclitaxel of which he received only two cycles, as he developed both G2 anaemia and melena. A new colonoscopy showed cancer relapse at the site of the previous surgery, whereas a CT scan performed in January 2019 revealed nodal and hepatic progression, along with a femoral vein thrombosis. Because of the latter finding, interventional radiologists positioned an inferior vena cava filter. The patient continued best supportive care and died in August 2019.
3. Discussion
We describe here two cases of metastatic NSCLC with unusual early gastrointestinal progression to the immune checkpoint inhibitor nivolumab. Both patients were heavy smokers (i.e., >30 pack-years) presenting with a squamous cell carcinoma or an adenocarcinoma, the histological variants most frequently associated with pancreatic and intestinal involvement, respectively [3, 4, 8]. However, no data are currently available concerning the EGFR, ALK, and PD-L1 status of these tumours. Consistent with preexisting evidence, clinical manifestations of gastrointestinal metastases were severe and led to treatment discontinuation, heavily worsening the patients' quality of life [5]. Moreover, symptoms were difficult to recognize, and even after radiological diagnosis, a biopsy was mandatory to rule out a second synchronous cancer. Although our patients received additional chemotherapy after discontinuing nivolumab, they lacked any consistent benefit from the subsequent treatment (weekly paclitaxel). However, our patients experienced a 9-month and a 12-month survival from the detection of the enteric lesions, respectively. Hence, their survival is significantly longer than the one reported in the literature (2.8 months) [4, 5].
To the best of our knowledge, this is the first report of gastrointestinal hyperprogression to immunotherapy in lung cancer. Of note, Miyazawa and colleagues reported two cases of metastatic melanoma spreading to the small bowel and the colon during nivolumab treatment [9]. Due to the rapid and extensive disease progression that our patients experienced, we deemed them “hyper-progressors.” Although several studies recently provided an overview about HP, this phenomenon is still matter of debate [10–12]. However, preliminary evidences are emerging about potential molecular biomarkers useful in the timely identification of hyperprogressing patients [11, 13–15]. It is crucial to promptly and correctly recognize NSCLC gastrointestinal progression as this atypical metastatic spread, usually associated with subtle and equivocal symptoms, may result in diagnostic delay. In addition, if an intestinal progression occurs during immunotherapy, its clinical identification can be extremely challenging as it may be potentially mistaken for an immune-related complication. The present report emphasizes the possibility of an unusual enteric metastatic disease in patients affected by NSCLC treated with immune checkpoint inhibitors. As an increasing number of patients will receive anti-PD-1 or anti-PD-L1 antibodies, a concerted effort is needed in order to identify biomarkers predictive of HP.
Data Availability
The underlying data supporting the results of the study can be found in the manuscript.
Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
Authors' Contributions
FM, KL, GP, LM, GM, NI, RC, HSP, AZ, and PV participated in the patient's treatment. GMV and GAM reviewed the histological samples. FM and LM did the literature search. PV, FM, KL, GP, and LM drafted the manuscript. All authors read and approved the final manuscript.
Figure 1 MR imaging of the pancreatic head mass (a) of the larger liver metastasis (b) and of the biliary dilatation (c). CT imaging of the biliary drainage (d).
Figure 2 Endoscopic imaging of lung adenocarcinoma metastasis in the splenic flexure and (a) CT imaging of left colonic wall thickening (b).
Figure 3 Intestinal biopsy: normal colonic mucosa infiltrated by solid-pseudoglandolar carcinoma, positive for CK7 and negative for intestinal differentiation markers, such as CK20 and CDX2 (arrows). Lung adenocarcinomas with prevalent solid pattern may be negative for TTF-1 but often positive for CK7. On the basis of the morpho-immunohistochemical data and clinical history, the diagnosis of intestinal metastasis of lung adenocarcinoma was made.
Figure 4 Surgical findings: the diagnosis of lung adenocarcinoma metastasis was confirmed after surgical resection. The figure shows intramural CK7 positive neoplasia, with a normal underlying colonic mucosa. | FOUR CYCLES | DrugDosageText | CC BY | 33728080 | 19,198,284 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug intolerance'. | Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided.
The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
1. Background
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive occurrence of typical motor dysfunctions such as resting tremor, rigidity, bradykinesia, and postural instability as well as concurrent nonmotor dysfunctions such as hyposomnia, REM (rapid eye movement) sleep behavior disorder, depression, autonomic dysregulation, cognitive impairments, psychosis, and anxiety disorders [1]. This clinical complexity of PD is mirrored by the current neuropathological understanding of PD. Subsequent disruption of nigrostriatal dopaminergic neurotransmission through degeneration of mesencephalic neurons located in the substantia nigra is accompanied by neurodegenerative processes in other brain areas leading to complex disturbances of neurobiological systems beyond the dopaminergic system including serotonergic and noradrenergic pathways [2]. Notably, dopaminergic dysfunction and serotonergic neuropathology of the basolateral amygdala were associated with anxiety in a rat model of PD and responsive to treatment with levodopa (L-DOPA) [3]. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), anxiety spectrum disorders consist of 12 diagnostic entities [4]. A panic attack is defined as a “discrete period of intense fear or discomfort” where symptoms such as palpitations, sweating, trembling or shaking, shortness of breath, chest pain or discomfort, nausea, dizziness, derealisation or depersonalisation, and fear of dying develop abruptly and can reach their peak within minutes [5]. In a recent cross-sectional study, Rai and colleagues investigated the prevalence of neuropsychiatric disorders, focussing on depression, anxiety, and psychosis in patients with PD. The results indicate depression to be the most common neuropsychiatric comorbidity with a prevalence of 43.7%; anxiety was found in 35.7% of patients with PD [6]. A high prevalence of anxiety disorders in PD was confirmed in other studies [7–9] describing a heterogeneous clinical picture with both sustained and episodic anxiety [8]. However, specific treatment options for anxiety disorders in PD have not been investigated in randomized controlled trials, as stated in a review from 2011 [10]. This high comorbidity of depressive and anxiety symptoms in patients with PD a combination of anti-Parkinson and antidepressant drugs is often clinically indicated. This case demonstrates that drug-drug interactions of antidepressant and anti-Parkinson medications, particularly when including monoamine oxidase (MAO) inhibitors, may result in serotonergic overstimulation and thus require careful consideration and monitoring. Clinically, the combination of moclobemide and rasagiline is hardly encountered and moreover explicitly contraindicated by regulatory agencies. Currently, two isoforms of MAOs, MAO-A and MAO-B, have been characterized in cerebral as well as extracerebral tissues [11] by means of their expression, molecular characteristics, differences in their preferred endogenous, and exogenous substrates and inhibitor-sensitivity [12, 13]. Substrates of MAO-A include serotonin, norepinephrine, and dopamine, whereas MAO-B preferentially degrades the monoamine alkaloid phenylethylamine (regulating the release of norepinephrine and dopamine) as well as the precursor molecule of various organic compounds such as benzylamine [14, 15]. Interestingly, MAO-B activity distinctively increases with age and has repeatedly been shown to be associated with neurodegenerative processes in dementia and PD [16] strengthening the therapeutic rationale and relevance of MAO-inhibitors in PD. The antidepressant moclobemide acts as a reversible and selective inhibitor of MAO-A and is effective in treating major depression [17]. The drug is a prototype of reversible inhibitors of MAO-A agents which target this enzyme in intraneuronal presynaptic regions [18]. A near-maximum inhibitory effect in healthy male volunteers was achieved with a single dosage of 300 mg. Maximum effects, as measured by decreased plasma concentrations of the serotonin-metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxphenyl-glycol, a peripheral noradrenaline-metabolite, were apparent at moclobemide plasma levels greater than 1000 ng/ml [19]. Only one study showed the antidepressant potency of moclobemide in depressed patients with PD and the superior effectiveness of the combination therapy with the MAO-B-inhibitor selegiline on affective symptoms as well as cognition. However, the small number of included patients does not allow to draw conclusions for clinical considerations [20]. Rasagiline belongs to selective blockers of MAO-B, such as selegiline. Rasagiline shows neuroprotective actions in vitro and is used as an anti-Parkinson drug. Chronic administration of a MAO-B-selective dose (0.2 mg/kg daily for 3 weeks) increased striatal dopamine and serotonin levels, while decreasing their metabolism. The drug restored the reduced activity in aged animals in behavioral paradigms to levels seen in young animals [21, 22]. However, in a therapeutic dose alone, it did not alter cerebral monoamine levels in another animal study [22]. Pramipexole is a non-ergoline dopamine receptor agonist (D2-like, D2S full, and D2L, D3, and D4 partial) for the treatment of PD and restless legs syndrome [23, 24]. Moreover, potential effects in treating symptoms of major depression have been reported [25]. Pramipexole also influences serotonergic neurotransmission by increasing activity of serotonergic neurons in the dorsal raphe. [26, 27]. Agomelatine belongs to a new generation of antidepressants since it elicits a dual mechanism of action by targeting the melatonergic system as an antagonist but also works as a serotonin 2C (5-HT2C) receptor antagonist. Studies have shown that treatment with agomelatine results in improvements in depressive symptoms, anxiety, and hypochondria in depressed patients [28].
2. Case Presentation
The 62-year-old female patient was referred to and admitted at the clinic of the Max-Planck-Institute of Psychiatry in Munich, Germany, for diagnostic clarification and treatment of recurring paroxysmal psychovegetative episodes. The patient, a retired school teacher from an urban upper-middle-class socioeconomic background, reported a history of insomnia, fatigue, and depressed mood, which preceded the onset of PD symptoms and worsened after being diagnosed with PD. She was premorbidly well-adjusted before the onset of motor symptoms and had no prior neurologic or psychiatric history. No developmental difficulties were reported. The patient's medical history includes the diagnosis of idiopathic Parkinson's syndrome, a moderate obstructive sleep apnea syndrome treated with a continuous positive airway pressure (CPAP) device, and chronic hypothyroidism following Hashimoto's disease approximately three decades ago and treated with thyroid hormone replacement since. About 6 months before clinical admission in our psychiatric ward, the patient noticed a reduced resilience to physical activity. In the last 4 months, she experienced shortness of breath after walking short distances and her general condition was affected by a feeling of physical weakness, shivering, headaches, and the sensation of facial heat. Unpredictable episodes of anxiety and vegetative symptoms occurred even out of quiescent states. Three months prior to this admission, she was assessed at an emergency department for thoracic pain and dyspnoea. Electrocardiogram (ECG), echocardiography, and blood work did not reveal any abnormalities. She was discharged with the suspected diagnosis of arterial hypertension and was started on ranolazine. Despite this intervention, her symptoms reoccurred and additionally worsened in the weeks prior to this admission. Her general practitioner (GP) recommended a beta blocker to be taken as needed. As ranolazine had no effect on her symptoms, the patient took ranolazine occasionally and discontinued the beta blocker treatment. There was no history of fever, altered sensorium, or neurological deficits except fluctuating motor symptoms associated with her diagnosis of PD. The patient described weight gain of approximately 4 kg during the last year. The patient's prevailing difficulties over the 4 months prior to admission were described as recurring paroxysmal episodes of jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and a darkish red discoloration of scalp and neck. These episodes emerged unexpectedly and were not associated with physical or emotional stress or other triggering factors. The patient reported that she had contacted an emergency physician on several occasions and had been admitted to hospitals twice approximately 3-4 months before her neurologist referred her to the clinic at the Max-Planck-Institute of Psychiatry in Munich, Germany, with a working diagnosis of panic disorder. Medication at admission consisted of moclobemide (450 mg/day), agomelatine (50 mg/day), pramipexole (0.525 mg/day), rasagiline (1 mg/day), L-DOPA+benserazide retard (200+50 mg/day), ranolazine (375 mg/day), and L-thyroxine (100 μg/day). The dose of moclobemide had been increased from 150 mg/day to the current dose about 1 year prior to admission. At the time of the initial mental status examination, the patient was fully alert, attentive, and oriented. She maintained eye contact and provided an informative report. No apparent abnormalities in thought form and content were observed. Cognitive and amnestic functions were intact. Her effect initially appeared euthymic with a normal range though intermittently depressed during the conversation. Her impetus towards social activities and daily activities was decreased. Her psychomotor domain was calm; her voice was quiet and showed tendencies towards decreased prosody. Both her mimic and overall expressive gestures were scarce. Severe insomnia with sleep-onset and disturbed sleep, and daytime fatigue were reported. Appetite was reported as increased over the past months. The patient did not endorse symptoms indicating specific phobia, social anxiety, or generalized anxiety. She reported paroxysmal episodes of psychovegetative strain. The patient was not suicidal; there were no safety concerns with respect to herself or others. General and neurological examination of the 62-year-old female patient (height: 165 cm, weight: 65 kg; BMI: 23.9 kg/m2) revealed a moderate rigor of the right upper extremity, adiadochokinesia, normal gait pattern, onychomycosis of toe nails, bilateral hallux valgus, and hyperkyphosis of the thoracic spine. No other physical or neurological abnormalities were detected. There was no postural imbalance or tremor. Vital signs at admission included blood pressure of 140/80 mmHg, heartrate of 84/min, and temperature of 36.4°C. Differential diagnoses considered at admission for reported paroxysmal episodes of psychovegetative symptoms included panic attacks/panic disorder, somatoform autonomic disorder, arterial hypertension with hypertensive exacerbations, iatrogenic hyperthyroidism, asthmatic disorder, and drug-induced serotonin toxicity. Clinical laboratory analyses did not reveal abnormal findings in CBC (complete blood count), hepatic and renal function, glucose and lipid profile, and electrolytes. Free T3 (triiodothyronine), free T4 (thyroxine), and TSH (thyroid stimulating hormone) were within normal limits. The plasma concentration of moclobemide (3310 ng/ml) was above the reference range of 300-1000 ng/ml. Plasma concentrations of agomelatine were not detectable (<1 ng/ml). We suspected potential pharmacological interactions to be a contributing factor to the symptoms reported by the patient at admission, and moclobemide, rasagiline, and ranolazine were discontinued. On the following day, the patient already experienced a decrease of psychovegetative symptoms. The blood work showed normal thyroid parameters, and no remarkable structural abnormalities of the thyroid gland were detected by sonography. Thus, we could rule out the possibility of iatrogenic hyperthyroidism. Moreover, repeated ECG examinations did not show signs of cardiac abnormalities explaining the patient's vegetative symptoms (ECG showed normal sinus rhythm, heart rate 81/min, QTc 429 ms, and vertical position). The changes of anti-parkinson medications during the stay were performed under repeated supervision of the consultant neurologists. As the discontinuation of ranolazine, which was prescribed as an antianginal medication, did not result in changes of blood pressure, we could also rule out arterial hypertension as a causative factor. The electroencephalogram (EEG) showed a regular, well-modulated, indistinct alpha-EEG with occipital accentuation and a frequency of 10-11 Hz and amplitudes reaching up to 100 μV, a well-pronounced visual blockade and intermitted alpha-disintegration. A second EEG did not show any relevant changes. The magnetic resonance imaging (MRI) of the brain showed a slight expansion of the external frontal cerebrospinal fluid space and around the upper cerebellar vermis space. Disseminated, age-inappropriate, supratentorial small hyperintensities of the medullary layer were found. MRI-scan of the cervical and thoracic spine did not show any pathological findings. Due to the atypical localization of some lesions (i.e., near the corpus callosum and the right temporo-polar region), additional brain MRI-scan with contrast (gadolinium) was performed but results did not indicate an inflammatory process. In addition, lumbar puncture was discussed with the patient, who decided not to undergo this procedure after risks and benefits were explained. As the patient reported insomnia for nearly one decade and as agomelatine 50 mg daily was not effective, this medication was discontinued. After moclobemide, rasagiline, and ranolazine were discontinued based on the hypothesis of serotonergic overstimulation, no further episodic psychovegetative or panic-related symptoms occurred during hospitalization. The patient's blood pressure, which initially showed hypertensive episodes, went back to normal, and no antihypertensive medication was required. For persistent insomnia treatment trials with mirtazapine and trazodone were conducted, mirtazapine was not tolerated and trazodone was inefficient. Finally, sleep-associated symptoms slightly decreased with trimipramine 10 mg at bedtime. We established an antidepressive treatment with escitalopram, which was titrated to a dose of 10 mg. As per suggestions of consulting neurologists, pramipexole was reduced and discontinued. Because this was followed by an increase in PD-associated motor symptoms, we initiated treatment with rotigotine transdermal application of 8 mg/day. Levodopa/benserazide retard was switched to nonretard formulation of 125 mg three times a day. With this medication regimen, a stable and sufficient mobility could be achieved. Medication at discharge included escitalopram 10 mg/day, levodopa/benserazide 125 mg three times per day, rotigotine transdermal 8 mg/day, trimipramine 10 mg/day, and levothyroxine 100 μg/day. The patient rated her mood as 9-10/10 on a scale from 0 to 10 with 10 being euthymic mood. The symptoms leading to admission subsided following discontinuation of MAO inhibitors moclobemide and rasagiline and did not reoccur during hospitalization.
3. Discussion and Conclusions
In this case report, we describe a probable drug-induced serotonergic overstimulation with paroxysmal exacerbations in a patient with PD. As other differential diagnoses could be ruled out, we suggest an interaction of several serotonergic medications, i.e., MAO-A inhibitor moclobemide and MAO-B inhibitor rasagiline as a causal factor. The hypothesis of a drug-induced symptomatology rather than genuine panic attacks is supported by subsiding of symptoms after discontinuation of both moclobemide and rasagiline, together with ranolazine. In addition, the paroxysmal episodes including jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and darkish red discoloration (flush) of the scalp and neck were suggestive of drug-induced monoaminergic overstimulation. We are not aware of another case report describing serotonin toxicity with this combination in the context of Parkinson's disease. Several subtypes of panic attacks have been described in the literature [29] postulating cardiac, cardiovascular, neurological, respiratory, and vestibular classifications of panic attacks [30]. Patients presenting with chest pain frequently show symptoms/criteria for panic disorder [31] which results in diagnostic uncertainty, and in the presented case, coronary vasospasms of unknown origin had been previously suspected and treated with ranolazine. However, as the patient did not experience a significant effect on her symptoms, she reported at admission that she had been taking ranolazine not regularly and the discontinuation of ranolazine at admission did not result in the occurrence of cardiovascular symptoms. On the contrary, the patient's physical activity, i.e., walking longer distances, was restored after motor symptoms were additionally stabilized by adjusting anti-Parkinson medication as described in detail above. The serotonin syndrome is commonly perceived as a potentially fatal entity following exposure to serotonergic substances. The risk is increased with combination of two or more drugs which directly enhance postsynaptic serotonin levels. However, serotonin toxicity could reflect a continuous, dose-related phenomenon with serotonin syndrome being the maximum clinical manifestation of serotonin toxicity [32]. Frequently, the clinical symptoms of serotonin toxicity develop rapidly when a serotonergic drug is added to a preexisting medication with stimulating effects on serotonin neurotransmission [33]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs of these compounds as well as that of levodopa/benserazide and to our knowledge clinical guidelines are not supporting this combination. Due to the high prevalence of psychiatric symptoms and psychiatric comorbidities in patients with PD, combined pharmacological treatment with anti-Parkinson drugs and drugs for treatment of depression and anxiety symptoms are often inevitable. In general, hypotheses and assumptions described in this case report have certain limitations. Quantitative measurements of plasma serotonin and other monoamines as well as their respective metabolites, i.e., urinary or CSF levels of 5-HIAA, have not been determined. Thus, our conclusions with respect to the aetiology of the patient's symptoms are mainly supported by the patient's medical history, clinical symptoms, considerations of drug-drug interactions, and rapid clinical improvement after discontinuation of suspected drugs, i.e., moclobemide and rasagiline. The pharmacological interactions between moclobemide (MAO-A inhibitor) and rasagiline (MAO-B inhibitor) likely resulted in intolerable side effects as described above. We speculate that the dual inhibition of MAO-A and MAO-B may have led to MAO-inhibition comparable to the effect of irreversible MAO-inhibitors such as tranylcypromine despite the reversible nature of MAO-A inhibition by moclobemide. This may have been intermittently potentiated by dietary amines since the patient was not on a low tyramine diet [17]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs and to our knowledge clinical guidelines are not supporting this combination. We assume that moclobemide had been taken into consideration despite strong arguments against, including formal contraindication label, after a number of antidepressants were previously prescribed but eventually discontinued due to side effects and recurrence of depressive symptoms. Interestingly, when moclobemide had been given at a low dose of 150 mg daily in combination with rasagiline, the patient did indeed benefit for approximately 3 years describing improvement of depressive symptoms and good tolerability. Reported psychovegetative symptoms occurred for the first time 6 months after the dose increase of moclobemide to 450 mg daily. This long delay in onset of adverse effects related to increasing oscillations of serotonin toxicity may explain why drug-drug interactions were discarded as a potential cause by physicians. The aspect that MAO-B activity increases with age [16] may have additionally contributed to this delayed onset of symptoms. The significant reduction of MAO-B as demonstrated by Bitsios et al. who found an approximately 29% reduction in human platelet MAO-B activity after a single dosage of 450 mg moclobemide [34] and the supratherapeutic plasma concentration of moclobemide (3310 ng/ml) we detected in our patient likely constitute additional contributing factors. Hence, the following clinically relevant main aspects can be derived from the case report at hand to improve patient safety and care: The importance of assessing and considering drug-drug interactions: our patient has been prescribed with a contraindicated combination of two drugs. We believe that the association of reported symptoms with adverse effects due to a drug-drug interaction was not addressed by the patient's initial prescriber, GP and ER (emergency room) physicians. The fact that the treatment was well tolerated by the patient for a prolonged period of time has likely contributed to this outcome. The case presented here highlights the importance of comprehensive and thorough assessment of pharmacological treatment and medication history and that drug-drug interactions should always be considered a potential etiological factor of clinical symptoms. This is of particular relevance for drugs where interactions have been reported as well as drugs that are not commonly prescribed or usually prescribed by different disciplines.
Drug-induced serotonergic overstimulation occurring on a continuous spectrum of changes in serotonergic neurotransmission: to the best of our knowledge, this is the first case report of a patient with PD with potentially drug-induced chronic serotonergic overstimulation with intermittent clinical exacerbations mimicking panic attacks. Most likely, this was caused by combined treatment with an antidepressant (moclobemide; MAO-A inhibitor) and anti-Parkinson medication (rasagiline; MAO-B inhibitor). Interestingly, signs of serotonin toxicity probably developed following an increase of moclobemide from 150 to 450 mg daily and “although polypharmacy is an important etiological factor in the development of serotonin syndrome per se, dose and speed of distribution may determine its severity" [35]. We believe that this case report can support the clinically relevant assumption that drug-induced serotonergic overstimulation may occur on a continuous spectrum of changes in serotonergic neurotransmission which may present as mild clinical symptoms, clinical exacerbations, or the potentially life-threatening condition of serotonin syndrome.
Acknowledgments
We are grateful to our patient who has provided consent for the publication of this case report.
Abbreviations
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-Hydroxytryptamine/serotonin
CBC: Complete blood count
ECG: Electrocardiogram
EEG: Electroencephalogram
ER: Emergency room
L-DOPA: Levodopa/L-3,4-dihydroxyphenylalanine
GP: General practitioner
MAO: Monoamine oxidase
MRI: Magnetic resonance imaging
PD: Parkinson's disease
REM: Rapid eye movement
T3: Triiodothyronine
T4: Thyroxine
TSH: Thyroid stimulating hormone.
Consent
The patient has provided written consent for publication.
Conflicts of Interest
The authors report no competing interests/conflicts of interest.
Authors' Contributions
All authors substantially contributed to the clinical assessments, evaluation, and treatment of the patient as well as generation and interpretation of results. M.P. drafted the initial version of the manuscript. All authors reviewed and substantially revised the manuscript. All authors have approved the submitted manuscript, are accountable for this contribution, and ensure accuracy and integrity of this work. | AGOMELATINE, BENSERAZIDE\LEVODOPA, LEVOTHYROXINE, MIRTAZAPINE, MOCLOBEMIDE, PRAMIPEXOLE, RANOLAZINE, RASAGILINE, TRAZODONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33728085 | 19,155,273 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided.
The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
1. Background
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive occurrence of typical motor dysfunctions such as resting tremor, rigidity, bradykinesia, and postural instability as well as concurrent nonmotor dysfunctions such as hyposomnia, REM (rapid eye movement) sleep behavior disorder, depression, autonomic dysregulation, cognitive impairments, psychosis, and anxiety disorders [1]. This clinical complexity of PD is mirrored by the current neuropathological understanding of PD. Subsequent disruption of nigrostriatal dopaminergic neurotransmission through degeneration of mesencephalic neurons located in the substantia nigra is accompanied by neurodegenerative processes in other brain areas leading to complex disturbances of neurobiological systems beyond the dopaminergic system including serotonergic and noradrenergic pathways [2]. Notably, dopaminergic dysfunction and serotonergic neuropathology of the basolateral amygdala were associated with anxiety in a rat model of PD and responsive to treatment with levodopa (L-DOPA) [3]. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), anxiety spectrum disorders consist of 12 diagnostic entities [4]. A panic attack is defined as a “discrete period of intense fear or discomfort” where symptoms such as palpitations, sweating, trembling or shaking, shortness of breath, chest pain or discomfort, nausea, dizziness, derealisation or depersonalisation, and fear of dying develop abruptly and can reach their peak within minutes [5]. In a recent cross-sectional study, Rai and colleagues investigated the prevalence of neuropsychiatric disorders, focussing on depression, anxiety, and psychosis in patients with PD. The results indicate depression to be the most common neuropsychiatric comorbidity with a prevalence of 43.7%; anxiety was found in 35.7% of patients with PD [6]. A high prevalence of anxiety disorders in PD was confirmed in other studies [7–9] describing a heterogeneous clinical picture with both sustained and episodic anxiety [8]. However, specific treatment options for anxiety disorders in PD have not been investigated in randomized controlled trials, as stated in a review from 2011 [10]. This high comorbidity of depressive and anxiety symptoms in patients with PD a combination of anti-Parkinson and antidepressant drugs is often clinically indicated. This case demonstrates that drug-drug interactions of antidepressant and anti-Parkinson medications, particularly when including monoamine oxidase (MAO) inhibitors, may result in serotonergic overstimulation and thus require careful consideration and monitoring. Clinically, the combination of moclobemide and rasagiline is hardly encountered and moreover explicitly contraindicated by regulatory agencies. Currently, two isoforms of MAOs, MAO-A and MAO-B, have been characterized in cerebral as well as extracerebral tissues [11] by means of their expression, molecular characteristics, differences in their preferred endogenous, and exogenous substrates and inhibitor-sensitivity [12, 13]. Substrates of MAO-A include serotonin, norepinephrine, and dopamine, whereas MAO-B preferentially degrades the monoamine alkaloid phenylethylamine (regulating the release of norepinephrine and dopamine) as well as the precursor molecule of various organic compounds such as benzylamine [14, 15]. Interestingly, MAO-B activity distinctively increases with age and has repeatedly been shown to be associated with neurodegenerative processes in dementia and PD [16] strengthening the therapeutic rationale and relevance of MAO-inhibitors in PD. The antidepressant moclobemide acts as a reversible and selective inhibitor of MAO-A and is effective in treating major depression [17]. The drug is a prototype of reversible inhibitors of MAO-A agents which target this enzyme in intraneuronal presynaptic regions [18]. A near-maximum inhibitory effect in healthy male volunteers was achieved with a single dosage of 300 mg. Maximum effects, as measured by decreased plasma concentrations of the serotonin-metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxphenyl-glycol, a peripheral noradrenaline-metabolite, were apparent at moclobemide plasma levels greater than 1000 ng/ml [19]. Only one study showed the antidepressant potency of moclobemide in depressed patients with PD and the superior effectiveness of the combination therapy with the MAO-B-inhibitor selegiline on affective symptoms as well as cognition. However, the small number of included patients does not allow to draw conclusions for clinical considerations [20]. Rasagiline belongs to selective blockers of MAO-B, such as selegiline. Rasagiline shows neuroprotective actions in vitro and is used as an anti-Parkinson drug. Chronic administration of a MAO-B-selective dose (0.2 mg/kg daily for 3 weeks) increased striatal dopamine and serotonin levels, while decreasing their metabolism. The drug restored the reduced activity in aged animals in behavioral paradigms to levels seen in young animals [21, 22]. However, in a therapeutic dose alone, it did not alter cerebral monoamine levels in another animal study [22]. Pramipexole is a non-ergoline dopamine receptor agonist (D2-like, D2S full, and D2L, D3, and D4 partial) for the treatment of PD and restless legs syndrome [23, 24]. Moreover, potential effects in treating symptoms of major depression have been reported [25]. Pramipexole also influences serotonergic neurotransmission by increasing activity of serotonergic neurons in the dorsal raphe. [26, 27]. Agomelatine belongs to a new generation of antidepressants since it elicits a dual mechanism of action by targeting the melatonergic system as an antagonist but also works as a serotonin 2C (5-HT2C) receptor antagonist. Studies have shown that treatment with agomelatine results in improvements in depressive symptoms, anxiety, and hypochondria in depressed patients [28].
2. Case Presentation
The 62-year-old female patient was referred to and admitted at the clinic of the Max-Planck-Institute of Psychiatry in Munich, Germany, for diagnostic clarification and treatment of recurring paroxysmal psychovegetative episodes. The patient, a retired school teacher from an urban upper-middle-class socioeconomic background, reported a history of insomnia, fatigue, and depressed mood, which preceded the onset of PD symptoms and worsened after being diagnosed with PD. She was premorbidly well-adjusted before the onset of motor symptoms and had no prior neurologic or psychiatric history. No developmental difficulties were reported. The patient's medical history includes the diagnosis of idiopathic Parkinson's syndrome, a moderate obstructive sleep apnea syndrome treated with a continuous positive airway pressure (CPAP) device, and chronic hypothyroidism following Hashimoto's disease approximately three decades ago and treated with thyroid hormone replacement since. About 6 months before clinical admission in our psychiatric ward, the patient noticed a reduced resilience to physical activity. In the last 4 months, she experienced shortness of breath after walking short distances and her general condition was affected by a feeling of physical weakness, shivering, headaches, and the sensation of facial heat. Unpredictable episodes of anxiety and vegetative symptoms occurred even out of quiescent states. Three months prior to this admission, she was assessed at an emergency department for thoracic pain and dyspnoea. Electrocardiogram (ECG), echocardiography, and blood work did not reveal any abnormalities. She was discharged with the suspected diagnosis of arterial hypertension and was started on ranolazine. Despite this intervention, her symptoms reoccurred and additionally worsened in the weeks prior to this admission. Her general practitioner (GP) recommended a beta blocker to be taken as needed. As ranolazine had no effect on her symptoms, the patient took ranolazine occasionally and discontinued the beta blocker treatment. There was no history of fever, altered sensorium, or neurological deficits except fluctuating motor symptoms associated with her diagnosis of PD. The patient described weight gain of approximately 4 kg during the last year. The patient's prevailing difficulties over the 4 months prior to admission were described as recurring paroxysmal episodes of jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and a darkish red discoloration of scalp and neck. These episodes emerged unexpectedly and were not associated with physical or emotional stress or other triggering factors. The patient reported that she had contacted an emergency physician on several occasions and had been admitted to hospitals twice approximately 3-4 months before her neurologist referred her to the clinic at the Max-Planck-Institute of Psychiatry in Munich, Germany, with a working diagnosis of panic disorder. Medication at admission consisted of moclobemide (450 mg/day), agomelatine (50 mg/day), pramipexole (0.525 mg/day), rasagiline (1 mg/day), L-DOPA+benserazide retard (200+50 mg/day), ranolazine (375 mg/day), and L-thyroxine (100 μg/day). The dose of moclobemide had been increased from 150 mg/day to the current dose about 1 year prior to admission. At the time of the initial mental status examination, the patient was fully alert, attentive, and oriented. She maintained eye contact and provided an informative report. No apparent abnormalities in thought form and content were observed. Cognitive and amnestic functions were intact. Her effect initially appeared euthymic with a normal range though intermittently depressed during the conversation. Her impetus towards social activities and daily activities was decreased. Her psychomotor domain was calm; her voice was quiet and showed tendencies towards decreased prosody. Both her mimic and overall expressive gestures were scarce. Severe insomnia with sleep-onset and disturbed sleep, and daytime fatigue were reported. Appetite was reported as increased over the past months. The patient did not endorse symptoms indicating specific phobia, social anxiety, or generalized anxiety. She reported paroxysmal episodes of psychovegetative strain. The patient was not suicidal; there were no safety concerns with respect to herself or others. General and neurological examination of the 62-year-old female patient (height: 165 cm, weight: 65 kg; BMI: 23.9 kg/m2) revealed a moderate rigor of the right upper extremity, adiadochokinesia, normal gait pattern, onychomycosis of toe nails, bilateral hallux valgus, and hyperkyphosis of the thoracic spine. No other physical or neurological abnormalities were detected. There was no postural imbalance or tremor. Vital signs at admission included blood pressure of 140/80 mmHg, heartrate of 84/min, and temperature of 36.4°C. Differential diagnoses considered at admission for reported paroxysmal episodes of psychovegetative symptoms included panic attacks/panic disorder, somatoform autonomic disorder, arterial hypertension with hypertensive exacerbations, iatrogenic hyperthyroidism, asthmatic disorder, and drug-induced serotonin toxicity. Clinical laboratory analyses did not reveal abnormal findings in CBC (complete blood count), hepatic and renal function, glucose and lipid profile, and electrolytes. Free T3 (triiodothyronine), free T4 (thyroxine), and TSH (thyroid stimulating hormone) were within normal limits. The plasma concentration of moclobemide (3310 ng/ml) was above the reference range of 300-1000 ng/ml. Plasma concentrations of agomelatine were not detectable (<1 ng/ml). We suspected potential pharmacological interactions to be a contributing factor to the symptoms reported by the patient at admission, and moclobemide, rasagiline, and ranolazine were discontinued. On the following day, the patient already experienced a decrease of psychovegetative symptoms. The blood work showed normal thyroid parameters, and no remarkable structural abnormalities of the thyroid gland were detected by sonography. Thus, we could rule out the possibility of iatrogenic hyperthyroidism. Moreover, repeated ECG examinations did not show signs of cardiac abnormalities explaining the patient's vegetative symptoms (ECG showed normal sinus rhythm, heart rate 81/min, QTc 429 ms, and vertical position). The changes of anti-parkinson medications during the stay were performed under repeated supervision of the consultant neurologists. As the discontinuation of ranolazine, which was prescribed as an antianginal medication, did not result in changes of blood pressure, we could also rule out arterial hypertension as a causative factor. The electroencephalogram (EEG) showed a regular, well-modulated, indistinct alpha-EEG with occipital accentuation and a frequency of 10-11 Hz and amplitudes reaching up to 100 μV, a well-pronounced visual blockade and intermitted alpha-disintegration. A second EEG did not show any relevant changes. The magnetic resonance imaging (MRI) of the brain showed a slight expansion of the external frontal cerebrospinal fluid space and around the upper cerebellar vermis space. Disseminated, age-inappropriate, supratentorial small hyperintensities of the medullary layer were found. MRI-scan of the cervical and thoracic spine did not show any pathological findings. Due to the atypical localization of some lesions (i.e., near the corpus callosum and the right temporo-polar region), additional brain MRI-scan with contrast (gadolinium) was performed but results did not indicate an inflammatory process. In addition, lumbar puncture was discussed with the patient, who decided not to undergo this procedure after risks and benefits were explained. As the patient reported insomnia for nearly one decade and as agomelatine 50 mg daily was not effective, this medication was discontinued. After moclobemide, rasagiline, and ranolazine were discontinued based on the hypothesis of serotonergic overstimulation, no further episodic psychovegetative or panic-related symptoms occurred during hospitalization. The patient's blood pressure, which initially showed hypertensive episodes, went back to normal, and no antihypertensive medication was required. For persistent insomnia treatment trials with mirtazapine and trazodone were conducted, mirtazapine was not tolerated and trazodone was inefficient. Finally, sleep-associated symptoms slightly decreased with trimipramine 10 mg at bedtime. We established an antidepressive treatment with escitalopram, which was titrated to a dose of 10 mg. As per suggestions of consulting neurologists, pramipexole was reduced and discontinued. Because this was followed by an increase in PD-associated motor symptoms, we initiated treatment with rotigotine transdermal application of 8 mg/day. Levodopa/benserazide retard was switched to nonretard formulation of 125 mg three times a day. With this medication regimen, a stable and sufficient mobility could be achieved. Medication at discharge included escitalopram 10 mg/day, levodopa/benserazide 125 mg three times per day, rotigotine transdermal 8 mg/day, trimipramine 10 mg/day, and levothyroxine 100 μg/day. The patient rated her mood as 9-10/10 on a scale from 0 to 10 with 10 being euthymic mood. The symptoms leading to admission subsided following discontinuation of MAO inhibitors moclobemide and rasagiline and did not reoccur during hospitalization.
3. Discussion and Conclusions
In this case report, we describe a probable drug-induced serotonergic overstimulation with paroxysmal exacerbations in a patient with PD. As other differential diagnoses could be ruled out, we suggest an interaction of several serotonergic medications, i.e., MAO-A inhibitor moclobemide and MAO-B inhibitor rasagiline as a causal factor. The hypothesis of a drug-induced symptomatology rather than genuine panic attacks is supported by subsiding of symptoms after discontinuation of both moclobemide and rasagiline, together with ranolazine. In addition, the paroxysmal episodes including jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and darkish red discoloration (flush) of the scalp and neck were suggestive of drug-induced monoaminergic overstimulation. We are not aware of another case report describing serotonin toxicity with this combination in the context of Parkinson's disease. Several subtypes of panic attacks have been described in the literature [29] postulating cardiac, cardiovascular, neurological, respiratory, and vestibular classifications of panic attacks [30]. Patients presenting with chest pain frequently show symptoms/criteria for panic disorder [31] which results in diagnostic uncertainty, and in the presented case, coronary vasospasms of unknown origin had been previously suspected and treated with ranolazine. However, as the patient did not experience a significant effect on her symptoms, she reported at admission that she had been taking ranolazine not regularly and the discontinuation of ranolazine at admission did not result in the occurrence of cardiovascular symptoms. On the contrary, the patient's physical activity, i.e., walking longer distances, was restored after motor symptoms were additionally stabilized by adjusting anti-Parkinson medication as described in detail above. The serotonin syndrome is commonly perceived as a potentially fatal entity following exposure to serotonergic substances. The risk is increased with combination of two or more drugs which directly enhance postsynaptic serotonin levels. However, serotonin toxicity could reflect a continuous, dose-related phenomenon with serotonin syndrome being the maximum clinical manifestation of serotonin toxicity [32]. Frequently, the clinical symptoms of serotonin toxicity develop rapidly when a serotonergic drug is added to a preexisting medication with stimulating effects on serotonin neurotransmission [33]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs of these compounds as well as that of levodopa/benserazide and to our knowledge clinical guidelines are not supporting this combination. Due to the high prevalence of psychiatric symptoms and psychiatric comorbidities in patients with PD, combined pharmacological treatment with anti-Parkinson drugs and drugs for treatment of depression and anxiety symptoms are often inevitable. In general, hypotheses and assumptions described in this case report have certain limitations. Quantitative measurements of plasma serotonin and other monoamines as well as their respective metabolites, i.e., urinary or CSF levels of 5-HIAA, have not been determined. Thus, our conclusions with respect to the aetiology of the patient's symptoms are mainly supported by the patient's medical history, clinical symptoms, considerations of drug-drug interactions, and rapid clinical improvement after discontinuation of suspected drugs, i.e., moclobemide and rasagiline. The pharmacological interactions between moclobemide (MAO-A inhibitor) and rasagiline (MAO-B inhibitor) likely resulted in intolerable side effects as described above. We speculate that the dual inhibition of MAO-A and MAO-B may have led to MAO-inhibition comparable to the effect of irreversible MAO-inhibitors such as tranylcypromine despite the reversible nature of MAO-A inhibition by moclobemide. This may have been intermittently potentiated by dietary amines since the patient was not on a low tyramine diet [17]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs and to our knowledge clinical guidelines are not supporting this combination. We assume that moclobemide had been taken into consideration despite strong arguments against, including formal contraindication label, after a number of antidepressants were previously prescribed but eventually discontinued due to side effects and recurrence of depressive symptoms. Interestingly, when moclobemide had been given at a low dose of 150 mg daily in combination with rasagiline, the patient did indeed benefit for approximately 3 years describing improvement of depressive symptoms and good tolerability. Reported psychovegetative symptoms occurred for the first time 6 months after the dose increase of moclobemide to 450 mg daily. This long delay in onset of adverse effects related to increasing oscillations of serotonin toxicity may explain why drug-drug interactions were discarded as a potential cause by physicians. The aspect that MAO-B activity increases with age [16] may have additionally contributed to this delayed onset of symptoms. The significant reduction of MAO-B as demonstrated by Bitsios et al. who found an approximately 29% reduction in human platelet MAO-B activity after a single dosage of 450 mg moclobemide [34] and the supratherapeutic plasma concentration of moclobemide (3310 ng/ml) we detected in our patient likely constitute additional contributing factors. Hence, the following clinically relevant main aspects can be derived from the case report at hand to improve patient safety and care: The importance of assessing and considering drug-drug interactions: our patient has been prescribed with a contraindicated combination of two drugs. We believe that the association of reported symptoms with adverse effects due to a drug-drug interaction was not addressed by the patient's initial prescriber, GP and ER (emergency room) physicians. The fact that the treatment was well tolerated by the patient for a prolonged period of time has likely contributed to this outcome. The case presented here highlights the importance of comprehensive and thorough assessment of pharmacological treatment and medication history and that drug-drug interactions should always be considered a potential etiological factor of clinical symptoms. This is of particular relevance for drugs where interactions have been reported as well as drugs that are not commonly prescribed or usually prescribed by different disciplines.
Drug-induced serotonergic overstimulation occurring on a continuous spectrum of changes in serotonergic neurotransmission: to the best of our knowledge, this is the first case report of a patient with PD with potentially drug-induced chronic serotonergic overstimulation with intermittent clinical exacerbations mimicking panic attacks. Most likely, this was caused by combined treatment with an antidepressant (moclobemide; MAO-A inhibitor) and anti-Parkinson medication (rasagiline; MAO-B inhibitor). Interestingly, signs of serotonin toxicity probably developed following an increase of moclobemide from 150 to 450 mg daily and “although polypharmacy is an important etiological factor in the development of serotonin syndrome per se, dose and speed of distribution may determine its severity" [35]. We believe that this case report can support the clinically relevant assumption that drug-induced serotonergic overstimulation may occur on a continuous spectrum of changes in serotonergic neurotransmission which may present as mild clinical symptoms, clinical exacerbations, or the potentially life-threatening condition of serotonin syndrome.
Acknowledgments
We are grateful to our patient who has provided consent for the publication of this case report.
Abbreviations
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-Hydroxytryptamine/serotonin
CBC: Complete blood count
ECG: Electrocardiogram
EEG: Electroencephalogram
ER: Emergency room
L-DOPA: Levodopa/L-3,4-dihydroxyphenylalanine
GP: General practitioner
MAO: Monoamine oxidase
MRI: Magnetic resonance imaging
PD: Parkinson's disease
REM: Rapid eye movement
T3: Triiodothyronine
T4: Thyroxine
TSH: Thyroid stimulating hormone.
Consent
The patient has provided written consent for publication.
Conflicts of Interest
The authors report no competing interests/conflicts of interest.
Authors' Contributions
All authors substantially contributed to the clinical assessments, evaluation, and treatment of the patient as well as generation and interpretation of results. M.P. drafted the initial version of the manuscript. All authors reviewed and substantially revised the manuscript. All authors have approved the submitted manuscript, are accountable for this contribution, and ensure accuracy and integrity of this work. | AGOMELATINE, BENSERAZIDE HYDROCHLORIDE\LEVODOPA, LEVOTHYROXINE, MOCLOBEMIDE, PRAMIPEXOLE, RANOLAZINE, RASAGILINE | DrugsGivenReaction | CC BY | 33728085 | 19,135,231 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'. | Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided.
The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
1. Background
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive occurrence of typical motor dysfunctions such as resting tremor, rigidity, bradykinesia, and postural instability as well as concurrent nonmotor dysfunctions such as hyposomnia, REM (rapid eye movement) sleep behavior disorder, depression, autonomic dysregulation, cognitive impairments, psychosis, and anxiety disorders [1]. This clinical complexity of PD is mirrored by the current neuropathological understanding of PD. Subsequent disruption of nigrostriatal dopaminergic neurotransmission through degeneration of mesencephalic neurons located in the substantia nigra is accompanied by neurodegenerative processes in other brain areas leading to complex disturbances of neurobiological systems beyond the dopaminergic system including serotonergic and noradrenergic pathways [2]. Notably, dopaminergic dysfunction and serotonergic neuropathology of the basolateral amygdala were associated with anxiety in a rat model of PD and responsive to treatment with levodopa (L-DOPA) [3]. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), anxiety spectrum disorders consist of 12 diagnostic entities [4]. A panic attack is defined as a “discrete period of intense fear or discomfort” where symptoms such as palpitations, sweating, trembling or shaking, shortness of breath, chest pain or discomfort, nausea, dizziness, derealisation or depersonalisation, and fear of dying develop abruptly and can reach their peak within minutes [5]. In a recent cross-sectional study, Rai and colleagues investigated the prevalence of neuropsychiatric disorders, focussing on depression, anxiety, and psychosis in patients with PD. The results indicate depression to be the most common neuropsychiatric comorbidity with a prevalence of 43.7%; anxiety was found in 35.7% of patients with PD [6]. A high prevalence of anxiety disorders in PD was confirmed in other studies [7–9] describing a heterogeneous clinical picture with both sustained and episodic anxiety [8]. However, specific treatment options for anxiety disorders in PD have not been investigated in randomized controlled trials, as stated in a review from 2011 [10]. This high comorbidity of depressive and anxiety symptoms in patients with PD a combination of anti-Parkinson and antidepressant drugs is often clinically indicated. This case demonstrates that drug-drug interactions of antidepressant and anti-Parkinson medications, particularly when including monoamine oxidase (MAO) inhibitors, may result in serotonergic overstimulation and thus require careful consideration and monitoring. Clinically, the combination of moclobemide and rasagiline is hardly encountered and moreover explicitly contraindicated by regulatory agencies. Currently, two isoforms of MAOs, MAO-A and MAO-B, have been characterized in cerebral as well as extracerebral tissues [11] by means of their expression, molecular characteristics, differences in their preferred endogenous, and exogenous substrates and inhibitor-sensitivity [12, 13]. Substrates of MAO-A include serotonin, norepinephrine, and dopamine, whereas MAO-B preferentially degrades the monoamine alkaloid phenylethylamine (regulating the release of norepinephrine and dopamine) as well as the precursor molecule of various organic compounds such as benzylamine [14, 15]. Interestingly, MAO-B activity distinctively increases with age and has repeatedly been shown to be associated with neurodegenerative processes in dementia and PD [16] strengthening the therapeutic rationale and relevance of MAO-inhibitors in PD. The antidepressant moclobemide acts as a reversible and selective inhibitor of MAO-A and is effective in treating major depression [17]. The drug is a prototype of reversible inhibitors of MAO-A agents which target this enzyme in intraneuronal presynaptic regions [18]. A near-maximum inhibitory effect in healthy male volunteers was achieved with a single dosage of 300 mg. Maximum effects, as measured by decreased plasma concentrations of the serotonin-metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxphenyl-glycol, a peripheral noradrenaline-metabolite, were apparent at moclobemide plasma levels greater than 1000 ng/ml [19]. Only one study showed the antidepressant potency of moclobemide in depressed patients with PD and the superior effectiveness of the combination therapy with the MAO-B-inhibitor selegiline on affective symptoms as well as cognition. However, the small number of included patients does not allow to draw conclusions for clinical considerations [20]. Rasagiline belongs to selective blockers of MAO-B, such as selegiline. Rasagiline shows neuroprotective actions in vitro and is used as an anti-Parkinson drug. Chronic administration of a MAO-B-selective dose (0.2 mg/kg daily for 3 weeks) increased striatal dopamine and serotonin levels, while decreasing their metabolism. The drug restored the reduced activity in aged animals in behavioral paradigms to levels seen in young animals [21, 22]. However, in a therapeutic dose alone, it did not alter cerebral monoamine levels in another animal study [22]. Pramipexole is a non-ergoline dopamine receptor agonist (D2-like, D2S full, and D2L, D3, and D4 partial) for the treatment of PD and restless legs syndrome [23, 24]. Moreover, potential effects in treating symptoms of major depression have been reported [25]. Pramipexole also influences serotonergic neurotransmission by increasing activity of serotonergic neurons in the dorsal raphe. [26, 27]. Agomelatine belongs to a new generation of antidepressants since it elicits a dual mechanism of action by targeting the melatonergic system as an antagonist but also works as a serotonin 2C (5-HT2C) receptor antagonist. Studies have shown that treatment with agomelatine results in improvements in depressive symptoms, anxiety, and hypochondria in depressed patients [28].
2. Case Presentation
The 62-year-old female patient was referred to and admitted at the clinic of the Max-Planck-Institute of Psychiatry in Munich, Germany, for diagnostic clarification and treatment of recurring paroxysmal psychovegetative episodes. The patient, a retired school teacher from an urban upper-middle-class socioeconomic background, reported a history of insomnia, fatigue, and depressed mood, which preceded the onset of PD symptoms and worsened after being diagnosed with PD. She was premorbidly well-adjusted before the onset of motor symptoms and had no prior neurologic or psychiatric history. No developmental difficulties were reported. The patient's medical history includes the diagnosis of idiopathic Parkinson's syndrome, a moderate obstructive sleep apnea syndrome treated with a continuous positive airway pressure (CPAP) device, and chronic hypothyroidism following Hashimoto's disease approximately three decades ago and treated with thyroid hormone replacement since. About 6 months before clinical admission in our psychiatric ward, the patient noticed a reduced resilience to physical activity. In the last 4 months, she experienced shortness of breath after walking short distances and her general condition was affected by a feeling of physical weakness, shivering, headaches, and the sensation of facial heat. Unpredictable episodes of anxiety and vegetative symptoms occurred even out of quiescent states. Three months prior to this admission, she was assessed at an emergency department for thoracic pain and dyspnoea. Electrocardiogram (ECG), echocardiography, and blood work did not reveal any abnormalities. She was discharged with the suspected diagnosis of arterial hypertension and was started on ranolazine. Despite this intervention, her symptoms reoccurred and additionally worsened in the weeks prior to this admission. Her general practitioner (GP) recommended a beta blocker to be taken as needed. As ranolazine had no effect on her symptoms, the patient took ranolazine occasionally and discontinued the beta blocker treatment. There was no history of fever, altered sensorium, or neurological deficits except fluctuating motor symptoms associated with her diagnosis of PD. The patient described weight gain of approximately 4 kg during the last year. The patient's prevailing difficulties over the 4 months prior to admission were described as recurring paroxysmal episodes of jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and a darkish red discoloration of scalp and neck. These episodes emerged unexpectedly and were not associated with physical or emotional stress or other triggering factors. The patient reported that she had contacted an emergency physician on several occasions and had been admitted to hospitals twice approximately 3-4 months before her neurologist referred her to the clinic at the Max-Planck-Institute of Psychiatry in Munich, Germany, with a working diagnosis of panic disorder. Medication at admission consisted of moclobemide (450 mg/day), agomelatine (50 mg/day), pramipexole (0.525 mg/day), rasagiline (1 mg/day), L-DOPA+benserazide retard (200+50 mg/day), ranolazine (375 mg/day), and L-thyroxine (100 μg/day). The dose of moclobemide had been increased from 150 mg/day to the current dose about 1 year prior to admission. At the time of the initial mental status examination, the patient was fully alert, attentive, and oriented. She maintained eye contact and provided an informative report. No apparent abnormalities in thought form and content were observed. Cognitive and amnestic functions were intact. Her effect initially appeared euthymic with a normal range though intermittently depressed during the conversation. Her impetus towards social activities and daily activities was decreased. Her psychomotor domain was calm; her voice was quiet and showed tendencies towards decreased prosody. Both her mimic and overall expressive gestures were scarce. Severe insomnia with sleep-onset and disturbed sleep, and daytime fatigue were reported. Appetite was reported as increased over the past months. The patient did not endorse symptoms indicating specific phobia, social anxiety, or generalized anxiety. She reported paroxysmal episodes of psychovegetative strain. The patient was not suicidal; there were no safety concerns with respect to herself or others. General and neurological examination of the 62-year-old female patient (height: 165 cm, weight: 65 kg; BMI: 23.9 kg/m2) revealed a moderate rigor of the right upper extremity, adiadochokinesia, normal gait pattern, onychomycosis of toe nails, bilateral hallux valgus, and hyperkyphosis of the thoracic spine. No other physical or neurological abnormalities were detected. There was no postural imbalance or tremor. Vital signs at admission included blood pressure of 140/80 mmHg, heartrate of 84/min, and temperature of 36.4°C. Differential diagnoses considered at admission for reported paroxysmal episodes of psychovegetative symptoms included panic attacks/panic disorder, somatoform autonomic disorder, arterial hypertension with hypertensive exacerbations, iatrogenic hyperthyroidism, asthmatic disorder, and drug-induced serotonin toxicity. Clinical laboratory analyses did not reveal abnormal findings in CBC (complete blood count), hepatic and renal function, glucose and lipid profile, and electrolytes. Free T3 (triiodothyronine), free T4 (thyroxine), and TSH (thyroid stimulating hormone) were within normal limits. The plasma concentration of moclobemide (3310 ng/ml) was above the reference range of 300-1000 ng/ml. Plasma concentrations of agomelatine were not detectable (<1 ng/ml). We suspected potential pharmacological interactions to be a contributing factor to the symptoms reported by the patient at admission, and moclobemide, rasagiline, and ranolazine were discontinued. On the following day, the patient already experienced a decrease of psychovegetative symptoms. The blood work showed normal thyroid parameters, and no remarkable structural abnormalities of the thyroid gland were detected by sonography. Thus, we could rule out the possibility of iatrogenic hyperthyroidism. Moreover, repeated ECG examinations did not show signs of cardiac abnormalities explaining the patient's vegetative symptoms (ECG showed normal sinus rhythm, heart rate 81/min, QTc 429 ms, and vertical position). The changes of anti-parkinson medications during the stay were performed under repeated supervision of the consultant neurologists. As the discontinuation of ranolazine, which was prescribed as an antianginal medication, did not result in changes of blood pressure, we could also rule out arterial hypertension as a causative factor. The electroencephalogram (EEG) showed a regular, well-modulated, indistinct alpha-EEG with occipital accentuation and a frequency of 10-11 Hz and amplitudes reaching up to 100 μV, a well-pronounced visual blockade and intermitted alpha-disintegration. A second EEG did not show any relevant changes. The magnetic resonance imaging (MRI) of the brain showed a slight expansion of the external frontal cerebrospinal fluid space and around the upper cerebellar vermis space. Disseminated, age-inappropriate, supratentorial small hyperintensities of the medullary layer were found. MRI-scan of the cervical and thoracic spine did not show any pathological findings. Due to the atypical localization of some lesions (i.e., near the corpus callosum and the right temporo-polar region), additional brain MRI-scan with contrast (gadolinium) was performed but results did not indicate an inflammatory process. In addition, lumbar puncture was discussed with the patient, who decided not to undergo this procedure after risks and benefits were explained. As the patient reported insomnia for nearly one decade and as agomelatine 50 mg daily was not effective, this medication was discontinued. After moclobemide, rasagiline, and ranolazine were discontinued based on the hypothesis of serotonergic overstimulation, no further episodic psychovegetative or panic-related symptoms occurred during hospitalization. The patient's blood pressure, which initially showed hypertensive episodes, went back to normal, and no antihypertensive medication was required. For persistent insomnia treatment trials with mirtazapine and trazodone were conducted, mirtazapine was not tolerated and trazodone was inefficient. Finally, sleep-associated symptoms slightly decreased with trimipramine 10 mg at bedtime. We established an antidepressive treatment with escitalopram, which was titrated to a dose of 10 mg. As per suggestions of consulting neurologists, pramipexole was reduced and discontinued. Because this was followed by an increase in PD-associated motor symptoms, we initiated treatment with rotigotine transdermal application of 8 mg/day. Levodopa/benserazide retard was switched to nonretard formulation of 125 mg three times a day. With this medication regimen, a stable and sufficient mobility could be achieved. Medication at discharge included escitalopram 10 mg/day, levodopa/benserazide 125 mg three times per day, rotigotine transdermal 8 mg/day, trimipramine 10 mg/day, and levothyroxine 100 μg/day. The patient rated her mood as 9-10/10 on a scale from 0 to 10 with 10 being euthymic mood. The symptoms leading to admission subsided following discontinuation of MAO inhibitors moclobemide and rasagiline and did not reoccur during hospitalization.
3. Discussion and Conclusions
In this case report, we describe a probable drug-induced serotonergic overstimulation with paroxysmal exacerbations in a patient with PD. As other differential diagnoses could be ruled out, we suggest an interaction of several serotonergic medications, i.e., MAO-A inhibitor moclobemide and MAO-B inhibitor rasagiline as a causal factor. The hypothesis of a drug-induced symptomatology rather than genuine panic attacks is supported by subsiding of symptoms after discontinuation of both moclobemide and rasagiline, together with ranolazine. In addition, the paroxysmal episodes including jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and darkish red discoloration (flush) of the scalp and neck were suggestive of drug-induced monoaminergic overstimulation. We are not aware of another case report describing serotonin toxicity with this combination in the context of Parkinson's disease. Several subtypes of panic attacks have been described in the literature [29] postulating cardiac, cardiovascular, neurological, respiratory, and vestibular classifications of panic attacks [30]. Patients presenting with chest pain frequently show symptoms/criteria for panic disorder [31] which results in diagnostic uncertainty, and in the presented case, coronary vasospasms of unknown origin had been previously suspected and treated with ranolazine. However, as the patient did not experience a significant effect on her symptoms, she reported at admission that she had been taking ranolazine not regularly and the discontinuation of ranolazine at admission did not result in the occurrence of cardiovascular symptoms. On the contrary, the patient's physical activity, i.e., walking longer distances, was restored after motor symptoms were additionally stabilized by adjusting anti-Parkinson medication as described in detail above. The serotonin syndrome is commonly perceived as a potentially fatal entity following exposure to serotonergic substances. The risk is increased with combination of two or more drugs which directly enhance postsynaptic serotonin levels. However, serotonin toxicity could reflect a continuous, dose-related phenomenon with serotonin syndrome being the maximum clinical manifestation of serotonin toxicity [32]. Frequently, the clinical symptoms of serotonin toxicity develop rapidly when a serotonergic drug is added to a preexisting medication with stimulating effects on serotonin neurotransmission [33]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs of these compounds as well as that of levodopa/benserazide and to our knowledge clinical guidelines are not supporting this combination. Due to the high prevalence of psychiatric symptoms and psychiatric comorbidities in patients with PD, combined pharmacological treatment with anti-Parkinson drugs and drugs for treatment of depression and anxiety symptoms are often inevitable. In general, hypotheses and assumptions described in this case report have certain limitations. Quantitative measurements of plasma serotonin and other monoamines as well as their respective metabolites, i.e., urinary or CSF levels of 5-HIAA, have not been determined. Thus, our conclusions with respect to the aetiology of the patient's symptoms are mainly supported by the patient's medical history, clinical symptoms, considerations of drug-drug interactions, and rapid clinical improvement after discontinuation of suspected drugs, i.e., moclobemide and rasagiline. The pharmacological interactions between moclobemide (MAO-A inhibitor) and rasagiline (MAO-B inhibitor) likely resulted in intolerable side effects as described above. We speculate that the dual inhibition of MAO-A and MAO-B may have led to MAO-inhibition comparable to the effect of irreversible MAO-inhibitors such as tranylcypromine despite the reversible nature of MAO-A inhibition by moclobemide. This may have been intermittently potentiated by dietary amines since the patient was not on a low tyramine diet [17]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs and to our knowledge clinical guidelines are not supporting this combination. We assume that moclobemide had been taken into consideration despite strong arguments against, including formal contraindication label, after a number of antidepressants were previously prescribed but eventually discontinued due to side effects and recurrence of depressive symptoms. Interestingly, when moclobemide had been given at a low dose of 150 mg daily in combination with rasagiline, the patient did indeed benefit for approximately 3 years describing improvement of depressive symptoms and good tolerability. Reported psychovegetative symptoms occurred for the first time 6 months after the dose increase of moclobemide to 450 mg daily. This long delay in onset of adverse effects related to increasing oscillations of serotonin toxicity may explain why drug-drug interactions were discarded as a potential cause by physicians. The aspect that MAO-B activity increases with age [16] may have additionally contributed to this delayed onset of symptoms. The significant reduction of MAO-B as demonstrated by Bitsios et al. who found an approximately 29% reduction in human platelet MAO-B activity after a single dosage of 450 mg moclobemide [34] and the supratherapeutic plasma concentration of moclobemide (3310 ng/ml) we detected in our patient likely constitute additional contributing factors. Hence, the following clinically relevant main aspects can be derived from the case report at hand to improve patient safety and care: The importance of assessing and considering drug-drug interactions: our patient has been prescribed with a contraindicated combination of two drugs. We believe that the association of reported symptoms with adverse effects due to a drug-drug interaction was not addressed by the patient's initial prescriber, GP and ER (emergency room) physicians. The fact that the treatment was well tolerated by the patient for a prolonged period of time has likely contributed to this outcome. The case presented here highlights the importance of comprehensive and thorough assessment of pharmacological treatment and medication history and that drug-drug interactions should always be considered a potential etiological factor of clinical symptoms. This is of particular relevance for drugs where interactions have been reported as well as drugs that are not commonly prescribed or usually prescribed by different disciplines.
Drug-induced serotonergic overstimulation occurring on a continuous spectrum of changes in serotonergic neurotransmission: to the best of our knowledge, this is the first case report of a patient with PD with potentially drug-induced chronic serotonergic overstimulation with intermittent clinical exacerbations mimicking panic attacks. Most likely, this was caused by combined treatment with an antidepressant (moclobemide; MAO-A inhibitor) and anti-Parkinson medication (rasagiline; MAO-B inhibitor). Interestingly, signs of serotonin toxicity probably developed following an increase of moclobemide from 150 to 450 mg daily and “although polypharmacy is an important etiological factor in the development of serotonin syndrome per se, dose and speed of distribution may determine its severity" [35]. We believe that this case report can support the clinically relevant assumption that drug-induced serotonergic overstimulation may occur on a continuous spectrum of changes in serotonergic neurotransmission which may present as mild clinical symptoms, clinical exacerbations, or the potentially life-threatening condition of serotonin syndrome.
Acknowledgments
We are grateful to our patient who has provided consent for the publication of this case report.
Abbreviations
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-Hydroxytryptamine/serotonin
CBC: Complete blood count
ECG: Electrocardiogram
EEG: Electroencephalogram
ER: Emergency room
L-DOPA: Levodopa/L-3,4-dihydroxyphenylalanine
GP: General practitioner
MAO: Monoamine oxidase
MRI: Magnetic resonance imaging
PD: Parkinson's disease
REM: Rapid eye movement
T3: Triiodothyronine
T4: Thyroxine
TSH: Thyroid stimulating hormone.
Consent
The patient has provided written consent for publication.
Conflicts of Interest
The authors report no competing interests/conflicts of interest.
Authors' Contributions
All authors substantially contributed to the clinical assessments, evaluation, and treatment of the patient as well as generation and interpretation of results. M.P. drafted the initial version of the manuscript. All authors reviewed and substantially revised the manuscript. All authors have approved the submitted manuscript, are accountable for this contribution, and ensure accuracy and integrity of this work. | AGOMELATINE, BENSERAZIDE\LEVODOPA, LEVOTHYROXINE, MIRTAZAPINE, MOCLOBEMIDE, PRAMIPEXOLE, RANOLAZINE, RASAGILINE, TRAZODONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33728085 | 19,155,273 | 2021 |
What is the weight of the patient? | Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided.
The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
1. Background
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive occurrence of typical motor dysfunctions such as resting tremor, rigidity, bradykinesia, and postural instability as well as concurrent nonmotor dysfunctions such as hyposomnia, REM (rapid eye movement) sleep behavior disorder, depression, autonomic dysregulation, cognitive impairments, psychosis, and anxiety disorders [1]. This clinical complexity of PD is mirrored by the current neuropathological understanding of PD. Subsequent disruption of nigrostriatal dopaminergic neurotransmission through degeneration of mesencephalic neurons located in the substantia nigra is accompanied by neurodegenerative processes in other brain areas leading to complex disturbances of neurobiological systems beyond the dopaminergic system including serotonergic and noradrenergic pathways [2]. Notably, dopaminergic dysfunction and serotonergic neuropathology of the basolateral amygdala were associated with anxiety in a rat model of PD and responsive to treatment with levodopa (L-DOPA) [3]. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), anxiety spectrum disorders consist of 12 diagnostic entities [4]. A panic attack is defined as a “discrete period of intense fear or discomfort” where symptoms such as palpitations, sweating, trembling or shaking, shortness of breath, chest pain or discomfort, nausea, dizziness, derealisation or depersonalisation, and fear of dying develop abruptly and can reach their peak within minutes [5]. In a recent cross-sectional study, Rai and colleagues investigated the prevalence of neuropsychiatric disorders, focussing on depression, anxiety, and psychosis in patients with PD. The results indicate depression to be the most common neuropsychiatric comorbidity with a prevalence of 43.7%; anxiety was found in 35.7% of patients with PD [6]. A high prevalence of anxiety disorders in PD was confirmed in other studies [7–9] describing a heterogeneous clinical picture with both sustained and episodic anxiety [8]. However, specific treatment options for anxiety disorders in PD have not been investigated in randomized controlled trials, as stated in a review from 2011 [10]. This high comorbidity of depressive and anxiety symptoms in patients with PD a combination of anti-Parkinson and antidepressant drugs is often clinically indicated. This case demonstrates that drug-drug interactions of antidepressant and anti-Parkinson medications, particularly when including monoamine oxidase (MAO) inhibitors, may result in serotonergic overstimulation and thus require careful consideration and monitoring. Clinically, the combination of moclobemide and rasagiline is hardly encountered and moreover explicitly contraindicated by regulatory agencies. Currently, two isoforms of MAOs, MAO-A and MAO-B, have been characterized in cerebral as well as extracerebral tissues [11] by means of their expression, molecular characteristics, differences in their preferred endogenous, and exogenous substrates and inhibitor-sensitivity [12, 13]. Substrates of MAO-A include serotonin, norepinephrine, and dopamine, whereas MAO-B preferentially degrades the monoamine alkaloid phenylethylamine (regulating the release of norepinephrine and dopamine) as well as the precursor molecule of various organic compounds such as benzylamine [14, 15]. Interestingly, MAO-B activity distinctively increases with age and has repeatedly been shown to be associated with neurodegenerative processes in dementia and PD [16] strengthening the therapeutic rationale and relevance of MAO-inhibitors in PD. The antidepressant moclobemide acts as a reversible and selective inhibitor of MAO-A and is effective in treating major depression [17]. The drug is a prototype of reversible inhibitors of MAO-A agents which target this enzyme in intraneuronal presynaptic regions [18]. A near-maximum inhibitory effect in healthy male volunteers was achieved with a single dosage of 300 mg. Maximum effects, as measured by decreased plasma concentrations of the serotonin-metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxphenyl-glycol, a peripheral noradrenaline-metabolite, were apparent at moclobemide plasma levels greater than 1000 ng/ml [19]. Only one study showed the antidepressant potency of moclobemide in depressed patients with PD and the superior effectiveness of the combination therapy with the MAO-B-inhibitor selegiline on affective symptoms as well as cognition. However, the small number of included patients does not allow to draw conclusions for clinical considerations [20]. Rasagiline belongs to selective blockers of MAO-B, such as selegiline. Rasagiline shows neuroprotective actions in vitro and is used as an anti-Parkinson drug. Chronic administration of a MAO-B-selective dose (0.2 mg/kg daily for 3 weeks) increased striatal dopamine and serotonin levels, while decreasing their metabolism. The drug restored the reduced activity in aged animals in behavioral paradigms to levels seen in young animals [21, 22]. However, in a therapeutic dose alone, it did not alter cerebral monoamine levels in another animal study [22]. Pramipexole is a non-ergoline dopamine receptor agonist (D2-like, D2S full, and D2L, D3, and D4 partial) for the treatment of PD and restless legs syndrome [23, 24]. Moreover, potential effects in treating symptoms of major depression have been reported [25]. Pramipexole also influences serotonergic neurotransmission by increasing activity of serotonergic neurons in the dorsal raphe. [26, 27]. Agomelatine belongs to a new generation of antidepressants since it elicits a dual mechanism of action by targeting the melatonergic system as an antagonist but also works as a serotonin 2C (5-HT2C) receptor antagonist. Studies have shown that treatment with agomelatine results in improvements in depressive symptoms, anxiety, and hypochondria in depressed patients [28].
2. Case Presentation
The 62-year-old female patient was referred to and admitted at the clinic of the Max-Planck-Institute of Psychiatry in Munich, Germany, for diagnostic clarification and treatment of recurring paroxysmal psychovegetative episodes. The patient, a retired school teacher from an urban upper-middle-class socioeconomic background, reported a history of insomnia, fatigue, and depressed mood, which preceded the onset of PD symptoms and worsened after being diagnosed with PD. She was premorbidly well-adjusted before the onset of motor symptoms and had no prior neurologic or psychiatric history. No developmental difficulties were reported. The patient's medical history includes the diagnosis of idiopathic Parkinson's syndrome, a moderate obstructive sleep apnea syndrome treated with a continuous positive airway pressure (CPAP) device, and chronic hypothyroidism following Hashimoto's disease approximately three decades ago and treated with thyroid hormone replacement since. About 6 months before clinical admission in our psychiatric ward, the patient noticed a reduced resilience to physical activity. In the last 4 months, she experienced shortness of breath after walking short distances and her general condition was affected by a feeling of physical weakness, shivering, headaches, and the sensation of facial heat. Unpredictable episodes of anxiety and vegetative symptoms occurred even out of quiescent states. Three months prior to this admission, she was assessed at an emergency department for thoracic pain and dyspnoea. Electrocardiogram (ECG), echocardiography, and blood work did not reveal any abnormalities. She was discharged with the suspected diagnosis of arterial hypertension and was started on ranolazine. Despite this intervention, her symptoms reoccurred and additionally worsened in the weeks prior to this admission. Her general practitioner (GP) recommended a beta blocker to be taken as needed. As ranolazine had no effect on her symptoms, the patient took ranolazine occasionally and discontinued the beta blocker treatment. There was no history of fever, altered sensorium, or neurological deficits except fluctuating motor symptoms associated with her diagnosis of PD. The patient described weight gain of approximately 4 kg during the last year. The patient's prevailing difficulties over the 4 months prior to admission were described as recurring paroxysmal episodes of jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and a darkish red discoloration of scalp and neck. These episodes emerged unexpectedly and were not associated with physical or emotional stress or other triggering factors. The patient reported that she had contacted an emergency physician on several occasions and had been admitted to hospitals twice approximately 3-4 months before her neurologist referred her to the clinic at the Max-Planck-Institute of Psychiatry in Munich, Germany, with a working diagnosis of panic disorder. Medication at admission consisted of moclobemide (450 mg/day), agomelatine (50 mg/day), pramipexole (0.525 mg/day), rasagiline (1 mg/day), L-DOPA+benserazide retard (200+50 mg/day), ranolazine (375 mg/day), and L-thyroxine (100 μg/day). The dose of moclobemide had been increased from 150 mg/day to the current dose about 1 year prior to admission. At the time of the initial mental status examination, the patient was fully alert, attentive, and oriented. She maintained eye contact and provided an informative report. No apparent abnormalities in thought form and content were observed. Cognitive and amnestic functions were intact. Her effect initially appeared euthymic with a normal range though intermittently depressed during the conversation. Her impetus towards social activities and daily activities was decreased. Her psychomotor domain was calm; her voice was quiet and showed tendencies towards decreased prosody. Both her mimic and overall expressive gestures were scarce. Severe insomnia with sleep-onset and disturbed sleep, and daytime fatigue were reported. Appetite was reported as increased over the past months. The patient did not endorse symptoms indicating specific phobia, social anxiety, or generalized anxiety. She reported paroxysmal episodes of psychovegetative strain. The patient was not suicidal; there were no safety concerns with respect to herself or others. General and neurological examination of the 62-year-old female patient (height: 165 cm, weight: 65 kg; BMI: 23.9 kg/m2) revealed a moderate rigor of the right upper extremity, adiadochokinesia, normal gait pattern, onychomycosis of toe nails, bilateral hallux valgus, and hyperkyphosis of the thoracic spine. No other physical or neurological abnormalities were detected. There was no postural imbalance or tremor. Vital signs at admission included blood pressure of 140/80 mmHg, heartrate of 84/min, and temperature of 36.4°C. Differential diagnoses considered at admission for reported paroxysmal episodes of psychovegetative symptoms included panic attacks/panic disorder, somatoform autonomic disorder, arterial hypertension with hypertensive exacerbations, iatrogenic hyperthyroidism, asthmatic disorder, and drug-induced serotonin toxicity. Clinical laboratory analyses did not reveal abnormal findings in CBC (complete blood count), hepatic and renal function, glucose and lipid profile, and electrolytes. Free T3 (triiodothyronine), free T4 (thyroxine), and TSH (thyroid stimulating hormone) were within normal limits. The plasma concentration of moclobemide (3310 ng/ml) was above the reference range of 300-1000 ng/ml. Plasma concentrations of agomelatine were not detectable (<1 ng/ml). We suspected potential pharmacological interactions to be a contributing factor to the symptoms reported by the patient at admission, and moclobemide, rasagiline, and ranolazine were discontinued. On the following day, the patient already experienced a decrease of psychovegetative symptoms. The blood work showed normal thyroid parameters, and no remarkable structural abnormalities of the thyroid gland were detected by sonography. Thus, we could rule out the possibility of iatrogenic hyperthyroidism. Moreover, repeated ECG examinations did not show signs of cardiac abnormalities explaining the patient's vegetative symptoms (ECG showed normal sinus rhythm, heart rate 81/min, QTc 429 ms, and vertical position). The changes of anti-parkinson medications during the stay were performed under repeated supervision of the consultant neurologists. As the discontinuation of ranolazine, which was prescribed as an antianginal medication, did not result in changes of blood pressure, we could also rule out arterial hypertension as a causative factor. The electroencephalogram (EEG) showed a regular, well-modulated, indistinct alpha-EEG with occipital accentuation and a frequency of 10-11 Hz and amplitudes reaching up to 100 μV, a well-pronounced visual blockade and intermitted alpha-disintegration. A second EEG did not show any relevant changes. The magnetic resonance imaging (MRI) of the brain showed a slight expansion of the external frontal cerebrospinal fluid space and around the upper cerebellar vermis space. Disseminated, age-inappropriate, supratentorial small hyperintensities of the medullary layer were found. MRI-scan of the cervical and thoracic spine did not show any pathological findings. Due to the atypical localization of some lesions (i.e., near the corpus callosum and the right temporo-polar region), additional brain MRI-scan with contrast (gadolinium) was performed but results did not indicate an inflammatory process. In addition, lumbar puncture was discussed with the patient, who decided not to undergo this procedure after risks and benefits were explained. As the patient reported insomnia for nearly one decade and as agomelatine 50 mg daily was not effective, this medication was discontinued. After moclobemide, rasagiline, and ranolazine were discontinued based on the hypothesis of serotonergic overstimulation, no further episodic psychovegetative or panic-related symptoms occurred during hospitalization. The patient's blood pressure, which initially showed hypertensive episodes, went back to normal, and no antihypertensive medication was required. For persistent insomnia treatment trials with mirtazapine and trazodone were conducted, mirtazapine was not tolerated and trazodone was inefficient. Finally, sleep-associated symptoms slightly decreased with trimipramine 10 mg at bedtime. We established an antidepressive treatment with escitalopram, which was titrated to a dose of 10 mg. As per suggestions of consulting neurologists, pramipexole was reduced and discontinued. Because this was followed by an increase in PD-associated motor symptoms, we initiated treatment with rotigotine transdermal application of 8 mg/day. Levodopa/benserazide retard was switched to nonretard formulation of 125 mg three times a day. With this medication regimen, a stable and sufficient mobility could be achieved. Medication at discharge included escitalopram 10 mg/day, levodopa/benserazide 125 mg three times per day, rotigotine transdermal 8 mg/day, trimipramine 10 mg/day, and levothyroxine 100 μg/day. The patient rated her mood as 9-10/10 on a scale from 0 to 10 with 10 being euthymic mood. The symptoms leading to admission subsided following discontinuation of MAO inhibitors moclobemide and rasagiline and did not reoccur during hospitalization.
3. Discussion and Conclusions
In this case report, we describe a probable drug-induced serotonergic overstimulation with paroxysmal exacerbations in a patient with PD. As other differential diagnoses could be ruled out, we suggest an interaction of several serotonergic medications, i.e., MAO-A inhibitor moclobemide and MAO-B inhibitor rasagiline as a causal factor. The hypothesis of a drug-induced symptomatology rather than genuine panic attacks is supported by subsiding of symptoms after discontinuation of both moclobemide and rasagiline, together with ranolazine. In addition, the paroxysmal episodes including jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and darkish red discoloration (flush) of the scalp and neck were suggestive of drug-induced monoaminergic overstimulation. We are not aware of another case report describing serotonin toxicity with this combination in the context of Parkinson's disease. Several subtypes of panic attacks have been described in the literature [29] postulating cardiac, cardiovascular, neurological, respiratory, and vestibular classifications of panic attacks [30]. Patients presenting with chest pain frequently show symptoms/criteria for panic disorder [31] which results in diagnostic uncertainty, and in the presented case, coronary vasospasms of unknown origin had been previously suspected and treated with ranolazine. However, as the patient did not experience a significant effect on her symptoms, she reported at admission that she had been taking ranolazine not regularly and the discontinuation of ranolazine at admission did not result in the occurrence of cardiovascular symptoms. On the contrary, the patient's physical activity, i.e., walking longer distances, was restored after motor symptoms were additionally stabilized by adjusting anti-Parkinson medication as described in detail above. The serotonin syndrome is commonly perceived as a potentially fatal entity following exposure to serotonergic substances. The risk is increased with combination of two or more drugs which directly enhance postsynaptic serotonin levels. However, serotonin toxicity could reflect a continuous, dose-related phenomenon with serotonin syndrome being the maximum clinical manifestation of serotonin toxicity [32]. Frequently, the clinical symptoms of serotonin toxicity develop rapidly when a serotonergic drug is added to a preexisting medication with stimulating effects on serotonin neurotransmission [33]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs of these compounds as well as that of levodopa/benserazide and to our knowledge clinical guidelines are not supporting this combination. Due to the high prevalence of psychiatric symptoms and psychiatric comorbidities in patients with PD, combined pharmacological treatment with anti-Parkinson drugs and drugs for treatment of depression and anxiety symptoms are often inevitable. In general, hypotheses and assumptions described in this case report have certain limitations. Quantitative measurements of plasma serotonin and other monoamines as well as their respective metabolites, i.e., urinary or CSF levels of 5-HIAA, have not been determined. Thus, our conclusions with respect to the aetiology of the patient's symptoms are mainly supported by the patient's medical history, clinical symptoms, considerations of drug-drug interactions, and rapid clinical improvement after discontinuation of suspected drugs, i.e., moclobemide and rasagiline. The pharmacological interactions between moclobemide (MAO-A inhibitor) and rasagiline (MAO-B inhibitor) likely resulted in intolerable side effects as described above. We speculate that the dual inhibition of MAO-A and MAO-B may have led to MAO-inhibition comparable to the effect of irreversible MAO-inhibitors such as tranylcypromine despite the reversible nature of MAO-A inhibition by moclobemide. This may have been intermittently potentiated by dietary amines since the patient was not on a low tyramine diet [17]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs and to our knowledge clinical guidelines are not supporting this combination. We assume that moclobemide had been taken into consideration despite strong arguments against, including formal contraindication label, after a number of antidepressants were previously prescribed but eventually discontinued due to side effects and recurrence of depressive symptoms. Interestingly, when moclobemide had been given at a low dose of 150 mg daily in combination with rasagiline, the patient did indeed benefit for approximately 3 years describing improvement of depressive symptoms and good tolerability. Reported psychovegetative symptoms occurred for the first time 6 months after the dose increase of moclobemide to 450 mg daily. This long delay in onset of adverse effects related to increasing oscillations of serotonin toxicity may explain why drug-drug interactions were discarded as a potential cause by physicians. The aspect that MAO-B activity increases with age [16] may have additionally contributed to this delayed onset of symptoms. The significant reduction of MAO-B as demonstrated by Bitsios et al. who found an approximately 29% reduction in human platelet MAO-B activity after a single dosage of 450 mg moclobemide [34] and the supratherapeutic plasma concentration of moclobemide (3310 ng/ml) we detected in our patient likely constitute additional contributing factors. Hence, the following clinically relevant main aspects can be derived from the case report at hand to improve patient safety and care: The importance of assessing and considering drug-drug interactions: our patient has been prescribed with a contraindicated combination of two drugs. We believe that the association of reported symptoms with adverse effects due to a drug-drug interaction was not addressed by the patient's initial prescriber, GP and ER (emergency room) physicians. The fact that the treatment was well tolerated by the patient for a prolonged period of time has likely contributed to this outcome. The case presented here highlights the importance of comprehensive and thorough assessment of pharmacological treatment and medication history and that drug-drug interactions should always be considered a potential etiological factor of clinical symptoms. This is of particular relevance for drugs where interactions have been reported as well as drugs that are not commonly prescribed or usually prescribed by different disciplines.
Drug-induced serotonergic overstimulation occurring on a continuous spectrum of changes in serotonergic neurotransmission: to the best of our knowledge, this is the first case report of a patient with PD with potentially drug-induced chronic serotonergic overstimulation with intermittent clinical exacerbations mimicking panic attacks. Most likely, this was caused by combined treatment with an antidepressant (moclobemide; MAO-A inhibitor) and anti-Parkinson medication (rasagiline; MAO-B inhibitor). Interestingly, signs of serotonin toxicity probably developed following an increase of moclobemide from 150 to 450 mg daily and “although polypharmacy is an important etiological factor in the development of serotonin syndrome per se, dose and speed of distribution may determine its severity" [35]. We believe that this case report can support the clinically relevant assumption that drug-induced serotonergic overstimulation may occur on a continuous spectrum of changes in serotonergic neurotransmission which may present as mild clinical symptoms, clinical exacerbations, or the potentially life-threatening condition of serotonin syndrome.
Acknowledgments
We are grateful to our patient who has provided consent for the publication of this case report.
Abbreviations
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-Hydroxytryptamine/serotonin
CBC: Complete blood count
ECG: Electrocardiogram
EEG: Electroencephalogram
ER: Emergency room
L-DOPA: Levodopa/L-3,4-dihydroxyphenylalanine
GP: General practitioner
MAO: Monoamine oxidase
MRI: Magnetic resonance imaging
PD: Parkinson's disease
REM: Rapid eye movement
T3: Triiodothyronine
T4: Thyroxine
TSH: Thyroid stimulating hormone.
Consent
The patient has provided written consent for publication.
Conflicts of Interest
The authors report no competing interests/conflicts of interest.
Authors' Contributions
All authors substantially contributed to the clinical assessments, evaluation, and treatment of the patient as well as generation and interpretation of results. M.P. drafted the initial version of the manuscript. All authors reviewed and substantially revised the manuscript. All authors have approved the submitted manuscript, are accountable for this contribution, and ensure accuracy and integrity of this work. | 65 kg. | Weight | CC BY | 33728085 | 19,194,247 | 2021 |
What was the administration route of drug 'ROTIGOTINE'? | Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided.
The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
1. Background
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive occurrence of typical motor dysfunctions such as resting tremor, rigidity, bradykinesia, and postural instability as well as concurrent nonmotor dysfunctions such as hyposomnia, REM (rapid eye movement) sleep behavior disorder, depression, autonomic dysregulation, cognitive impairments, psychosis, and anxiety disorders [1]. This clinical complexity of PD is mirrored by the current neuropathological understanding of PD. Subsequent disruption of nigrostriatal dopaminergic neurotransmission through degeneration of mesencephalic neurons located in the substantia nigra is accompanied by neurodegenerative processes in other brain areas leading to complex disturbances of neurobiological systems beyond the dopaminergic system including serotonergic and noradrenergic pathways [2]. Notably, dopaminergic dysfunction and serotonergic neuropathology of the basolateral amygdala were associated with anxiety in a rat model of PD and responsive to treatment with levodopa (L-DOPA) [3]. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), anxiety spectrum disorders consist of 12 diagnostic entities [4]. A panic attack is defined as a “discrete period of intense fear or discomfort” where symptoms such as palpitations, sweating, trembling or shaking, shortness of breath, chest pain or discomfort, nausea, dizziness, derealisation or depersonalisation, and fear of dying develop abruptly and can reach their peak within minutes [5]. In a recent cross-sectional study, Rai and colleagues investigated the prevalence of neuropsychiatric disorders, focussing on depression, anxiety, and psychosis in patients with PD. The results indicate depression to be the most common neuropsychiatric comorbidity with a prevalence of 43.7%; anxiety was found in 35.7% of patients with PD [6]. A high prevalence of anxiety disorders in PD was confirmed in other studies [7–9] describing a heterogeneous clinical picture with both sustained and episodic anxiety [8]. However, specific treatment options for anxiety disorders in PD have not been investigated in randomized controlled trials, as stated in a review from 2011 [10]. This high comorbidity of depressive and anxiety symptoms in patients with PD a combination of anti-Parkinson and antidepressant drugs is often clinically indicated. This case demonstrates that drug-drug interactions of antidepressant and anti-Parkinson medications, particularly when including monoamine oxidase (MAO) inhibitors, may result in serotonergic overstimulation and thus require careful consideration and monitoring. Clinically, the combination of moclobemide and rasagiline is hardly encountered and moreover explicitly contraindicated by regulatory agencies. Currently, two isoforms of MAOs, MAO-A and MAO-B, have been characterized in cerebral as well as extracerebral tissues [11] by means of their expression, molecular characteristics, differences in their preferred endogenous, and exogenous substrates and inhibitor-sensitivity [12, 13]. Substrates of MAO-A include serotonin, norepinephrine, and dopamine, whereas MAO-B preferentially degrades the monoamine alkaloid phenylethylamine (regulating the release of norepinephrine and dopamine) as well as the precursor molecule of various organic compounds such as benzylamine [14, 15]. Interestingly, MAO-B activity distinctively increases with age and has repeatedly been shown to be associated with neurodegenerative processes in dementia and PD [16] strengthening the therapeutic rationale and relevance of MAO-inhibitors in PD. The antidepressant moclobemide acts as a reversible and selective inhibitor of MAO-A and is effective in treating major depression [17]. The drug is a prototype of reversible inhibitors of MAO-A agents which target this enzyme in intraneuronal presynaptic regions [18]. A near-maximum inhibitory effect in healthy male volunteers was achieved with a single dosage of 300 mg. Maximum effects, as measured by decreased plasma concentrations of the serotonin-metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxphenyl-glycol, a peripheral noradrenaline-metabolite, were apparent at moclobemide plasma levels greater than 1000 ng/ml [19]. Only one study showed the antidepressant potency of moclobemide in depressed patients with PD and the superior effectiveness of the combination therapy with the MAO-B-inhibitor selegiline on affective symptoms as well as cognition. However, the small number of included patients does not allow to draw conclusions for clinical considerations [20]. Rasagiline belongs to selective blockers of MAO-B, such as selegiline. Rasagiline shows neuroprotective actions in vitro and is used as an anti-Parkinson drug. Chronic administration of a MAO-B-selective dose (0.2 mg/kg daily for 3 weeks) increased striatal dopamine and serotonin levels, while decreasing their metabolism. The drug restored the reduced activity in aged animals in behavioral paradigms to levels seen in young animals [21, 22]. However, in a therapeutic dose alone, it did not alter cerebral monoamine levels in another animal study [22]. Pramipexole is a non-ergoline dopamine receptor agonist (D2-like, D2S full, and D2L, D3, and D4 partial) for the treatment of PD and restless legs syndrome [23, 24]. Moreover, potential effects in treating symptoms of major depression have been reported [25]. Pramipexole also influences serotonergic neurotransmission by increasing activity of serotonergic neurons in the dorsal raphe. [26, 27]. Agomelatine belongs to a new generation of antidepressants since it elicits a dual mechanism of action by targeting the melatonergic system as an antagonist but also works as a serotonin 2C (5-HT2C) receptor antagonist. Studies have shown that treatment with agomelatine results in improvements in depressive symptoms, anxiety, and hypochondria in depressed patients [28].
2. Case Presentation
The 62-year-old female patient was referred to and admitted at the clinic of the Max-Planck-Institute of Psychiatry in Munich, Germany, for diagnostic clarification and treatment of recurring paroxysmal psychovegetative episodes. The patient, a retired school teacher from an urban upper-middle-class socioeconomic background, reported a history of insomnia, fatigue, and depressed mood, which preceded the onset of PD symptoms and worsened after being diagnosed with PD. She was premorbidly well-adjusted before the onset of motor symptoms and had no prior neurologic or psychiatric history. No developmental difficulties were reported. The patient's medical history includes the diagnosis of idiopathic Parkinson's syndrome, a moderate obstructive sleep apnea syndrome treated with a continuous positive airway pressure (CPAP) device, and chronic hypothyroidism following Hashimoto's disease approximately three decades ago and treated with thyroid hormone replacement since. About 6 months before clinical admission in our psychiatric ward, the patient noticed a reduced resilience to physical activity. In the last 4 months, she experienced shortness of breath after walking short distances and her general condition was affected by a feeling of physical weakness, shivering, headaches, and the sensation of facial heat. Unpredictable episodes of anxiety and vegetative symptoms occurred even out of quiescent states. Three months prior to this admission, she was assessed at an emergency department for thoracic pain and dyspnoea. Electrocardiogram (ECG), echocardiography, and blood work did not reveal any abnormalities. She was discharged with the suspected diagnosis of arterial hypertension and was started on ranolazine. Despite this intervention, her symptoms reoccurred and additionally worsened in the weeks prior to this admission. Her general practitioner (GP) recommended a beta blocker to be taken as needed. As ranolazine had no effect on her symptoms, the patient took ranolazine occasionally and discontinued the beta blocker treatment. There was no history of fever, altered sensorium, or neurological deficits except fluctuating motor symptoms associated with her diagnosis of PD. The patient described weight gain of approximately 4 kg during the last year. The patient's prevailing difficulties over the 4 months prior to admission were described as recurring paroxysmal episodes of jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and a darkish red discoloration of scalp and neck. These episodes emerged unexpectedly and were not associated with physical or emotional stress or other triggering factors. The patient reported that she had contacted an emergency physician on several occasions and had been admitted to hospitals twice approximately 3-4 months before her neurologist referred her to the clinic at the Max-Planck-Institute of Psychiatry in Munich, Germany, with a working diagnosis of panic disorder. Medication at admission consisted of moclobemide (450 mg/day), agomelatine (50 mg/day), pramipexole (0.525 mg/day), rasagiline (1 mg/day), L-DOPA+benserazide retard (200+50 mg/day), ranolazine (375 mg/day), and L-thyroxine (100 μg/day). The dose of moclobemide had been increased from 150 mg/day to the current dose about 1 year prior to admission. At the time of the initial mental status examination, the patient was fully alert, attentive, and oriented. She maintained eye contact and provided an informative report. No apparent abnormalities in thought form and content were observed. Cognitive and amnestic functions were intact. Her effect initially appeared euthymic with a normal range though intermittently depressed during the conversation. Her impetus towards social activities and daily activities was decreased. Her psychomotor domain was calm; her voice was quiet and showed tendencies towards decreased prosody. Both her mimic and overall expressive gestures were scarce. Severe insomnia with sleep-onset and disturbed sleep, and daytime fatigue were reported. Appetite was reported as increased over the past months. The patient did not endorse symptoms indicating specific phobia, social anxiety, or generalized anxiety. She reported paroxysmal episodes of psychovegetative strain. The patient was not suicidal; there were no safety concerns with respect to herself or others. General and neurological examination of the 62-year-old female patient (height: 165 cm, weight: 65 kg; BMI: 23.9 kg/m2) revealed a moderate rigor of the right upper extremity, adiadochokinesia, normal gait pattern, onychomycosis of toe nails, bilateral hallux valgus, and hyperkyphosis of the thoracic spine. No other physical or neurological abnormalities were detected. There was no postural imbalance or tremor. Vital signs at admission included blood pressure of 140/80 mmHg, heartrate of 84/min, and temperature of 36.4°C. Differential diagnoses considered at admission for reported paroxysmal episodes of psychovegetative symptoms included panic attacks/panic disorder, somatoform autonomic disorder, arterial hypertension with hypertensive exacerbations, iatrogenic hyperthyroidism, asthmatic disorder, and drug-induced serotonin toxicity. Clinical laboratory analyses did not reveal abnormal findings in CBC (complete blood count), hepatic and renal function, glucose and lipid profile, and electrolytes. Free T3 (triiodothyronine), free T4 (thyroxine), and TSH (thyroid stimulating hormone) were within normal limits. The plasma concentration of moclobemide (3310 ng/ml) was above the reference range of 300-1000 ng/ml. Plasma concentrations of agomelatine were not detectable (<1 ng/ml). We suspected potential pharmacological interactions to be a contributing factor to the symptoms reported by the patient at admission, and moclobemide, rasagiline, and ranolazine were discontinued. On the following day, the patient already experienced a decrease of psychovegetative symptoms. The blood work showed normal thyroid parameters, and no remarkable structural abnormalities of the thyroid gland were detected by sonography. Thus, we could rule out the possibility of iatrogenic hyperthyroidism. Moreover, repeated ECG examinations did not show signs of cardiac abnormalities explaining the patient's vegetative symptoms (ECG showed normal sinus rhythm, heart rate 81/min, QTc 429 ms, and vertical position). The changes of anti-parkinson medications during the stay were performed under repeated supervision of the consultant neurologists. As the discontinuation of ranolazine, which was prescribed as an antianginal medication, did not result in changes of blood pressure, we could also rule out arterial hypertension as a causative factor. The electroencephalogram (EEG) showed a regular, well-modulated, indistinct alpha-EEG with occipital accentuation and a frequency of 10-11 Hz and amplitudes reaching up to 100 μV, a well-pronounced visual blockade and intermitted alpha-disintegration. A second EEG did not show any relevant changes. The magnetic resonance imaging (MRI) of the brain showed a slight expansion of the external frontal cerebrospinal fluid space and around the upper cerebellar vermis space. Disseminated, age-inappropriate, supratentorial small hyperintensities of the medullary layer were found. MRI-scan of the cervical and thoracic spine did not show any pathological findings. Due to the atypical localization of some lesions (i.e., near the corpus callosum and the right temporo-polar region), additional brain MRI-scan with contrast (gadolinium) was performed but results did not indicate an inflammatory process. In addition, lumbar puncture was discussed with the patient, who decided not to undergo this procedure after risks and benefits were explained. As the patient reported insomnia for nearly one decade and as agomelatine 50 mg daily was not effective, this medication was discontinued. After moclobemide, rasagiline, and ranolazine were discontinued based on the hypothesis of serotonergic overstimulation, no further episodic psychovegetative or panic-related symptoms occurred during hospitalization. The patient's blood pressure, which initially showed hypertensive episodes, went back to normal, and no antihypertensive medication was required. For persistent insomnia treatment trials with mirtazapine and trazodone were conducted, mirtazapine was not tolerated and trazodone was inefficient. Finally, sleep-associated symptoms slightly decreased with trimipramine 10 mg at bedtime. We established an antidepressive treatment with escitalopram, which was titrated to a dose of 10 mg. As per suggestions of consulting neurologists, pramipexole was reduced and discontinued. Because this was followed by an increase in PD-associated motor symptoms, we initiated treatment with rotigotine transdermal application of 8 mg/day. Levodopa/benserazide retard was switched to nonretard formulation of 125 mg three times a day. With this medication regimen, a stable and sufficient mobility could be achieved. Medication at discharge included escitalopram 10 mg/day, levodopa/benserazide 125 mg three times per day, rotigotine transdermal 8 mg/day, trimipramine 10 mg/day, and levothyroxine 100 μg/day. The patient rated her mood as 9-10/10 on a scale from 0 to 10 with 10 being euthymic mood. The symptoms leading to admission subsided following discontinuation of MAO inhibitors moclobemide and rasagiline and did not reoccur during hospitalization.
3. Discussion and Conclusions
In this case report, we describe a probable drug-induced serotonergic overstimulation with paroxysmal exacerbations in a patient with PD. As other differential diagnoses could be ruled out, we suggest an interaction of several serotonergic medications, i.e., MAO-A inhibitor moclobemide and MAO-B inhibitor rasagiline as a causal factor. The hypothesis of a drug-induced symptomatology rather than genuine panic attacks is supported by subsiding of symptoms after discontinuation of both moclobemide and rasagiline, together with ranolazine. In addition, the paroxysmal episodes including jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and darkish red discoloration (flush) of the scalp and neck were suggestive of drug-induced monoaminergic overstimulation. We are not aware of another case report describing serotonin toxicity with this combination in the context of Parkinson's disease. Several subtypes of panic attacks have been described in the literature [29] postulating cardiac, cardiovascular, neurological, respiratory, and vestibular classifications of panic attacks [30]. Patients presenting with chest pain frequently show symptoms/criteria for panic disorder [31] which results in diagnostic uncertainty, and in the presented case, coronary vasospasms of unknown origin had been previously suspected and treated with ranolazine. However, as the patient did not experience a significant effect on her symptoms, she reported at admission that she had been taking ranolazine not regularly and the discontinuation of ranolazine at admission did not result in the occurrence of cardiovascular symptoms. On the contrary, the patient's physical activity, i.e., walking longer distances, was restored after motor symptoms were additionally stabilized by adjusting anti-Parkinson medication as described in detail above. The serotonin syndrome is commonly perceived as a potentially fatal entity following exposure to serotonergic substances. The risk is increased with combination of two or more drugs which directly enhance postsynaptic serotonin levels. However, serotonin toxicity could reflect a continuous, dose-related phenomenon with serotonin syndrome being the maximum clinical manifestation of serotonin toxicity [32]. Frequently, the clinical symptoms of serotonin toxicity develop rapidly when a serotonergic drug is added to a preexisting medication with stimulating effects on serotonin neurotransmission [33]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs of these compounds as well as that of levodopa/benserazide and to our knowledge clinical guidelines are not supporting this combination. Due to the high prevalence of psychiatric symptoms and psychiatric comorbidities in patients with PD, combined pharmacological treatment with anti-Parkinson drugs and drugs for treatment of depression and anxiety symptoms are often inevitable. In general, hypotheses and assumptions described in this case report have certain limitations. Quantitative measurements of plasma serotonin and other monoamines as well as their respective metabolites, i.e., urinary or CSF levels of 5-HIAA, have not been determined. Thus, our conclusions with respect to the aetiology of the patient's symptoms are mainly supported by the patient's medical history, clinical symptoms, considerations of drug-drug interactions, and rapid clinical improvement after discontinuation of suspected drugs, i.e., moclobemide and rasagiline. The pharmacological interactions between moclobemide (MAO-A inhibitor) and rasagiline (MAO-B inhibitor) likely resulted in intolerable side effects as described above. We speculate that the dual inhibition of MAO-A and MAO-B may have led to MAO-inhibition comparable to the effect of irreversible MAO-inhibitors such as tranylcypromine despite the reversible nature of MAO-A inhibition by moclobemide. This may have been intermittently potentiated by dietary amines since the patient was not on a low tyramine diet [17]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs and to our knowledge clinical guidelines are not supporting this combination. We assume that moclobemide had been taken into consideration despite strong arguments against, including formal contraindication label, after a number of antidepressants were previously prescribed but eventually discontinued due to side effects and recurrence of depressive symptoms. Interestingly, when moclobemide had been given at a low dose of 150 mg daily in combination with rasagiline, the patient did indeed benefit for approximately 3 years describing improvement of depressive symptoms and good tolerability. Reported psychovegetative symptoms occurred for the first time 6 months after the dose increase of moclobemide to 450 mg daily. This long delay in onset of adverse effects related to increasing oscillations of serotonin toxicity may explain why drug-drug interactions were discarded as a potential cause by physicians. The aspect that MAO-B activity increases with age [16] may have additionally contributed to this delayed onset of symptoms. The significant reduction of MAO-B as demonstrated by Bitsios et al. who found an approximately 29% reduction in human platelet MAO-B activity after a single dosage of 450 mg moclobemide [34] and the supratherapeutic plasma concentration of moclobemide (3310 ng/ml) we detected in our patient likely constitute additional contributing factors. Hence, the following clinically relevant main aspects can be derived from the case report at hand to improve patient safety and care: The importance of assessing and considering drug-drug interactions: our patient has been prescribed with a contraindicated combination of two drugs. We believe that the association of reported symptoms with adverse effects due to a drug-drug interaction was not addressed by the patient's initial prescriber, GP and ER (emergency room) physicians. The fact that the treatment was well tolerated by the patient for a prolonged period of time has likely contributed to this outcome. The case presented here highlights the importance of comprehensive and thorough assessment of pharmacological treatment and medication history and that drug-drug interactions should always be considered a potential etiological factor of clinical symptoms. This is of particular relevance for drugs where interactions have been reported as well as drugs that are not commonly prescribed or usually prescribed by different disciplines.
Drug-induced serotonergic overstimulation occurring on a continuous spectrum of changes in serotonergic neurotransmission: to the best of our knowledge, this is the first case report of a patient with PD with potentially drug-induced chronic serotonergic overstimulation with intermittent clinical exacerbations mimicking panic attacks. Most likely, this was caused by combined treatment with an antidepressant (moclobemide; MAO-A inhibitor) and anti-Parkinson medication (rasagiline; MAO-B inhibitor). Interestingly, signs of serotonin toxicity probably developed following an increase of moclobemide from 150 to 450 mg daily and “although polypharmacy is an important etiological factor in the development of serotonin syndrome per se, dose and speed of distribution may determine its severity" [35]. We believe that this case report can support the clinically relevant assumption that drug-induced serotonergic overstimulation may occur on a continuous spectrum of changes in serotonergic neurotransmission which may present as mild clinical symptoms, clinical exacerbations, or the potentially life-threatening condition of serotonin syndrome.
Acknowledgments
We are grateful to our patient who has provided consent for the publication of this case report.
Abbreviations
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-Hydroxytryptamine/serotonin
CBC: Complete blood count
ECG: Electrocardiogram
EEG: Electroencephalogram
ER: Emergency room
L-DOPA: Levodopa/L-3,4-dihydroxyphenylalanine
GP: General practitioner
MAO: Monoamine oxidase
MRI: Magnetic resonance imaging
PD: Parkinson's disease
REM: Rapid eye movement
T3: Triiodothyronine
T4: Thyroxine
TSH: Thyroid stimulating hormone.
Consent
The patient has provided written consent for publication.
Conflicts of Interest
The authors report no competing interests/conflicts of interest.
Authors' Contributions
All authors substantially contributed to the clinical assessments, evaluation, and treatment of the patient as well as generation and interpretation of results. M.P. drafted the initial version of the manuscript. All authors reviewed and substantially revised the manuscript. All authors have approved the submitted manuscript, are accountable for this contribution, and ensure accuracy and integrity of this work. | Transdermal | DrugAdministrationRoute | CC BY | 33728085 | 19,194,247 | 2021 |
What was the dosage of drug 'MIRTAZAPINE'? | Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided.
The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
1. Background
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive occurrence of typical motor dysfunctions such as resting tremor, rigidity, bradykinesia, and postural instability as well as concurrent nonmotor dysfunctions such as hyposomnia, REM (rapid eye movement) sleep behavior disorder, depression, autonomic dysregulation, cognitive impairments, psychosis, and anxiety disorders [1]. This clinical complexity of PD is mirrored by the current neuropathological understanding of PD. Subsequent disruption of nigrostriatal dopaminergic neurotransmission through degeneration of mesencephalic neurons located in the substantia nigra is accompanied by neurodegenerative processes in other brain areas leading to complex disturbances of neurobiological systems beyond the dopaminergic system including serotonergic and noradrenergic pathways [2]. Notably, dopaminergic dysfunction and serotonergic neuropathology of the basolateral amygdala were associated with anxiety in a rat model of PD and responsive to treatment with levodopa (L-DOPA) [3]. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), anxiety spectrum disorders consist of 12 diagnostic entities [4]. A panic attack is defined as a “discrete period of intense fear or discomfort” where symptoms such as palpitations, sweating, trembling or shaking, shortness of breath, chest pain or discomfort, nausea, dizziness, derealisation or depersonalisation, and fear of dying develop abruptly and can reach their peak within minutes [5]. In a recent cross-sectional study, Rai and colleagues investigated the prevalence of neuropsychiatric disorders, focussing on depression, anxiety, and psychosis in patients with PD. The results indicate depression to be the most common neuropsychiatric comorbidity with a prevalence of 43.7%; anxiety was found in 35.7% of patients with PD [6]. A high prevalence of anxiety disorders in PD was confirmed in other studies [7–9] describing a heterogeneous clinical picture with both sustained and episodic anxiety [8]. However, specific treatment options for anxiety disorders in PD have not been investigated in randomized controlled trials, as stated in a review from 2011 [10]. This high comorbidity of depressive and anxiety symptoms in patients with PD a combination of anti-Parkinson and antidepressant drugs is often clinically indicated. This case demonstrates that drug-drug interactions of antidepressant and anti-Parkinson medications, particularly when including monoamine oxidase (MAO) inhibitors, may result in serotonergic overstimulation and thus require careful consideration and monitoring. Clinically, the combination of moclobemide and rasagiline is hardly encountered and moreover explicitly contraindicated by regulatory agencies. Currently, two isoforms of MAOs, MAO-A and MAO-B, have been characterized in cerebral as well as extracerebral tissues [11] by means of their expression, molecular characteristics, differences in their preferred endogenous, and exogenous substrates and inhibitor-sensitivity [12, 13]. Substrates of MAO-A include serotonin, norepinephrine, and dopamine, whereas MAO-B preferentially degrades the monoamine alkaloid phenylethylamine (regulating the release of norepinephrine and dopamine) as well as the precursor molecule of various organic compounds such as benzylamine [14, 15]. Interestingly, MAO-B activity distinctively increases with age and has repeatedly been shown to be associated with neurodegenerative processes in dementia and PD [16] strengthening the therapeutic rationale and relevance of MAO-inhibitors in PD. The antidepressant moclobemide acts as a reversible and selective inhibitor of MAO-A and is effective in treating major depression [17]. The drug is a prototype of reversible inhibitors of MAO-A agents which target this enzyme in intraneuronal presynaptic regions [18]. A near-maximum inhibitory effect in healthy male volunteers was achieved with a single dosage of 300 mg. Maximum effects, as measured by decreased plasma concentrations of the serotonin-metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxphenyl-glycol, a peripheral noradrenaline-metabolite, were apparent at moclobemide plasma levels greater than 1000 ng/ml [19]. Only one study showed the antidepressant potency of moclobemide in depressed patients with PD and the superior effectiveness of the combination therapy with the MAO-B-inhibitor selegiline on affective symptoms as well as cognition. However, the small number of included patients does not allow to draw conclusions for clinical considerations [20]. Rasagiline belongs to selective blockers of MAO-B, such as selegiline. Rasagiline shows neuroprotective actions in vitro and is used as an anti-Parkinson drug. Chronic administration of a MAO-B-selective dose (0.2 mg/kg daily for 3 weeks) increased striatal dopamine and serotonin levels, while decreasing their metabolism. The drug restored the reduced activity in aged animals in behavioral paradigms to levels seen in young animals [21, 22]. However, in a therapeutic dose alone, it did not alter cerebral monoamine levels in another animal study [22]. Pramipexole is a non-ergoline dopamine receptor agonist (D2-like, D2S full, and D2L, D3, and D4 partial) for the treatment of PD and restless legs syndrome [23, 24]. Moreover, potential effects in treating symptoms of major depression have been reported [25]. Pramipexole also influences serotonergic neurotransmission by increasing activity of serotonergic neurons in the dorsal raphe. [26, 27]. Agomelatine belongs to a new generation of antidepressants since it elicits a dual mechanism of action by targeting the melatonergic system as an antagonist but also works as a serotonin 2C (5-HT2C) receptor antagonist. Studies have shown that treatment with agomelatine results in improvements in depressive symptoms, anxiety, and hypochondria in depressed patients [28].
2. Case Presentation
The 62-year-old female patient was referred to and admitted at the clinic of the Max-Planck-Institute of Psychiatry in Munich, Germany, for diagnostic clarification and treatment of recurring paroxysmal psychovegetative episodes. The patient, a retired school teacher from an urban upper-middle-class socioeconomic background, reported a history of insomnia, fatigue, and depressed mood, which preceded the onset of PD symptoms and worsened after being diagnosed with PD. She was premorbidly well-adjusted before the onset of motor symptoms and had no prior neurologic or psychiatric history. No developmental difficulties were reported. The patient's medical history includes the diagnosis of idiopathic Parkinson's syndrome, a moderate obstructive sleep apnea syndrome treated with a continuous positive airway pressure (CPAP) device, and chronic hypothyroidism following Hashimoto's disease approximately three decades ago and treated with thyroid hormone replacement since. About 6 months before clinical admission in our psychiatric ward, the patient noticed a reduced resilience to physical activity. In the last 4 months, she experienced shortness of breath after walking short distances and her general condition was affected by a feeling of physical weakness, shivering, headaches, and the sensation of facial heat. Unpredictable episodes of anxiety and vegetative symptoms occurred even out of quiescent states. Three months prior to this admission, she was assessed at an emergency department for thoracic pain and dyspnoea. Electrocardiogram (ECG), echocardiography, and blood work did not reveal any abnormalities. She was discharged with the suspected diagnosis of arterial hypertension and was started on ranolazine. Despite this intervention, her symptoms reoccurred and additionally worsened in the weeks prior to this admission. Her general practitioner (GP) recommended a beta blocker to be taken as needed. As ranolazine had no effect on her symptoms, the patient took ranolazine occasionally and discontinued the beta blocker treatment. There was no history of fever, altered sensorium, or neurological deficits except fluctuating motor symptoms associated with her diagnosis of PD. The patient described weight gain of approximately 4 kg during the last year. The patient's prevailing difficulties over the 4 months prior to admission were described as recurring paroxysmal episodes of jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and a darkish red discoloration of scalp and neck. These episodes emerged unexpectedly and were not associated with physical or emotional stress or other triggering factors. The patient reported that she had contacted an emergency physician on several occasions and had been admitted to hospitals twice approximately 3-4 months before her neurologist referred her to the clinic at the Max-Planck-Institute of Psychiatry in Munich, Germany, with a working diagnosis of panic disorder. Medication at admission consisted of moclobemide (450 mg/day), agomelatine (50 mg/day), pramipexole (0.525 mg/day), rasagiline (1 mg/day), L-DOPA+benserazide retard (200+50 mg/day), ranolazine (375 mg/day), and L-thyroxine (100 μg/day). The dose of moclobemide had been increased from 150 mg/day to the current dose about 1 year prior to admission. At the time of the initial mental status examination, the patient was fully alert, attentive, and oriented. She maintained eye contact and provided an informative report. No apparent abnormalities in thought form and content were observed. Cognitive and amnestic functions were intact. Her effect initially appeared euthymic with a normal range though intermittently depressed during the conversation. Her impetus towards social activities and daily activities was decreased. Her psychomotor domain was calm; her voice was quiet and showed tendencies towards decreased prosody. Both her mimic and overall expressive gestures were scarce. Severe insomnia with sleep-onset and disturbed sleep, and daytime fatigue were reported. Appetite was reported as increased over the past months. The patient did not endorse symptoms indicating specific phobia, social anxiety, or generalized anxiety. She reported paroxysmal episodes of psychovegetative strain. The patient was not suicidal; there were no safety concerns with respect to herself or others. General and neurological examination of the 62-year-old female patient (height: 165 cm, weight: 65 kg; BMI: 23.9 kg/m2) revealed a moderate rigor of the right upper extremity, adiadochokinesia, normal gait pattern, onychomycosis of toe nails, bilateral hallux valgus, and hyperkyphosis of the thoracic spine. No other physical or neurological abnormalities were detected. There was no postural imbalance or tremor. Vital signs at admission included blood pressure of 140/80 mmHg, heartrate of 84/min, and temperature of 36.4°C. Differential diagnoses considered at admission for reported paroxysmal episodes of psychovegetative symptoms included panic attacks/panic disorder, somatoform autonomic disorder, arterial hypertension with hypertensive exacerbations, iatrogenic hyperthyroidism, asthmatic disorder, and drug-induced serotonin toxicity. Clinical laboratory analyses did not reveal abnormal findings in CBC (complete blood count), hepatic and renal function, glucose and lipid profile, and electrolytes. Free T3 (triiodothyronine), free T4 (thyroxine), and TSH (thyroid stimulating hormone) were within normal limits. The plasma concentration of moclobemide (3310 ng/ml) was above the reference range of 300-1000 ng/ml. Plasma concentrations of agomelatine were not detectable (<1 ng/ml). We suspected potential pharmacological interactions to be a contributing factor to the symptoms reported by the patient at admission, and moclobemide, rasagiline, and ranolazine were discontinued. On the following day, the patient already experienced a decrease of psychovegetative symptoms. The blood work showed normal thyroid parameters, and no remarkable structural abnormalities of the thyroid gland were detected by sonography. Thus, we could rule out the possibility of iatrogenic hyperthyroidism. Moreover, repeated ECG examinations did not show signs of cardiac abnormalities explaining the patient's vegetative symptoms (ECG showed normal sinus rhythm, heart rate 81/min, QTc 429 ms, and vertical position). The changes of anti-parkinson medications during the stay were performed under repeated supervision of the consultant neurologists. As the discontinuation of ranolazine, which was prescribed as an antianginal medication, did not result in changes of blood pressure, we could also rule out arterial hypertension as a causative factor. The electroencephalogram (EEG) showed a regular, well-modulated, indistinct alpha-EEG with occipital accentuation and a frequency of 10-11 Hz and amplitudes reaching up to 100 μV, a well-pronounced visual blockade and intermitted alpha-disintegration. A second EEG did not show any relevant changes. The magnetic resonance imaging (MRI) of the brain showed a slight expansion of the external frontal cerebrospinal fluid space and around the upper cerebellar vermis space. Disseminated, age-inappropriate, supratentorial small hyperintensities of the medullary layer were found. MRI-scan of the cervical and thoracic spine did not show any pathological findings. Due to the atypical localization of some lesions (i.e., near the corpus callosum and the right temporo-polar region), additional brain MRI-scan with contrast (gadolinium) was performed but results did not indicate an inflammatory process. In addition, lumbar puncture was discussed with the patient, who decided not to undergo this procedure after risks and benefits were explained. As the patient reported insomnia for nearly one decade and as agomelatine 50 mg daily was not effective, this medication was discontinued. After moclobemide, rasagiline, and ranolazine were discontinued based on the hypothesis of serotonergic overstimulation, no further episodic psychovegetative or panic-related symptoms occurred during hospitalization. The patient's blood pressure, which initially showed hypertensive episodes, went back to normal, and no antihypertensive medication was required. For persistent insomnia treatment trials with mirtazapine and trazodone were conducted, mirtazapine was not tolerated and trazodone was inefficient. Finally, sleep-associated symptoms slightly decreased with trimipramine 10 mg at bedtime. We established an antidepressive treatment with escitalopram, which was titrated to a dose of 10 mg. As per suggestions of consulting neurologists, pramipexole was reduced and discontinued. Because this was followed by an increase in PD-associated motor symptoms, we initiated treatment with rotigotine transdermal application of 8 mg/day. Levodopa/benserazide retard was switched to nonretard formulation of 125 mg three times a day. With this medication regimen, a stable and sufficient mobility could be achieved. Medication at discharge included escitalopram 10 mg/day, levodopa/benserazide 125 mg three times per day, rotigotine transdermal 8 mg/day, trimipramine 10 mg/day, and levothyroxine 100 μg/day. The patient rated her mood as 9-10/10 on a scale from 0 to 10 with 10 being euthymic mood. The symptoms leading to admission subsided following discontinuation of MAO inhibitors moclobemide and rasagiline and did not reoccur during hospitalization.
3. Discussion and Conclusions
In this case report, we describe a probable drug-induced serotonergic overstimulation with paroxysmal exacerbations in a patient with PD. As other differential diagnoses could be ruled out, we suggest an interaction of several serotonergic medications, i.e., MAO-A inhibitor moclobemide and MAO-B inhibitor rasagiline as a causal factor. The hypothesis of a drug-induced symptomatology rather than genuine panic attacks is supported by subsiding of symptoms after discontinuation of both moclobemide and rasagiline, together with ranolazine. In addition, the paroxysmal episodes including jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and darkish red discoloration (flush) of the scalp and neck were suggestive of drug-induced monoaminergic overstimulation. We are not aware of another case report describing serotonin toxicity with this combination in the context of Parkinson's disease. Several subtypes of panic attacks have been described in the literature [29] postulating cardiac, cardiovascular, neurological, respiratory, and vestibular classifications of panic attacks [30]. Patients presenting with chest pain frequently show symptoms/criteria for panic disorder [31] which results in diagnostic uncertainty, and in the presented case, coronary vasospasms of unknown origin had been previously suspected and treated with ranolazine. However, as the patient did not experience a significant effect on her symptoms, she reported at admission that she had been taking ranolazine not regularly and the discontinuation of ranolazine at admission did not result in the occurrence of cardiovascular symptoms. On the contrary, the patient's physical activity, i.e., walking longer distances, was restored after motor symptoms were additionally stabilized by adjusting anti-Parkinson medication as described in detail above. The serotonin syndrome is commonly perceived as a potentially fatal entity following exposure to serotonergic substances. The risk is increased with combination of two or more drugs which directly enhance postsynaptic serotonin levels. However, serotonin toxicity could reflect a continuous, dose-related phenomenon with serotonin syndrome being the maximum clinical manifestation of serotonin toxicity [32]. Frequently, the clinical symptoms of serotonin toxicity develop rapidly when a serotonergic drug is added to a preexisting medication with stimulating effects on serotonin neurotransmission [33]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs of these compounds as well as that of levodopa/benserazide and to our knowledge clinical guidelines are not supporting this combination. Due to the high prevalence of psychiatric symptoms and psychiatric comorbidities in patients with PD, combined pharmacological treatment with anti-Parkinson drugs and drugs for treatment of depression and anxiety symptoms are often inevitable. In general, hypotheses and assumptions described in this case report have certain limitations. Quantitative measurements of plasma serotonin and other monoamines as well as their respective metabolites, i.e., urinary or CSF levels of 5-HIAA, have not been determined. Thus, our conclusions with respect to the aetiology of the patient's symptoms are mainly supported by the patient's medical history, clinical symptoms, considerations of drug-drug interactions, and rapid clinical improvement after discontinuation of suspected drugs, i.e., moclobemide and rasagiline. The pharmacological interactions between moclobemide (MAO-A inhibitor) and rasagiline (MAO-B inhibitor) likely resulted in intolerable side effects as described above. We speculate that the dual inhibition of MAO-A and MAO-B may have led to MAO-inhibition comparable to the effect of irreversible MAO-inhibitors such as tranylcypromine despite the reversible nature of MAO-A inhibition by moclobemide. This may have been intermittently potentiated by dietary amines since the patient was not on a low tyramine diet [17]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs and to our knowledge clinical guidelines are not supporting this combination. We assume that moclobemide had been taken into consideration despite strong arguments against, including formal contraindication label, after a number of antidepressants were previously prescribed but eventually discontinued due to side effects and recurrence of depressive symptoms. Interestingly, when moclobemide had been given at a low dose of 150 mg daily in combination with rasagiline, the patient did indeed benefit for approximately 3 years describing improvement of depressive symptoms and good tolerability. Reported psychovegetative symptoms occurred for the first time 6 months after the dose increase of moclobemide to 450 mg daily. This long delay in onset of adverse effects related to increasing oscillations of serotonin toxicity may explain why drug-drug interactions were discarded as a potential cause by physicians. The aspect that MAO-B activity increases with age [16] may have additionally contributed to this delayed onset of symptoms. The significant reduction of MAO-B as demonstrated by Bitsios et al. who found an approximately 29% reduction in human platelet MAO-B activity after a single dosage of 450 mg moclobemide [34] and the supratherapeutic plasma concentration of moclobemide (3310 ng/ml) we detected in our patient likely constitute additional contributing factors. Hence, the following clinically relevant main aspects can be derived from the case report at hand to improve patient safety and care: The importance of assessing and considering drug-drug interactions: our patient has been prescribed with a contraindicated combination of two drugs. We believe that the association of reported symptoms with adverse effects due to a drug-drug interaction was not addressed by the patient's initial prescriber, GP and ER (emergency room) physicians. The fact that the treatment was well tolerated by the patient for a prolonged period of time has likely contributed to this outcome. The case presented here highlights the importance of comprehensive and thorough assessment of pharmacological treatment and medication history and that drug-drug interactions should always be considered a potential etiological factor of clinical symptoms. This is of particular relevance for drugs where interactions have been reported as well as drugs that are not commonly prescribed or usually prescribed by different disciplines.
Drug-induced serotonergic overstimulation occurring on a continuous spectrum of changes in serotonergic neurotransmission: to the best of our knowledge, this is the first case report of a patient with PD with potentially drug-induced chronic serotonergic overstimulation with intermittent clinical exacerbations mimicking panic attacks. Most likely, this was caused by combined treatment with an antidepressant (moclobemide; MAO-A inhibitor) and anti-Parkinson medication (rasagiline; MAO-B inhibitor). Interestingly, signs of serotonin toxicity probably developed following an increase of moclobemide from 150 to 450 mg daily and “although polypharmacy is an important etiological factor in the development of serotonin syndrome per se, dose and speed of distribution may determine its severity" [35]. We believe that this case report can support the clinically relevant assumption that drug-induced serotonergic overstimulation may occur on a continuous spectrum of changes in serotonergic neurotransmission which may present as mild clinical symptoms, clinical exacerbations, or the potentially life-threatening condition of serotonin syndrome.
Acknowledgments
We are grateful to our patient who has provided consent for the publication of this case report.
Abbreviations
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-Hydroxytryptamine/serotonin
CBC: Complete blood count
ECG: Electrocardiogram
EEG: Electroencephalogram
ER: Emergency room
L-DOPA: Levodopa/L-3,4-dihydroxyphenylalanine
GP: General practitioner
MAO: Monoamine oxidase
MRI: Magnetic resonance imaging
PD: Parkinson's disease
REM: Rapid eye movement
T3: Triiodothyronine
T4: Thyroxine
TSH: Thyroid stimulating hormone.
Consent
The patient has provided written consent for publication.
Conflicts of Interest
The authors report no competing interests/conflicts of interest.
Authors' Contributions
All authors substantially contributed to the clinical assessments, evaluation, and treatment of the patient as well as generation and interpretation of results. M.P. drafted the initial version of the manuscript. All authors reviewed and substantially revised the manuscript. All authors have approved the submitted manuscript, are accountable for this contribution, and ensure accuracy and integrity of this work. | TREATMENT TRIAL | DrugDosageText | CC BY | 33728085 | 19,165,149 | 2021 |
What was the dosage of drug 'RANOLAZINE HYDROCHLORIDE'? | Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided.
The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
1. Background
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive occurrence of typical motor dysfunctions such as resting tremor, rigidity, bradykinesia, and postural instability as well as concurrent nonmotor dysfunctions such as hyposomnia, REM (rapid eye movement) sleep behavior disorder, depression, autonomic dysregulation, cognitive impairments, psychosis, and anxiety disorders [1]. This clinical complexity of PD is mirrored by the current neuropathological understanding of PD. Subsequent disruption of nigrostriatal dopaminergic neurotransmission through degeneration of mesencephalic neurons located in the substantia nigra is accompanied by neurodegenerative processes in other brain areas leading to complex disturbances of neurobiological systems beyond the dopaminergic system including serotonergic and noradrenergic pathways [2]. Notably, dopaminergic dysfunction and serotonergic neuropathology of the basolateral amygdala were associated with anxiety in a rat model of PD and responsive to treatment with levodopa (L-DOPA) [3]. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), anxiety spectrum disorders consist of 12 diagnostic entities [4]. A panic attack is defined as a “discrete period of intense fear or discomfort” where symptoms such as palpitations, sweating, trembling or shaking, shortness of breath, chest pain or discomfort, nausea, dizziness, derealisation or depersonalisation, and fear of dying develop abruptly and can reach their peak within minutes [5]. In a recent cross-sectional study, Rai and colleagues investigated the prevalence of neuropsychiatric disorders, focussing on depression, anxiety, and psychosis in patients with PD. The results indicate depression to be the most common neuropsychiatric comorbidity with a prevalence of 43.7%; anxiety was found in 35.7% of patients with PD [6]. A high prevalence of anxiety disorders in PD was confirmed in other studies [7–9] describing a heterogeneous clinical picture with both sustained and episodic anxiety [8]. However, specific treatment options for anxiety disorders in PD have not been investigated in randomized controlled trials, as stated in a review from 2011 [10]. This high comorbidity of depressive and anxiety symptoms in patients with PD a combination of anti-Parkinson and antidepressant drugs is often clinically indicated. This case demonstrates that drug-drug interactions of antidepressant and anti-Parkinson medications, particularly when including monoamine oxidase (MAO) inhibitors, may result in serotonergic overstimulation and thus require careful consideration and monitoring. Clinically, the combination of moclobemide and rasagiline is hardly encountered and moreover explicitly contraindicated by regulatory agencies. Currently, two isoforms of MAOs, MAO-A and MAO-B, have been characterized in cerebral as well as extracerebral tissues [11] by means of their expression, molecular characteristics, differences in their preferred endogenous, and exogenous substrates and inhibitor-sensitivity [12, 13]. Substrates of MAO-A include serotonin, norepinephrine, and dopamine, whereas MAO-B preferentially degrades the monoamine alkaloid phenylethylamine (regulating the release of norepinephrine and dopamine) as well as the precursor molecule of various organic compounds such as benzylamine [14, 15]. Interestingly, MAO-B activity distinctively increases with age and has repeatedly been shown to be associated with neurodegenerative processes in dementia and PD [16] strengthening the therapeutic rationale and relevance of MAO-inhibitors in PD. The antidepressant moclobemide acts as a reversible and selective inhibitor of MAO-A and is effective in treating major depression [17]. The drug is a prototype of reversible inhibitors of MAO-A agents which target this enzyme in intraneuronal presynaptic regions [18]. A near-maximum inhibitory effect in healthy male volunteers was achieved with a single dosage of 300 mg. Maximum effects, as measured by decreased plasma concentrations of the serotonin-metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxphenyl-glycol, a peripheral noradrenaline-metabolite, were apparent at moclobemide plasma levels greater than 1000 ng/ml [19]. Only one study showed the antidepressant potency of moclobemide in depressed patients with PD and the superior effectiveness of the combination therapy with the MAO-B-inhibitor selegiline on affective symptoms as well as cognition. However, the small number of included patients does not allow to draw conclusions for clinical considerations [20]. Rasagiline belongs to selective blockers of MAO-B, such as selegiline. Rasagiline shows neuroprotective actions in vitro and is used as an anti-Parkinson drug. Chronic administration of a MAO-B-selective dose (0.2 mg/kg daily for 3 weeks) increased striatal dopamine and serotonin levels, while decreasing their metabolism. The drug restored the reduced activity in aged animals in behavioral paradigms to levels seen in young animals [21, 22]. However, in a therapeutic dose alone, it did not alter cerebral monoamine levels in another animal study [22]. Pramipexole is a non-ergoline dopamine receptor agonist (D2-like, D2S full, and D2L, D3, and D4 partial) for the treatment of PD and restless legs syndrome [23, 24]. Moreover, potential effects in treating symptoms of major depression have been reported [25]. Pramipexole also influences serotonergic neurotransmission by increasing activity of serotonergic neurons in the dorsal raphe. [26, 27]. Agomelatine belongs to a new generation of antidepressants since it elicits a dual mechanism of action by targeting the melatonergic system as an antagonist but also works as a serotonin 2C (5-HT2C) receptor antagonist. Studies have shown that treatment with agomelatine results in improvements in depressive symptoms, anxiety, and hypochondria in depressed patients [28].
2. Case Presentation
The 62-year-old female patient was referred to and admitted at the clinic of the Max-Planck-Institute of Psychiatry in Munich, Germany, for diagnostic clarification and treatment of recurring paroxysmal psychovegetative episodes. The patient, a retired school teacher from an urban upper-middle-class socioeconomic background, reported a history of insomnia, fatigue, and depressed mood, which preceded the onset of PD symptoms and worsened after being diagnosed with PD. She was premorbidly well-adjusted before the onset of motor symptoms and had no prior neurologic or psychiatric history. No developmental difficulties were reported. The patient's medical history includes the diagnosis of idiopathic Parkinson's syndrome, a moderate obstructive sleep apnea syndrome treated with a continuous positive airway pressure (CPAP) device, and chronic hypothyroidism following Hashimoto's disease approximately three decades ago and treated with thyroid hormone replacement since. About 6 months before clinical admission in our psychiatric ward, the patient noticed a reduced resilience to physical activity. In the last 4 months, she experienced shortness of breath after walking short distances and her general condition was affected by a feeling of physical weakness, shivering, headaches, and the sensation of facial heat. Unpredictable episodes of anxiety and vegetative symptoms occurred even out of quiescent states. Three months prior to this admission, she was assessed at an emergency department for thoracic pain and dyspnoea. Electrocardiogram (ECG), echocardiography, and blood work did not reveal any abnormalities. She was discharged with the suspected diagnosis of arterial hypertension and was started on ranolazine. Despite this intervention, her symptoms reoccurred and additionally worsened in the weeks prior to this admission. Her general practitioner (GP) recommended a beta blocker to be taken as needed. As ranolazine had no effect on her symptoms, the patient took ranolazine occasionally and discontinued the beta blocker treatment. There was no history of fever, altered sensorium, or neurological deficits except fluctuating motor symptoms associated with her diagnosis of PD. The patient described weight gain of approximately 4 kg during the last year. The patient's prevailing difficulties over the 4 months prior to admission were described as recurring paroxysmal episodes of jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and a darkish red discoloration of scalp and neck. These episodes emerged unexpectedly and were not associated with physical or emotional stress or other triggering factors. The patient reported that she had contacted an emergency physician on several occasions and had been admitted to hospitals twice approximately 3-4 months before her neurologist referred her to the clinic at the Max-Planck-Institute of Psychiatry in Munich, Germany, with a working diagnosis of panic disorder. Medication at admission consisted of moclobemide (450 mg/day), agomelatine (50 mg/day), pramipexole (0.525 mg/day), rasagiline (1 mg/day), L-DOPA+benserazide retard (200+50 mg/day), ranolazine (375 mg/day), and L-thyroxine (100 μg/day). The dose of moclobemide had been increased from 150 mg/day to the current dose about 1 year prior to admission. At the time of the initial mental status examination, the patient was fully alert, attentive, and oriented. She maintained eye contact and provided an informative report. No apparent abnormalities in thought form and content were observed. Cognitive and amnestic functions were intact. Her effect initially appeared euthymic with a normal range though intermittently depressed during the conversation. Her impetus towards social activities and daily activities was decreased. Her psychomotor domain was calm; her voice was quiet and showed tendencies towards decreased prosody. Both her mimic and overall expressive gestures were scarce. Severe insomnia with sleep-onset and disturbed sleep, and daytime fatigue were reported. Appetite was reported as increased over the past months. The patient did not endorse symptoms indicating specific phobia, social anxiety, or generalized anxiety. She reported paroxysmal episodes of psychovegetative strain. The patient was not suicidal; there were no safety concerns with respect to herself or others. General and neurological examination of the 62-year-old female patient (height: 165 cm, weight: 65 kg; BMI: 23.9 kg/m2) revealed a moderate rigor of the right upper extremity, adiadochokinesia, normal gait pattern, onychomycosis of toe nails, bilateral hallux valgus, and hyperkyphosis of the thoracic spine. No other physical or neurological abnormalities were detected. There was no postural imbalance or tremor. Vital signs at admission included blood pressure of 140/80 mmHg, heartrate of 84/min, and temperature of 36.4°C. Differential diagnoses considered at admission for reported paroxysmal episodes of psychovegetative symptoms included panic attacks/panic disorder, somatoform autonomic disorder, arterial hypertension with hypertensive exacerbations, iatrogenic hyperthyroidism, asthmatic disorder, and drug-induced serotonin toxicity. Clinical laboratory analyses did not reveal abnormal findings in CBC (complete blood count), hepatic and renal function, glucose and lipid profile, and electrolytes. Free T3 (triiodothyronine), free T4 (thyroxine), and TSH (thyroid stimulating hormone) were within normal limits. The plasma concentration of moclobemide (3310 ng/ml) was above the reference range of 300-1000 ng/ml. Plasma concentrations of agomelatine were not detectable (<1 ng/ml). We suspected potential pharmacological interactions to be a contributing factor to the symptoms reported by the patient at admission, and moclobemide, rasagiline, and ranolazine were discontinued. On the following day, the patient already experienced a decrease of psychovegetative symptoms. The blood work showed normal thyroid parameters, and no remarkable structural abnormalities of the thyroid gland were detected by sonography. Thus, we could rule out the possibility of iatrogenic hyperthyroidism. Moreover, repeated ECG examinations did not show signs of cardiac abnormalities explaining the patient's vegetative symptoms (ECG showed normal sinus rhythm, heart rate 81/min, QTc 429 ms, and vertical position). The changes of anti-parkinson medications during the stay were performed under repeated supervision of the consultant neurologists. As the discontinuation of ranolazine, which was prescribed as an antianginal medication, did not result in changes of blood pressure, we could also rule out arterial hypertension as a causative factor. The electroencephalogram (EEG) showed a regular, well-modulated, indistinct alpha-EEG with occipital accentuation and a frequency of 10-11 Hz and amplitudes reaching up to 100 μV, a well-pronounced visual blockade and intermitted alpha-disintegration. A second EEG did not show any relevant changes. The magnetic resonance imaging (MRI) of the brain showed a slight expansion of the external frontal cerebrospinal fluid space and around the upper cerebellar vermis space. Disseminated, age-inappropriate, supratentorial small hyperintensities of the medullary layer were found. MRI-scan of the cervical and thoracic spine did not show any pathological findings. Due to the atypical localization of some lesions (i.e., near the corpus callosum and the right temporo-polar region), additional brain MRI-scan with contrast (gadolinium) was performed but results did not indicate an inflammatory process. In addition, lumbar puncture was discussed with the patient, who decided not to undergo this procedure after risks and benefits were explained. As the patient reported insomnia for nearly one decade and as agomelatine 50 mg daily was not effective, this medication was discontinued. After moclobemide, rasagiline, and ranolazine were discontinued based on the hypothesis of serotonergic overstimulation, no further episodic psychovegetative or panic-related symptoms occurred during hospitalization. The patient's blood pressure, which initially showed hypertensive episodes, went back to normal, and no antihypertensive medication was required. For persistent insomnia treatment trials with mirtazapine and trazodone were conducted, mirtazapine was not tolerated and trazodone was inefficient. Finally, sleep-associated symptoms slightly decreased with trimipramine 10 mg at bedtime. We established an antidepressive treatment with escitalopram, which was titrated to a dose of 10 mg. As per suggestions of consulting neurologists, pramipexole was reduced and discontinued. Because this was followed by an increase in PD-associated motor symptoms, we initiated treatment with rotigotine transdermal application of 8 mg/day. Levodopa/benserazide retard was switched to nonretard formulation of 125 mg three times a day. With this medication regimen, a stable and sufficient mobility could be achieved. Medication at discharge included escitalopram 10 mg/day, levodopa/benserazide 125 mg three times per day, rotigotine transdermal 8 mg/day, trimipramine 10 mg/day, and levothyroxine 100 μg/day. The patient rated her mood as 9-10/10 on a scale from 0 to 10 with 10 being euthymic mood. The symptoms leading to admission subsided following discontinuation of MAO inhibitors moclobemide and rasagiline and did not reoccur during hospitalization.
3. Discussion and Conclusions
In this case report, we describe a probable drug-induced serotonergic overstimulation with paroxysmal exacerbations in a patient with PD. As other differential diagnoses could be ruled out, we suggest an interaction of several serotonergic medications, i.e., MAO-A inhibitor moclobemide and MAO-B inhibitor rasagiline as a causal factor. The hypothesis of a drug-induced symptomatology rather than genuine panic attacks is supported by subsiding of symptoms after discontinuation of both moclobemide and rasagiline, together with ranolazine. In addition, the paroxysmal episodes including jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and darkish red discoloration (flush) of the scalp and neck were suggestive of drug-induced monoaminergic overstimulation. We are not aware of another case report describing serotonin toxicity with this combination in the context of Parkinson's disease. Several subtypes of panic attacks have been described in the literature [29] postulating cardiac, cardiovascular, neurological, respiratory, and vestibular classifications of panic attacks [30]. Patients presenting with chest pain frequently show symptoms/criteria for panic disorder [31] which results in diagnostic uncertainty, and in the presented case, coronary vasospasms of unknown origin had been previously suspected and treated with ranolazine. However, as the patient did not experience a significant effect on her symptoms, she reported at admission that she had been taking ranolazine not regularly and the discontinuation of ranolazine at admission did not result in the occurrence of cardiovascular symptoms. On the contrary, the patient's physical activity, i.e., walking longer distances, was restored after motor symptoms were additionally stabilized by adjusting anti-Parkinson medication as described in detail above. The serotonin syndrome is commonly perceived as a potentially fatal entity following exposure to serotonergic substances. The risk is increased with combination of two or more drugs which directly enhance postsynaptic serotonin levels. However, serotonin toxicity could reflect a continuous, dose-related phenomenon with serotonin syndrome being the maximum clinical manifestation of serotonin toxicity [32]. Frequently, the clinical symptoms of serotonin toxicity develop rapidly when a serotonergic drug is added to a preexisting medication with stimulating effects on serotonin neurotransmission [33]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs of these compounds as well as that of levodopa/benserazide and to our knowledge clinical guidelines are not supporting this combination. Due to the high prevalence of psychiatric symptoms and psychiatric comorbidities in patients with PD, combined pharmacological treatment with anti-Parkinson drugs and drugs for treatment of depression and anxiety symptoms are often inevitable. In general, hypotheses and assumptions described in this case report have certain limitations. Quantitative measurements of plasma serotonin and other monoamines as well as their respective metabolites, i.e., urinary or CSF levels of 5-HIAA, have not been determined. Thus, our conclusions with respect to the aetiology of the patient's symptoms are mainly supported by the patient's medical history, clinical symptoms, considerations of drug-drug interactions, and rapid clinical improvement after discontinuation of suspected drugs, i.e., moclobemide and rasagiline. The pharmacological interactions between moclobemide (MAO-A inhibitor) and rasagiline (MAO-B inhibitor) likely resulted in intolerable side effects as described above. We speculate that the dual inhibition of MAO-A and MAO-B may have led to MAO-inhibition comparable to the effect of irreversible MAO-inhibitors such as tranylcypromine despite the reversible nature of MAO-A inhibition by moclobemide. This may have been intermittently potentiated by dietary amines since the patient was not on a low tyramine diet [17]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs and to our knowledge clinical guidelines are not supporting this combination. We assume that moclobemide had been taken into consideration despite strong arguments against, including formal contraindication label, after a number of antidepressants were previously prescribed but eventually discontinued due to side effects and recurrence of depressive symptoms. Interestingly, when moclobemide had been given at a low dose of 150 mg daily in combination with rasagiline, the patient did indeed benefit for approximately 3 years describing improvement of depressive symptoms and good tolerability. Reported psychovegetative symptoms occurred for the first time 6 months after the dose increase of moclobemide to 450 mg daily. This long delay in onset of adverse effects related to increasing oscillations of serotonin toxicity may explain why drug-drug interactions were discarded as a potential cause by physicians. The aspect that MAO-B activity increases with age [16] may have additionally contributed to this delayed onset of symptoms. The significant reduction of MAO-B as demonstrated by Bitsios et al. who found an approximately 29% reduction in human platelet MAO-B activity after a single dosage of 450 mg moclobemide [34] and the supratherapeutic plasma concentration of moclobemide (3310 ng/ml) we detected in our patient likely constitute additional contributing factors. Hence, the following clinically relevant main aspects can be derived from the case report at hand to improve patient safety and care: The importance of assessing and considering drug-drug interactions: our patient has been prescribed with a contraindicated combination of two drugs. We believe that the association of reported symptoms with adverse effects due to a drug-drug interaction was not addressed by the patient's initial prescriber, GP and ER (emergency room) physicians. The fact that the treatment was well tolerated by the patient for a prolonged period of time has likely contributed to this outcome. The case presented here highlights the importance of comprehensive and thorough assessment of pharmacological treatment and medication history and that drug-drug interactions should always be considered a potential etiological factor of clinical symptoms. This is of particular relevance for drugs where interactions have been reported as well as drugs that are not commonly prescribed or usually prescribed by different disciplines.
Drug-induced serotonergic overstimulation occurring on a continuous spectrum of changes in serotonergic neurotransmission: to the best of our knowledge, this is the first case report of a patient with PD with potentially drug-induced chronic serotonergic overstimulation with intermittent clinical exacerbations mimicking panic attacks. Most likely, this was caused by combined treatment with an antidepressant (moclobemide; MAO-A inhibitor) and anti-Parkinson medication (rasagiline; MAO-B inhibitor). Interestingly, signs of serotonin toxicity probably developed following an increase of moclobemide from 150 to 450 mg daily and “although polypharmacy is an important etiological factor in the development of serotonin syndrome per se, dose and speed of distribution may determine its severity" [35]. We believe that this case report can support the clinically relevant assumption that drug-induced serotonergic overstimulation may occur on a continuous spectrum of changes in serotonergic neurotransmission which may present as mild clinical symptoms, clinical exacerbations, or the potentially life-threatening condition of serotonin syndrome.
Acknowledgments
We are grateful to our patient who has provided consent for the publication of this case report.
Abbreviations
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-Hydroxytryptamine/serotonin
CBC: Complete blood count
ECG: Electrocardiogram
EEG: Electroencephalogram
ER: Emergency room
L-DOPA: Levodopa/L-3,4-dihydroxyphenylalanine
GP: General practitioner
MAO: Monoamine oxidase
MRI: Magnetic resonance imaging
PD: Parkinson's disease
REM: Rapid eye movement
T3: Triiodothyronine
T4: Thyroxine
TSH: Thyroid stimulating hormone.
Consent
The patient has provided written consent for publication.
Conflicts of Interest
The authors report no competing interests/conflicts of interest.
Authors' Contributions
All authors substantially contributed to the clinical assessments, evaluation, and treatment of the patient as well as generation and interpretation of results. M.P. drafted the initial version of the manuscript. All authors reviewed and substantially revised the manuscript. All authors have approved the submitted manuscript, are accountable for this contribution, and ensure accuracy and integrity of this work. | 375 mg (milligrams). | DrugDosage | CC BY | 33728085 | 19,085,716 | 2021 |
What was the dosage of drug 'RASAGILINE MESYLATE'? | Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided.
The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
1. Background
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive occurrence of typical motor dysfunctions such as resting tremor, rigidity, bradykinesia, and postural instability as well as concurrent nonmotor dysfunctions such as hyposomnia, REM (rapid eye movement) sleep behavior disorder, depression, autonomic dysregulation, cognitive impairments, psychosis, and anxiety disorders [1]. This clinical complexity of PD is mirrored by the current neuropathological understanding of PD. Subsequent disruption of nigrostriatal dopaminergic neurotransmission through degeneration of mesencephalic neurons located in the substantia nigra is accompanied by neurodegenerative processes in other brain areas leading to complex disturbances of neurobiological systems beyond the dopaminergic system including serotonergic and noradrenergic pathways [2]. Notably, dopaminergic dysfunction and serotonergic neuropathology of the basolateral amygdala were associated with anxiety in a rat model of PD and responsive to treatment with levodopa (L-DOPA) [3]. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), anxiety spectrum disorders consist of 12 diagnostic entities [4]. A panic attack is defined as a “discrete period of intense fear or discomfort” where symptoms such as palpitations, sweating, trembling or shaking, shortness of breath, chest pain or discomfort, nausea, dizziness, derealisation or depersonalisation, and fear of dying develop abruptly and can reach their peak within minutes [5]. In a recent cross-sectional study, Rai and colleagues investigated the prevalence of neuropsychiatric disorders, focussing on depression, anxiety, and psychosis in patients with PD. The results indicate depression to be the most common neuropsychiatric comorbidity with a prevalence of 43.7%; anxiety was found in 35.7% of patients with PD [6]. A high prevalence of anxiety disorders in PD was confirmed in other studies [7–9] describing a heterogeneous clinical picture with both sustained and episodic anxiety [8]. However, specific treatment options for anxiety disorders in PD have not been investigated in randomized controlled trials, as stated in a review from 2011 [10]. This high comorbidity of depressive and anxiety symptoms in patients with PD a combination of anti-Parkinson and antidepressant drugs is often clinically indicated. This case demonstrates that drug-drug interactions of antidepressant and anti-Parkinson medications, particularly when including monoamine oxidase (MAO) inhibitors, may result in serotonergic overstimulation and thus require careful consideration and monitoring. Clinically, the combination of moclobemide and rasagiline is hardly encountered and moreover explicitly contraindicated by regulatory agencies. Currently, two isoforms of MAOs, MAO-A and MAO-B, have been characterized in cerebral as well as extracerebral tissues [11] by means of their expression, molecular characteristics, differences in their preferred endogenous, and exogenous substrates and inhibitor-sensitivity [12, 13]. Substrates of MAO-A include serotonin, norepinephrine, and dopamine, whereas MAO-B preferentially degrades the monoamine alkaloid phenylethylamine (regulating the release of norepinephrine and dopamine) as well as the precursor molecule of various organic compounds such as benzylamine [14, 15]. Interestingly, MAO-B activity distinctively increases with age and has repeatedly been shown to be associated with neurodegenerative processes in dementia and PD [16] strengthening the therapeutic rationale and relevance of MAO-inhibitors in PD. The antidepressant moclobemide acts as a reversible and selective inhibitor of MAO-A and is effective in treating major depression [17]. The drug is a prototype of reversible inhibitors of MAO-A agents which target this enzyme in intraneuronal presynaptic regions [18]. A near-maximum inhibitory effect in healthy male volunteers was achieved with a single dosage of 300 mg. Maximum effects, as measured by decreased plasma concentrations of the serotonin-metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxphenyl-glycol, a peripheral noradrenaline-metabolite, were apparent at moclobemide plasma levels greater than 1000 ng/ml [19]. Only one study showed the antidepressant potency of moclobemide in depressed patients with PD and the superior effectiveness of the combination therapy with the MAO-B-inhibitor selegiline on affective symptoms as well as cognition. However, the small number of included patients does not allow to draw conclusions for clinical considerations [20]. Rasagiline belongs to selective blockers of MAO-B, such as selegiline. Rasagiline shows neuroprotective actions in vitro and is used as an anti-Parkinson drug. Chronic administration of a MAO-B-selective dose (0.2 mg/kg daily for 3 weeks) increased striatal dopamine and serotonin levels, while decreasing their metabolism. The drug restored the reduced activity in aged animals in behavioral paradigms to levels seen in young animals [21, 22]. However, in a therapeutic dose alone, it did not alter cerebral monoamine levels in another animal study [22]. Pramipexole is a non-ergoline dopamine receptor agonist (D2-like, D2S full, and D2L, D3, and D4 partial) for the treatment of PD and restless legs syndrome [23, 24]. Moreover, potential effects in treating symptoms of major depression have been reported [25]. Pramipexole also influences serotonergic neurotransmission by increasing activity of serotonergic neurons in the dorsal raphe. [26, 27]. Agomelatine belongs to a new generation of antidepressants since it elicits a dual mechanism of action by targeting the melatonergic system as an antagonist but also works as a serotonin 2C (5-HT2C) receptor antagonist. Studies have shown that treatment with agomelatine results in improvements in depressive symptoms, anxiety, and hypochondria in depressed patients [28].
2. Case Presentation
The 62-year-old female patient was referred to and admitted at the clinic of the Max-Planck-Institute of Psychiatry in Munich, Germany, for diagnostic clarification and treatment of recurring paroxysmal psychovegetative episodes. The patient, a retired school teacher from an urban upper-middle-class socioeconomic background, reported a history of insomnia, fatigue, and depressed mood, which preceded the onset of PD symptoms and worsened after being diagnosed with PD. She was premorbidly well-adjusted before the onset of motor symptoms and had no prior neurologic or psychiatric history. No developmental difficulties were reported. The patient's medical history includes the diagnosis of idiopathic Parkinson's syndrome, a moderate obstructive sleep apnea syndrome treated with a continuous positive airway pressure (CPAP) device, and chronic hypothyroidism following Hashimoto's disease approximately three decades ago and treated with thyroid hormone replacement since. About 6 months before clinical admission in our psychiatric ward, the patient noticed a reduced resilience to physical activity. In the last 4 months, she experienced shortness of breath after walking short distances and her general condition was affected by a feeling of physical weakness, shivering, headaches, and the sensation of facial heat. Unpredictable episodes of anxiety and vegetative symptoms occurred even out of quiescent states. Three months prior to this admission, she was assessed at an emergency department for thoracic pain and dyspnoea. Electrocardiogram (ECG), echocardiography, and blood work did not reveal any abnormalities. She was discharged with the suspected diagnosis of arterial hypertension and was started on ranolazine. Despite this intervention, her symptoms reoccurred and additionally worsened in the weeks prior to this admission. Her general practitioner (GP) recommended a beta blocker to be taken as needed. As ranolazine had no effect on her symptoms, the patient took ranolazine occasionally and discontinued the beta blocker treatment. There was no history of fever, altered sensorium, or neurological deficits except fluctuating motor symptoms associated with her diagnosis of PD. The patient described weight gain of approximately 4 kg during the last year. The patient's prevailing difficulties over the 4 months prior to admission were described as recurring paroxysmal episodes of jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and a darkish red discoloration of scalp and neck. These episodes emerged unexpectedly and were not associated with physical or emotional stress or other triggering factors. The patient reported that she had contacted an emergency physician on several occasions and had been admitted to hospitals twice approximately 3-4 months before her neurologist referred her to the clinic at the Max-Planck-Institute of Psychiatry in Munich, Germany, with a working diagnosis of panic disorder. Medication at admission consisted of moclobemide (450 mg/day), agomelatine (50 mg/day), pramipexole (0.525 mg/day), rasagiline (1 mg/day), L-DOPA+benserazide retard (200+50 mg/day), ranolazine (375 mg/day), and L-thyroxine (100 μg/day). The dose of moclobemide had been increased from 150 mg/day to the current dose about 1 year prior to admission. At the time of the initial mental status examination, the patient was fully alert, attentive, and oriented. She maintained eye contact and provided an informative report. No apparent abnormalities in thought form and content were observed. Cognitive and amnestic functions were intact. Her effect initially appeared euthymic with a normal range though intermittently depressed during the conversation. Her impetus towards social activities and daily activities was decreased. Her psychomotor domain was calm; her voice was quiet and showed tendencies towards decreased prosody. Both her mimic and overall expressive gestures were scarce. Severe insomnia with sleep-onset and disturbed sleep, and daytime fatigue were reported. Appetite was reported as increased over the past months. The patient did not endorse symptoms indicating specific phobia, social anxiety, or generalized anxiety. She reported paroxysmal episodes of psychovegetative strain. The patient was not suicidal; there were no safety concerns with respect to herself or others. General and neurological examination of the 62-year-old female patient (height: 165 cm, weight: 65 kg; BMI: 23.9 kg/m2) revealed a moderate rigor of the right upper extremity, adiadochokinesia, normal gait pattern, onychomycosis of toe nails, bilateral hallux valgus, and hyperkyphosis of the thoracic spine. No other physical or neurological abnormalities were detected. There was no postural imbalance or tremor. Vital signs at admission included blood pressure of 140/80 mmHg, heartrate of 84/min, and temperature of 36.4°C. Differential diagnoses considered at admission for reported paroxysmal episodes of psychovegetative symptoms included panic attacks/panic disorder, somatoform autonomic disorder, arterial hypertension with hypertensive exacerbations, iatrogenic hyperthyroidism, asthmatic disorder, and drug-induced serotonin toxicity. Clinical laboratory analyses did not reveal abnormal findings in CBC (complete blood count), hepatic and renal function, glucose and lipid profile, and electrolytes. Free T3 (triiodothyronine), free T4 (thyroxine), and TSH (thyroid stimulating hormone) were within normal limits. The plasma concentration of moclobemide (3310 ng/ml) was above the reference range of 300-1000 ng/ml. Plasma concentrations of agomelatine were not detectable (<1 ng/ml). We suspected potential pharmacological interactions to be a contributing factor to the symptoms reported by the patient at admission, and moclobemide, rasagiline, and ranolazine were discontinued. On the following day, the patient already experienced a decrease of psychovegetative symptoms. The blood work showed normal thyroid parameters, and no remarkable structural abnormalities of the thyroid gland were detected by sonography. Thus, we could rule out the possibility of iatrogenic hyperthyroidism. Moreover, repeated ECG examinations did not show signs of cardiac abnormalities explaining the patient's vegetative symptoms (ECG showed normal sinus rhythm, heart rate 81/min, QTc 429 ms, and vertical position). The changes of anti-parkinson medications during the stay were performed under repeated supervision of the consultant neurologists. As the discontinuation of ranolazine, which was prescribed as an antianginal medication, did not result in changes of blood pressure, we could also rule out arterial hypertension as a causative factor. The electroencephalogram (EEG) showed a regular, well-modulated, indistinct alpha-EEG with occipital accentuation and a frequency of 10-11 Hz and amplitudes reaching up to 100 μV, a well-pronounced visual blockade and intermitted alpha-disintegration. A second EEG did not show any relevant changes. The magnetic resonance imaging (MRI) of the brain showed a slight expansion of the external frontal cerebrospinal fluid space and around the upper cerebellar vermis space. Disseminated, age-inappropriate, supratentorial small hyperintensities of the medullary layer were found. MRI-scan of the cervical and thoracic spine did not show any pathological findings. Due to the atypical localization of some lesions (i.e., near the corpus callosum and the right temporo-polar region), additional brain MRI-scan with contrast (gadolinium) was performed but results did not indicate an inflammatory process. In addition, lumbar puncture was discussed with the patient, who decided not to undergo this procedure after risks and benefits were explained. As the patient reported insomnia for nearly one decade and as agomelatine 50 mg daily was not effective, this medication was discontinued. After moclobemide, rasagiline, and ranolazine were discontinued based on the hypothesis of serotonergic overstimulation, no further episodic psychovegetative or panic-related symptoms occurred during hospitalization. The patient's blood pressure, which initially showed hypertensive episodes, went back to normal, and no antihypertensive medication was required. For persistent insomnia treatment trials with mirtazapine and trazodone were conducted, mirtazapine was not tolerated and trazodone was inefficient. Finally, sleep-associated symptoms slightly decreased with trimipramine 10 mg at bedtime. We established an antidepressive treatment with escitalopram, which was titrated to a dose of 10 mg. As per suggestions of consulting neurologists, pramipexole was reduced and discontinued. Because this was followed by an increase in PD-associated motor symptoms, we initiated treatment with rotigotine transdermal application of 8 mg/day. Levodopa/benserazide retard was switched to nonretard formulation of 125 mg three times a day. With this medication regimen, a stable and sufficient mobility could be achieved. Medication at discharge included escitalopram 10 mg/day, levodopa/benserazide 125 mg three times per day, rotigotine transdermal 8 mg/day, trimipramine 10 mg/day, and levothyroxine 100 μg/day. The patient rated her mood as 9-10/10 on a scale from 0 to 10 with 10 being euthymic mood. The symptoms leading to admission subsided following discontinuation of MAO inhibitors moclobemide and rasagiline and did not reoccur during hospitalization.
3. Discussion and Conclusions
In this case report, we describe a probable drug-induced serotonergic overstimulation with paroxysmal exacerbations in a patient with PD. As other differential diagnoses could be ruled out, we suggest an interaction of several serotonergic medications, i.e., MAO-A inhibitor moclobemide and MAO-B inhibitor rasagiline as a causal factor. The hypothesis of a drug-induced symptomatology rather than genuine panic attacks is supported by subsiding of symptoms after discontinuation of both moclobemide and rasagiline, together with ranolazine. In addition, the paroxysmal episodes including jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and darkish red discoloration (flush) of the scalp and neck were suggestive of drug-induced monoaminergic overstimulation. We are not aware of another case report describing serotonin toxicity with this combination in the context of Parkinson's disease. Several subtypes of panic attacks have been described in the literature [29] postulating cardiac, cardiovascular, neurological, respiratory, and vestibular classifications of panic attacks [30]. Patients presenting with chest pain frequently show symptoms/criteria for panic disorder [31] which results in diagnostic uncertainty, and in the presented case, coronary vasospasms of unknown origin had been previously suspected and treated with ranolazine. However, as the patient did not experience a significant effect on her symptoms, she reported at admission that she had been taking ranolazine not regularly and the discontinuation of ranolazine at admission did not result in the occurrence of cardiovascular symptoms. On the contrary, the patient's physical activity, i.e., walking longer distances, was restored after motor symptoms were additionally stabilized by adjusting anti-Parkinson medication as described in detail above. The serotonin syndrome is commonly perceived as a potentially fatal entity following exposure to serotonergic substances. The risk is increased with combination of two or more drugs which directly enhance postsynaptic serotonin levels. However, serotonin toxicity could reflect a continuous, dose-related phenomenon with serotonin syndrome being the maximum clinical manifestation of serotonin toxicity [32]. Frequently, the clinical symptoms of serotonin toxicity develop rapidly when a serotonergic drug is added to a preexisting medication with stimulating effects on serotonin neurotransmission [33]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs of these compounds as well as that of levodopa/benserazide and to our knowledge clinical guidelines are not supporting this combination. Due to the high prevalence of psychiatric symptoms and psychiatric comorbidities in patients with PD, combined pharmacological treatment with anti-Parkinson drugs and drugs for treatment of depression and anxiety symptoms are often inevitable. In general, hypotheses and assumptions described in this case report have certain limitations. Quantitative measurements of plasma serotonin and other monoamines as well as their respective metabolites, i.e., urinary or CSF levels of 5-HIAA, have not been determined. Thus, our conclusions with respect to the aetiology of the patient's symptoms are mainly supported by the patient's medical history, clinical symptoms, considerations of drug-drug interactions, and rapid clinical improvement after discontinuation of suspected drugs, i.e., moclobemide and rasagiline. The pharmacological interactions between moclobemide (MAO-A inhibitor) and rasagiline (MAO-B inhibitor) likely resulted in intolerable side effects as described above. We speculate that the dual inhibition of MAO-A and MAO-B may have led to MAO-inhibition comparable to the effect of irreversible MAO-inhibitors such as tranylcypromine despite the reversible nature of MAO-A inhibition by moclobemide. This may have been intermittently potentiated by dietary amines since the patient was not on a low tyramine diet [17]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs and to our knowledge clinical guidelines are not supporting this combination. We assume that moclobemide had been taken into consideration despite strong arguments against, including formal contraindication label, after a number of antidepressants were previously prescribed but eventually discontinued due to side effects and recurrence of depressive symptoms. Interestingly, when moclobemide had been given at a low dose of 150 mg daily in combination with rasagiline, the patient did indeed benefit for approximately 3 years describing improvement of depressive symptoms and good tolerability. Reported psychovegetative symptoms occurred for the first time 6 months after the dose increase of moclobemide to 450 mg daily. This long delay in onset of adverse effects related to increasing oscillations of serotonin toxicity may explain why drug-drug interactions were discarded as a potential cause by physicians. The aspect that MAO-B activity increases with age [16] may have additionally contributed to this delayed onset of symptoms. The significant reduction of MAO-B as demonstrated by Bitsios et al. who found an approximately 29% reduction in human platelet MAO-B activity after a single dosage of 450 mg moclobemide [34] and the supratherapeutic plasma concentration of moclobemide (3310 ng/ml) we detected in our patient likely constitute additional contributing factors. Hence, the following clinically relevant main aspects can be derived from the case report at hand to improve patient safety and care: The importance of assessing and considering drug-drug interactions: our patient has been prescribed with a contraindicated combination of two drugs. We believe that the association of reported symptoms with adverse effects due to a drug-drug interaction was not addressed by the patient's initial prescriber, GP and ER (emergency room) physicians. The fact that the treatment was well tolerated by the patient for a prolonged period of time has likely contributed to this outcome. The case presented here highlights the importance of comprehensive and thorough assessment of pharmacological treatment and medication history and that drug-drug interactions should always be considered a potential etiological factor of clinical symptoms. This is of particular relevance for drugs where interactions have been reported as well as drugs that are not commonly prescribed or usually prescribed by different disciplines.
Drug-induced serotonergic overstimulation occurring on a continuous spectrum of changes in serotonergic neurotransmission: to the best of our knowledge, this is the first case report of a patient with PD with potentially drug-induced chronic serotonergic overstimulation with intermittent clinical exacerbations mimicking panic attacks. Most likely, this was caused by combined treatment with an antidepressant (moclobemide; MAO-A inhibitor) and anti-Parkinson medication (rasagiline; MAO-B inhibitor). Interestingly, signs of serotonin toxicity probably developed following an increase of moclobemide from 150 to 450 mg daily and “although polypharmacy is an important etiological factor in the development of serotonin syndrome per se, dose and speed of distribution may determine its severity" [35]. We believe that this case report can support the clinically relevant assumption that drug-induced serotonergic overstimulation may occur on a continuous spectrum of changes in serotonergic neurotransmission which may present as mild clinical symptoms, clinical exacerbations, or the potentially life-threatening condition of serotonin syndrome.
Acknowledgments
We are grateful to our patient who has provided consent for the publication of this case report.
Abbreviations
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-Hydroxytryptamine/serotonin
CBC: Complete blood count
ECG: Electrocardiogram
EEG: Electroencephalogram
ER: Emergency room
L-DOPA: Levodopa/L-3,4-dihydroxyphenylalanine
GP: General practitioner
MAO: Monoamine oxidase
MRI: Magnetic resonance imaging
PD: Parkinson's disease
REM: Rapid eye movement
T3: Triiodothyronine
T4: Thyroxine
TSH: Thyroid stimulating hormone.
Consent
The patient has provided written consent for publication.
Conflicts of Interest
The authors report no competing interests/conflicts of interest.
Authors' Contributions
All authors substantially contributed to the clinical assessments, evaluation, and treatment of the patient as well as generation and interpretation of results. M.P. drafted the initial version of the manuscript. All authors reviewed and substantially revised the manuscript. All authors have approved the submitted manuscript, are accountable for this contribution, and ensure accuracy and integrity of this work. | 1 MILLIGRAM, QD | DrugDosageText | CC BY | 33728085 | 19,165,149 | 2021 |
What was the dosage of drug 'TRAZODONE HYDROCHLORIDE'? | Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided.
The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
1. Background
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive occurrence of typical motor dysfunctions such as resting tremor, rigidity, bradykinesia, and postural instability as well as concurrent nonmotor dysfunctions such as hyposomnia, REM (rapid eye movement) sleep behavior disorder, depression, autonomic dysregulation, cognitive impairments, psychosis, and anxiety disorders [1]. This clinical complexity of PD is mirrored by the current neuropathological understanding of PD. Subsequent disruption of nigrostriatal dopaminergic neurotransmission through degeneration of mesencephalic neurons located in the substantia nigra is accompanied by neurodegenerative processes in other brain areas leading to complex disturbances of neurobiological systems beyond the dopaminergic system including serotonergic and noradrenergic pathways [2]. Notably, dopaminergic dysfunction and serotonergic neuropathology of the basolateral amygdala were associated with anxiety in a rat model of PD and responsive to treatment with levodopa (L-DOPA) [3]. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), anxiety spectrum disorders consist of 12 diagnostic entities [4]. A panic attack is defined as a “discrete period of intense fear or discomfort” where symptoms such as palpitations, sweating, trembling or shaking, shortness of breath, chest pain or discomfort, nausea, dizziness, derealisation or depersonalisation, and fear of dying develop abruptly and can reach their peak within minutes [5]. In a recent cross-sectional study, Rai and colleagues investigated the prevalence of neuropsychiatric disorders, focussing on depression, anxiety, and psychosis in patients with PD. The results indicate depression to be the most common neuropsychiatric comorbidity with a prevalence of 43.7%; anxiety was found in 35.7% of patients with PD [6]. A high prevalence of anxiety disorders in PD was confirmed in other studies [7–9] describing a heterogeneous clinical picture with both sustained and episodic anxiety [8]. However, specific treatment options for anxiety disorders in PD have not been investigated in randomized controlled trials, as stated in a review from 2011 [10]. This high comorbidity of depressive and anxiety symptoms in patients with PD a combination of anti-Parkinson and antidepressant drugs is often clinically indicated. This case demonstrates that drug-drug interactions of antidepressant and anti-Parkinson medications, particularly when including monoamine oxidase (MAO) inhibitors, may result in serotonergic overstimulation and thus require careful consideration and monitoring. Clinically, the combination of moclobemide and rasagiline is hardly encountered and moreover explicitly contraindicated by regulatory agencies. Currently, two isoforms of MAOs, MAO-A and MAO-B, have been characterized in cerebral as well as extracerebral tissues [11] by means of their expression, molecular characteristics, differences in their preferred endogenous, and exogenous substrates and inhibitor-sensitivity [12, 13]. Substrates of MAO-A include serotonin, norepinephrine, and dopamine, whereas MAO-B preferentially degrades the monoamine alkaloid phenylethylamine (regulating the release of norepinephrine and dopamine) as well as the precursor molecule of various organic compounds such as benzylamine [14, 15]. Interestingly, MAO-B activity distinctively increases with age and has repeatedly been shown to be associated with neurodegenerative processes in dementia and PD [16] strengthening the therapeutic rationale and relevance of MAO-inhibitors in PD. The antidepressant moclobemide acts as a reversible and selective inhibitor of MAO-A and is effective in treating major depression [17]. The drug is a prototype of reversible inhibitors of MAO-A agents which target this enzyme in intraneuronal presynaptic regions [18]. A near-maximum inhibitory effect in healthy male volunteers was achieved with a single dosage of 300 mg. Maximum effects, as measured by decreased plasma concentrations of the serotonin-metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxphenyl-glycol, a peripheral noradrenaline-metabolite, were apparent at moclobemide plasma levels greater than 1000 ng/ml [19]. Only one study showed the antidepressant potency of moclobemide in depressed patients with PD and the superior effectiveness of the combination therapy with the MAO-B-inhibitor selegiline on affective symptoms as well as cognition. However, the small number of included patients does not allow to draw conclusions for clinical considerations [20]. Rasagiline belongs to selective blockers of MAO-B, such as selegiline. Rasagiline shows neuroprotective actions in vitro and is used as an anti-Parkinson drug. Chronic administration of a MAO-B-selective dose (0.2 mg/kg daily for 3 weeks) increased striatal dopamine and serotonin levels, while decreasing their metabolism. The drug restored the reduced activity in aged animals in behavioral paradigms to levels seen in young animals [21, 22]. However, in a therapeutic dose alone, it did not alter cerebral monoamine levels in another animal study [22]. Pramipexole is a non-ergoline dopamine receptor agonist (D2-like, D2S full, and D2L, D3, and D4 partial) for the treatment of PD and restless legs syndrome [23, 24]. Moreover, potential effects in treating symptoms of major depression have been reported [25]. Pramipexole also influences serotonergic neurotransmission by increasing activity of serotonergic neurons in the dorsal raphe. [26, 27]. Agomelatine belongs to a new generation of antidepressants since it elicits a dual mechanism of action by targeting the melatonergic system as an antagonist but also works as a serotonin 2C (5-HT2C) receptor antagonist. Studies have shown that treatment with agomelatine results in improvements in depressive symptoms, anxiety, and hypochondria in depressed patients [28].
2. Case Presentation
The 62-year-old female patient was referred to and admitted at the clinic of the Max-Planck-Institute of Psychiatry in Munich, Germany, for diagnostic clarification and treatment of recurring paroxysmal psychovegetative episodes. The patient, a retired school teacher from an urban upper-middle-class socioeconomic background, reported a history of insomnia, fatigue, and depressed mood, which preceded the onset of PD symptoms and worsened after being diagnosed with PD. She was premorbidly well-adjusted before the onset of motor symptoms and had no prior neurologic or psychiatric history. No developmental difficulties were reported. The patient's medical history includes the diagnosis of idiopathic Parkinson's syndrome, a moderate obstructive sleep apnea syndrome treated with a continuous positive airway pressure (CPAP) device, and chronic hypothyroidism following Hashimoto's disease approximately three decades ago and treated with thyroid hormone replacement since. About 6 months before clinical admission in our psychiatric ward, the patient noticed a reduced resilience to physical activity. In the last 4 months, she experienced shortness of breath after walking short distances and her general condition was affected by a feeling of physical weakness, shivering, headaches, and the sensation of facial heat. Unpredictable episodes of anxiety and vegetative symptoms occurred even out of quiescent states. Three months prior to this admission, she was assessed at an emergency department for thoracic pain and dyspnoea. Electrocardiogram (ECG), echocardiography, and blood work did not reveal any abnormalities. She was discharged with the suspected diagnosis of arterial hypertension and was started on ranolazine. Despite this intervention, her symptoms reoccurred and additionally worsened in the weeks prior to this admission. Her general practitioner (GP) recommended a beta blocker to be taken as needed. As ranolazine had no effect on her symptoms, the patient took ranolazine occasionally and discontinued the beta blocker treatment. There was no history of fever, altered sensorium, or neurological deficits except fluctuating motor symptoms associated with her diagnosis of PD. The patient described weight gain of approximately 4 kg during the last year. The patient's prevailing difficulties over the 4 months prior to admission were described as recurring paroxysmal episodes of jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and a darkish red discoloration of scalp and neck. These episodes emerged unexpectedly and were not associated with physical or emotional stress or other triggering factors. The patient reported that she had contacted an emergency physician on several occasions and had been admitted to hospitals twice approximately 3-4 months before her neurologist referred her to the clinic at the Max-Planck-Institute of Psychiatry in Munich, Germany, with a working diagnosis of panic disorder. Medication at admission consisted of moclobemide (450 mg/day), agomelatine (50 mg/day), pramipexole (0.525 mg/day), rasagiline (1 mg/day), L-DOPA+benserazide retard (200+50 mg/day), ranolazine (375 mg/day), and L-thyroxine (100 μg/day). The dose of moclobemide had been increased from 150 mg/day to the current dose about 1 year prior to admission. At the time of the initial mental status examination, the patient was fully alert, attentive, and oriented. She maintained eye contact and provided an informative report. No apparent abnormalities in thought form and content were observed. Cognitive and amnestic functions were intact. Her effect initially appeared euthymic with a normal range though intermittently depressed during the conversation. Her impetus towards social activities and daily activities was decreased. Her psychomotor domain was calm; her voice was quiet and showed tendencies towards decreased prosody. Both her mimic and overall expressive gestures were scarce. Severe insomnia with sleep-onset and disturbed sleep, and daytime fatigue were reported. Appetite was reported as increased over the past months. The patient did not endorse symptoms indicating specific phobia, social anxiety, or generalized anxiety. She reported paroxysmal episodes of psychovegetative strain. The patient was not suicidal; there were no safety concerns with respect to herself or others. General and neurological examination of the 62-year-old female patient (height: 165 cm, weight: 65 kg; BMI: 23.9 kg/m2) revealed a moderate rigor of the right upper extremity, adiadochokinesia, normal gait pattern, onychomycosis of toe nails, bilateral hallux valgus, and hyperkyphosis of the thoracic spine. No other physical or neurological abnormalities were detected. There was no postural imbalance or tremor. Vital signs at admission included blood pressure of 140/80 mmHg, heartrate of 84/min, and temperature of 36.4°C. Differential diagnoses considered at admission for reported paroxysmal episodes of psychovegetative symptoms included panic attacks/panic disorder, somatoform autonomic disorder, arterial hypertension with hypertensive exacerbations, iatrogenic hyperthyroidism, asthmatic disorder, and drug-induced serotonin toxicity. Clinical laboratory analyses did not reveal abnormal findings in CBC (complete blood count), hepatic and renal function, glucose and lipid profile, and electrolytes. Free T3 (triiodothyronine), free T4 (thyroxine), and TSH (thyroid stimulating hormone) were within normal limits. The plasma concentration of moclobemide (3310 ng/ml) was above the reference range of 300-1000 ng/ml. Plasma concentrations of agomelatine were not detectable (<1 ng/ml). We suspected potential pharmacological interactions to be a contributing factor to the symptoms reported by the patient at admission, and moclobemide, rasagiline, and ranolazine were discontinued. On the following day, the patient already experienced a decrease of psychovegetative symptoms. The blood work showed normal thyroid parameters, and no remarkable structural abnormalities of the thyroid gland were detected by sonography. Thus, we could rule out the possibility of iatrogenic hyperthyroidism. Moreover, repeated ECG examinations did not show signs of cardiac abnormalities explaining the patient's vegetative symptoms (ECG showed normal sinus rhythm, heart rate 81/min, QTc 429 ms, and vertical position). The changes of anti-parkinson medications during the stay were performed under repeated supervision of the consultant neurologists. As the discontinuation of ranolazine, which was prescribed as an antianginal medication, did not result in changes of blood pressure, we could also rule out arterial hypertension as a causative factor. The electroencephalogram (EEG) showed a regular, well-modulated, indistinct alpha-EEG with occipital accentuation and a frequency of 10-11 Hz and amplitudes reaching up to 100 μV, a well-pronounced visual blockade and intermitted alpha-disintegration. A second EEG did not show any relevant changes. The magnetic resonance imaging (MRI) of the brain showed a slight expansion of the external frontal cerebrospinal fluid space and around the upper cerebellar vermis space. Disseminated, age-inappropriate, supratentorial small hyperintensities of the medullary layer were found. MRI-scan of the cervical and thoracic spine did not show any pathological findings. Due to the atypical localization of some lesions (i.e., near the corpus callosum and the right temporo-polar region), additional brain MRI-scan with contrast (gadolinium) was performed but results did not indicate an inflammatory process. In addition, lumbar puncture was discussed with the patient, who decided not to undergo this procedure after risks and benefits were explained. As the patient reported insomnia for nearly one decade and as agomelatine 50 mg daily was not effective, this medication was discontinued. After moclobemide, rasagiline, and ranolazine were discontinued based on the hypothesis of serotonergic overstimulation, no further episodic psychovegetative or panic-related symptoms occurred during hospitalization. The patient's blood pressure, which initially showed hypertensive episodes, went back to normal, and no antihypertensive medication was required. For persistent insomnia treatment trials with mirtazapine and trazodone were conducted, mirtazapine was not tolerated and trazodone was inefficient. Finally, sleep-associated symptoms slightly decreased with trimipramine 10 mg at bedtime. We established an antidepressive treatment with escitalopram, which was titrated to a dose of 10 mg. As per suggestions of consulting neurologists, pramipexole was reduced and discontinued. Because this was followed by an increase in PD-associated motor symptoms, we initiated treatment with rotigotine transdermal application of 8 mg/day. Levodopa/benserazide retard was switched to nonretard formulation of 125 mg three times a day. With this medication regimen, a stable and sufficient mobility could be achieved. Medication at discharge included escitalopram 10 mg/day, levodopa/benserazide 125 mg three times per day, rotigotine transdermal 8 mg/day, trimipramine 10 mg/day, and levothyroxine 100 μg/day. The patient rated her mood as 9-10/10 on a scale from 0 to 10 with 10 being euthymic mood. The symptoms leading to admission subsided following discontinuation of MAO inhibitors moclobemide and rasagiline and did not reoccur during hospitalization.
3. Discussion and Conclusions
In this case report, we describe a probable drug-induced serotonergic overstimulation with paroxysmal exacerbations in a patient with PD. As other differential diagnoses could be ruled out, we suggest an interaction of several serotonergic medications, i.e., MAO-A inhibitor moclobemide and MAO-B inhibitor rasagiline as a causal factor. The hypothesis of a drug-induced symptomatology rather than genuine panic attacks is supported by subsiding of symptoms after discontinuation of both moclobemide and rasagiline, together with ranolazine. In addition, the paroxysmal episodes including jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and darkish red discoloration (flush) of the scalp and neck were suggestive of drug-induced monoaminergic overstimulation. We are not aware of another case report describing serotonin toxicity with this combination in the context of Parkinson's disease. Several subtypes of panic attacks have been described in the literature [29] postulating cardiac, cardiovascular, neurological, respiratory, and vestibular classifications of panic attacks [30]. Patients presenting with chest pain frequently show symptoms/criteria for panic disorder [31] which results in diagnostic uncertainty, and in the presented case, coronary vasospasms of unknown origin had been previously suspected and treated with ranolazine. However, as the patient did not experience a significant effect on her symptoms, she reported at admission that she had been taking ranolazine not regularly and the discontinuation of ranolazine at admission did not result in the occurrence of cardiovascular symptoms. On the contrary, the patient's physical activity, i.e., walking longer distances, was restored after motor symptoms were additionally stabilized by adjusting anti-Parkinson medication as described in detail above. The serotonin syndrome is commonly perceived as a potentially fatal entity following exposure to serotonergic substances. The risk is increased with combination of two or more drugs which directly enhance postsynaptic serotonin levels. However, serotonin toxicity could reflect a continuous, dose-related phenomenon with serotonin syndrome being the maximum clinical manifestation of serotonin toxicity [32]. Frequently, the clinical symptoms of serotonin toxicity develop rapidly when a serotonergic drug is added to a preexisting medication with stimulating effects on serotonin neurotransmission [33]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs of these compounds as well as that of levodopa/benserazide and to our knowledge clinical guidelines are not supporting this combination. Due to the high prevalence of psychiatric symptoms and psychiatric comorbidities in patients with PD, combined pharmacological treatment with anti-Parkinson drugs and drugs for treatment of depression and anxiety symptoms are often inevitable. In general, hypotheses and assumptions described in this case report have certain limitations. Quantitative measurements of plasma serotonin and other monoamines as well as their respective metabolites, i.e., urinary or CSF levels of 5-HIAA, have not been determined. Thus, our conclusions with respect to the aetiology of the patient's symptoms are mainly supported by the patient's medical history, clinical symptoms, considerations of drug-drug interactions, and rapid clinical improvement after discontinuation of suspected drugs, i.e., moclobemide and rasagiline. The pharmacological interactions between moclobemide (MAO-A inhibitor) and rasagiline (MAO-B inhibitor) likely resulted in intolerable side effects as described above. We speculate that the dual inhibition of MAO-A and MAO-B may have led to MAO-inhibition comparable to the effect of irreversible MAO-inhibitors such as tranylcypromine despite the reversible nature of MAO-A inhibition by moclobemide. This may have been intermittently potentiated by dietary amines since the patient was not on a low tyramine diet [17]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs and to our knowledge clinical guidelines are not supporting this combination. We assume that moclobemide had been taken into consideration despite strong arguments against, including formal contraindication label, after a number of antidepressants were previously prescribed but eventually discontinued due to side effects and recurrence of depressive symptoms. Interestingly, when moclobemide had been given at a low dose of 150 mg daily in combination with rasagiline, the patient did indeed benefit for approximately 3 years describing improvement of depressive symptoms and good tolerability. Reported psychovegetative symptoms occurred for the first time 6 months after the dose increase of moclobemide to 450 mg daily. This long delay in onset of adverse effects related to increasing oscillations of serotonin toxicity may explain why drug-drug interactions were discarded as a potential cause by physicians. The aspect that MAO-B activity increases with age [16] may have additionally contributed to this delayed onset of symptoms. The significant reduction of MAO-B as demonstrated by Bitsios et al. who found an approximately 29% reduction in human platelet MAO-B activity after a single dosage of 450 mg moclobemide [34] and the supratherapeutic plasma concentration of moclobemide (3310 ng/ml) we detected in our patient likely constitute additional contributing factors. Hence, the following clinically relevant main aspects can be derived from the case report at hand to improve patient safety and care: The importance of assessing and considering drug-drug interactions: our patient has been prescribed with a contraindicated combination of two drugs. We believe that the association of reported symptoms with adverse effects due to a drug-drug interaction was not addressed by the patient's initial prescriber, GP and ER (emergency room) physicians. The fact that the treatment was well tolerated by the patient for a prolonged period of time has likely contributed to this outcome. The case presented here highlights the importance of comprehensive and thorough assessment of pharmacological treatment and medication history and that drug-drug interactions should always be considered a potential etiological factor of clinical symptoms. This is of particular relevance for drugs where interactions have been reported as well as drugs that are not commonly prescribed or usually prescribed by different disciplines.
Drug-induced serotonergic overstimulation occurring on a continuous spectrum of changes in serotonergic neurotransmission: to the best of our knowledge, this is the first case report of a patient with PD with potentially drug-induced chronic serotonergic overstimulation with intermittent clinical exacerbations mimicking panic attacks. Most likely, this was caused by combined treatment with an antidepressant (moclobemide; MAO-A inhibitor) and anti-Parkinson medication (rasagiline; MAO-B inhibitor). Interestingly, signs of serotonin toxicity probably developed following an increase of moclobemide from 150 to 450 mg daily and “although polypharmacy is an important etiological factor in the development of serotonin syndrome per se, dose and speed of distribution may determine its severity" [35]. We believe that this case report can support the clinically relevant assumption that drug-induced serotonergic overstimulation may occur on a continuous spectrum of changes in serotonergic neurotransmission which may present as mild clinical symptoms, clinical exacerbations, or the potentially life-threatening condition of serotonin syndrome.
Acknowledgments
We are grateful to our patient who has provided consent for the publication of this case report.
Abbreviations
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-Hydroxytryptamine/serotonin
CBC: Complete blood count
ECG: Electrocardiogram
EEG: Electroencephalogram
ER: Emergency room
L-DOPA: Levodopa/L-3,4-dihydroxyphenylalanine
GP: General practitioner
MAO: Monoamine oxidase
MRI: Magnetic resonance imaging
PD: Parkinson's disease
REM: Rapid eye movement
T3: Triiodothyronine
T4: Thyroxine
TSH: Thyroid stimulating hormone.
Consent
The patient has provided written consent for publication.
Conflicts of Interest
The authors report no competing interests/conflicts of interest.
Authors' Contributions
All authors substantially contributed to the clinical assessments, evaluation, and treatment of the patient as well as generation and interpretation of results. M.P. drafted the initial version of the manuscript. All authors reviewed and substantially revised the manuscript. All authors have approved the submitted manuscript, are accountable for this contribution, and ensure accuracy and integrity of this work. | TREATMENT TRIAL | DrugDosageText | CC BY | 33728085 | 19,165,149 | 2021 |
What was the outcome of reaction 'Condition aggravated'? | Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided.
The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
1. Background
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive occurrence of typical motor dysfunctions such as resting tremor, rigidity, bradykinesia, and postural instability as well as concurrent nonmotor dysfunctions such as hyposomnia, REM (rapid eye movement) sleep behavior disorder, depression, autonomic dysregulation, cognitive impairments, psychosis, and anxiety disorders [1]. This clinical complexity of PD is mirrored by the current neuropathological understanding of PD. Subsequent disruption of nigrostriatal dopaminergic neurotransmission through degeneration of mesencephalic neurons located in the substantia nigra is accompanied by neurodegenerative processes in other brain areas leading to complex disturbances of neurobiological systems beyond the dopaminergic system including serotonergic and noradrenergic pathways [2]. Notably, dopaminergic dysfunction and serotonergic neuropathology of the basolateral amygdala were associated with anxiety in a rat model of PD and responsive to treatment with levodopa (L-DOPA) [3]. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), anxiety spectrum disorders consist of 12 diagnostic entities [4]. A panic attack is defined as a “discrete period of intense fear or discomfort” where symptoms such as palpitations, sweating, trembling or shaking, shortness of breath, chest pain or discomfort, nausea, dizziness, derealisation or depersonalisation, and fear of dying develop abruptly and can reach their peak within minutes [5]. In a recent cross-sectional study, Rai and colleagues investigated the prevalence of neuropsychiatric disorders, focussing on depression, anxiety, and psychosis in patients with PD. The results indicate depression to be the most common neuropsychiatric comorbidity with a prevalence of 43.7%; anxiety was found in 35.7% of patients with PD [6]. A high prevalence of anxiety disorders in PD was confirmed in other studies [7–9] describing a heterogeneous clinical picture with both sustained and episodic anxiety [8]. However, specific treatment options for anxiety disorders in PD have not been investigated in randomized controlled trials, as stated in a review from 2011 [10]. This high comorbidity of depressive and anxiety symptoms in patients with PD a combination of anti-Parkinson and antidepressant drugs is often clinically indicated. This case demonstrates that drug-drug interactions of antidepressant and anti-Parkinson medications, particularly when including monoamine oxidase (MAO) inhibitors, may result in serotonergic overstimulation and thus require careful consideration and monitoring. Clinically, the combination of moclobemide and rasagiline is hardly encountered and moreover explicitly contraindicated by regulatory agencies. Currently, two isoforms of MAOs, MAO-A and MAO-B, have been characterized in cerebral as well as extracerebral tissues [11] by means of their expression, molecular characteristics, differences in their preferred endogenous, and exogenous substrates and inhibitor-sensitivity [12, 13]. Substrates of MAO-A include serotonin, norepinephrine, and dopamine, whereas MAO-B preferentially degrades the monoamine alkaloid phenylethylamine (regulating the release of norepinephrine and dopamine) as well as the precursor molecule of various organic compounds such as benzylamine [14, 15]. Interestingly, MAO-B activity distinctively increases with age and has repeatedly been shown to be associated with neurodegenerative processes in dementia and PD [16] strengthening the therapeutic rationale and relevance of MAO-inhibitors in PD. The antidepressant moclobemide acts as a reversible and selective inhibitor of MAO-A and is effective in treating major depression [17]. The drug is a prototype of reversible inhibitors of MAO-A agents which target this enzyme in intraneuronal presynaptic regions [18]. A near-maximum inhibitory effect in healthy male volunteers was achieved with a single dosage of 300 mg. Maximum effects, as measured by decreased plasma concentrations of the serotonin-metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxphenyl-glycol, a peripheral noradrenaline-metabolite, were apparent at moclobemide plasma levels greater than 1000 ng/ml [19]. Only one study showed the antidepressant potency of moclobemide in depressed patients with PD and the superior effectiveness of the combination therapy with the MAO-B-inhibitor selegiline on affective symptoms as well as cognition. However, the small number of included patients does not allow to draw conclusions for clinical considerations [20]. Rasagiline belongs to selective blockers of MAO-B, such as selegiline. Rasagiline shows neuroprotective actions in vitro and is used as an anti-Parkinson drug. Chronic administration of a MAO-B-selective dose (0.2 mg/kg daily for 3 weeks) increased striatal dopamine and serotonin levels, while decreasing their metabolism. The drug restored the reduced activity in aged animals in behavioral paradigms to levels seen in young animals [21, 22]. However, in a therapeutic dose alone, it did not alter cerebral monoamine levels in another animal study [22]. Pramipexole is a non-ergoline dopamine receptor agonist (D2-like, D2S full, and D2L, D3, and D4 partial) for the treatment of PD and restless legs syndrome [23, 24]. Moreover, potential effects in treating symptoms of major depression have been reported [25]. Pramipexole also influences serotonergic neurotransmission by increasing activity of serotonergic neurons in the dorsal raphe. [26, 27]. Agomelatine belongs to a new generation of antidepressants since it elicits a dual mechanism of action by targeting the melatonergic system as an antagonist but also works as a serotonin 2C (5-HT2C) receptor antagonist. Studies have shown that treatment with agomelatine results in improvements in depressive symptoms, anxiety, and hypochondria in depressed patients [28].
2. Case Presentation
The 62-year-old female patient was referred to and admitted at the clinic of the Max-Planck-Institute of Psychiatry in Munich, Germany, for diagnostic clarification and treatment of recurring paroxysmal psychovegetative episodes. The patient, a retired school teacher from an urban upper-middle-class socioeconomic background, reported a history of insomnia, fatigue, and depressed mood, which preceded the onset of PD symptoms and worsened after being diagnosed with PD. She was premorbidly well-adjusted before the onset of motor symptoms and had no prior neurologic or psychiatric history. No developmental difficulties were reported. The patient's medical history includes the diagnosis of idiopathic Parkinson's syndrome, a moderate obstructive sleep apnea syndrome treated with a continuous positive airway pressure (CPAP) device, and chronic hypothyroidism following Hashimoto's disease approximately three decades ago and treated with thyroid hormone replacement since. About 6 months before clinical admission in our psychiatric ward, the patient noticed a reduced resilience to physical activity. In the last 4 months, she experienced shortness of breath after walking short distances and her general condition was affected by a feeling of physical weakness, shivering, headaches, and the sensation of facial heat. Unpredictable episodes of anxiety and vegetative symptoms occurred even out of quiescent states. Three months prior to this admission, she was assessed at an emergency department for thoracic pain and dyspnoea. Electrocardiogram (ECG), echocardiography, and blood work did not reveal any abnormalities. She was discharged with the suspected diagnosis of arterial hypertension and was started on ranolazine. Despite this intervention, her symptoms reoccurred and additionally worsened in the weeks prior to this admission. Her general practitioner (GP) recommended a beta blocker to be taken as needed. As ranolazine had no effect on her symptoms, the patient took ranolazine occasionally and discontinued the beta blocker treatment. There was no history of fever, altered sensorium, or neurological deficits except fluctuating motor symptoms associated with her diagnosis of PD. The patient described weight gain of approximately 4 kg during the last year. The patient's prevailing difficulties over the 4 months prior to admission were described as recurring paroxysmal episodes of jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and a darkish red discoloration of scalp and neck. These episodes emerged unexpectedly and were not associated with physical or emotional stress or other triggering factors. The patient reported that she had contacted an emergency physician on several occasions and had been admitted to hospitals twice approximately 3-4 months before her neurologist referred her to the clinic at the Max-Planck-Institute of Psychiatry in Munich, Germany, with a working diagnosis of panic disorder. Medication at admission consisted of moclobemide (450 mg/day), agomelatine (50 mg/day), pramipexole (0.525 mg/day), rasagiline (1 mg/day), L-DOPA+benserazide retard (200+50 mg/day), ranolazine (375 mg/day), and L-thyroxine (100 μg/day). The dose of moclobemide had been increased from 150 mg/day to the current dose about 1 year prior to admission. At the time of the initial mental status examination, the patient was fully alert, attentive, and oriented. She maintained eye contact and provided an informative report. No apparent abnormalities in thought form and content were observed. Cognitive and amnestic functions were intact. Her effect initially appeared euthymic with a normal range though intermittently depressed during the conversation. Her impetus towards social activities and daily activities was decreased. Her psychomotor domain was calm; her voice was quiet and showed tendencies towards decreased prosody. Both her mimic and overall expressive gestures were scarce. Severe insomnia with sleep-onset and disturbed sleep, and daytime fatigue were reported. Appetite was reported as increased over the past months. The patient did not endorse symptoms indicating specific phobia, social anxiety, or generalized anxiety. She reported paroxysmal episodes of psychovegetative strain. The patient was not suicidal; there were no safety concerns with respect to herself or others. General and neurological examination of the 62-year-old female patient (height: 165 cm, weight: 65 kg; BMI: 23.9 kg/m2) revealed a moderate rigor of the right upper extremity, adiadochokinesia, normal gait pattern, onychomycosis of toe nails, bilateral hallux valgus, and hyperkyphosis of the thoracic spine. No other physical or neurological abnormalities were detected. There was no postural imbalance or tremor. Vital signs at admission included blood pressure of 140/80 mmHg, heartrate of 84/min, and temperature of 36.4°C. Differential diagnoses considered at admission for reported paroxysmal episodes of psychovegetative symptoms included panic attacks/panic disorder, somatoform autonomic disorder, arterial hypertension with hypertensive exacerbations, iatrogenic hyperthyroidism, asthmatic disorder, and drug-induced serotonin toxicity. Clinical laboratory analyses did not reveal abnormal findings in CBC (complete blood count), hepatic and renal function, glucose and lipid profile, and electrolytes. Free T3 (triiodothyronine), free T4 (thyroxine), and TSH (thyroid stimulating hormone) were within normal limits. The plasma concentration of moclobemide (3310 ng/ml) was above the reference range of 300-1000 ng/ml. Plasma concentrations of agomelatine were not detectable (<1 ng/ml). We suspected potential pharmacological interactions to be a contributing factor to the symptoms reported by the patient at admission, and moclobemide, rasagiline, and ranolazine were discontinued. On the following day, the patient already experienced a decrease of psychovegetative symptoms. The blood work showed normal thyroid parameters, and no remarkable structural abnormalities of the thyroid gland were detected by sonography. Thus, we could rule out the possibility of iatrogenic hyperthyroidism. Moreover, repeated ECG examinations did not show signs of cardiac abnormalities explaining the patient's vegetative symptoms (ECG showed normal sinus rhythm, heart rate 81/min, QTc 429 ms, and vertical position). The changes of anti-parkinson medications during the stay were performed under repeated supervision of the consultant neurologists. As the discontinuation of ranolazine, which was prescribed as an antianginal medication, did not result in changes of blood pressure, we could also rule out arterial hypertension as a causative factor. The electroencephalogram (EEG) showed a regular, well-modulated, indistinct alpha-EEG with occipital accentuation and a frequency of 10-11 Hz and amplitudes reaching up to 100 μV, a well-pronounced visual blockade and intermitted alpha-disintegration. A second EEG did not show any relevant changes. The magnetic resonance imaging (MRI) of the brain showed a slight expansion of the external frontal cerebrospinal fluid space and around the upper cerebellar vermis space. Disseminated, age-inappropriate, supratentorial small hyperintensities of the medullary layer were found. MRI-scan of the cervical and thoracic spine did not show any pathological findings. Due to the atypical localization of some lesions (i.e., near the corpus callosum and the right temporo-polar region), additional brain MRI-scan with contrast (gadolinium) was performed but results did not indicate an inflammatory process. In addition, lumbar puncture was discussed with the patient, who decided not to undergo this procedure after risks and benefits were explained. As the patient reported insomnia for nearly one decade and as agomelatine 50 mg daily was not effective, this medication was discontinued. After moclobemide, rasagiline, and ranolazine were discontinued based on the hypothesis of serotonergic overstimulation, no further episodic psychovegetative or panic-related symptoms occurred during hospitalization. The patient's blood pressure, which initially showed hypertensive episodes, went back to normal, and no antihypertensive medication was required. For persistent insomnia treatment trials with mirtazapine and trazodone were conducted, mirtazapine was not tolerated and trazodone was inefficient. Finally, sleep-associated symptoms slightly decreased with trimipramine 10 mg at bedtime. We established an antidepressive treatment with escitalopram, which was titrated to a dose of 10 mg. As per suggestions of consulting neurologists, pramipexole was reduced and discontinued. Because this was followed by an increase in PD-associated motor symptoms, we initiated treatment with rotigotine transdermal application of 8 mg/day. Levodopa/benserazide retard was switched to nonretard formulation of 125 mg three times a day. With this medication regimen, a stable and sufficient mobility could be achieved. Medication at discharge included escitalopram 10 mg/day, levodopa/benserazide 125 mg three times per day, rotigotine transdermal 8 mg/day, trimipramine 10 mg/day, and levothyroxine 100 μg/day. The patient rated her mood as 9-10/10 on a scale from 0 to 10 with 10 being euthymic mood. The symptoms leading to admission subsided following discontinuation of MAO inhibitors moclobemide and rasagiline and did not reoccur during hospitalization.
3. Discussion and Conclusions
In this case report, we describe a probable drug-induced serotonergic overstimulation with paroxysmal exacerbations in a patient with PD. As other differential diagnoses could be ruled out, we suggest an interaction of several serotonergic medications, i.e., MAO-A inhibitor moclobemide and MAO-B inhibitor rasagiline as a causal factor. The hypothesis of a drug-induced symptomatology rather than genuine panic attacks is supported by subsiding of symptoms after discontinuation of both moclobemide and rasagiline, together with ranolazine. In addition, the paroxysmal episodes including jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and darkish red discoloration (flush) of the scalp and neck were suggestive of drug-induced monoaminergic overstimulation. We are not aware of another case report describing serotonin toxicity with this combination in the context of Parkinson's disease. Several subtypes of panic attacks have been described in the literature [29] postulating cardiac, cardiovascular, neurological, respiratory, and vestibular classifications of panic attacks [30]. Patients presenting with chest pain frequently show symptoms/criteria for panic disorder [31] which results in diagnostic uncertainty, and in the presented case, coronary vasospasms of unknown origin had been previously suspected and treated with ranolazine. However, as the patient did not experience a significant effect on her symptoms, she reported at admission that she had been taking ranolazine not regularly and the discontinuation of ranolazine at admission did not result in the occurrence of cardiovascular symptoms. On the contrary, the patient's physical activity, i.e., walking longer distances, was restored after motor symptoms were additionally stabilized by adjusting anti-Parkinson medication as described in detail above. The serotonin syndrome is commonly perceived as a potentially fatal entity following exposure to serotonergic substances. The risk is increased with combination of two or more drugs which directly enhance postsynaptic serotonin levels. However, serotonin toxicity could reflect a continuous, dose-related phenomenon with serotonin syndrome being the maximum clinical manifestation of serotonin toxicity [32]. Frequently, the clinical symptoms of serotonin toxicity develop rapidly when a serotonergic drug is added to a preexisting medication with stimulating effects on serotonin neurotransmission [33]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs of these compounds as well as that of levodopa/benserazide and to our knowledge clinical guidelines are not supporting this combination. Due to the high prevalence of psychiatric symptoms and psychiatric comorbidities in patients with PD, combined pharmacological treatment with anti-Parkinson drugs and drugs for treatment of depression and anxiety symptoms are often inevitable. In general, hypotheses and assumptions described in this case report have certain limitations. Quantitative measurements of plasma serotonin and other monoamines as well as their respective metabolites, i.e., urinary or CSF levels of 5-HIAA, have not been determined. Thus, our conclusions with respect to the aetiology of the patient's symptoms are mainly supported by the patient's medical history, clinical symptoms, considerations of drug-drug interactions, and rapid clinical improvement after discontinuation of suspected drugs, i.e., moclobemide and rasagiline. The pharmacological interactions between moclobemide (MAO-A inhibitor) and rasagiline (MAO-B inhibitor) likely resulted in intolerable side effects as described above. We speculate that the dual inhibition of MAO-A and MAO-B may have led to MAO-inhibition comparable to the effect of irreversible MAO-inhibitors such as tranylcypromine despite the reversible nature of MAO-A inhibition by moclobemide. This may have been intermittently potentiated by dietary amines since the patient was not on a low tyramine diet [17]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs and to our knowledge clinical guidelines are not supporting this combination. We assume that moclobemide had been taken into consideration despite strong arguments against, including formal contraindication label, after a number of antidepressants were previously prescribed but eventually discontinued due to side effects and recurrence of depressive symptoms. Interestingly, when moclobemide had been given at a low dose of 150 mg daily in combination with rasagiline, the patient did indeed benefit for approximately 3 years describing improvement of depressive symptoms and good tolerability. Reported psychovegetative symptoms occurred for the first time 6 months after the dose increase of moclobemide to 450 mg daily. This long delay in onset of adverse effects related to increasing oscillations of serotonin toxicity may explain why drug-drug interactions were discarded as a potential cause by physicians. The aspect that MAO-B activity increases with age [16] may have additionally contributed to this delayed onset of symptoms. The significant reduction of MAO-B as demonstrated by Bitsios et al. who found an approximately 29% reduction in human platelet MAO-B activity after a single dosage of 450 mg moclobemide [34] and the supratherapeutic plasma concentration of moclobemide (3310 ng/ml) we detected in our patient likely constitute additional contributing factors. Hence, the following clinically relevant main aspects can be derived from the case report at hand to improve patient safety and care: The importance of assessing and considering drug-drug interactions: our patient has been prescribed with a contraindicated combination of two drugs. We believe that the association of reported symptoms with adverse effects due to a drug-drug interaction was not addressed by the patient's initial prescriber, GP and ER (emergency room) physicians. The fact that the treatment was well tolerated by the patient for a prolonged period of time has likely contributed to this outcome. The case presented here highlights the importance of comprehensive and thorough assessment of pharmacological treatment and medication history and that drug-drug interactions should always be considered a potential etiological factor of clinical symptoms. This is of particular relevance for drugs where interactions have been reported as well as drugs that are not commonly prescribed or usually prescribed by different disciplines.
Drug-induced serotonergic overstimulation occurring on a continuous spectrum of changes in serotonergic neurotransmission: to the best of our knowledge, this is the first case report of a patient with PD with potentially drug-induced chronic serotonergic overstimulation with intermittent clinical exacerbations mimicking panic attacks. Most likely, this was caused by combined treatment with an antidepressant (moclobemide; MAO-A inhibitor) and anti-Parkinson medication (rasagiline; MAO-B inhibitor). Interestingly, signs of serotonin toxicity probably developed following an increase of moclobemide from 150 to 450 mg daily and “although polypharmacy is an important etiological factor in the development of serotonin syndrome per se, dose and speed of distribution may determine its severity" [35]. We believe that this case report can support the clinically relevant assumption that drug-induced serotonergic overstimulation may occur on a continuous spectrum of changes in serotonergic neurotransmission which may present as mild clinical symptoms, clinical exacerbations, or the potentially life-threatening condition of serotonin syndrome.
Acknowledgments
We are grateful to our patient who has provided consent for the publication of this case report.
Abbreviations
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-Hydroxytryptamine/serotonin
CBC: Complete blood count
ECG: Electrocardiogram
EEG: Electroencephalogram
ER: Emergency room
L-DOPA: Levodopa/L-3,4-dihydroxyphenylalanine
GP: General practitioner
MAO: Monoamine oxidase
MRI: Magnetic resonance imaging
PD: Parkinson's disease
REM: Rapid eye movement
T3: Triiodothyronine
T4: Thyroxine
TSH: Thyroid stimulating hormone.
Consent
The patient has provided written consent for publication.
Conflicts of Interest
The authors report no competing interests/conflicts of interest.
Authors' Contributions
All authors substantially contributed to the clinical assessments, evaluation, and treatment of the patient as well as generation and interpretation of results. M.P. drafted the initial version of the manuscript. All authors reviewed and substantially revised the manuscript. All authors have approved the submitted manuscript, are accountable for this contribution, and ensure accuracy and integrity of this work. | Recovered | ReactionOutcome | CC BY | 33728085 | 19,095,322 | 2021 |
What was the outcome of reaction 'Drug interaction'? | Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided.
The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
1. Background
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive occurrence of typical motor dysfunctions such as resting tremor, rigidity, bradykinesia, and postural instability as well as concurrent nonmotor dysfunctions such as hyposomnia, REM (rapid eye movement) sleep behavior disorder, depression, autonomic dysregulation, cognitive impairments, psychosis, and anxiety disorders [1]. This clinical complexity of PD is mirrored by the current neuropathological understanding of PD. Subsequent disruption of nigrostriatal dopaminergic neurotransmission through degeneration of mesencephalic neurons located in the substantia nigra is accompanied by neurodegenerative processes in other brain areas leading to complex disturbances of neurobiological systems beyond the dopaminergic system including serotonergic and noradrenergic pathways [2]. Notably, dopaminergic dysfunction and serotonergic neuropathology of the basolateral amygdala were associated with anxiety in a rat model of PD and responsive to treatment with levodopa (L-DOPA) [3]. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), anxiety spectrum disorders consist of 12 diagnostic entities [4]. A panic attack is defined as a “discrete period of intense fear or discomfort” where symptoms such as palpitations, sweating, trembling or shaking, shortness of breath, chest pain or discomfort, nausea, dizziness, derealisation or depersonalisation, and fear of dying develop abruptly and can reach their peak within minutes [5]. In a recent cross-sectional study, Rai and colleagues investigated the prevalence of neuropsychiatric disorders, focussing on depression, anxiety, and psychosis in patients with PD. The results indicate depression to be the most common neuropsychiatric comorbidity with a prevalence of 43.7%; anxiety was found in 35.7% of patients with PD [6]. A high prevalence of anxiety disorders in PD was confirmed in other studies [7–9] describing a heterogeneous clinical picture with both sustained and episodic anxiety [8]. However, specific treatment options for anxiety disorders in PD have not been investigated in randomized controlled trials, as stated in a review from 2011 [10]. This high comorbidity of depressive and anxiety symptoms in patients with PD a combination of anti-Parkinson and antidepressant drugs is often clinically indicated. This case demonstrates that drug-drug interactions of antidepressant and anti-Parkinson medications, particularly when including monoamine oxidase (MAO) inhibitors, may result in serotonergic overstimulation and thus require careful consideration and monitoring. Clinically, the combination of moclobemide and rasagiline is hardly encountered and moreover explicitly contraindicated by regulatory agencies. Currently, two isoforms of MAOs, MAO-A and MAO-B, have been characterized in cerebral as well as extracerebral tissues [11] by means of their expression, molecular characteristics, differences in their preferred endogenous, and exogenous substrates and inhibitor-sensitivity [12, 13]. Substrates of MAO-A include serotonin, norepinephrine, and dopamine, whereas MAO-B preferentially degrades the monoamine alkaloid phenylethylamine (regulating the release of norepinephrine and dopamine) as well as the precursor molecule of various organic compounds such as benzylamine [14, 15]. Interestingly, MAO-B activity distinctively increases with age and has repeatedly been shown to be associated with neurodegenerative processes in dementia and PD [16] strengthening the therapeutic rationale and relevance of MAO-inhibitors in PD. The antidepressant moclobemide acts as a reversible and selective inhibitor of MAO-A and is effective in treating major depression [17]. The drug is a prototype of reversible inhibitors of MAO-A agents which target this enzyme in intraneuronal presynaptic regions [18]. A near-maximum inhibitory effect in healthy male volunteers was achieved with a single dosage of 300 mg. Maximum effects, as measured by decreased plasma concentrations of the serotonin-metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxphenyl-glycol, a peripheral noradrenaline-metabolite, were apparent at moclobemide plasma levels greater than 1000 ng/ml [19]. Only one study showed the antidepressant potency of moclobemide in depressed patients with PD and the superior effectiveness of the combination therapy with the MAO-B-inhibitor selegiline on affective symptoms as well as cognition. However, the small number of included patients does not allow to draw conclusions for clinical considerations [20]. Rasagiline belongs to selective blockers of MAO-B, such as selegiline. Rasagiline shows neuroprotective actions in vitro and is used as an anti-Parkinson drug. Chronic administration of a MAO-B-selective dose (0.2 mg/kg daily for 3 weeks) increased striatal dopamine and serotonin levels, while decreasing their metabolism. The drug restored the reduced activity in aged animals in behavioral paradigms to levels seen in young animals [21, 22]. However, in a therapeutic dose alone, it did not alter cerebral monoamine levels in another animal study [22]. Pramipexole is a non-ergoline dopamine receptor agonist (D2-like, D2S full, and D2L, D3, and D4 partial) for the treatment of PD and restless legs syndrome [23, 24]. Moreover, potential effects in treating symptoms of major depression have been reported [25]. Pramipexole also influences serotonergic neurotransmission by increasing activity of serotonergic neurons in the dorsal raphe. [26, 27]. Agomelatine belongs to a new generation of antidepressants since it elicits a dual mechanism of action by targeting the melatonergic system as an antagonist but also works as a serotonin 2C (5-HT2C) receptor antagonist. Studies have shown that treatment with agomelatine results in improvements in depressive symptoms, anxiety, and hypochondria in depressed patients [28].
2. Case Presentation
The 62-year-old female patient was referred to and admitted at the clinic of the Max-Planck-Institute of Psychiatry in Munich, Germany, for diagnostic clarification and treatment of recurring paroxysmal psychovegetative episodes. The patient, a retired school teacher from an urban upper-middle-class socioeconomic background, reported a history of insomnia, fatigue, and depressed mood, which preceded the onset of PD symptoms and worsened after being diagnosed with PD. She was premorbidly well-adjusted before the onset of motor symptoms and had no prior neurologic or psychiatric history. No developmental difficulties were reported. The patient's medical history includes the diagnosis of idiopathic Parkinson's syndrome, a moderate obstructive sleep apnea syndrome treated with a continuous positive airway pressure (CPAP) device, and chronic hypothyroidism following Hashimoto's disease approximately three decades ago and treated with thyroid hormone replacement since. About 6 months before clinical admission in our psychiatric ward, the patient noticed a reduced resilience to physical activity. In the last 4 months, she experienced shortness of breath after walking short distances and her general condition was affected by a feeling of physical weakness, shivering, headaches, and the sensation of facial heat. Unpredictable episodes of anxiety and vegetative symptoms occurred even out of quiescent states. Three months prior to this admission, she was assessed at an emergency department for thoracic pain and dyspnoea. Electrocardiogram (ECG), echocardiography, and blood work did not reveal any abnormalities. She was discharged with the suspected diagnosis of arterial hypertension and was started on ranolazine. Despite this intervention, her symptoms reoccurred and additionally worsened in the weeks prior to this admission. Her general practitioner (GP) recommended a beta blocker to be taken as needed. As ranolazine had no effect on her symptoms, the patient took ranolazine occasionally and discontinued the beta blocker treatment. There was no history of fever, altered sensorium, or neurological deficits except fluctuating motor symptoms associated with her diagnosis of PD. The patient described weight gain of approximately 4 kg during the last year. The patient's prevailing difficulties over the 4 months prior to admission were described as recurring paroxysmal episodes of jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and a darkish red discoloration of scalp and neck. These episodes emerged unexpectedly and were not associated with physical or emotional stress or other triggering factors. The patient reported that she had contacted an emergency physician on several occasions and had been admitted to hospitals twice approximately 3-4 months before her neurologist referred her to the clinic at the Max-Planck-Institute of Psychiatry in Munich, Germany, with a working diagnosis of panic disorder. Medication at admission consisted of moclobemide (450 mg/day), agomelatine (50 mg/day), pramipexole (0.525 mg/day), rasagiline (1 mg/day), L-DOPA+benserazide retard (200+50 mg/day), ranolazine (375 mg/day), and L-thyroxine (100 μg/day). The dose of moclobemide had been increased from 150 mg/day to the current dose about 1 year prior to admission. At the time of the initial mental status examination, the patient was fully alert, attentive, and oriented. She maintained eye contact and provided an informative report. No apparent abnormalities in thought form and content were observed. Cognitive and amnestic functions were intact. Her effect initially appeared euthymic with a normal range though intermittently depressed during the conversation. Her impetus towards social activities and daily activities was decreased. Her psychomotor domain was calm; her voice was quiet and showed tendencies towards decreased prosody. Both her mimic and overall expressive gestures were scarce. Severe insomnia with sleep-onset and disturbed sleep, and daytime fatigue were reported. Appetite was reported as increased over the past months. The patient did not endorse symptoms indicating specific phobia, social anxiety, or generalized anxiety. She reported paroxysmal episodes of psychovegetative strain. The patient was not suicidal; there were no safety concerns with respect to herself or others. General and neurological examination of the 62-year-old female patient (height: 165 cm, weight: 65 kg; BMI: 23.9 kg/m2) revealed a moderate rigor of the right upper extremity, adiadochokinesia, normal gait pattern, onychomycosis of toe nails, bilateral hallux valgus, and hyperkyphosis of the thoracic spine. No other physical or neurological abnormalities were detected. There was no postural imbalance or tremor. Vital signs at admission included blood pressure of 140/80 mmHg, heartrate of 84/min, and temperature of 36.4°C. Differential diagnoses considered at admission for reported paroxysmal episodes of psychovegetative symptoms included panic attacks/panic disorder, somatoform autonomic disorder, arterial hypertension with hypertensive exacerbations, iatrogenic hyperthyroidism, asthmatic disorder, and drug-induced serotonin toxicity. Clinical laboratory analyses did not reveal abnormal findings in CBC (complete blood count), hepatic and renal function, glucose and lipid profile, and electrolytes. Free T3 (triiodothyronine), free T4 (thyroxine), and TSH (thyroid stimulating hormone) were within normal limits. The plasma concentration of moclobemide (3310 ng/ml) was above the reference range of 300-1000 ng/ml. Plasma concentrations of agomelatine were not detectable (<1 ng/ml). We suspected potential pharmacological interactions to be a contributing factor to the symptoms reported by the patient at admission, and moclobemide, rasagiline, and ranolazine were discontinued. On the following day, the patient already experienced a decrease of psychovegetative symptoms. The blood work showed normal thyroid parameters, and no remarkable structural abnormalities of the thyroid gland were detected by sonography. Thus, we could rule out the possibility of iatrogenic hyperthyroidism. Moreover, repeated ECG examinations did not show signs of cardiac abnormalities explaining the patient's vegetative symptoms (ECG showed normal sinus rhythm, heart rate 81/min, QTc 429 ms, and vertical position). The changes of anti-parkinson medications during the stay were performed under repeated supervision of the consultant neurologists. As the discontinuation of ranolazine, which was prescribed as an antianginal medication, did not result in changes of blood pressure, we could also rule out arterial hypertension as a causative factor. The electroencephalogram (EEG) showed a regular, well-modulated, indistinct alpha-EEG with occipital accentuation and a frequency of 10-11 Hz and amplitudes reaching up to 100 μV, a well-pronounced visual blockade and intermitted alpha-disintegration. A second EEG did not show any relevant changes. The magnetic resonance imaging (MRI) of the brain showed a slight expansion of the external frontal cerebrospinal fluid space and around the upper cerebellar vermis space. Disseminated, age-inappropriate, supratentorial small hyperintensities of the medullary layer were found. MRI-scan of the cervical and thoracic spine did not show any pathological findings. Due to the atypical localization of some lesions (i.e., near the corpus callosum and the right temporo-polar region), additional brain MRI-scan with contrast (gadolinium) was performed but results did not indicate an inflammatory process. In addition, lumbar puncture was discussed with the patient, who decided not to undergo this procedure after risks and benefits were explained. As the patient reported insomnia for nearly one decade and as agomelatine 50 mg daily was not effective, this medication was discontinued. After moclobemide, rasagiline, and ranolazine were discontinued based on the hypothesis of serotonergic overstimulation, no further episodic psychovegetative or panic-related symptoms occurred during hospitalization. The patient's blood pressure, which initially showed hypertensive episodes, went back to normal, and no antihypertensive medication was required. For persistent insomnia treatment trials with mirtazapine and trazodone were conducted, mirtazapine was not tolerated and trazodone was inefficient. Finally, sleep-associated symptoms slightly decreased with trimipramine 10 mg at bedtime. We established an antidepressive treatment with escitalopram, which was titrated to a dose of 10 mg. As per suggestions of consulting neurologists, pramipexole was reduced and discontinued. Because this was followed by an increase in PD-associated motor symptoms, we initiated treatment with rotigotine transdermal application of 8 mg/day. Levodopa/benserazide retard was switched to nonretard formulation of 125 mg three times a day. With this medication regimen, a stable and sufficient mobility could be achieved. Medication at discharge included escitalopram 10 mg/day, levodopa/benserazide 125 mg three times per day, rotigotine transdermal 8 mg/day, trimipramine 10 mg/day, and levothyroxine 100 μg/day. The patient rated her mood as 9-10/10 on a scale from 0 to 10 with 10 being euthymic mood. The symptoms leading to admission subsided following discontinuation of MAO inhibitors moclobemide and rasagiline and did not reoccur during hospitalization.
3. Discussion and Conclusions
In this case report, we describe a probable drug-induced serotonergic overstimulation with paroxysmal exacerbations in a patient with PD. As other differential diagnoses could be ruled out, we suggest an interaction of several serotonergic medications, i.e., MAO-A inhibitor moclobemide and MAO-B inhibitor rasagiline as a causal factor. The hypothesis of a drug-induced symptomatology rather than genuine panic attacks is supported by subsiding of symptoms after discontinuation of both moclobemide and rasagiline, together with ranolazine. In addition, the paroxysmal episodes including jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and darkish red discoloration (flush) of the scalp and neck were suggestive of drug-induced monoaminergic overstimulation. We are not aware of another case report describing serotonin toxicity with this combination in the context of Parkinson's disease. Several subtypes of panic attacks have been described in the literature [29] postulating cardiac, cardiovascular, neurological, respiratory, and vestibular classifications of panic attacks [30]. Patients presenting with chest pain frequently show symptoms/criteria for panic disorder [31] which results in diagnostic uncertainty, and in the presented case, coronary vasospasms of unknown origin had been previously suspected and treated with ranolazine. However, as the patient did not experience a significant effect on her symptoms, she reported at admission that she had been taking ranolazine not regularly and the discontinuation of ranolazine at admission did not result in the occurrence of cardiovascular symptoms. On the contrary, the patient's physical activity, i.e., walking longer distances, was restored after motor symptoms were additionally stabilized by adjusting anti-Parkinson medication as described in detail above. The serotonin syndrome is commonly perceived as a potentially fatal entity following exposure to serotonergic substances. The risk is increased with combination of two or more drugs which directly enhance postsynaptic serotonin levels. However, serotonin toxicity could reflect a continuous, dose-related phenomenon with serotonin syndrome being the maximum clinical manifestation of serotonin toxicity [32]. Frequently, the clinical symptoms of serotonin toxicity develop rapidly when a serotonergic drug is added to a preexisting medication with stimulating effects on serotonin neurotransmission [33]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs of these compounds as well as that of levodopa/benserazide and to our knowledge clinical guidelines are not supporting this combination. Due to the high prevalence of psychiatric symptoms and psychiatric comorbidities in patients with PD, combined pharmacological treatment with anti-Parkinson drugs and drugs for treatment of depression and anxiety symptoms are often inevitable. In general, hypotheses and assumptions described in this case report have certain limitations. Quantitative measurements of plasma serotonin and other monoamines as well as their respective metabolites, i.e., urinary or CSF levels of 5-HIAA, have not been determined. Thus, our conclusions with respect to the aetiology of the patient's symptoms are mainly supported by the patient's medical history, clinical symptoms, considerations of drug-drug interactions, and rapid clinical improvement after discontinuation of suspected drugs, i.e., moclobemide and rasagiline. The pharmacological interactions between moclobemide (MAO-A inhibitor) and rasagiline (MAO-B inhibitor) likely resulted in intolerable side effects as described above. We speculate that the dual inhibition of MAO-A and MAO-B may have led to MAO-inhibition comparable to the effect of irreversible MAO-inhibitors such as tranylcypromine despite the reversible nature of MAO-A inhibition by moclobemide. This may have been intermittently potentiated by dietary amines since the patient was not on a low tyramine diet [17]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs and to our knowledge clinical guidelines are not supporting this combination. We assume that moclobemide had been taken into consideration despite strong arguments against, including formal contraindication label, after a number of antidepressants were previously prescribed but eventually discontinued due to side effects and recurrence of depressive symptoms. Interestingly, when moclobemide had been given at a low dose of 150 mg daily in combination with rasagiline, the patient did indeed benefit for approximately 3 years describing improvement of depressive symptoms and good tolerability. Reported psychovegetative symptoms occurred for the first time 6 months after the dose increase of moclobemide to 450 mg daily. This long delay in onset of adverse effects related to increasing oscillations of serotonin toxicity may explain why drug-drug interactions were discarded as a potential cause by physicians. The aspect that MAO-B activity increases with age [16] may have additionally contributed to this delayed onset of symptoms. The significant reduction of MAO-B as demonstrated by Bitsios et al. who found an approximately 29% reduction in human platelet MAO-B activity after a single dosage of 450 mg moclobemide [34] and the supratherapeutic plasma concentration of moclobemide (3310 ng/ml) we detected in our patient likely constitute additional contributing factors. Hence, the following clinically relevant main aspects can be derived from the case report at hand to improve patient safety and care: The importance of assessing and considering drug-drug interactions: our patient has been prescribed with a contraindicated combination of two drugs. We believe that the association of reported symptoms with adverse effects due to a drug-drug interaction was not addressed by the patient's initial prescriber, GP and ER (emergency room) physicians. The fact that the treatment was well tolerated by the patient for a prolonged period of time has likely contributed to this outcome. The case presented here highlights the importance of comprehensive and thorough assessment of pharmacological treatment and medication history and that drug-drug interactions should always be considered a potential etiological factor of clinical symptoms. This is of particular relevance for drugs where interactions have been reported as well as drugs that are not commonly prescribed or usually prescribed by different disciplines.
Drug-induced serotonergic overstimulation occurring on a continuous spectrum of changes in serotonergic neurotransmission: to the best of our knowledge, this is the first case report of a patient with PD with potentially drug-induced chronic serotonergic overstimulation with intermittent clinical exacerbations mimicking panic attacks. Most likely, this was caused by combined treatment with an antidepressant (moclobemide; MAO-A inhibitor) and anti-Parkinson medication (rasagiline; MAO-B inhibitor). Interestingly, signs of serotonin toxicity probably developed following an increase of moclobemide from 150 to 450 mg daily and “although polypharmacy is an important etiological factor in the development of serotonin syndrome per se, dose and speed of distribution may determine its severity" [35]. We believe that this case report can support the clinically relevant assumption that drug-induced serotonergic overstimulation may occur on a continuous spectrum of changes in serotonergic neurotransmission which may present as mild clinical symptoms, clinical exacerbations, or the potentially life-threatening condition of serotonin syndrome.
Acknowledgments
We are grateful to our patient who has provided consent for the publication of this case report.
Abbreviations
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-Hydroxytryptamine/serotonin
CBC: Complete blood count
ECG: Electrocardiogram
EEG: Electroencephalogram
ER: Emergency room
L-DOPA: Levodopa/L-3,4-dihydroxyphenylalanine
GP: General practitioner
MAO: Monoamine oxidase
MRI: Magnetic resonance imaging
PD: Parkinson's disease
REM: Rapid eye movement
T3: Triiodothyronine
T4: Thyroxine
TSH: Thyroid stimulating hormone.
Consent
The patient has provided written consent for publication.
Conflicts of Interest
The authors report no competing interests/conflicts of interest.
Authors' Contributions
All authors substantially contributed to the clinical assessments, evaluation, and treatment of the patient as well as generation and interpretation of results. M.P. drafted the initial version of the manuscript. All authors reviewed and substantially revised the manuscript. All authors have approved the submitted manuscript, are accountable for this contribution, and ensure accuracy and integrity of this work. | Recovered | ReactionOutcome | CC BY | 33728085 | 19,165,149 | 2021 |
What was the outcome of reaction 'Off label use'? | Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided.
The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
1. Background
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive occurrence of typical motor dysfunctions such as resting tremor, rigidity, bradykinesia, and postural instability as well as concurrent nonmotor dysfunctions such as hyposomnia, REM (rapid eye movement) sleep behavior disorder, depression, autonomic dysregulation, cognitive impairments, psychosis, and anxiety disorders [1]. This clinical complexity of PD is mirrored by the current neuropathological understanding of PD. Subsequent disruption of nigrostriatal dopaminergic neurotransmission through degeneration of mesencephalic neurons located in the substantia nigra is accompanied by neurodegenerative processes in other brain areas leading to complex disturbances of neurobiological systems beyond the dopaminergic system including serotonergic and noradrenergic pathways [2]. Notably, dopaminergic dysfunction and serotonergic neuropathology of the basolateral amygdala were associated with anxiety in a rat model of PD and responsive to treatment with levodopa (L-DOPA) [3]. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), anxiety spectrum disorders consist of 12 diagnostic entities [4]. A panic attack is defined as a “discrete period of intense fear or discomfort” where symptoms such as palpitations, sweating, trembling or shaking, shortness of breath, chest pain or discomfort, nausea, dizziness, derealisation or depersonalisation, and fear of dying develop abruptly and can reach their peak within minutes [5]. In a recent cross-sectional study, Rai and colleagues investigated the prevalence of neuropsychiatric disorders, focussing on depression, anxiety, and psychosis in patients with PD. The results indicate depression to be the most common neuropsychiatric comorbidity with a prevalence of 43.7%; anxiety was found in 35.7% of patients with PD [6]. A high prevalence of anxiety disorders in PD was confirmed in other studies [7–9] describing a heterogeneous clinical picture with both sustained and episodic anxiety [8]. However, specific treatment options for anxiety disorders in PD have not been investigated in randomized controlled trials, as stated in a review from 2011 [10]. This high comorbidity of depressive and anxiety symptoms in patients with PD a combination of anti-Parkinson and antidepressant drugs is often clinically indicated. This case demonstrates that drug-drug interactions of antidepressant and anti-Parkinson medications, particularly when including monoamine oxidase (MAO) inhibitors, may result in serotonergic overstimulation and thus require careful consideration and monitoring. Clinically, the combination of moclobemide and rasagiline is hardly encountered and moreover explicitly contraindicated by regulatory agencies. Currently, two isoforms of MAOs, MAO-A and MAO-B, have been characterized in cerebral as well as extracerebral tissues [11] by means of their expression, molecular characteristics, differences in their preferred endogenous, and exogenous substrates and inhibitor-sensitivity [12, 13]. Substrates of MAO-A include serotonin, norepinephrine, and dopamine, whereas MAO-B preferentially degrades the monoamine alkaloid phenylethylamine (regulating the release of norepinephrine and dopamine) as well as the precursor molecule of various organic compounds such as benzylamine [14, 15]. Interestingly, MAO-B activity distinctively increases with age and has repeatedly been shown to be associated with neurodegenerative processes in dementia and PD [16] strengthening the therapeutic rationale and relevance of MAO-inhibitors in PD. The antidepressant moclobemide acts as a reversible and selective inhibitor of MAO-A and is effective in treating major depression [17]. The drug is a prototype of reversible inhibitors of MAO-A agents which target this enzyme in intraneuronal presynaptic regions [18]. A near-maximum inhibitory effect in healthy male volunteers was achieved with a single dosage of 300 mg. Maximum effects, as measured by decreased plasma concentrations of the serotonin-metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxphenyl-glycol, a peripheral noradrenaline-metabolite, were apparent at moclobemide plasma levels greater than 1000 ng/ml [19]. Only one study showed the antidepressant potency of moclobemide in depressed patients with PD and the superior effectiveness of the combination therapy with the MAO-B-inhibitor selegiline on affective symptoms as well as cognition. However, the small number of included patients does not allow to draw conclusions for clinical considerations [20]. Rasagiline belongs to selective blockers of MAO-B, such as selegiline. Rasagiline shows neuroprotective actions in vitro and is used as an anti-Parkinson drug. Chronic administration of a MAO-B-selective dose (0.2 mg/kg daily for 3 weeks) increased striatal dopamine and serotonin levels, while decreasing their metabolism. The drug restored the reduced activity in aged animals in behavioral paradigms to levels seen in young animals [21, 22]. However, in a therapeutic dose alone, it did not alter cerebral monoamine levels in another animal study [22]. Pramipexole is a non-ergoline dopamine receptor agonist (D2-like, D2S full, and D2L, D3, and D4 partial) for the treatment of PD and restless legs syndrome [23, 24]. Moreover, potential effects in treating symptoms of major depression have been reported [25]. Pramipexole also influences serotonergic neurotransmission by increasing activity of serotonergic neurons in the dorsal raphe. [26, 27]. Agomelatine belongs to a new generation of antidepressants since it elicits a dual mechanism of action by targeting the melatonergic system as an antagonist but also works as a serotonin 2C (5-HT2C) receptor antagonist. Studies have shown that treatment with agomelatine results in improvements in depressive symptoms, anxiety, and hypochondria in depressed patients [28].
2. Case Presentation
The 62-year-old female patient was referred to and admitted at the clinic of the Max-Planck-Institute of Psychiatry in Munich, Germany, for diagnostic clarification and treatment of recurring paroxysmal psychovegetative episodes. The patient, a retired school teacher from an urban upper-middle-class socioeconomic background, reported a history of insomnia, fatigue, and depressed mood, which preceded the onset of PD symptoms and worsened after being diagnosed with PD. She was premorbidly well-adjusted before the onset of motor symptoms and had no prior neurologic or psychiatric history. No developmental difficulties were reported. The patient's medical history includes the diagnosis of idiopathic Parkinson's syndrome, a moderate obstructive sleep apnea syndrome treated with a continuous positive airway pressure (CPAP) device, and chronic hypothyroidism following Hashimoto's disease approximately three decades ago and treated with thyroid hormone replacement since. About 6 months before clinical admission in our psychiatric ward, the patient noticed a reduced resilience to physical activity. In the last 4 months, she experienced shortness of breath after walking short distances and her general condition was affected by a feeling of physical weakness, shivering, headaches, and the sensation of facial heat. Unpredictable episodes of anxiety and vegetative symptoms occurred even out of quiescent states. Three months prior to this admission, she was assessed at an emergency department for thoracic pain and dyspnoea. Electrocardiogram (ECG), echocardiography, and blood work did not reveal any abnormalities. She was discharged with the suspected diagnosis of arterial hypertension and was started on ranolazine. Despite this intervention, her symptoms reoccurred and additionally worsened in the weeks prior to this admission. Her general practitioner (GP) recommended a beta blocker to be taken as needed. As ranolazine had no effect on her symptoms, the patient took ranolazine occasionally and discontinued the beta blocker treatment. There was no history of fever, altered sensorium, or neurological deficits except fluctuating motor symptoms associated with her diagnosis of PD. The patient described weight gain of approximately 4 kg during the last year. The patient's prevailing difficulties over the 4 months prior to admission were described as recurring paroxysmal episodes of jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and a darkish red discoloration of scalp and neck. These episodes emerged unexpectedly and were not associated with physical or emotional stress or other triggering factors. The patient reported that she had contacted an emergency physician on several occasions and had been admitted to hospitals twice approximately 3-4 months before her neurologist referred her to the clinic at the Max-Planck-Institute of Psychiatry in Munich, Germany, with a working diagnosis of panic disorder. Medication at admission consisted of moclobemide (450 mg/day), agomelatine (50 mg/day), pramipexole (0.525 mg/day), rasagiline (1 mg/day), L-DOPA+benserazide retard (200+50 mg/day), ranolazine (375 mg/day), and L-thyroxine (100 μg/day). The dose of moclobemide had been increased from 150 mg/day to the current dose about 1 year prior to admission. At the time of the initial mental status examination, the patient was fully alert, attentive, and oriented. She maintained eye contact and provided an informative report. No apparent abnormalities in thought form and content were observed. Cognitive and amnestic functions were intact. Her effect initially appeared euthymic with a normal range though intermittently depressed during the conversation. Her impetus towards social activities and daily activities was decreased. Her psychomotor domain was calm; her voice was quiet and showed tendencies towards decreased prosody. Both her mimic and overall expressive gestures were scarce. Severe insomnia with sleep-onset and disturbed sleep, and daytime fatigue were reported. Appetite was reported as increased over the past months. The patient did not endorse symptoms indicating specific phobia, social anxiety, or generalized anxiety. She reported paroxysmal episodes of psychovegetative strain. The patient was not suicidal; there were no safety concerns with respect to herself or others. General and neurological examination of the 62-year-old female patient (height: 165 cm, weight: 65 kg; BMI: 23.9 kg/m2) revealed a moderate rigor of the right upper extremity, adiadochokinesia, normal gait pattern, onychomycosis of toe nails, bilateral hallux valgus, and hyperkyphosis of the thoracic spine. No other physical or neurological abnormalities were detected. There was no postural imbalance or tremor. Vital signs at admission included blood pressure of 140/80 mmHg, heartrate of 84/min, and temperature of 36.4°C. Differential diagnoses considered at admission for reported paroxysmal episodes of psychovegetative symptoms included panic attacks/panic disorder, somatoform autonomic disorder, arterial hypertension with hypertensive exacerbations, iatrogenic hyperthyroidism, asthmatic disorder, and drug-induced serotonin toxicity. Clinical laboratory analyses did not reveal abnormal findings in CBC (complete blood count), hepatic and renal function, glucose and lipid profile, and electrolytes. Free T3 (triiodothyronine), free T4 (thyroxine), and TSH (thyroid stimulating hormone) were within normal limits. The plasma concentration of moclobemide (3310 ng/ml) was above the reference range of 300-1000 ng/ml. Plasma concentrations of agomelatine were not detectable (<1 ng/ml). We suspected potential pharmacological interactions to be a contributing factor to the symptoms reported by the patient at admission, and moclobemide, rasagiline, and ranolazine were discontinued. On the following day, the patient already experienced a decrease of psychovegetative symptoms. The blood work showed normal thyroid parameters, and no remarkable structural abnormalities of the thyroid gland were detected by sonography. Thus, we could rule out the possibility of iatrogenic hyperthyroidism. Moreover, repeated ECG examinations did not show signs of cardiac abnormalities explaining the patient's vegetative symptoms (ECG showed normal sinus rhythm, heart rate 81/min, QTc 429 ms, and vertical position). The changes of anti-parkinson medications during the stay were performed under repeated supervision of the consultant neurologists. As the discontinuation of ranolazine, which was prescribed as an antianginal medication, did not result in changes of blood pressure, we could also rule out arterial hypertension as a causative factor. The electroencephalogram (EEG) showed a regular, well-modulated, indistinct alpha-EEG with occipital accentuation and a frequency of 10-11 Hz and amplitudes reaching up to 100 μV, a well-pronounced visual blockade and intermitted alpha-disintegration. A second EEG did not show any relevant changes. The magnetic resonance imaging (MRI) of the brain showed a slight expansion of the external frontal cerebrospinal fluid space and around the upper cerebellar vermis space. Disseminated, age-inappropriate, supratentorial small hyperintensities of the medullary layer were found. MRI-scan of the cervical and thoracic spine did not show any pathological findings. Due to the atypical localization of some lesions (i.e., near the corpus callosum and the right temporo-polar region), additional brain MRI-scan with contrast (gadolinium) was performed but results did not indicate an inflammatory process. In addition, lumbar puncture was discussed with the patient, who decided not to undergo this procedure after risks and benefits were explained. As the patient reported insomnia for nearly one decade and as agomelatine 50 mg daily was not effective, this medication was discontinued. After moclobemide, rasagiline, and ranolazine were discontinued based on the hypothesis of serotonergic overstimulation, no further episodic psychovegetative or panic-related symptoms occurred during hospitalization. The patient's blood pressure, which initially showed hypertensive episodes, went back to normal, and no antihypertensive medication was required. For persistent insomnia treatment trials with mirtazapine and trazodone were conducted, mirtazapine was not tolerated and trazodone was inefficient. Finally, sleep-associated symptoms slightly decreased with trimipramine 10 mg at bedtime. We established an antidepressive treatment with escitalopram, which was titrated to a dose of 10 mg. As per suggestions of consulting neurologists, pramipexole was reduced and discontinued. Because this was followed by an increase in PD-associated motor symptoms, we initiated treatment with rotigotine transdermal application of 8 mg/day. Levodopa/benserazide retard was switched to nonretard formulation of 125 mg three times a day. With this medication regimen, a stable and sufficient mobility could be achieved. Medication at discharge included escitalopram 10 mg/day, levodopa/benserazide 125 mg three times per day, rotigotine transdermal 8 mg/day, trimipramine 10 mg/day, and levothyroxine 100 μg/day. The patient rated her mood as 9-10/10 on a scale from 0 to 10 with 10 being euthymic mood. The symptoms leading to admission subsided following discontinuation of MAO inhibitors moclobemide and rasagiline and did not reoccur during hospitalization.
3. Discussion and Conclusions
In this case report, we describe a probable drug-induced serotonergic overstimulation with paroxysmal exacerbations in a patient with PD. As other differential diagnoses could be ruled out, we suggest an interaction of several serotonergic medications, i.e., MAO-A inhibitor moclobemide and MAO-B inhibitor rasagiline as a causal factor. The hypothesis of a drug-induced symptomatology rather than genuine panic attacks is supported by subsiding of symptoms after discontinuation of both moclobemide and rasagiline, together with ranolazine. In addition, the paroxysmal episodes including jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and darkish red discoloration (flush) of the scalp and neck were suggestive of drug-induced monoaminergic overstimulation. We are not aware of another case report describing serotonin toxicity with this combination in the context of Parkinson's disease. Several subtypes of panic attacks have been described in the literature [29] postulating cardiac, cardiovascular, neurological, respiratory, and vestibular classifications of panic attacks [30]. Patients presenting with chest pain frequently show symptoms/criteria for panic disorder [31] which results in diagnostic uncertainty, and in the presented case, coronary vasospasms of unknown origin had been previously suspected and treated with ranolazine. However, as the patient did not experience a significant effect on her symptoms, she reported at admission that she had been taking ranolazine not regularly and the discontinuation of ranolazine at admission did not result in the occurrence of cardiovascular symptoms. On the contrary, the patient's physical activity, i.e., walking longer distances, was restored after motor symptoms were additionally stabilized by adjusting anti-Parkinson medication as described in detail above. The serotonin syndrome is commonly perceived as a potentially fatal entity following exposure to serotonergic substances. The risk is increased with combination of two or more drugs which directly enhance postsynaptic serotonin levels. However, serotonin toxicity could reflect a continuous, dose-related phenomenon with serotonin syndrome being the maximum clinical manifestation of serotonin toxicity [32]. Frequently, the clinical symptoms of serotonin toxicity develop rapidly when a serotonergic drug is added to a preexisting medication with stimulating effects on serotonin neurotransmission [33]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs of these compounds as well as that of levodopa/benserazide and to our knowledge clinical guidelines are not supporting this combination. Due to the high prevalence of psychiatric symptoms and psychiatric comorbidities in patients with PD, combined pharmacological treatment with anti-Parkinson drugs and drugs for treatment of depression and anxiety symptoms are often inevitable. In general, hypotheses and assumptions described in this case report have certain limitations. Quantitative measurements of plasma serotonin and other monoamines as well as their respective metabolites, i.e., urinary or CSF levels of 5-HIAA, have not been determined. Thus, our conclusions with respect to the aetiology of the patient's symptoms are mainly supported by the patient's medical history, clinical symptoms, considerations of drug-drug interactions, and rapid clinical improvement after discontinuation of suspected drugs, i.e., moclobemide and rasagiline. The pharmacological interactions between moclobemide (MAO-A inhibitor) and rasagiline (MAO-B inhibitor) likely resulted in intolerable side effects as described above. We speculate that the dual inhibition of MAO-A and MAO-B may have led to MAO-inhibition comparable to the effect of irreversible MAO-inhibitors such as tranylcypromine despite the reversible nature of MAO-A inhibition by moclobemide. This may have been intermittently potentiated by dietary amines since the patient was not on a low tyramine diet [17]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs and to our knowledge clinical guidelines are not supporting this combination. We assume that moclobemide had been taken into consideration despite strong arguments against, including formal contraindication label, after a number of antidepressants were previously prescribed but eventually discontinued due to side effects and recurrence of depressive symptoms. Interestingly, when moclobemide had been given at a low dose of 150 mg daily in combination with rasagiline, the patient did indeed benefit for approximately 3 years describing improvement of depressive symptoms and good tolerability. Reported psychovegetative symptoms occurred for the first time 6 months after the dose increase of moclobemide to 450 mg daily. This long delay in onset of adverse effects related to increasing oscillations of serotonin toxicity may explain why drug-drug interactions were discarded as a potential cause by physicians. The aspect that MAO-B activity increases with age [16] may have additionally contributed to this delayed onset of symptoms. The significant reduction of MAO-B as demonstrated by Bitsios et al. who found an approximately 29% reduction in human platelet MAO-B activity after a single dosage of 450 mg moclobemide [34] and the supratherapeutic plasma concentration of moclobemide (3310 ng/ml) we detected in our patient likely constitute additional contributing factors. Hence, the following clinically relevant main aspects can be derived from the case report at hand to improve patient safety and care: The importance of assessing and considering drug-drug interactions: our patient has been prescribed with a contraindicated combination of two drugs. We believe that the association of reported symptoms with adverse effects due to a drug-drug interaction was not addressed by the patient's initial prescriber, GP and ER (emergency room) physicians. The fact that the treatment was well tolerated by the patient for a prolonged period of time has likely contributed to this outcome. The case presented here highlights the importance of comprehensive and thorough assessment of pharmacological treatment and medication history and that drug-drug interactions should always be considered a potential etiological factor of clinical symptoms. This is of particular relevance for drugs where interactions have been reported as well as drugs that are not commonly prescribed or usually prescribed by different disciplines.
Drug-induced serotonergic overstimulation occurring on a continuous spectrum of changes in serotonergic neurotransmission: to the best of our knowledge, this is the first case report of a patient with PD with potentially drug-induced chronic serotonergic overstimulation with intermittent clinical exacerbations mimicking panic attacks. Most likely, this was caused by combined treatment with an antidepressant (moclobemide; MAO-A inhibitor) and anti-Parkinson medication (rasagiline; MAO-B inhibitor). Interestingly, signs of serotonin toxicity probably developed following an increase of moclobemide from 150 to 450 mg daily and “although polypharmacy is an important etiological factor in the development of serotonin syndrome per se, dose and speed of distribution may determine its severity" [35]. We believe that this case report can support the clinically relevant assumption that drug-induced serotonergic overstimulation may occur on a continuous spectrum of changes in serotonergic neurotransmission which may present as mild clinical symptoms, clinical exacerbations, or the potentially life-threatening condition of serotonin syndrome.
Acknowledgments
We are grateful to our patient who has provided consent for the publication of this case report.
Abbreviations
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-Hydroxytryptamine/serotonin
CBC: Complete blood count
ECG: Electrocardiogram
EEG: Electroencephalogram
ER: Emergency room
L-DOPA: Levodopa/L-3,4-dihydroxyphenylalanine
GP: General practitioner
MAO: Monoamine oxidase
MRI: Magnetic resonance imaging
PD: Parkinson's disease
REM: Rapid eye movement
T3: Triiodothyronine
T4: Thyroxine
TSH: Thyroid stimulating hormone.
Consent
The patient has provided written consent for publication.
Conflicts of Interest
The authors report no competing interests/conflicts of interest.
Authors' Contributions
All authors substantially contributed to the clinical assessments, evaluation, and treatment of the patient as well as generation and interpretation of results. M.P. drafted the initial version of the manuscript. All authors reviewed and substantially revised the manuscript. All authors have approved the submitted manuscript, are accountable for this contribution, and ensure accuracy and integrity of this work. | Recovered | ReactionOutcome | CC BY | 33728085 | 19,135,231 | 2021 |
What was the outcome of reaction 'Serotonin syndrome'? | Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided.
The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
1. Background
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive occurrence of typical motor dysfunctions such as resting tremor, rigidity, bradykinesia, and postural instability as well as concurrent nonmotor dysfunctions such as hyposomnia, REM (rapid eye movement) sleep behavior disorder, depression, autonomic dysregulation, cognitive impairments, psychosis, and anxiety disorders [1]. This clinical complexity of PD is mirrored by the current neuropathological understanding of PD. Subsequent disruption of nigrostriatal dopaminergic neurotransmission through degeneration of mesencephalic neurons located in the substantia nigra is accompanied by neurodegenerative processes in other brain areas leading to complex disturbances of neurobiological systems beyond the dopaminergic system including serotonergic and noradrenergic pathways [2]. Notably, dopaminergic dysfunction and serotonergic neuropathology of the basolateral amygdala were associated with anxiety in a rat model of PD and responsive to treatment with levodopa (L-DOPA) [3]. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), anxiety spectrum disorders consist of 12 diagnostic entities [4]. A panic attack is defined as a “discrete period of intense fear or discomfort” where symptoms such as palpitations, sweating, trembling or shaking, shortness of breath, chest pain or discomfort, nausea, dizziness, derealisation or depersonalisation, and fear of dying develop abruptly and can reach their peak within minutes [5]. In a recent cross-sectional study, Rai and colleagues investigated the prevalence of neuropsychiatric disorders, focussing on depression, anxiety, and psychosis in patients with PD. The results indicate depression to be the most common neuropsychiatric comorbidity with a prevalence of 43.7%; anxiety was found in 35.7% of patients with PD [6]. A high prevalence of anxiety disorders in PD was confirmed in other studies [7–9] describing a heterogeneous clinical picture with both sustained and episodic anxiety [8]. However, specific treatment options for anxiety disorders in PD have not been investigated in randomized controlled trials, as stated in a review from 2011 [10]. This high comorbidity of depressive and anxiety symptoms in patients with PD a combination of anti-Parkinson and antidepressant drugs is often clinically indicated. This case demonstrates that drug-drug interactions of antidepressant and anti-Parkinson medications, particularly when including monoamine oxidase (MAO) inhibitors, may result in serotonergic overstimulation and thus require careful consideration and monitoring. Clinically, the combination of moclobemide and rasagiline is hardly encountered and moreover explicitly contraindicated by regulatory agencies. Currently, two isoforms of MAOs, MAO-A and MAO-B, have been characterized in cerebral as well as extracerebral tissues [11] by means of their expression, molecular characteristics, differences in their preferred endogenous, and exogenous substrates and inhibitor-sensitivity [12, 13]. Substrates of MAO-A include serotonin, norepinephrine, and dopamine, whereas MAO-B preferentially degrades the monoamine alkaloid phenylethylamine (regulating the release of norepinephrine and dopamine) as well as the precursor molecule of various organic compounds such as benzylamine [14, 15]. Interestingly, MAO-B activity distinctively increases with age and has repeatedly been shown to be associated with neurodegenerative processes in dementia and PD [16] strengthening the therapeutic rationale and relevance of MAO-inhibitors in PD. The antidepressant moclobemide acts as a reversible and selective inhibitor of MAO-A and is effective in treating major depression [17]. The drug is a prototype of reversible inhibitors of MAO-A agents which target this enzyme in intraneuronal presynaptic regions [18]. A near-maximum inhibitory effect in healthy male volunteers was achieved with a single dosage of 300 mg. Maximum effects, as measured by decreased plasma concentrations of the serotonin-metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxphenyl-glycol, a peripheral noradrenaline-metabolite, were apparent at moclobemide plasma levels greater than 1000 ng/ml [19]. Only one study showed the antidepressant potency of moclobemide in depressed patients with PD and the superior effectiveness of the combination therapy with the MAO-B-inhibitor selegiline on affective symptoms as well as cognition. However, the small number of included patients does not allow to draw conclusions for clinical considerations [20]. Rasagiline belongs to selective blockers of MAO-B, such as selegiline. Rasagiline shows neuroprotective actions in vitro and is used as an anti-Parkinson drug. Chronic administration of a MAO-B-selective dose (0.2 mg/kg daily for 3 weeks) increased striatal dopamine and serotonin levels, while decreasing their metabolism. The drug restored the reduced activity in aged animals in behavioral paradigms to levels seen in young animals [21, 22]. However, in a therapeutic dose alone, it did not alter cerebral monoamine levels in another animal study [22]. Pramipexole is a non-ergoline dopamine receptor agonist (D2-like, D2S full, and D2L, D3, and D4 partial) for the treatment of PD and restless legs syndrome [23, 24]. Moreover, potential effects in treating symptoms of major depression have been reported [25]. Pramipexole also influences serotonergic neurotransmission by increasing activity of serotonergic neurons in the dorsal raphe. [26, 27]. Agomelatine belongs to a new generation of antidepressants since it elicits a dual mechanism of action by targeting the melatonergic system as an antagonist but also works as a serotonin 2C (5-HT2C) receptor antagonist. Studies have shown that treatment with agomelatine results in improvements in depressive symptoms, anxiety, and hypochondria in depressed patients [28].
2. Case Presentation
The 62-year-old female patient was referred to and admitted at the clinic of the Max-Planck-Institute of Psychiatry in Munich, Germany, for diagnostic clarification and treatment of recurring paroxysmal psychovegetative episodes. The patient, a retired school teacher from an urban upper-middle-class socioeconomic background, reported a history of insomnia, fatigue, and depressed mood, which preceded the onset of PD symptoms and worsened after being diagnosed with PD. She was premorbidly well-adjusted before the onset of motor symptoms and had no prior neurologic or psychiatric history. No developmental difficulties were reported. The patient's medical history includes the diagnosis of idiopathic Parkinson's syndrome, a moderate obstructive sleep apnea syndrome treated with a continuous positive airway pressure (CPAP) device, and chronic hypothyroidism following Hashimoto's disease approximately three decades ago and treated with thyroid hormone replacement since. About 6 months before clinical admission in our psychiatric ward, the patient noticed a reduced resilience to physical activity. In the last 4 months, she experienced shortness of breath after walking short distances and her general condition was affected by a feeling of physical weakness, shivering, headaches, and the sensation of facial heat. Unpredictable episodes of anxiety and vegetative symptoms occurred even out of quiescent states. Three months prior to this admission, she was assessed at an emergency department for thoracic pain and dyspnoea. Electrocardiogram (ECG), echocardiography, and blood work did not reveal any abnormalities. She was discharged with the suspected diagnosis of arterial hypertension and was started on ranolazine. Despite this intervention, her symptoms reoccurred and additionally worsened in the weeks prior to this admission. Her general practitioner (GP) recommended a beta blocker to be taken as needed. As ranolazine had no effect on her symptoms, the patient took ranolazine occasionally and discontinued the beta blocker treatment. There was no history of fever, altered sensorium, or neurological deficits except fluctuating motor symptoms associated with her diagnosis of PD. The patient described weight gain of approximately 4 kg during the last year. The patient's prevailing difficulties over the 4 months prior to admission were described as recurring paroxysmal episodes of jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and a darkish red discoloration of scalp and neck. These episodes emerged unexpectedly and were not associated with physical or emotional stress or other triggering factors. The patient reported that she had contacted an emergency physician on several occasions and had been admitted to hospitals twice approximately 3-4 months before her neurologist referred her to the clinic at the Max-Planck-Institute of Psychiatry in Munich, Germany, with a working diagnosis of panic disorder. Medication at admission consisted of moclobemide (450 mg/day), agomelatine (50 mg/day), pramipexole (0.525 mg/day), rasagiline (1 mg/day), L-DOPA+benserazide retard (200+50 mg/day), ranolazine (375 mg/day), and L-thyroxine (100 μg/day). The dose of moclobemide had been increased from 150 mg/day to the current dose about 1 year prior to admission. At the time of the initial mental status examination, the patient was fully alert, attentive, and oriented. She maintained eye contact and provided an informative report. No apparent abnormalities in thought form and content were observed. Cognitive and amnestic functions were intact. Her effect initially appeared euthymic with a normal range though intermittently depressed during the conversation. Her impetus towards social activities and daily activities was decreased. Her psychomotor domain was calm; her voice was quiet and showed tendencies towards decreased prosody. Both her mimic and overall expressive gestures were scarce. Severe insomnia with sleep-onset and disturbed sleep, and daytime fatigue were reported. Appetite was reported as increased over the past months. The patient did not endorse symptoms indicating specific phobia, social anxiety, or generalized anxiety. She reported paroxysmal episodes of psychovegetative strain. The patient was not suicidal; there were no safety concerns with respect to herself or others. General and neurological examination of the 62-year-old female patient (height: 165 cm, weight: 65 kg; BMI: 23.9 kg/m2) revealed a moderate rigor of the right upper extremity, adiadochokinesia, normal gait pattern, onychomycosis of toe nails, bilateral hallux valgus, and hyperkyphosis of the thoracic spine. No other physical or neurological abnormalities were detected. There was no postural imbalance or tremor. Vital signs at admission included blood pressure of 140/80 mmHg, heartrate of 84/min, and temperature of 36.4°C. Differential diagnoses considered at admission for reported paroxysmal episodes of psychovegetative symptoms included panic attacks/panic disorder, somatoform autonomic disorder, arterial hypertension with hypertensive exacerbations, iatrogenic hyperthyroidism, asthmatic disorder, and drug-induced serotonin toxicity. Clinical laboratory analyses did not reveal abnormal findings in CBC (complete blood count), hepatic and renal function, glucose and lipid profile, and electrolytes. Free T3 (triiodothyronine), free T4 (thyroxine), and TSH (thyroid stimulating hormone) were within normal limits. The plasma concentration of moclobemide (3310 ng/ml) was above the reference range of 300-1000 ng/ml. Plasma concentrations of agomelatine were not detectable (<1 ng/ml). We suspected potential pharmacological interactions to be a contributing factor to the symptoms reported by the patient at admission, and moclobemide, rasagiline, and ranolazine were discontinued. On the following day, the patient already experienced a decrease of psychovegetative symptoms. The blood work showed normal thyroid parameters, and no remarkable structural abnormalities of the thyroid gland were detected by sonography. Thus, we could rule out the possibility of iatrogenic hyperthyroidism. Moreover, repeated ECG examinations did not show signs of cardiac abnormalities explaining the patient's vegetative symptoms (ECG showed normal sinus rhythm, heart rate 81/min, QTc 429 ms, and vertical position). The changes of anti-parkinson medications during the stay were performed under repeated supervision of the consultant neurologists. As the discontinuation of ranolazine, which was prescribed as an antianginal medication, did not result in changes of blood pressure, we could also rule out arterial hypertension as a causative factor. The electroencephalogram (EEG) showed a regular, well-modulated, indistinct alpha-EEG with occipital accentuation and a frequency of 10-11 Hz and amplitudes reaching up to 100 μV, a well-pronounced visual blockade and intermitted alpha-disintegration. A second EEG did not show any relevant changes. The magnetic resonance imaging (MRI) of the brain showed a slight expansion of the external frontal cerebrospinal fluid space and around the upper cerebellar vermis space. Disseminated, age-inappropriate, supratentorial small hyperintensities of the medullary layer were found. MRI-scan of the cervical and thoracic spine did not show any pathological findings. Due to the atypical localization of some lesions (i.e., near the corpus callosum and the right temporo-polar region), additional brain MRI-scan with contrast (gadolinium) was performed but results did not indicate an inflammatory process. In addition, lumbar puncture was discussed with the patient, who decided not to undergo this procedure after risks and benefits were explained. As the patient reported insomnia for nearly one decade and as agomelatine 50 mg daily was not effective, this medication was discontinued. After moclobemide, rasagiline, and ranolazine were discontinued based on the hypothesis of serotonergic overstimulation, no further episodic psychovegetative or panic-related symptoms occurred during hospitalization. The patient's blood pressure, which initially showed hypertensive episodes, went back to normal, and no antihypertensive medication was required. For persistent insomnia treatment trials with mirtazapine and trazodone were conducted, mirtazapine was not tolerated and trazodone was inefficient. Finally, sleep-associated symptoms slightly decreased with trimipramine 10 mg at bedtime. We established an antidepressive treatment with escitalopram, which was titrated to a dose of 10 mg. As per suggestions of consulting neurologists, pramipexole was reduced and discontinued. Because this was followed by an increase in PD-associated motor symptoms, we initiated treatment with rotigotine transdermal application of 8 mg/day. Levodopa/benserazide retard was switched to nonretard formulation of 125 mg three times a day. With this medication regimen, a stable and sufficient mobility could be achieved. Medication at discharge included escitalopram 10 mg/day, levodopa/benserazide 125 mg three times per day, rotigotine transdermal 8 mg/day, trimipramine 10 mg/day, and levothyroxine 100 μg/day. The patient rated her mood as 9-10/10 on a scale from 0 to 10 with 10 being euthymic mood. The symptoms leading to admission subsided following discontinuation of MAO inhibitors moclobemide and rasagiline and did not reoccur during hospitalization.
3. Discussion and Conclusions
In this case report, we describe a probable drug-induced serotonergic overstimulation with paroxysmal exacerbations in a patient with PD. As other differential diagnoses could be ruled out, we suggest an interaction of several serotonergic medications, i.e., MAO-A inhibitor moclobemide and MAO-B inhibitor rasagiline as a causal factor. The hypothesis of a drug-induced symptomatology rather than genuine panic attacks is supported by subsiding of symptoms after discontinuation of both moclobemide and rasagiline, together with ranolazine. In addition, the paroxysmal episodes including jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and darkish red discoloration (flush) of the scalp and neck were suggestive of drug-induced monoaminergic overstimulation. We are not aware of another case report describing serotonin toxicity with this combination in the context of Parkinson's disease. Several subtypes of panic attacks have been described in the literature [29] postulating cardiac, cardiovascular, neurological, respiratory, and vestibular classifications of panic attacks [30]. Patients presenting with chest pain frequently show symptoms/criteria for panic disorder [31] which results in diagnostic uncertainty, and in the presented case, coronary vasospasms of unknown origin had been previously suspected and treated with ranolazine. However, as the patient did not experience a significant effect on her symptoms, she reported at admission that she had been taking ranolazine not regularly and the discontinuation of ranolazine at admission did not result in the occurrence of cardiovascular symptoms. On the contrary, the patient's physical activity, i.e., walking longer distances, was restored after motor symptoms were additionally stabilized by adjusting anti-Parkinson medication as described in detail above. The serotonin syndrome is commonly perceived as a potentially fatal entity following exposure to serotonergic substances. The risk is increased with combination of two or more drugs which directly enhance postsynaptic serotonin levels. However, serotonin toxicity could reflect a continuous, dose-related phenomenon with serotonin syndrome being the maximum clinical manifestation of serotonin toxicity [32]. Frequently, the clinical symptoms of serotonin toxicity develop rapidly when a serotonergic drug is added to a preexisting medication with stimulating effects on serotonin neurotransmission [33]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs of these compounds as well as that of levodopa/benserazide and to our knowledge clinical guidelines are not supporting this combination. Due to the high prevalence of psychiatric symptoms and psychiatric comorbidities in patients with PD, combined pharmacological treatment with anti-Parkinson drugs and drugs for treatment of depression and anxiety symptoms are often inevitable. In general, hypotheses and assumptions described in this case report have certain limitations. Quantitative measurements of plasma serotonin and other monoamines as well as their respective metabolites, i.e., urinary or CSF levels of 5-HIAA, have not been determined. Thus, our conclusions with respect to the aetiology of the patient's symptoms are mainly supported by the patient's medical history, clinical symptoms, considerations of drug-drug interactions, and rapid clinical improvement after discontinuation of suspected drugs, i.e., moclobemide and rasagiline. The pharmacological interactions between moclobemide (MAO-A inhibitor) and rasagiline (MAO-B inhibitor) likely resulted in intolerable side effects as described above. We speculate that the dual inhibition of MAO-A and MAO-B may have led to MAO-inhibition comparable to the effect of irreversible MAO-inhibitors such as tranylcypromine despite the reversible nature of MAO-A inhibition by moclobemide. This may have been intermittently potentiated by dietary amines since the patient was not on a low tyramine diet [17]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs and to our knowledge clinical guidelines are not supporting this combination. We assume that moclobemide had been taken into consideration despite strong arguments against, including formal contraindication label, after a number of antidepressants were previously prescribed but eventually discontinued due to side effects and recurrence of depressive symptoms. Interestingly, when moclobemide had been given at a low dose of 150 mg daily in combination with rasagiline, the patient did indeed benefit for approximately 3 years describing improvement of depressive symptoms and good tolerability. Reported psychovegetative symptoms occurred for the first time 6 months after the dose increase of moclobemide to 450 mg daily. This long delay in onset of adverse effects related to increasing oscillations of serotonin toxicity may explain why drug-drug interactions were discarded as a potential cause by physicians. The aspect that MAO-B activity increases with age [16] may have additionally contributed to this delayed onset of symptoms. The significant reduction of MAO-B as demonstrated by Bitsios et al. who found an approximately 29% reduction in human platelet MAO-B activity after a single dosage of 450 mg moclobemide [34] and the supratherapeutic plasma concentration of moclobemide (3310 ng/ml) we detected in our patient likely constitute additional contributing factors. Hence, the following clinically relevant main aspects can be derived from the case report at hand to improve patient safety and care: The importance of assessing and considering drug-drug interactions: our patient has been prescribed with a contraindicated combination of two drugs. We believe that the association of reported symptoms with adverse effects due to a drug-drug interaction was not addressed by the patient's initial prescriber, GP and ER (emergency room) physicians. The fact that the treatment was well tolerated by the patient for a prolonged period of time has likely contributed to this outcome. The case presented here highlights the importance of comprehensive and thorough assessment of pharmacological treatment and medication history and that drug-drug interactions should always be considered a potential etiological factor of clinical symptoms. This is of particular relevance for drugs where interactions have been reported as well as drugs that are not commonly prescribed or usually prescribed by different disciplines.
Drug-induced serotonergic overstimulation occurring on a continuous spectrum of changes in serotonergic neurotransmission: to the best of our knowledge, this is the first case report of a patient with PD with potentially drug-induced chronic serotonergic overstimulation with intermittent clinical exacerbations mimicking panic attacks. Most likely, this was caused by combined treatment with an antidepressant (moclobemide; MAO-A inhibitor) and anti-Parkinson medication (rasagiline; MAO-B inhibitor). Interestingly, signs of serotonin toxicity probably developed following an increase of moclobemide from 150 to 450 mg daily and “although polypharmacy is an important etiological factor in the development of serotonin syndrome per se, dose and speed of distribution may determine its severity" [35]. We believe that this case report can support the clinically relevant assumption that drug-induced serotonergic overstimulation may occur on a continuous spectrum of changes in serotonergic neurotransmission which may present as mild clinical symptoms, clinical exacerbations, or the potentially life-threatening condition of serotonin syndrome.
Acknowledgments
We are grateful to our patient who has provided consent for the publication of this case report.
Abbreviations
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-Hydroxytryptamine/serotonin
CBC: Complete blood count
ECG: Electrocardiogram
EEG: Electroencephalogram
ER: Emergency room
L-DOPA: Levodopa/L-3,4-dihydroxyphenylalanine
GP: General practitioner
MAO: Monoamine oxidase
MRI: Magnetic resonance imaging
PD: Parkinson's disease
REM: Rapid eye movement
T3: Triiodothyronine
T4: Thyroxine
TSH: Thyroid stimulating hormone.
Consent
The patient has provided written consent for publication.
Conflicts of Interest
The authors report no competing interests/conflicts of interest.
Authors' Contributions
All authors substantially contributed to the clinical assessments, evaluation, and treatment of the patient as well as generation and interpretation of results. M.P. drafted the initial version of the manuscript. All authors reviewed and substantially revised the manuscript. All authors have approved the submitted manuscript, are accountable for this contribution, and ensure accuracy and integrity of this work. | Recovered | ReactionOutcome | CC BY | 33728085 | 19,165,149 | 2021 |
What was the outcome of reaction 'Toxicity to various agents'? | Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided.
The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.
1. Background
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive occurrence of typical motor dysfunctions such as resting tremor, rigidity, bradykinesia, and postural instability as well as concurrent nonmotor dysfunctions such as hyposomnia, REM (rapid eye movement) sleep behavior disorder, depression, autonomic dysregulation, cognitive impairments, psychosis, and anxiety disorders [1]. This clinical complexity of PD is mirrored by the current neuropathological understanding of PD. Subsequent disruption of nigrostriatal dopaminergic neurotransmission through degeneration of mesencephalic neurons located in the substantia nigra is accompanied by neurodegenerative processes in other brain areas leading to complex disturbances of neurobiological systems beyond the dopaminergic system including serotonergic and noradrenergic pathways [2]. Notably, dopaminergic dysfunction and serotonergic neuropathology of the basolateral amygdala were associated with anxiety in a rat model of PD and responsive to treatment with levodopa (L-DOPA) [3]. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), anxiety spectrum disorders consist of 12 diagnostic entities [4]. A panic attack is defined as a “discrete period of intense fear or discomfort” where symptoms such as palpitations, sweating, trembling or shaking, shortness of breath, chest pain or discomfort, nausea, dizziness, derealisation or depersonalisation, and fear of dying develop abruptly and can reach their peak within minutes [5]. In a recent cross-sectional study, Rai and colleagues investigated the prevalence of neuropsychiatric disorders, focussing on depression, anxiety, and psychosis in patients with PD. The results indicate depression to be the most common neuropsychiatric comorbidity with a prevalence of 43.7%; anxiety was found in 35.7% of patients with PD [6]. A high prevalence of anxiety disorders in PD was confirmed in other studies [7–9] describing a heterogeneous clinical picture with both sustained and episodic anxiety [8]. However, specific treatment options for anxiety disorders in PD have not been investigated in randomized controlled trials, as stated in a review from 2011 [10]. This high comorbidity of depressive and anxiety symptoms in patients with PD a combination of anti-Parkinson and antidepressant drugs is often clinically indicated. This case demonstrates that drug-drug interactions of antidepressant and anti-Parkinson medications, particularly when including monoamine oxidase (MAO) inhibitors, may result in serotonergic overstimulation and thus require careful consideration and monitoring. Clinically, the combination of moclobemide and rasagiline is hardly encountered and moreover explicitly contraindicated by regulatory agencies. Currently, two isoforms of MAOs, MAO-A and MAO-B, have been characterized in cerebral as well as extracerebral tissues [11] by means of their expression, molecular characteristics, differences in their preferred endogenous, and exogenous substrates and inhibitor-sensitivity [12, 13]. Substrates of MAO-A include serotonin, norepinephrine, and dopamine, whereas MAO-B preferentially degrades the monoamine alkaloid phenylethylamine (regulating the release of norepinephrine and dopamine) as well as the precursor molecule of various organic compounds such as benzylamine [14, 15]. Interestingly, MAO-B activity distinctively increases with age and has repeatedly been shown to be associated with neurodegenerative processes in dementia and PD [16] strengthening the therapeutic rationale and relevance of MAO-inhibitors in PD. The antidepressant moclobemide acts as a reversible and selective inhibitor of MAO-A and is effective in treating major depression [17]. The drug is a prototype of reversible inhibitors of MAO-A agents which target this enzyme in intraneuronal presynaptic regions [18]. A near-maximum inhibitory effect in healthy male volunteers was achieved with a single dosage of 300 mg. Maximum effects, as measured by decreased plasma concentrations of the serotonin-metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxphenyl-glycol, a peripheral noradrenaline-metabolite, were apparent at moclobemide plasma levels greater than 1000 ng/ml [19]. Only one study showed the antidepressant potency of moclobemide in depressed patients with PD and the superior effectiveness of the combination therapy with the MAO-B-inhibitor selegiline on affective symptoms as well as cognition. However, the small number of included patients does not allow to draw conclusions for clinical considerations [20]. Rasagiline belongs to selective blockers of MAO-B, such as selegiline. Rasagiline shows neuroprotective actions in vitro and is used as an anti-Parkinson drug. Chronic administration of a MAO-B-selective dose (0.2 mg/kg daily for 3 weeks) increased striatal dopamine and serotonin levels, while decreasing their metabolism. The drug restored the reduced activity in aged animals in behavioral paradigms to levels seen in young animals [21, 22]. However, in a therapeutic dose alone, it did not alter cerebral monoamine levels in another animal study [22]. Pramipexole is a non-ergoline dopamine receptor agonist (D2-like, D2S full, and D2L, D3, and D4 partial) for the treatment of PD and restless legs syndrome [23, 24]. Moreover, potential effects in treating symptoms of major depression have been reported [25]. Pramipexole also influences serotonergic neurotransmission by increasing activity of serotonergic neurons in the dorsal raphe. [26, 27]. Agomelatine belongs to a new generation of antidepressants since it elicits a dual mechanism of action by targeting the melatonergic system as an antagonist but also works as a serotonin 2C (5-HT2C) receptor antagonist. Studies have shown that treatment with agomelatine results in improvements in depressive symptoms, anxiety, and hypochondria in depressed patients [28].
2. Case Presentation
The 62-year-old female patient was referred to and admitted at the clinic of the Max-Planck-Institute of Psychiatry in Munich, Germany, for diagnostic clarification and treatment of recurring paroxysmal psychovegetative episodes. The patient, a retired school teacher from an urban upper-middle-class socioeconomic background, reported a history of insomnia, fatigue, and depressed mood, which preceded the onset of PD symptoms and worsened after being diagnosed with PD. She was premorbidly well-adjusted before the onset of motor symptoms and had no prior neurologic or psychiatric history. No developmental difficulties were reported. The patient's medical history includes the diagnosis of idiopathic Parkinson's syndrome, a moderate obstructive sleep apnea syndrome treated with a continuous positive airway pressure (CPAP) device, and chronic hypothyroidism following Hashimoto's disease approximately three decades ago and treated with thyroid hormone replacement since. About 6 months before clinical admission in our psychiatric ward, the patient noticed a reduced resilience to physical activity. In the last 4 months, she experienced shortness of breath after walking short distances and her general condition was affected by a feeling of physical weakness, shivering, headaches, and the sensation of facial heat. Unpredictable episodes of anxiety and vegetative symptoms occurred even out of quiescent states. Three months prior to this admission, she was assessed at an emergency department for thoracic pain and dyspnoea. Electrocardiogram (ECG), echocardiography, and blood work did not reveal any abnormalities. She was discharged with the suspected diagnosis of arterial hypertension and was started on ranolazine. Despite this intervention, her symptoms reoccurred and additionally worsened in the weeks prior to this admission. Her general practitioner (GP) recommended a beta blocker to be taken as needed. As ranolazine had no effect on her symptoms, the patient took ranolazine occasionally and discontinued the beta blocker treatment. There was no history of fever, altered sensorium, or neurological deficits except fluctuating motor symptoms associated with her diagnosis of PD. The patient described weight gain of approximately 4 kg during the last year. The patient's prevailing difficulties over the 4 months prior to admission were described as recurring paroxysmal episodes of jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and a darkish red discoloration of scalp and neck. These episodes emerged unexpectedly and were not associated with physical or emotional stress or other triggering factors. The patient reported that she had contacted an emergency physician on several occasions and had been admitted to hospitals twice approximately 3-4 months before her neurologist referred her to the clinic at the Max-Planck-Institute of Psychiatry in Munich, Germany, with a working diagnosis of panic disorder. Medication at admission consisted of moclobemide (450 mg/day), agomelatine (50 mg/day), pramipexole (0.525 mg/day), rasagiline (1 mg/day), L-DOPA+benserazide retard (200+50 mg/day), ranolazine (375 mg/day), and L-thyroxine (100 μg/day). The dose of moclobemide had been increased from 150 mg/day to the current dose about 1 year prior to admission. At the time of the initial mental status examination, the patient was fully alert, attentive, and oriented. She maintained eye contact and provided an informative report. No apparent abnormalities in thought form and content were observed. Cognitive and amnestic functions were intact. Her effect initially appeared euthymic with a normal range though intermittently depressed during the conversation. Her impetus towards social activities and daily activities was decreased. Her psychomotor domain was calm; her voice was quiet and showed tendencies towards decreased prosody. Both her mimic and overall expressive gestures were scarce. Severe insomnia with sleep-onset and disturbed sleep, and daytime fatigue were reported. Appetite was reported as increased over the past months. The patient did not endorse symptoms indicating specific phobia, social anxiety, or generalized anxiety. She reported paroxysmal episodes of psychovegetative strain. The patient was not suicidal; there were no safety concerns with respect to herself or others. General and neurological examination of the 62-year-old female patient (height: 165 cm, weight: 65 kg; BMI: 23.9 kg/m2) revealed a moderate rigor of the right upper extremity, adiadochokinesia, normal gait pattern, onychomycosis of toe nails, bilateral hallux valgus, and hyperkyphosis of the thoracic spine. No other physical or neurological abnormalities were detected. There was no postural imbalance or tremor. Vital signs at admission included blood pressure of 140/80 mmHg, heartrate of 84/min, and temperature of 36.4°C. Differential diagnoses considered at admission for reported paroxysmal episodes of psychovegetative symptoms included panic attacks/panic disorder, somatoform autonomic disorder, arterial hypertension with hypertensive exacerbations, iatrogenic hyperthyroidism, asthmatic disorder, and drug-induced serotonin toxicity. Clinical laboratory analyses did not reveal abnormal findings in CBC (complete blood count), hepatic and renal function, glucose and lipid profile, and electrolytes. Free T3 (triiodothyronine), free T4 (thyroxine), and TSH (thyroid stimulating hormone) were within normal limits. The plasma concentration of moclobemide (3310 ng/ml) was above the reference range of 300-1000 ng/ml. Plasma concentrations of agomelatine were not detectable (<1 ng/ml). We suspected potential pharmacological interactions to be a contributing factor to the symptoms reported by the patient at admission, and moclobemide, rasagiline, and ranolazine were discontinued. On the following day, the patient already experienced a decrease of psychovegetative symptoms. The blood work showed normal thyroid parameters, and no remarkable structural abnormalities of the thyroid gland were detected by sonography. Thus, we could rule out the possibility of iatrogenic hyperthyroidism. Moreover, repeated ECG examinations did not show signs of cardiac abnormalities explaining the patient's vegetative symptoms (ECG showed normal sinus rhythm, heart rate 81/min, QTc 429 ms, and vertical position). The changes of anti-parkinson medications during the stay were performed under repeated supervision of the consultant neurologists. As the discontinuation of ranolazine, which was prescribed as an antianginal medication, did not result in changes of blood pressure, we could also rule out arterial hypertension as a causative factor. The electroencephalogram (EEG) showed a regular, well-modulated, indistinct alpha-EEG with occipital accentuation and a frequency of 10-11 Hz and amplitudes reaching up to 100 μV, a well-pronounced visual blockade and intermitted alpha-disintegration. A second EEG did not show any relevant changes. The magnetic resonance imaging (MRI) of the brain showed a slight expansion of the external frontal cerebrospinal fluid space and around the upper cerebellar vermis space. Disseminated, age-inappropriate, supratentorial small hyperintensities of the medullary layer were found. MRI-scan of the cervical and thoracic spine did not show any pathological findings. Due to the atypical localization of some lesions (i.e., near the corpus callosum and the right temporo-polar region), additional brain MRI-scan with contrast (gadolinium) was performed but results did not indicate an inflammatory process. In addition, lumbar puncture was discussed with the patient, who decided not to undergo this procedure after risks and benefits were explained. As the patient reported insomnia for nearly one decade and as agomelatine 50 mg daily was not effective, this medication was discontinued. After moclobemide, rasagiline, and ranolazine were discontinued based on the hypothesis of serotonergic overstimulation, no further episodic psychovegetative or panic-related symptoms occurred during hospitalization. The patient's blood pressure, which initially showed hypertensive episodes, went back to normal, and no antihypertensive medication was required. For persistent insomnia treatment trials with mirtazapine and trazodone were conducted, mirtazapine was not tolerated and trazodone was inefficient. Finally, sleep-associated symptoms slightly decreased with trimipramine 10 mg at bedtime. We established an antidepressive treatment with escitalopram, which was titrated to a dose of 10 mg. As per suggestions of consulting neurologists, pramipexole was reduced and discontinued. Because this was followed by an increase in PD-associated motor symptoms, we initiated treatment with rotigotine transdermal application of 8 mg/day. Levodopa/benserazide retard was switched to nonretard formulation of 125 mg three times a day. With this medication regimen, a stable and sufficient mobility could be achieved. Medication at discharge included escitalopram 10 mg/day, levodopa/benserazide 125 mg three times per day, rotigotine transdermal 8 mg/day, trimipramine 10 mg/day, and levothyroxine 100 μg/day. The patient rated her mood as 9-10/10 on a scale from 0 to 10 with 10 being euthymic mood. The symptoms leading to admission subsided following discontinuation of MAO inhibitors moclobemide and rasagiline and did not reoccur during hospitalization.
3. Discussion and Conclusions
In this case report, we describe a probable drug-induced serotonergic overstimulation with paroxysmal exacerbations in a patient with PD. As other differential diagnoses could be ruled out, we suggest an interaction of several serotonergic medications, i.e., MAO-A inhibitor moclobemide and MAO-B inhibitor rasagiline as a causal factor. The hypothesis of a drug-induced symptomatology rather than genuine panic attacks is supported by subsiding of symptoms after discontinuation of both moclobemide and rasagiline, together with ranolazine. In addition, the paroxysmal episodes including jitteriness, perioral and acral formications, palpitations, thoracic tightness, elevated blood pressure, and darkish red discoloration (flush) of the scalp and neck were suggestive of drug-induced monoaminergic overstimulation. We are not aware of another case report describing serotonin toxicity with this combination in the context of Parkinson's disease. Several subtypes of panic attacks have been described in the literature [29] postulating cardiac, cardiovascular, neurological, respiratory, and vestibular classifications of panic attacks [30]. Patients presenting with chest pain frequently show symptoms/criteria for panic disorder [31] which results in diagnostic uncertainty, and in the presented case, coronary vasospasms of unknown origin had been previously suspected and treated with ranolazine. However, as the patient did not experience a significant effect on her symptoms, she reported at admission that she had been taking ranolazine not regularly and the discontinuation of ranolazine at admission did not result in the occurrence of cardiovascular symptoms. On the contrary, the patient's physical activity, i.e., walking longer distances, was restored after motor symptoms were additionally stabilized by adjusting anti-Parkinson medication as described in detail above. The serotonin syndrome is commonly perceived as a potentially fatal entity following exposure to serotonergic substances. The risk is increased with combination of two or more drugs which directly enhance postsynaptic serotonin levels. However, serotonin toxicity could reflect a continuous, dose-related phenomenon with serotonin syndrome being the maximum clinical manifestation of serotonin toxicity [32]. Frequently, the clinical symptoms of serotonin toxicity develop rapidly when a serotonergic drug is added to a preexisting medication with stimulating effects on serotonin neurotransmission [33]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs of these compounds as well as that of levodopa/benserazide and to our knowledge clinical guidelines are not supporting this combination. Due to the high prevalence of psychiatric symptoms and psychiatric comorbidities in patients with PD, combined pharmacological treatment with anti-Parkinson drugs and drugs for treatment of depression and anxiety symptoms are often inevitable. In general, hypotheses and assumptions described in this case report have certain limitations. Quantitative measurements of plasma serotonin and other monoamines as well as their respective metabolites, i.e., urinary or CSF levels of 5-HIAA, have not been determined. Thus, our conclusions with respect to the aetiology of the patient's symptoms are mainly supported by the patient's medical history, clinical symptoms, considerations of drug-drug interactions, and rapid clinical improvement after discontinuation of suspected drugs, i.e., moclobemide and rasagiline. The pharmacological interactions between moclobemide (MAO-A inhibitor) and rasagiline (MAO-B inhibitor) likely resulted in intolerable side effects as described above. We speculate that the dual inhibition of MAO-A and MAO-B may have led to MAO-inhibition comparable to the effect of irreversible MAO-inhibitors such as tranylcypromine despite the reversible nature of MAO-A inhibition by moclobemide. This may have been intermittently potentiated by dietary amines since the patient was not on a low tyramine diet [17]. It is of note that the combined use of moclobemide and rasagiline is contraindicated in the product monographs and to our knowledge clinical guidelines are not supporting this combination. We assume that moclobemide had been taken into consideration despite strong arguments against, including formal contraindication label, after a number of antidepressants were previously prescribed but eventually discontinued due to side effects and recurrence of depressive symptoms. Interestingly, when moclobemide had been given at a low dose of 150 mg daily in combination with rasagiline, the patient did indeed benefit for approximately 3 years describing improvement of depressive symptoms and good tolerability. Reported psychovegetative symptoms occurred for the first time 6 months after the dose increase of moclobemide to 450 mg daily. This long delay in onset of adverse effects related to increasing oscillations of serotonin toxicity may explain why drug-drug interactions were discarded as a potential cause by physicians. The aspect that MAO-B activity increases with age [16] may have additionally contributed to this delayed onset of symptoms. The significant reduction of MAO-B as demonstrated by Bitsios et al. who found an approximately 29% reduction in human platelet MAO-B activity after a single dosage of 450 mg moclobemide [34] and the supratherapeutic plasma concentration of moclobemide (3310 ng/ml) we detected in our patient likely constitute additional contributing factors. Hence, the following clinically relevant main aspects can be derived from the case report at hand to improve patient safety and care: The importance of assessing and considering drug-drug interactions: our patient has been prescribed with a contraindicated combination of two drugs. We believe that the association of reported symptoms with adverse effects due to a drug-drug interaction was not addressed by the patient's initial prescriber, GP and ER (emergency room) physicians. The fact that the treatment was well tolerated by the patient for a prolonged period of time has likely contributed to this outcome. The case presented here highlights the importance of comprehensive and thorough assessment of pharmacological treatment and medication history and that drug-drug interactions should always be considered a potential etiological factor of clinical symptoms. This is of particular relevance for drugs where interactions have been reported as well as drugs that are not commonly prescribed or usually prescribed by different disciplines.
Drug-induced serotonergic overstimulation occurring on a continuous spectrum of changes in serotonergic neurotransmission: to the best of our knowledge, this is the first case report of a patient with PD with potentially drug-induced chronic serotonergic overstimulation with intermittent clinical exacerbations mimicking panic attacks. Most likely, this was caused by combined treatment with an antidepressant (moclobemide; MAO-A inhibitor) and anti-Parkinson medication (rasagiline; MAO-B inhibitor). Interestingly, signs of serotonin toxicity probably developed following an increase of moclobemide from 150 to 450 mg daily and “although polypharmacy is an important etiological factor in the development of serotonin syndrome per se, dose and speed of distribution may determine its severity" [35]. We believe that this case report can support the clinically relevant assumption that drug-induced serotonergic overstimulation may occur on a continuous spectrum of changes in serotonergic neurotransmission which may present as mild clinical symptoms, clinical exacerbations, or the potentially life-threatening condition of serotonin syndrome.
Acknowledgments
We are grateful to our patient who has provided consent for the publication of this case report.
Abbreviations
5-HIAA: 5-Hydroxyindoleacetic acid
5-HT: 5-Hydroxytryptamine/serotonin
CBC: Complete blood count
ECG: Electrocardiogram
EEG: Electroencephalogram
ER: Emergency room
L-DOPA: Levodopa/L-3,4-dihydroxyphenylalanine
GP: General practitioner
MAO: Monoamine oxidase
MRI: Magnetic resonance imaging
PD: Parkinson's disease
REM: Rapid eye movement
T3: Triiodothyronine
T4: Thyroxine
TSH: Thyroid stimulating hormone.
Consent
The patient has provided written consent for publication.
Conflicts of Interest
The authors report no competing interests/conflicts of interest.
Authors' Contributions
All authors substantially contributed to the clinical assessments, evaluation, and treatment of the patient as well as generation and interpretation of results. M.P. drafted the initial version of the manuscript. All authors reviewed and substantially revised the manuscript. All authors have approved the submitted manuscript, are accountable for this contribution, and ensure accuracy and integrity of this work. | Recovering | ReactionOutcome | CC BY | 33728085 | 19,155,273 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bordetella infection'. | Coinfection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Bordetella bronchiseptica Pneumonia in a Renal Transplant Patient.
Bordetella species cause respiratory infections in both humans and animals. Bordetella bronchiseptica (B. bronchiseptica) infection is an uncommon pathogen in humans. The clinical spectrum of infections with SARS-CoV-2 includes viral pneumonia of variable severity, with some patients developing acute respiratory distress syndrome (ARDS), requiring mechanical ventilation support. Transplant patients with coronavirus disease (COVID-19) infection have high mortality. Bacterial coinfection, including pneumonia, have been described in patients with COVID-19. We present a renal transplant patient with COVID-19 pneumonia who developed B. bronchiseptica superinfection and had a rapid clinical and radiological response to azithromycin treatment.
Introduction
Bordetella species respiratory infections are well known in both humans and animals. The most prevalent Bordetella subspecies in humans is Bordetella pertussis (B. pertussis), while in animals it is Bordetella bronchiseptica (B. bronchiseptica) [1]. B. bronchiseptica is a zoonotic organism, rarely described as the cause of infection in humans [2]. In humans, infections range from simple upper respiratory tract infection to severe sepsis [2]. Few cases have been described in transplant recipients. We present a renal transplant patient with coronavirus disease (COVID-19) pneumonia who developed a superinfection with B. bronchiseptica. To our knowledge, this is the first case of pneumonia with this organism reported in association with COVID-19.
Case presentation
A 48-year-old male patient was admitted with shortness of breath, fever, generalized malaise and worsening productive cough starting a week prior to admission. The patient’s past medical history was significant for chronic obstructive pulmonary disease, history of renal transplant in 2001, hypertension, diabetes mellitus, obesity, gout, and obstructive sleep apnea. His past surgical history was significant for amputation of the left fourth and fifth toes, and right nephrectomy in 2019. His immunosuppressive regimen consisted of mycophenolate mofetil 500 mg twice daily and prednisone 5 mg per day. He denied any exposure to pets.
On physical examination, the patient's weight was 123 kg with a BMI of 34.4, temperature 99.2 °F, blood pressure 116/56 mm/hg, heart rate 91 beats/minute. Oxygen (O2) saturation was 60% in room air. He was alert and oriented on arrival. Cardiac exam revealed regular heart sounds without murmurs. On lung exam, there were bibasilar crackles. The rest of his physical exam was normal.
White blood cell count was 7.7x10^3/µL ( 4-10.5^3/µL), 29% lymphocytes. Creatinine was 6.6 mg/dL (0.5-1.2 mg/dL) with a glomerular filtration rate (GFR) of 11 mL/min/1.73 m2 and serum glucose 151 mg/dL (range 65-109 mg/dL). His COVID-19 reverse transcription polymerase chain reaction (RT-PCR) test from nasopharyngeal swab was positive. Chest X-ray showed bilateral diffuse consolidations.
The patient was initially placed on a 100% non-rebreathing mask and later on a high flow O2 nasal cannula. The patient remained hypoxemic and developed respiratory failure. He was intubated and required mechanical ventilator support. The patient was also initiated on continuous renal replacement therapy. He was started on intravenous ceftriaxone 1 gm and oral azithromycin as well as a course of hydroxychloroquine 400 mg twice daily followed by 400 mg once daily. In addition, he was given intravenous methylprednisolone 100 mg daily. The patient completed five days of treatment of intravenous ceftriaxone and oral azithromycin with an improvement of radiologic findings. After a week, the patient started developing fevers up to 103 °F. Chest X-ray showed an increase in lung infiltrates (Figure 1).
Figure 1 Chest X-ray showing bilateral infiltrates
Intravenous cefepime 1 gm loading followed by 500 mg next day was given. The patient remained intubated, seemed to be clinically deteriorating, and continued to be febrile, and therefore, intravenous azithromycin 500 mg was given. The sputum sample sent 12 days after intubation grew B. bronchiseptica; blood cultures remained negative. The patient became afebrile and was extubated within 24 hours after starting intravenous azithromycin. Intravenous cefepime was stopped and intravenous piperacillin/tazobactam 2.25 gm every eight hours was started and the patient continued with intravenous azithromycin. The organism was resistant to cefepime, intermediately sensitive to ceftazidime, and sensitive to levofloxacin, trimethoprim-sulfamethoxazole, tigecycline, gentamicin, tobramycin, meropenem, and piperacillin/tazobactam. Due to the rapid response to azithromycin leading to extubation, a decision was made to discontinue piperacillin/tazobactam and to continue with azithromycin. The patient continued to improve clinically and remained afebrile. Treatment continued with intravenous azithromycin for a total of 10 days. Chest X-ray two weeks post-discharge showed pulmonary vascular congestion, left lung atelectasis, and resolution of his lung infiltrates (Figure 2). Two months after discharge, the patient was doing well clinically but required intermittent renal replacement therapy.
Figure 2 Chest X-ray showing improvement in infiltrates after treatment with azithromycin
Discussion
Nine different subspecies of Bordetella have been identified. B. pertussis and B. parapertussis are most commonly associated with human infections. Clinically, human infections consist of upper respiratory tract infection, pneumonia, endocarditis, peritonitis, meningitis, and bacteremia [2].
B. bronchiseptica is known to cause upper respiratory tract infections in dogs, cats, rabbits, swine, and guinea pigs. The organism is the causative agent of kennel cough in dogs and atrophic rhinitis in swine. B. bronchiseptica possesses genes similar to B. pertussis, suggesting a close relationship between them. The organism can cause serious infection in immunocompromised patients such as HIV-infected patients [3], acute leukemia [4], bone marrow transplant [5], and other malignancies. Patients infected with this organism often report contact with animals prior to the development of infection [6,7].
In the recent pandemic of COVID-19, patients with underlying diabetes mellitus, obesity, and immunocompromised patients are at an increased risk of developing severe disease. Patients with a history of solid organ transplantation on immunosuppression have been described with significantly higher mortality [8]. The spectrum of clinical disease with COVID-19 varies from a mild respiratory illness to fulminant pneumonia with ARDS requiring mechanical ventilation. Some patients present with a clinical picture as well as radiological appearance similar to bacterial or atypical pneumonia. In hospitalized patients, it is sometimes difficult to distinguish between SARS-CoV-2 pneumonia and hospital or ventilator-associated pneumonia. Many of these patients are therefore started on antibiotic treatment and are worked up for bacterial or atypical pneumonia. In a recent review, Rawson et al. [9] reviewed the current literature on evidence of bacterial/fungal coinfection in hospitalized COVID-19 patients. They found 62/806 (8%) coinfection with bacterial/fungal organisms. Zhou et al. [8] reported a 15% (28/191) secondary bacterial infection, of which 27 patients died. Reports on atypical organisms infecting COVID-19 patients are lacking, and to our knowledge, there is no report of Bordetella pneumonia associated with COVID-19.
Our patient had various risk factors for complicated SARS-CoV-2 infection [10]: he was obese, had diabetes mellitus, hypertension, history of renal transplantation, and was treated with immunosuppressants. Radiographic findings in COVID-19-associated pneumonia include bilateral, multifocal lung lesions, ground-glass opacities, consolidation, and pleural thickening [11]. Similar radiologic findings have been noted in B. bronchiseptica-associated pneumonia [3]. Infections with B. bronchiseptica in renal transplant patients have been uncommonly described. In one case, a patient with a history of renal transplant had bacteremia with B. bronchiseptica three weeks after undergoing a pancreas transplant who had exposure to dogs [12].
It is plausible to assume that our patient had an initial SARS-CoV-2 viral pneumonia, resulting in respiratory failure. B. bronchiseptica was cultured 12 days into his clinical course.
B. bronchiseptica infections in animals are usually treated with doxycycline, quinolones, or macrolides. Infections in humans have been treated with an anti-pseudomonal penicillins, quinolones, aminoglycosides, tetracycline, trimethoprim-sulfamethoxazole, or carbapenems [13]. Response to macrolides has been reported to be variable [14]. The frequency of macrolide resistance among Bordetella isolates in animals is low. In vitro experiments show that resistance to erythromycin develops quickly but that the organisms that developed resistance were unable to colonize mice, suggesting that the drugs may be effective in vivo [14].
Macrolides have not been the drugs of choice for treatment of B. bronchiseptica in humans, but it appears that susceptibility for this organism in vitro does not always predict clinical response [15]. It is therefore possible that this class of drugs may be effective in clinical settings, as happened in our case.
Conclusions
Bacterial coinfection or superinfections should be considered in patients hospitalized with COVID-19-associated pneumonia when the clinical status deteriorates after initial improvement. Severe infection with rare bacterial organisms, especially in transplant recipients, is a concern. An accurate microbiological diagnosis is essential so that patient can be treated appropriately. Clinical response may not coincide with microbiologic in vitro susceptibility results.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | MYCOPHENOLIC ACID, PREDNISONE | DrugsGivenReaction | CC BY | 33728132 | 19,089,181 | 2021-02-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'COVID-19'. | Coinfection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Bordetella bronchiseptica Pneumonia in a Renal Transplant Patient.
Bordetella species cause respiratory infections in both humans and animals. Bordetella bronchiseptica (B. bronchiseptica) infection is an uncommon pathogen in humans. The clinical spectrum of infections with SARS-CoV-2 includes viral pneumonia of variable severity, with some patients developing acute respiratory distress syndrome (ARDS), requiring mechanical ventilation support. Transplant patients with coronavirus disease (COVID-19) infection have high mortality. Bacterial coinfection, including pneumonia, have been described in patients with COVID-19. We present a renal transplant patient with COVID-19 pneumonia who developed B. bronchiseptica superinfection and had a rapid clinical and radiological response to azithromycin treatment.
Introduction
Bordetella species respiratory infections are well known in both humans and animals. The most prevalent Bordetella subspecies in humans is Bordetella pertussis (B. pertussis), while in animals it is Bordetella bronchiseptica (B. bronchiseptica) [1]. B. bronchiseptica is a zoonotic organism, rarely described as the cause of infection in humans [2]. In humans, infections range from simple upper respiratory tract infection to severe sepsis [2]. Few cases have been described in transplant recipients. We present a renal transplant patient with coronavirus disease (COVID-19) pneumonia who developed a superinfection with B. bronchiseptica. To our knowledge, this is the first case of pneumonia with this organism reported in association with COVID-19.
Case presentation
A 48-year-old male patient was admitted with shortness of breath, fever, generalized malaise and worsening productive cough starting a week prior to admission. The patient’s past medical history was significant for chronic obstructive pulmonary disease, history of renal transplant in 2001, hypertension, diabetes mellitus, obesity, gout, and obstructive sleep apnea. His past surgical history was significant for amputation of the left fourth and fifth toes, and right nephrectomy in 2019. His immunosuppressive regimen consisted of mycophenolate mofetil 500 mg twice daily and prednisone 5 mg per day. He denied any exposure to pets.
On physical examination, the patient's weight was 123 kg with a BMI of 34.4, temperature 99.2 °F, blood pressure 116/56 mm/hg, heart rate 91 beats/minute. Oxygen (O2) saturation was 60% in room air. He was alert and oriented on arrival. Cardiac exam revealed regular heart sounds without murmurs. On lung exam, there were bibasilar crackles. The rest of his physical exam was normal.
White blood cell count was 7.7x10^3/µL ( 4-10.5^3/µL), 29% lymphocytes. Creatinine was 6.6 mg/dL (0.5-1.2 mg/dL) with a glomerular filtration rate (GFR) of 11 mL/min/1.73 m2 and serum glucose 151 mg/dL (range 65-109 mg/dL). His COVID-19 reverse transcription polymerase chain reaction (RT-PCR) test from nasopharyngeal swab was positive. Chest X-ray showed bilateral diffuse consolidations.
The patient was initially placed on a 100% non-rebreathing mask and later on a high flow O2 nasal cannula. The patient remained hypoxemic and developed respiratory failure. He was intubated and required mechanical ventilator support. The patient was also initiated on continuous renal replacement therapy. He was started on intravenous ceftriaxone 1 gm and oral azithromycin as well as a course of hydroxychloroquine 400 mg twice daily followed by 400 mg once daily. In addition, he was given intravenous methylprednisolone 100 mg daily. The patient completed five days of treatment of intravenous ceftriaxone and oral azithromycin with an improvement of radiologic findings. After a week, the patient started developing fevers up to 103 °F. Chest X-ray showed an increase in lung infiltrates (Figure 1).
Figure 1 Chest X-ray showing bilateral infiltrates
Intravenous cefepime 1 gm loading followed by 500 mg next day was given. The patient remained intubated, seemed to be clinically deteriorating, and continued to be febrile, and therefore, intravenous azithromycin 500 mg was given. The sputum sample sent 12 days after intubation grew B. bronchiseptica; blood cultures remained negative. The patient became afebrile and was extubated within 24 hours after starting intravenous azithromycin. Intravenous cefepime was stopped and intravenous piperacillin/tazobactam 2.25 gm every eight hours was started and the patient continued with intravenous azithromycin. The organism was resistant to cefepime, intermediately sensitive to ceftazidime, and sensitive to levofloxacin, trimethoprim-sulfamethoxazole, tigecycline, gentamicin, tobramycin, meropenem, and piperacillin/tazobactam. Due to the rapid response to azithromycin leading to extubation, a decision was made to discontinue piperacillin/tazobactam and to continue with azithromycin. The patient continued to improve clinically and remained afebrile. Treatment continued with intravenous azithromycin for a total of 10 days. Chest X-ray two weeks post-discharge showed pulmonary vascular congestion, left lung atelectasis, and resolution of his lung infiltrates (Figure 2). Two months after discharge, the patient was doing well clinically but required intermittent renal replacement therapy.
Figure 2 Chest X-ray showing improvement in infiltrates after treatment with azithromycin
Discussion
Nine different subspecies of Bordetella have been identified. B. pertussis and B. parapertussis are most commonly associated with human infections. Clinically, human infections consist of upper respiratory tract infection, pneumonia, endocarditis, peritonitis, meningitis, and bacteremia [2].
B. bronchiseptica is known to cause upper respiratory tract infections in dogs, cats, rabbits, swine, and guinea pigs. The organism is the causative agent of kennel cough in dogs and atrophic rhinitis in swine. B. bronchiseptica possesses genes similar to B. pertussis, suggesting a close relationship between them. The organism can cause serious infection in immunocompromised patients such as HIV-infected patients [3], acute leukemia [4], bone marrow transplant [5], and other malignancies. Patients infected with this organism often report contact with animals prior to the development of infection [6,7].
In the recent pandemic of COVID-19, patients with underlying diabetes mellitus, obesity, and immunocompromised patients are at an increased risk of developing severe disease. Patients with a history of solid organ transplantation on immunosuppression have been described with significantly higher mortality [8]. The spectrum of clinical disease with COVID-19 varies from a mild respiratory illness to fulminant pneumonia with ARDS requiring mechanical ventilation. Some patients present with a clinical picture as well as radiological appearance similar to bacterial or atypical pneumonia. In hospitalized patients, it is sometimes difficult to distinguish between SARS-CoV-2 pneumonia and hospital or ventilator-associated pneumonia. Many of these patients are therefore started on antibiotic treatment and are worked up for bacterial or atypical pneumonia. In a recent review, Rawson et al. [9] reviewed the current literature on evidence of bacterial/fungal coinfection in hospitalized COVID-19 patients. They found 62/806 (8%) coinfection with bacterial/fungal organisms. Zhou et al. [8] reported a 15% (28/191) secondary bacterial infection, of which 27 patients died. Reports on atypical organisms infecting COVID-19 patients are lacking, and to our knowledge, there is no report of Bordetella pneumonia associated with COVID-19.
Our patient had various risk factors for complicated SARS-CoV-2 infection [10]: he was obese, had diabetes mellitus, hypertension, history of renal transplantation, and was treated with immunosuppressants. Radiographic findings in COVID-19-associated pneumonia include bilateral, multifocal lung lesions, ground-glass opacities, consolidation, and pleural thickening [11]. Similar radiologic findings have been noted in B. bronchiseptica-associated pneumonia [3]. Infections with B. bronchiseptica in renal transplant patients have been uncommonly described. In one case, a patient with a history of renal transplant had bacteremia with B. bronchiseptica three weeks after undergoing a pancreas transplant who had exposure to dogs [12].
It is plausible to assume that our patient had an initial SARS-CoV-2 viral pneumonia, resulting in respiratory failure. B. bronchiseptica was cultured 12 days into his clinical course.
B. bronchiseptica infections in animals are usually treated with doxycycline, quinolones, or macrolides. Infections in humans have been treated with an anti-pseudomonal penicillins, quinolones, aminoglycosides, tetracycline, trimethoprim-sulfamethoxazole, or carbapenems [13]. Response to macrolides has been reported to be variable [14]. The frequency of macrolide resistance among Bordetella isolates in animals is low. In vitro experiments show that resistance to erythromycin develops quickly but that the organisms that developed resistance were unable to colonize mice, suggesting that the drugs may be effective in vivo [14].
Macrolides have not been the drugs of choice for treatment of B. bronchiseptica in humans, but it appears that susceptibility for this organism in vitro does not always predict clinical response [15]. It is therefore possible that this class of drugs may be effective in clinical settings, as happened in our case.
Conclusions
Bacterial coinfection or superinfections should be considered in patients hospitalized with COVID-19-associated pneumonia when the clinical status deteriorates after initial improvement. Severe infection with rare bacterial organisms, especially in transplant recipients, is a concern. An accurate microbiological diagnosis is essential so that patient can be treated appropriately. Clinical response may not coincide with microbiologic in vitro susceptibility results.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | MYCOPHENOLIC ACID, PREDNISONE | DrugsGivenReaction | CC BY | 33728132 | 19,089,181 | 2021-02-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia bacterial'. | Coinfection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Bordetella bronchiseptica Pneumonia in a Renal Transplant Patient.
Bordetella species cause respiratory infections in both humans and animals. Bordetella bronchiseptica (B. bronchiseptica) infection is an uncommon pathogen in humans. The clinical spectrum of infections with SARS-CoV-2 includes viral pneumonia of variable severity, with some patients developing acute respiratory distress syndrome (ARDS), requiring mechanical ventilation support. Transplant patients with coronavirus disease (COVID-19) infection have high mortality. Bacterial coinfection, including pneumonia, have been described in patients with COVID-19. We present a renal transplant patient with COVID-19 pneumonia who developed B. bronchiseptica superinfection and had a rapid clinical and radiological response to azithromycin treatment.
Introduction
Bordetella species respiratory infections are well known in both humans and animals. The most prevalent Bordetella subspecies in humans is Bordetella pertussis (B. pertussis), while in animals it is Bordetella bronchiseptica (B. bronchiseptica) [1]. B. bronchiseptica is a zoonotic organism, rarely described as the cause of infection in humans [2]. In humans, infections range from simple upper respiratory tract infection to severe sepsis [2]. Few cases have been described in transplant recipients. We present a renal transplant patient with coronavirus disease (COVID-19) pneumonia who developed a superinfection with B. bronchiseptica. To our knowledge, this is the first case of pneumonia with this organism reported in association with COVID-19.
Case presentation
A 48-year-old male patient was admitted with shortness of breath, fever, generalized malaise and worsening productive cough starting a week prior to admission. The patient’s past medical history was significant for chronic obstructive pulmonary disease, history of renal transplant in 2001, hypertension, diabetes mellitus, obesity, gout, and obstructive sleep apnea. His past surgical history was significant for amputation of the left fourth and fifth toes, and right nephrectomy in 2019. His immunosuppressive regimen consisted of mycophenolate mofetil 500 mg twice daily and prednisone 5 mg per day. He denied any exposure to pets.
On physical examination, the patient's weight was 123 kg with a BMI of 34.4, temperature 99.2 °F, blood pressure 116/56 mm/hg, heart rate 91 beats/minute. Oxygen (O2) saturation was 60% in room air. He was alert and oriented on arrival. Cardiac exam revealed regular heart sounds without murmurs. On lung exam, there were bibasilar crackles. The rest of his physical exam was normal.
White blood cell count was 7.7x10^3/µL ( 4-10.5^3/µL), 29% lymphocytes. Creatinine was 6.6 mg/dL (0.5-1.2 mg/dL) with a glomerular filtration rate (GFR) of 11 mL/min/1.73 m2 and serum glucose 151 mg/dL (range 65-109 mg/dL). His COVID-19 reverse transcription polymerase chain reaction (RT-PCR) test from nasopharyngeal swab was positive. Chest X-ray showed bilateral diffuse consolidations.
The patient was initially placed on a 100% non-rebreathing mask and later on a high flow O2 nasal cannula. The patient remained hypoxemic and developed respiratory failure. He was intubated and required mechanical ventilator support. The patient was also initiated on continuous renal replacement therapy. He was started on intravenous ceftriaxone 1 gm and oral azithromycin as well as a course of hydroxychloroquine 400 mg twice daily followed by 400 mg once daily. In addition, he was given intravenous methylprednisolone 100 mg daily. The patient completed five days of treatment of intravenous ceftriaxone and oral azithromycin with an improvement of radiologic findings. After a week, the patient started developing fevers up to 103 °F. Chest X-ray showed an increase in lung infiltrates (Figure 1).
Figure 1 Chest X-ray showing bilateral infiltrates
Intravenous cefepime 1 gm loading followed by 500 mg next day was given. The patient remained intubated, seemed to be clinically deteriorating, and continued to be febrile, and therefore, intravenous azithromycin 500 mg was given. The sputum sample sent 12 days after intubation grew B. bronchiseptica; blood cultures remained negative. The patient became afebrile and was extubated within 24 hours after starting intravenous azithromycin. Intravenous cefepime was stopped and intravenous piperacillin/tazobactam 2.25 gm every eight hours was started and the patient continued with intravenous azithromycin. The organism was resistant to cefepime, intermediately sensitive to ceftazidime, and sensitive to levofloxacin, trimethoprim-sulfamethoxazole, tigecycline, gentamicin, tobramycin, meropenem, and piperacillin/tazobactam. Due to the rapid response to azithromycin leading to extubation, a decision was made to discontinue piperacillin/tazobactam and to continue with azithromycin. The patient continued to improve clinically and remained afebrile. Treatment continued with intravenous azithromycin for a total of 10 days. Chest X-ray two weeks post-discharge showed pulmonary vascular congestion, left lung atelectasis, and resolution of his lung infiltrates (Figure 2). Two months after discharge, the patient was doing well clinically but required intermittent renal replacement therapy.
Figure 2 Chest X-ray showing improvement in infiltrates after treatment with azithromycin
Discussion
Nine different subspecies of Bordetella have been identified. B. pertussis and B. parapertussis are most commonly associated with human infections. Clinically, human infections consist of upper respiratory tract infection, pneumonia, endocarditis, peritonitis, meningitis, and bacteremia [2].
B. bronchiseptica is known to cause upper respiratory tract infections in dogs, cats, rabbits, swine, and guinea pigs. The organism is the causative agent of kennel cough in dogs and atrophic rhinitis in swine. B. bronchiseptica possesses genes similar to B. pertussis, suggesting a close relationship between them. The organism can cause serious infection in immunocompromised patients such as HIV-infected patients [3], acute leukemia [4], bone marrow transplant [5], and other malignancies. Patients infected with this organism often report contact with animals prior to the development of infection [6,7].
In the recent pandemic of COVID-19, patients with underlying diabetes mellitus, obesity, and immunocompromised patients are at an increased risk of developing severe disease. Patients with a history of solid organ transplantation on immunosuppression have been described with significantly higher mortality [8]. The spectrum of clinical disease with COVID-19 varies from a mild respiratory illness to fulminant pneumonia with ARDS requiring mechanical ventilation. Some patients present with a clinical picture as well as radiological appearance similar to bacterial or atypical pneumonia. In hospitalized patients, it is sometimes difficult to distinguish between SARS-CoV-2 pneumonia and hospital or ventilator-associated pneumonia. Many of these patients are therefore started on antibiotic treatment and are worked up for bacterial or atypical pneumonia. In a recent review, Rawson et al. [9] reviewed the current literature on evidence of bacterial/fungal coinfection in hospitalized COVID-19 patients. They found 62/806 (8%) coinfection with bacterial/fungal organisms. Zhou et al. [8] reported a 15% (28/191) secondary bacterial infection, of which 27 patients died. Reports on atypical organisms infecting COVID-19 patients are lacking, and to our knowledge, there is no report of Bordetella pneumonia associated with COVID-19.
Our patient had various risk factors for complicated SARS-CoV-2 infection [10]: he was obese, had diabetes mellitus, hypertension, history of renal transplantation, and was treated with immunosuppressants. Radiographic findings in COVID-19-associated pneumonia include bilateral, multifocal lung lesions, ground-glass opacities, consolidation, and pleural thickening [11]. Similar radiologic findings have been noted in B. bronchiseptica-associated pneumonia [3]. Infections with B. bronchiseptica in renal transplant patients have been uncommonly described. In one case, a patient with a history of renal transplant had bacteremia with B. bronchiseptica three weeks after undergoing a pancreas transplant who had exposure to dogs [12].
It is plausible to assume that our patient had an initial SARS-CoV-2 viral pneumonia, resulting in respiratory failure. B. bronchiseptica was cultured 12 days into his clinical course.
B. bronchiseptica infections in animals are usually treated with doxycycline, quinolones, or macrolides. Infections in humans have been treated with an anti-pseudomonal penicillins, quinolones, aminoglycosides, tetracycline, trimethoprim-sulfamethoxazole, or carbapenems [13]. Response to macrolides has been reported to be variable [14]. The frequency of macrolide resistance among Bordetella isolates in animals is low. In vitro experiments show that resistance to erythromycin develops quickly but that the organisms that developed resistance were unable to colonize mice, suggesting that the drugs may be effective in vivo [14].
Macrolides have not been the drugs of choice for treatment of B. bronchiseptica in humans, but it appears that susceptibility for this organism in vitro does not always predict clinical response [15]. It is therefore possible that this class of drugs may be effective in clinical settings, as happened in our case.
Conclusions
Bacterial coinfection or superinfections should be considered in patients hospitalized with COVID-19-associated pneumonia when the clinical status deteriorates after initial improvement. Severe infection with rare bacterial organisms, especially in transplant recipients, is a concern. An accurate microbiological diagnosis is essential so that patient can be treated appropriately. Clinical response may not coincide with microbiologic in vitro susceptibility results.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | MYCOPHENOLIC ACID, PREDNISONE | DrugsGivenReaction | CC BY | 33728132 | 19,089,181 | 2021-02-03 |
What is the weight of the patient? | Coinfection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Bordetella bronchiseptica Pneumonia in a Renal Transplant Patient.
Bordetella species cause respiratory infections in both humans and animals. Bordetella bronchiseptica (B. bronchiseptica) infection is an uncommon pathogen in humans. The clinical spectrum of infections with SARS-CoV-2 includes viral pneumonia of variable severity, with some patients developing acute respiratory distress syndrome (ARDS), requiring mechanical ventilation support. Transplant patients with coronavirus disease (COVID-19) infection have high mortality. Bacterial coinfection, including pneumonia, have been described in patients with COVID-19. We present a renal transplant patient with COVID-19 pneumonia who developed B. bronchiseptica superinfection and had a rapid clinical and radiological response to azithromycin treatment.
Introduction
Bordetella species respiratory infections are well known in both humans and animals. The most prevalent Bordetella subspecies in humans is Bordetella pertussis (B. pertussis), while in animals it is Bordetella bronchiseptica (B. bronchiseptica) [1]. B. bronchiseptica is a zoonotic organism, rarely described as the cause of infection in humans [2]. In humans, infections range from simple upper respiratory tract infection to severe sepsis [2]. Few cases have been described in transplant recipients. We present a renal transplant patient with coronavirus disease (COVID-19) pneumonia who developed a superinfection with B. bronchiseptica. To our knowledge, this is the first case of pneumonia with this organism reported in association with COVID-19.
Case presentation
A 48-year-old male patient was admitted with shortness of breath, fever, generalized malaise and worsening productive cough starting a week prior to admission. The patient’s past medical history was significant for chronic obstructive pulmonary disease, history of renal transplant in 2001, hypertension, diabetes mellitus, obesity, gout, and obstructive sleep apnea. His past surgical history was significant for amputation of the left fourth and fifth toes, and right nephrectomy in 2019. His immunosuppressive regimen consisted of mycophenolate mofetil 500 mg twice daily and prednisone 5 mg per day. He denied any exposure to pets.
On physical examination, the patient's weight was 123 kg with a BMI of 34.4, temperature 99.2 °F, blood pressure 116/56 mm/hg, heart rate 91 beats/minute. Oxygen (O2) saturation was 60% in room air. He was alert and oriented on arrival. Cardiac exam revealed regular heart sounds without murmurs. On lung exam, there were bibasilar crackles. The rest of his physical exam was normal.
White blood cell count was 7.7x10^3/µL ( 4-10.5^3/µL), 29% lymphocytes. Creatinine was 6.6 mg/dL (0.5-1.2 mg/dL) with a glomerular filtration rate (GFR) of 11 mL/min/1.73 m2 and serum glucose 151 mg/dL (range 65-109 mg/dL). His COVID-19 reverse transcription polymerase chain reaction (RT-PCR) test from nasopharyngeal swab was positive. Chest X-ray showed bilateral diffuse consolidations.
The patient was initially placed on a 100% non-rebreathing mask and later on a high flow O2 nasal cannula. The patient remained hypoxemic and developed respiratory failure. He was intubated and required mechanical ventilator support. The patient was also initiated on continuous renal replacement therapy. He was started on intravenous ceftriaxone 1 gm and oral azithromycin as well as a course of hydroxychloroquine 400 mg twice daily followed by 400 mg once daily. In addition, he was given intravenous methylprednisolone 100 mg daily. The patient completed five days of treatment of intravenous ceftriaxone and oral azithromycin with an improvement of radiologic findings. After a week, the patient started developing fevers up to 103 °F. Chest X-ray showed an increase in lung infiltrates (Figure 1).
Figure 1 Chest X-ray showing bilateral infiltrates
Intravenous cefepime 1 gm loading followed by 500 mg next day was given. The patient remained intubated, seemed to be clinically deteriorating, and continued to be febrile, and therefore, intravenous azithromycin 500 mg was given. The sputum sample sent 12 days after intubation grew B. bronchiseptica; blood cultures remained negative. The patient became afebrile and was extubated within 24 hours after starting intravenous azithromycin. Intravenous cefepime was stopped and intravenous piperacillin/tazobactam 2.25 gm every eight hours was started and the patient continued with intravenous azithromycin. The organism was resistant to cefepime, intermediately sensitive to ceftazidime, and sensitive to levofloxacin, trimethoprim-sulfamethoxazole, tigecycline, gentamicin, tobramycin, meropenem, and piperacillin/tazobactam. Due to the rapid response to azithromycin leading to extubation, a decision was made to discontinue piperacillin/tazobactam and to continue with azithromycin. The patient continued to improve clinically and remained afebrile. Treatment continued with intravenous azithromycin for a total of 10 days. Chest X-ray two weeks post-discharge showed pulmonary vascular congestion, left lung atelectasis, and resolution of his lung infiltrates (Figure 2). Two months after discharge, the patient was doing well clinically but required intermittent renal replacement therapy.
Figure 2 Chest X-ray showing improvement in infiltrates after treatment with azithromycin
Discussion
Nine different subspecies of Bordetella have been identified. B. pertussis and B. parapertussis are most commonly associated with human infections. Clinically, human infections consist of upper respiratory tract infection, pneumonia, endocarditis, peritonitis, meningitis, and bacteremia [2].
B. bronchiseptica is known to cause upper respiratory tract infections in dogs, cats, rabbits, swine, and guinea pigs. The organism is the causative agent of kennel cough in dogs and atrophic rhinitis in swine. B. bronchiseptica possesses genes similar to B. pertussis, suggesting a close relationship between them. The organism can cause serious infection in immunocompromised patients such as HIV-infected patients [3], acute leukemia [4], bone marrow transplant [5], and other malignancies. Patients infected with this organism often report contact with animals prior to the development of infection [6,7].
In the recent pandemic of COVID-19, patients with underlying diabetes mellitus, obesity, and immunocompromised patients are at an increased risk of developing severe disease. Patients with a history of solid organ transplantation on immunosuppression have been described with significantly higher mortality [8]. The spectrum of clinical disease with COVID-19 varies from a mild respiratory illness to fulminant pneumonia with ARDS requiring mechanical ventilation. Some patients present with a clinical picture as well as radiological appearance similar to bacterial or atypical pneumonia. In hospitalized patients, it is sometimes difficult to distinguish between SARS-CoV-2 pneumonia and hospital or ventilator-associated pneumonia. Many of these patients are therefore started on antibiotic treatment and are worked up for bacterial or atypical pneumonia. In a recent review, Rawson et al. [9] reviewed the current literature on evidence of bacterial/fungal coinfection in hospitalized COVID-19 patients. They found 62/806 (8%) coinfection with bacterial/fungal organisms. Zhou et al. [8] reported a 15% (28/191) secondary bacterial infection, of which 27 patients died. Reports on atypical organisms infecting COVID-19 patients are lacking, and to our knowledge, there is no report of Bordetella pneumonia associated with COVID-19.
Our patient had various risk factors for complicated SARS-CoV-2 infection [10]: he was obese, had diabetes mellitus, hypertension, history of renal transplantation, and was treated with immunosuppressants. Radiographic findings in COVID-19-associated pneumonia include bilateral, multifocal lung lesions, ground-glass opacities, consolidation, and pleural thickening [11]. Similar radiologic findings have been noted in B. bronchiseptica-associated pneumonia [3]. Infections with B. bronchiseptica in renal transplant patients have been uncommonly described. In one case, a patient with a history of renal transplant had bacteremia with B. bronchiseptica three weeks after undergoing a pancreas transplant who had exposure to dogs [12].
It is plausible to assume that our patient had an initial SARS-CoV-2 viral pneumonia, resulting in respiratory failure. B. bronchiseptica was cultured 12 days into his clinical course.
B. bronchiseptica infections in animals are usually treated with doxycycline, quinolones, or macrolides. Infections in humans have been treated with an anti-pseudomonal penicillins, quinolones, aminoglycosides, tetracycline, trimethoprim-sulfamethoxazole, or carbapenems [13]. Response to macrolides has been reported to be variable [14]. The frequency of macrolide resistance among Bordetella isolates in animals is low. In vitro experiments show that resistance to erythromycin develops quickly but that the organisms that developed resistance were unable to colonize mice, suggesting that the drugs may be effective in vivo [14].
Macrolides have not been the drugs of choice for treatment of B. bronchiseptica in humans, but it appears that susceptibility for this organism in vitro does not always predict clinical response [15]. It is therefore possible that this class of drugs may be effective in clinical settings, as happened in our case.
Conclusions
Bacterial coinfection or superinfections should be considered in patients hospitalized with COVID-19-associated pneumonia when the clinical status deteriorates after initial improvement. Severe infection with rare bacterial organisms, especially in transplant recipients, is a concern. An accurate microbiological diagnosis is essential so that patient can be treated appropriately. Clinical response may not coincide with microbiologic in vitro susceptibility results.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | 123 kg. | Weight | CC BY | 33728132 | 19,089,181 | 2021-02-03 |
What was the dosage of drug 'MYCOPHENOLIC ACID'? | Coinfection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Bordetella bronchiseptica Pneumonia in a Renal Transplant Patient.
Bordetella species cause respiratory infections in both humans and animals. Bordetella bronchiseptica (B. bronchiseptica) infection is an uncommon pathogen in humans. The clinical spectrum of infections with SARS-CoV-2 includes viral pneumonia of variable severity, with some patients developing acute respiratory distress syndrome (ARDS), requiring mechanical ventilation support. Transplant patients with coronavirus disease (COVID-19) infection have high mortality. Bacterial coinfection, including pneumonia, have been described in patients with COVID-19. We present a renal transplant patient with COVID-19 pneumonia who developed B. bronchiseptica superinfection and had a rapid clinical and radiological response to azithromycin treatment.
Introduction
Bordetella species respiratory infections are well known in both humans and animals. The most prevalent Bordetella subspecies in humans is Bordetella pertussis (B. pertussis), while in animals it is Bordetella bronchiseptica (B. bronchiseptica) [1]. B. bronchiseptica is a zoonotic organism, rarely described as the cause of infection in humans [2]. In humans, infections range from simple upper respiratory tract infection to severe sepsis [2]. Few cases have been described in transplant recipients. We present a renal transplant patient with coronavirus disease (COVID-19) pneumonia who developed a superinfection with B. bronchiseptica. To our knowledge, this is the first case of pneumonia with this organism reported in association with COVID-19.
Case presentation
A 48-year-old male patient was admitted with shortness of breath, fever, generalized malaise and worsening productive cough starting a week prior to admission. The patient’s past medical history was significant for chronic obstructive pulmonary disease, history of renal transplant in 2001, hypertension, diabetes mellitus, obesity, gout, and obstructive sleep apnea. His past surgical history was significant for amputation of the left fourth and fifth toes, and right nephrectomy in 2019. His immunosuppressive regimen consisted of mycophenolate mofetil 500 mg twice daily and prednisone 5 mg per day. He denied any exposure to pets.
On physical examination, the patient's weight was 123 kg with a BMI of 34.4, temperature 99.2 °F, blood pressure 116/56 mm/hg, heart rate 91 beats/minute. Oxygen (O2) saturation was 60% in room air. He was alert and oriented on arrival. Cardiac exam revealed regular heart sounds without murmurs. On lung exam, there were bibasilar crackles. The rest of his physical exam was normal.
White blood cell count was 7.7x10^3/µL ( 4-10.5^3/µL), 29% lymphocytes. Creatinine was 6.6 mg/dL (0.5-1.2 mg/dL) with a glomerular filtration rate (GFR) of 11 mL/min/1.73 m2 and serum glucose 151 mg/dL (range 65-109 mg/dL). His COVID-19 reverse transcription polymerase chain reaction (RT-PCR) test from nasopharyngeal swab was positive. Chest X-ray showed bilateral diffuse consolidations.
The patient was initially placed on a 100% non-rebreathing mask and later on a high flow O2 nasal cannula. The patient remained hypoxemic and developed respiratory failure. He was intubated and required mechanical ventilator support. The patient was also initiated on continuous renal replacement therapy. He was started on intravenous ceftriaxone 1 gm and oral azithromycin as well as a course of hydroxychloroquine 400 mg twice daily followed by 400 mg once daily. In addition, he was given intravenous methylprednisolone 100 mg daily. The patient completed five days of treatment of intravenous ceftriaxone and oral azithromycin with an improvement of radiologic findings. After a week, the patient started developing fevers up to 103 °F. Chest X-ray showed an increase in lung infiltrates (Figure 1).
Figure 1 Chest X-ray showing bilateral infiltrates
Intravenous cefepime 1 gm loading followed by 500 mg next day was given. The patient remained intubated, seemed to be clinically deteriorating, and continued to be febrile, and therefore, intravenous azithromycin 500 mg was given. The sputum sample sent 12 days after intubation grew B. bronchiseptica; blood cultures remained negative. The patient became afebrile and was extubated within 24 hours after starting intravenous azithromycin. Intravenous cefepime was stopped and intravenous piperacillin/tazobactam 2.25 gm every eight hours was started and the patient continued with intravenous azithromycin. The organism was resistant to cefepime, intermediately sensitive to ceftazidime, and sensitive to levofloxacin, trimethoprim-sulfamethoxazole, tigecycline, gentamicin, tobramycin, meropenem, and piperacillin/tazobactam. Due to the rapid response to azithromycin leading to extubation, a decision was made to discontinue piperacillin/tazobactam and to continue with azithromycin. The patient continued to improve clinically and remained afebrile. Treatment continued with intravenous azithromycin for a total of 10 days. Chest X-ray two weeks post-discharge showed pulmonary vascular congestion, left lung atelectasis, and resolution of his lung infiltrates (Figure 2). Two months after discharge, the patient was doing well clinically but required intermittent renal replacement therapy.
Figure 2 Chest X-ray showing improvement in infiltrates after treatment with azithromycin
Discussion
Nine different subspecies of Bordetella have been identified. B. pertussis and B. parapertussis are most commonly associated with human infections. Clinically, human infections consist of upper respiratory tract infection, pneumonia, endocarditis, peritonitis, meningitis, and bacteremia [2].
B. bronchiseptica is known to cause upper respiratory tract infections in dogs, cats, rabbits, swine, and guinea pigs. The organism is the causative agent of kennel cough in dogs and atrophic rhinitis in swine. B. bronchiseptica possesses genes similar to B. pertussis, suggesting a close relationship between them. The organism can cause serious infection in immunocompromised patients such as HIV-infected patients [3], acute leukemia [4], bone marrow transplant [5], and other malignancies. Patients infected with this organism often report contact with animals prior to the development of infection [6,7].
In the recent pandemic of COVID-19, patients with underlying diabetes mellitus, obesity, and immunocompromised patients are at an increased risk of developing severe disease. Patients with a history of solid organ transplantation on immunosuppression have been described with significantly higher mortality [8]. The spectrum of clinical disease with COVID-19 varies from a mild respiratory illness to fulminant pneumonia with ARDS requiring mechanical ventilation. Some patients present with a clinical picture as well as radiological appearance similar to bacterial or atypical pneumonia. In hospitalized patients, it is sometimes difficult to distinguish between SARS-CoV-2 pneumonia and hospital or ventilator-associated pneumonia. Many of these patients are therefore started on antibiotic treatment and are worked up for bacterial or atypical pneumonia. In a recent review, Rawson et al. [9] reviewed the current literature on evidence of bacterial/fungal coinfection in hospitalized COVID-19 patients. They found 62/806 (8%) coinfection with bacterial/fungal organisms. Zhou et al. [8] reported a 15% (28/191) secondary bacterial infection, of which 27 patients died. Reports on atypical organisms infecting COVID-19 patients are lacking, and to our knowledge, there is no report of Bordetella pneumonia associated with COVID-19.
Our patient had various risk factors for complicated SARS-CoV-2 infection [10]: he was obese, had diabetes mellitus, hypertension, history of renal transplantation, and was treated with immunosuppressants. Radiographic findings in COVID-19-associated pneumonia include bilateral, multifocal lung lesions, ground-glass opacities, consolidation, and pleural thickening [11]. Similar radiologic findings have been noted in B. bronchiseptica-associated pneumonia [3]. Infections with B. bronchiseptica in renal transplant patients have been uncommonly described. In one case, a patient with a history of renal transplant had bacteremia with B. bronchiseptica three weeks after undergoing a pancreas transplant who had exposure to dogs [12].
It is plausible to assume that our patient had an initial SARS-CoV-2 viral pneumonia, resulting in respiratory failure. B. bronchiseptica was cultured 12 days into his clinical course.
B. bronchiseptica infections in animals are usually treated with doxycycline, quinolones, or macrolides. Infections in humans have been treated with an anti-pseudomonal penicillins, quinolones, aminoglycosides, tetracycline, trimethoprim-sulfamethoxazole, or carbapenems [13]. Response to macrolides has been reported to be variable [14]. The frequency of macrolide resistance among Bordetella isolates in animals is low. In vitro experiments show that resistance to erythromycin develops quickly but that the organisms that developed resistance were unable to colonize mice, suggesting that the drugs may be effective in vivo [14].
Macrolides have not been the drugs of choice for treatment of B. bronchiseptica in humans, but it appears that susceptibility for this organism in vitro does not always predict clinical response [15]. It is therefore possible that this class of drugs may be effective in clinical settings, as happened in our case.
Conclusions
Bacterial coinfection or superinfections should be considered in patients hospitalized with COVID-19-associated pneumonia when the clinical status deteriorates after initial improvement. Severe infection with rare bacterial organisms, especially in transplant recipients, is a concern. An accurate microbiological diagnosis is essential so that patient can be treated appropriately. Clinical response may not coincide with microbiologic in vitro susceptibility results.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | 500 mg (milligrams). | DrugDosage | CC BY | 33728132 | 19,089,181 | 2021-02-03 |
What was the dosage of drug 'PREDNISONE'? | Coinfection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Bordetella bronchiseptica Pneumonia in a Renal Transplant Patient.
Bordetella species cause respiratory infections in both humans and animals. Bordetella bronchiseptica (B. bronchiseptica) infection is an uncommon pathogen in humans. The clinical spectrum of infections with SARS-CoV-2 includes viral pneumonia of variable severity, with some patients developing acute respiratory distress syndrome (ARDS), requiring mechanical ventilation support. Transplant patients with coronavirus disease (COVID-19) infection have high mortality. Bacterial coinfection, including pneumonia, have been described in patients with COVID-19. We present a renal transplant patient with COVID-19 pneumonia who developed B. bronchiseptica superinfection and had a rapid clinical and radiological response to azithromycin treatment.
Introduction
Bordetella species respiratory infections are well known in both humans and animals. The most prevalent Bordetella subspecies in humans is Bordetella pertussis (B. pertussis), while in animals it is Bordetella bronchiseptica (B. bronchiseptica) [1]. B. bronchiseptica is a zoonotic organism, rarely described as the cause of infection in humans [2]. In humans, infections range from simple upper respiratory tract infection to severe sepsis [2]. Few cases have been described in transplant recipients. We present a renal transplant patient with coronavirus disease (COVID-19) pneumonia who developed a superinfection with B. bronchiseptica. To our knowledge, this is the first case of pneumonia with this organism reported in association with COVID-19.
Case presentation
A 48-year-old male patient was admitted with shortness of breath, fever, generalized malaise and worsening productive cough starting a week prior to admission. The patient’s past medical history was significant for chronic obstructive pulmonary disease, history of renal transplant in 2001, hypertension, diabetes mellitus, obesity, gout, and obstructive sleep apnea. His past surgical history was significant for amputation of the left fourth and fifth toes, and right nephrectomy in 2019. His immunosuppressive regimen consisted of mycophenolate mofetil 500 mg twice daily and prednisone 5 mg per day. He denied any exposure to pets.
On physical examination, the patient's weight was 123 kg with a BMI of 34.4, temperature 99.2 °F, blood pressure 116/56 mm/hg, heart rate 91 beats/minute. Oxygen (O2) saturation was 60% in room air. He was alert and oriented on arrival. Cardiac exam revealed regular heart sounds without murmurs. On lung exam, there were bibasilar crackles. The rest of his physical exam was normal.
White blood cell count was 7.7x10^3/µL ( 4-10.5^3/µL), 29% lymphocytes. Creatinine was 6.6 mg/dL (0.5-1.2 mg/dL) with a glomerular filtration rate (GFR) of 11 mL/min/1.73 m2 and serum glucose 151 mg/dL (range 65-109 mg/dL). His COVID-19 reverse transcription polymerase chain reaction (RT-PCR) test from nasopharyngeal swab was positive. Chest X-ray showed bilateral diffuse consolidations.
The patient was initially placed on a 100% non-rebreathing mask and later on a high flow O2 nasal cannula. The patient remained hypoxemic and developed respiratory failure. He was intubated and required mechanical ventilator support. The patient was also initiated on continuous renal replacement therapy. He was started on intravenous ceftriaxone 1 gm and oral azithromycin as well as a course of hydroxychloroquine 400 mg twice daily followed by 400 mg once daily. In addition, he was given intravenous methylprednisolone 100 mg daily. The patient completed five days of treatment of intravenous ceftriaxone and oral azithromycin with an improvement of radiologic findings. After a week, the patient started developing fevers up to 103 °F. Chest X-ray showed an increase in lung infiltrates (Figure 1).
Figure 1 Chest X-ray showing bilateral infiltrates
Intravenous cefepime 1 gm loading followed by 500 mg next day was given. The patient remained intubated, seemed to be clinically deteriorating, and continued to be febrile, and therefore, intravenous azithromycin 500 mg was given. The sputum sample sent 12 days after intubation grew B. bronchiseptica; blood cultures remained negative. The patient became afebrile and was extubated within 24 hours after starting intravenous azithromycin. Intravenous cefepime was stopped and intravenous piperacillin/tazobactam 2.25 gm every eight hours was started and the patient continued with intravenous azithromycin. The organism was resistant to cefepime, intermediately sensitive to ceftazidime, and sensitive to levofloxacin, trimethoprim-sulfamethoxazole, tigecycline, gentamicin, tobramycin, meropenem, and piperacillin/tazobactam. Due to the rapid response to azithromycin leading to extubation, a decision was made to discontinue piperacillin/tazobactam and to continue with azithromycin. The patient continued to improve clinically and remained afebrile. Treatment continued with intravenous azithromycin for a total of 10 days. Chest X-ray two weeks post-discharge showed pulmonary vascular congestion, left lung atelectasis, and resolution of his lung infiltrates (Figure 2). Two months after discharge, the patient was doing well clinically but required intermittent renal replacement therapy.
Figure 2 Chest X-ray showing improvement in infiltrates after treatment with azithromycin
Discussion
Nine different subspecies of Bordetella have been identified. B. pertussis and B. parapertussis are most commonly associated with human infections. Clinically, human infections consist of upper respiratory tract infection, pneumonia, endocarditis, peritonitis, meningitis, and bacteremia [2].
B. bronchiseptica is known to cause upper respiratory tract infections in dogs, cats, rabbits, swine, and guinea pigs. The organism is the causative agent of kennel cough in dogs and atrophic rhinitis in swine. B. bronchiseptica possesses genes similar to B. pertussis, suggesting a close relationship between them. The organism can cause serious infection in immunocompromised patients such as HIV-infected patients [3], acute leukemia [4], bone marrow transplant [5], and other malignancies. Patients infected with this organism often report contact with animals prior to the development of infection [6,7].
In the recent pandemic of COVID-19, patients with underlying diabetes mellitus, obesity, and immunocompromised patients are at an increased risk of developing severe disease. Patients with a history of solid organ transplantation on immunosuppression have been described with significantly higher mortality [8]. The spectrum of clinical disease with COVID-19 varies from a mild respiratory illness to fulminant pneumonia with ARDS requiring mechanical ventilation. Some patients present with a clinical picture as well as radiological appearance similar to bacterial or atypical pneumonia. In hospitalized patients, it is sometimes difficult to distinguish between SARS-CoV-2 pneumonia and hospital or ventilator-associated pneumonia. Many of these patients are therefore started on antibiotic treatment and are worked up for bacterial or atypical pneumonia. In a recent review, Rawson et al. [9] reviewed the current literature on evidence of bacterial/fungal coinfection in hospitalized COVID-19 patients. They found 62/806 (8%) coinfection with bacterial/fungal organisms. Zhou et al. [8] reported a 15% (28/191) secondary bacterial infection, of which 27 patients died. Reports on atypical organisms infecting COVID-19 patients are lacking, and to our knowledge, there is no report of Bordetella pneumonia associated with COVID-19.
Our patient had various risk factors for complicated SARS-CoV-2 infection [10]: he was obese, had diabetes mellitus, hypertension, history of renal transplantation, and was treated with immunosuppressants. Radiographic findings in COVID-19-associated pneumonia include bilateral, multifocal lung lesions, ground-glass opacities, consolidation, and pleural thickening [11]. Similar radiologic findings have been noted in B. bronchiseptica-associated pneumonia [3]. Infections with B. bronchiseptica in renal transplant patients have been uncommonly described. In one case, a patient with a history of renal transplant had bacteremia with B. bronchiseptica three weeks after undergoing a pancreas transplant who had exposure to dogs [12].
It is plausible to assume that our patient had an initial SARS-CoV-2 viral pneumonia, resulting in respiratory failure. B. bronchiseptica was cultured 12 days into his clinical course.
B. bronchiseptica infections in animals are usually treated with doxycycline, quinolones, or macrolides. Infections in humans have been treated with an anti-pseudomonal penicillins, quinolones, aminoglycosides, tetracycline, trimethoprim-sulfamethoxazole, or carbapenems [13]. Response to macrolides has been reported to be variable [14]. The frequency of macrolide resistance among Bordetella isolates in animals is low. In vitro experiments show that resistance to erythromycin develops quickly but that the organisms that developed resistance were unable to colonize mice, suggesting that the drugs may be effective in vivo [14].
Macrolides have not been the drugs of choice for treatment of B. bronchiseptica in humans, but it appears that susceptibility for this organism in vitro does not always predict clinical response [15]. It is therefore possible that this class of drugs may be effective in clinical settings, as happened in our case.
Conclusions
Bacterial coinfection or superinfections should be considered in patients hospitalized with COVID-19-associated pneumonia when the clinical status deteriorates after initial improvement. Severe infection with rare bacterial organisms, especially in transplant recipients, is a concern. An accurate microbiological diagnosis is essential so that patient can be treated appropriately. Clinical response may not coincide with microbiologic in vitro susceptibility results.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | 5 mg (milligrams). | DrugDosage | CC BY | 33728132 | 19,089,181 | 2021-02-03 |
What was the outcome of reaction 'Bordetella infection'? | Coinfection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Bordetella bronchiseptica Pneumonia in a Renal Transplant Patient.
Bordetella species cause respiratory infections in both humans and animals. Bordetella bronchiseptica (B. bronchiseptica) infection is an uncommon pathogen in humans. The clinical spectrum of infections with SARS-CoV-2 includes viral pneumonia of variable severity, with some patients developing acute respiratory distress syndrome (ARDS), requiring mechanical ventilation support. Transplant patients with coronavirus disease (COVID-19) infection have high mortality. Bacterial coinfection, including pneumonia, have been described in patients with COVID-19. We present a renal transplant patient with COVID-19 pneumonia who developed B. bronchiseptica superinfection and had a rapid clinical and radiological response to azithromycin treatment.
Introduction
Bordetella species respiratory infections are well known in both humans and animals. The most prevalent Bordetella subspecies in humans is Bordetella pertussis (B. pertussis), while in animals it is Bordetella bronchiseptica (B. bronchiseptica) [1]. B. bronchiseptica is a zoonotic organism, rarely described as the cause of infection in humans [2]. In humans, infections range from simple upper respiratory tract infection to severe sepsis [2]. Few cases have been described in transplant recipients. We present a renal transplant patient with coronavirus disease (COVID-19) pneumonia who developed a superinfection with B. bronchiseptica. To our knowledge, this is the first case of pneumonia with this organism reported in association with COVID-19.
Case presentation
A 48-year-old male patient was admitted with shortness of breath, fever, generalized malaise and worsening productive cough starting a week prior to admission. The patient’s past medical history was significant for chronic obstructive pulmonary disease, history of renal transplant in 2001, hypertension, diabetes mellitus, obesity, gout, and obstructive sleep apnea. His past surgical history was significant for amputation of the left fourth and fifth toes, and right nephrectomy in 2019. His immunosuppressive regimen consisted of mycophenolate mofetil 500 mg twice daily and prednisone 5 mg per day. He denied any exposure to pets.
On physical examination, the patient's weight was 123 kg with a BMI of 34.4, temperature 99.2 °F, blood pressure 116/56 mm/hg, heart rate 91 beats/minute. Oxygen (O2) saturation was 60% in room air. He was alert and oriented on arrival. Cardiac exam revealed regular heart sounds without murmurs. On lung exam, there were bibasilar crackles. The rest of his physical exam was normal.
White blood cell count was 7.7x10^3/µL ( 4-10.5^3/µL), 29% lymphocytes. Creatinine was 6.6 mg/dL (0.5-1.2 mg/dL) with a glomerular filtration rate (GFR) of 11 mL/min/1.73 m2 and serum glucose 151 mg/dL (range 65-109 mg/dL). His COVID-19 reverse transcription polymerase chain reaction (RT-PCR) test from nasopharyngeal swab was positive. Chest X-ray showed bilateral diffuse consolidations.
The patient was initially placed on a 100% non-rebreathing mask and later on a high flow O2 nasal cannula. The patient remained hypoxemic and developed respiratory failure. He was intubated and required mechanical ventilator support. The patient was also initiated on continuous renal replacement therapy. He was started on intravenous ceftriaxone 1 gm and oral azithromycin as well as a course of hydroxychloroquine 400 mg twice daily followed by 400 mg once daily. In addition, he was given intravenous methylprednisolone 100 mg daily. The patient completed five days of treatment of intravenous ceftriaxone and oral azithromycin with an improvement of radiologic findings. After a week, the patient started developing fevers up to 103 °F. Chest X-ray showed an increase in lung infiltrates (Figure 1).
Figure 1 Chest X-ray showing bilateral infiltrates
Intravenous cefepime 1 gm loading followed by 500 mg next day was given. The patient remained intubated, seemed to be clinically deteriorating, and continued to be febrile, and therefore, intravenous azithromycin 500 mg was given. The sputum sample sent 12 days after intubation grew B. bronchiseptica; blood cultures remained negative. The patient became afebrile and was extubated within 24 hours after starting intravenous azithromycin. Intravenous cefepime was stopped and intravenous piperacillin/tazobactam 2.25 gm every eight hours was started and the patient continued with intravenous azithromycin. The organism was resistant to cefepime, intermediately sensitive to ceftazidime, and sensitive to levofloxacin, trimethoprim-sulfamethoxazole, tigecycline, gentamicin, tobramycin, meropenem, and piperacillin/tazobactam. Due to the rapid response to azithromycin leading to extubation, a decision was made to discontinue piperacillin/tazobactam and to continue with azithromycin. The patient continued to improve clinically and remained afebrile. Treatment continued with intravenous azithromycin for a total of 10 days. Chest X-ray two weeks post-discharge showed pulmonary vascular congestion, left lung atelectasis, and resolution of his lung infiltrates (Figure 2). Two months after discharge, the patient was doing well clinically but required intermittent renal replacement therapy.
Figure 2 Chest X-ray showing improvement in infiltrates after treatment with azithromycin
Discussion
Nine different subspecies of Bordetella have been identified. B. pertussis and B. parapertussis are most commonly associated with human infections. Clinically, human infections consist of upper respiratory tract infection, pneumonia, endocarditis, peritonitis, meningitis, and bacteremia [2].
B. bronchiseptica is known to cause upper respiratory tract infections in dogs, cats, rabbits, swine, and guinea pigs. The organism is the causative agent of kennel cough in dogs and atrophic rhinitis in swine. B. bronchiseptica possesses genes similar to B. pertussis, suggesting a close relationship between them. The organism can cause serious infection in immunocompromised patients such as HIV-infected patients [3], acute leukemia [4], bone marrow transplant [5], and other malignancies. Patients infected with this organism often report contact with animals prior to the development of infection [6,7].
In the recent pandemic of COVID-19, patients with underlying diabetes mellitus, obesity, and immunocompromised patients are at an increased risk of developing severe disease. Patients with a history of solid organ transplantation on immunosuppression have been described with significantly higher mortality [8]. The spectrum of clinical disease with COVID-19 varies from a mild respiratory illness to fulminant pneumonia with ARDS requiring mechanical ventilation. Some patients present with a clinical picture as well as radiological appearance similar to bacterial or atypical pneumonia. In hospitalized patients, it is sometimes difficult to distinguish between SARS-CoV-2 pneumonia and hospital or ventilator-associated pneumonia. Many of these patients are therefore started on antibiotic treatment and are worked up for bacterial or atypical pneumonia. In a recent review, Rawson et al. [9] reviewed the current literature on evidence of bacterial/fungal coinfection in hospitalized COVID-19 patients. They found 62/806 (8%) coinfection with bacterial/fungal organisms. Zhou et al. [8] reported a 15% (28/191) secondary bacterial infection, of which 27 patients died. Reports on atypical organisms infecting COVID-19 patients are lacking, and to our knowledge, there is no report of Bordetella pneumonia associated with COVID-19.
Our patient had various risk factors for complicated SARS-CoV-2 infection [10]: he was obese, had diabetes mellitus, hypertension, history of renal transplantation, and was treated with immunosuppressants. Radiographic findings in COVID-19-associated pneumonia include bilateral, multifocal lung lesions, ground-glass opacities, consolidation, and pleural thickening [11]. Similar radiologic findings have been noted in B. bronchiseptica-associated pneumonia [3]. Infections with B. bronchiseptica in renal transplant patients have been uncommonly described. In one case, a patient with a history of renal transplant had bacteremia with B. bronchiseptica three weeks after undergoing a pancreas transplant who had exposure to dogs [12].
It is plausible to assume that our patient had an initial SARS-CoV-2 viral pneumonia, resulting in respiratory failure. B. bronchiseptica was cultured 12 days into his clinical course.
B. bronchiseptica infections in animals are usually treated with doxycycline, quinolones, or macrolides. Infections in humans have been treated with an anti-pseudomonal penicillins, quinolones, aminoglycosides, tetracycline, trimethoprim-sulfamethoxazole, or carbapenems [13]. Response to macrolides has been reported to be variable [14]. The frequency of macrolide resistance among Bordetella isolates in animals is low. In vitro experiments show that resistance to erythromycin develops quickly but that the organisms that developed resistance were unable to colonize mice, suggesting that the drugs may be effective in vivo [14].
Macrolides have not been the drugs of choice for treatment of B. bronchiseptica in humans, but it appears that susceptibility for this organism in vitro does not always predict clinical response [15]. It is therefore possible that this class of drugs may be effective in clinical settings, as happened in our case.
Conclusions
Bacterial coinfection or superinfections should be considered in patients hospitalized with COVID-19-associated pneumonia when the clinical status deteriorates after initial improvement. Severe infection with rare bacterial organisms, especially in transplant recipients, is a concern. An accurate microbiological diagnosis is essential so that patient can be treated appropriately. Clinical response may not coincide with microbiologic in vitro susceptibility results.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33728132 | 19,089,181 | 2021-02-03 |
What was the outcome of reaction 'COVID-19'? | Coinfection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Bordetella bronchiseptica Pneumonia in a Renal Transplant Patient.
Bordetella species cause respiratory infections in both humans and animals. Bordetella bronchiseptica (B. bronchiseptica) infection is an uncommon pathogen in humans. The clinical spectrum of infections with SARS-CoV-2 includes viral pneumonia of variable severity, with some patients developing acute respiratory distress syndrome (ARDS), requiring mechanical ventilation support. Transplant patients with coronavirus disease (COVID-19) infection have high mortality. Bacterial coinfection, including pneumonia, have been described in patients with COVID-19. We present a renal transplant patient with COVID-19 pneumonia who developed B. bronchiseptica superinfection and had a rapid clinical and radiological response to azithromycin treatment.
Introduction
Bordetella species respiratory infections are well known in both humans and animals. The most prevalent Bordetella subspecies in humans is Bordetella pertussis (B. pertussis), while in animals it is Bordetella bronchiseptica (B. bronchiseptica) [1]. B. bronchiseptica is a zoonotic organism, rarely described as the cause of infection in humans [2]. In humans, infections range from simple upper respiratory tract infection to severe sepsis [2]. Few cases have been described in transplant recipients. We present a renal transplant patient with coronavirus disease (COVID-19) pneumonia who developed a superinfection with B. bronchiseptica. To our knowledge, this is the first case of pneumonia with this organism reported in association with COVID-19.
Case presentation
A 48-year-old male patient was admitted with shortness of breath, fever, generalized malaise and worsening productive cough starting a week prior to admission. The patient’s past medical history was significant for chronic obstructive pulmonary disease, history of renal transplant in 2001, hypertension, diabetes mellitus, obesity, gout, and obstructive sleep apnea. His past surgical history was significant for amputation of the left fourth and fifth toes, and right nephrectomy in 2019. His immunosuppressive regimen consisted of mycophenolate mofetil 500 mg twice daily and prednisone 5 mg per day. He denied any exposure to pets.
On physical examination, the patient's weight was 123 kg with a BMI of 34.4, temperature 99.2 °F, blood pressure 116/56 mm/hg, heart rate 91 beats/minute. Oxygen (O2) saturation was 60% in room air. He was alert and oriented on arrival. Cardiac exam revealed regular heart sounds without murmurs. On lung exam, there were bibasilar crackles. The rest of his physical exam was normal.
White blood cell count was 7.7x10^3/µL ( 4-10.5^3/µL), 29% lymphocytes. Creatinine was 6.6 mg/dL (0.5-1.2 mg/dL) with a glomerular filtration rate (GFR) of 11 mL/min/1.73 m2 and serum glucose 151 mg/dL (range 65-109 mg/dL). His COVID-19 reverse transcription polymerase chain reaction (RT-PCR) test from nasopharyngeal swab was positive. Chest X-ray showed bilateral diffuse consolidations.
The patient was initially placed on a 100% non-rebreathing mask and later on a high flow O2 nasal cannula. The patient remained hypoxemic and developed respiratory failure. He was intubated and required mechanical ventilator support. The patient was also initiated on continuous renal replacement therapy. He was started on intravenous ceftriaxone 1 gm and oral azithromycin as well as a course of hydroxychloroquine 400 mg twice daily followed by 400 mg once daily. In addition, he was given intravenous methylprednisolone 100 mg daily. The patient completed five days of treatment of intravenous ceftriaxone and oral azithromycin with an improvement of radiologic findings. After a week, the patient started developing fevers up to 103 °F. Chest X-ray showed an increase in lung infiltrates (Figure 1).
Figure 1 Chest X-ray showing bilateral infiltrates
Intravenous cefepime 1 gm loading followed by 500 mg next day was given. The patient remained intubated, seemed to be clinically deteriorating, and continued to be febrile, and therefore, intravenous azithromycin 500 mg was given. The sputum sample sent 12 days after intubation grew B. bronchiseptica; blood cultures remained negative. The patient became afebrile and was extubated within 24 hours after starting intravenous azithromycin. Intravenous cefepime was stopped and intravenous piperacillin/tazobactam 2.25 gm every eight hours was started and the patient continued with intravenous azithromycin. The organism was resistant to cefepime, intermediately sensitive to ceftazidime, and sensitive to levofloxacin, trimethoprim-sulfamethoxazole, tigecycline, gentamicin, tobramycin, meropenem, and piperacillin/tazobactam. Due to the rapid response to azithromycin leading to extubation, a decision was made to discontinue piperacillin/tazobactam and to continue with azithromycin. The patient continued to improve clinically and remained afebrile. Treatment continued with intravenous azithromycin for a total of 10 days. Chest X-ray two weeks post-discharge showed pulmonary vascular congestion, left lung atelectasis, and resolution of his lung infiltrates (Figure 2). Two months after discharge, the patient was doing well clinically but required intermittent renal replacement therapy.
Figure 2 Chest X-ray showing improvement in infiltrates after treatment with azithromycin
Discussion
Nine different subspecies of Bordetella have been identified. B. pertussis and B. parapertussis are most commonly associated with human infections. Clinically, human infections consist of upper respiratory tract infection, pneumonia, endocarditis, peritonitis, meningitis, and bacteremia [2].
B. bronchiseptica is known to cause upper respiratory tract infections in dogs, cats, rabbits, swine, and guinea pigs. The organism is the causative agent of kennel cough in dogs and atrophic rhinitis in swine. B. bronchiseptica possesses genes similar to B. pertussis, suggesting a close relationship between them. The organism can cause serious infection in immunocompromised patients such as HIV-infected patients [3], acute leukemia [4], bone marrow transplant [5], and other malignancies. Patients infected with this organism often report contact with animals prior to the development of infection [6,7].
In the recent pandemic of COVID-19, patients with underlying diabetes mellitus, obesity, and immunocompromised patients are at an increased risk of developing severe disease. Patients with a history of solid organ transplantation on immunosuppression have been described with significantly higher mortality [8]. The spectrum of clinical disease with COVID-19 varies from a mild respiratory illness to fulminant pneumonia with ARDS requiring mechanical ventilation. Some patients present with a clinical picture as well as radiological appearance similar to bacterial or atypical pneumonia. In hospitalized patients, it is sometimes difficult to distinguish between SARS-CoV-2 pneumonia and hospital or ventilator-associated pneumonia. Many of these patients are therefore started on antibiotic treatment and are worked up for bacterial or atypical pneumonia. In a recent review, Rawson et al. [9] reviewed the current literature on evidence of bacterial/fungal coinfection in hospitalized COVID-19 patients. They found 62/806 (8%) coinfection with bacterial/fungal organisms. Zhou et al. [8] reported a 15% (28/191) secondary bacterial infection, of which 27 patients died. Reports on atypical organisms infecting COVID-19 patients are lacking, and to our knowledge, there is no report of Bordetella pneumonia associated with COVID-19.
Our patient had various risk factors for complicated SARS-CoV-2 infection [10]: he was obese, had diabetes mellitus, hypertension, history of renal transplantation, and was treated with immunosuppressants. Radiographic findings in COVID-19-associated pneumonia include bilateral, multifocal lung lesions, ground-glass opacities, consolidation, and pleural thickening [11]. Similar radiologic findings have been noted in B. bronchiseptica-associated pneumonia [3]. Infections with B. bronchiseptica in renal transplant patients have been uncommonly described. In one case, a patient with a history of renal transplant had bacteremia with B. bronchiseptica three weeks after undergoing a pancreas transplant who had exposure to dogs [12].
It is plausible to assume that our patient had an initial SARS-CoV-2 viral pneumonia, resulting in respiratory failure. B. bronchiseptica was cultured 12 days into his clinical course.
B. bronchiseptica infections in animals are usually treated with doxycycline, quinolones, or macrolides. Infections in humans have been treated with an anti-pseudomonal penicillins, quinolones, aminoglycosides, tetracycline, trimethoprim-sulfamethoxazole, or carbapenems [13]. Response to macrolides has been reported to be variable [14]. The frequency of macrolide resistance among Bordetella isolates in animals is low. In vitro experiments show that resistance to erythromycin develops quickly but that the organisms that developed resistance were unable to colonize mice, suggesting that the drugs may be effective in vivo [14].
Macrolides have not been the drugs of choice for treatment of B. bronchiseptica in humans, but it appears that susceptibility for this organism in vitro does not always predict clinical response [15]. It is therefore possible that this class of drugs may be effective in clinical settings, as happened in our case.
Conclusions
Bacterial coinfection or superinfections should be considered in patients hospitalized with COVID-19-associated pneumonia when the clinical status deteriorates after initial improvement. Severe infection with rare bacterial organisms, especially in transplant recipients, is a concern. An accurate microbiological diagnosis is essential so that patient can be treated appropriately. Clinical response may not coincide with microbiologic in vitro susceptibility results.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33728132 | 19,089,181 | 2021-02-03 |
What was the outcome of reaction 'Pneumonia bacterial'? | Coinfection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Bordetella bronchiseptica Pneumonia in a Renal Transplant Patient.
Bordetella species cause respiratory infections in both humans and animals. Bordetella bronchiseptica (B. bronchiseptica) infection is an uncommon pathogen in humans. The clinical spectrum of infections with SARS-CoV-2 includes viral pneumonia of variable severity, with some patients developing acute respiratory distress syndrome (ARDS), requiring mechanical ventilation support. Transplant patients with coronavirus disease (COVID-19) infection have high mortality. Bacterial coinfection, including pneumonia, have been described in patients with COVID-19. We present a renal transplant patient with COVID-19 pneumonia who developed B. bronchiseptica superinfection and had a rapid clinical and radiological response to azithromycin treatment.
Introduction
Bordetella species respiratory infections are well known in both humans and animals. The most prevalent Bordetella subspecies in humans is Bordetella pertussis (B. pertussis), while in animals it is Bordetella bronchiseptica (B. bronchiseptica) [1]. B. bronchiseptica is a zoonotic organism, rarely described as the cause of infection in humans [2]. In humans, infections range from simple upper respiratory tract infection to severe sepsis [2]. Few cases have been described in transplant recipients. We present a renal transplant patient with coronavirus disease (COVID-19) pneumonia who developed a superinfection with B. bronchiseptica. To our knowledge, this is the first case of pneumonia with this organism reported in association with COVID-19.
Case presentation
A 48-year-old male patient was admitted with shortness of breath, fever, generalized malaise and worsening productive cough starting a week prior to admission. The patient’s past medical history was significant for chronic obstructive pulmonary disease, history of renal transplant in 2001, hypertension, diabetes mellitus, obesity, gout, and obstructive sleep apnea. His past surgical history was significant for amputation of the left fourth and fifth toes, and right nephrectomy in 2019. His immunosuppressive regimen consisted of mycophenolate mofetil 500 mg twice daily and prednisone 5 mg per day. He denied any exposure to pets.
On physical examination, the patient's weight was 123 kg with a BMI of 34.4, temperature 99.2 °F, blood pressure 116/56 mm/hg, heart rate 91 beats/minute. Oxygen (O2) saturation was 60% in room air. He was alert and oriented on arrival. Cardiac exam revealed regular heart sounds without murmurs. On lung exam, there were bibasilar crackles. The rest of his physical exam was normal.
White blood cell count was 7.7x10^3/µL ( 4-10.5^3/µL), 29% lymphocytes. Creatinine was 6.6 mg/dL (0.5-1.2 mg/dL) with a glomerular filtration rate (GFR) of 11 mL/min/1.73 m2 and serum glucose 151 mg/dL (range 65-109 mg/dL). His COVID-19 reverse transcription polymerase chain reaction (RT-PCR) test from nasopharyngeal swab was positive. Chest X-ray showed bilateral diffuse consolidations.
The patient was initially placed on a 100% non-rebreathing mask and later on a high flow O2 nasal cannula. The patient remained hypoxemic and developed respiratory failure. He was intubated and required mechanical ventilator support. The patient was also initiated on continuous renal replacement therapy. He was started on intravenous ceftriaxone 1 gm and oral azithromycin as well as a course of hydroxychloroquine 400 mg twice daily followed by 400 mg once daily. In addition, he was given intravenous methylprednisolone 100 mg daily. The patient completed five days of treatment of intravenous ceftriaxone and oral azithromycin with an improvement of radiologic findings. After a week, the patient started developing fevers up to 103 °F. Chest X-ray showed an increase in lung infiltrates (Figure 1).
Figure 1 Chest X-ray showing bilateral infiltrates
Intravenous cefepime 1 gm loading followed by 500 mg next day was given. The patient remained intubated, seemed to be clinically deteriorating, and continued to be febrile, and therefore, intravenous azithromycin 500 mg was given. The sputum sample sent 12 days after intubation grew B. bronchiseptica; blood cultures remained negative. The patient became afebrile and was extubated within 24 hours after starting intravenous azithromycin. Intravenous cefepime was stopped and intravenous piperacillin/tazobactam 2.25 gm every eight hours was started and the patient continued with intravenous azithromycin. The organism was resistant to cefepime, intermediately sensitive to ceftazidime, and sensitive to levofloxacin, trimethoprim-sulfamethoxazole, tigecycline, gentamicin, tobramycin, meropenem, and piperacillin/tazobactam. Due to the rapid response to azithromycin leading to extubation, a decision was made to discontinue piperacillin/tazobactam and to continue with azithromycin. The patient continued to improve clinically and remained afebrile. Treatment continued with intravenous azithromycin for a total of 10 days. Chest X-ray two weeks post-discharge showed pulmonary vascular congestion, left lung atelectasis, and resolution of his lung infiltrates (Figure 2). Two months after discharge, the patient was doing well clinically but required intermittent renal replacement therapy.
Figure 2 Chest X-ray showing improvement in infiltrates after treatment with azithromycin
Discussion
Nine different subspecies of Bordetella have been identified. B. pertussis and B. parapertussis are most commonly associated with human infections. Clinically, human infections consist of upper respiratory tract infection, pneumonia, endocarditis, peritonitis, meningitis, and bacteremia [2].
B. bronchiseptica is known to cause upper respiratory tract infections in dogs, cats, rabbits, swine, and guinea pigs. The organism is the causative agent of kennel cough in dogs and atrophic rhinitis in swine. B. bronchiseptica possesses genes similar to B. pertussis, suggesting a close relationship between them. The organism can cause serious infection in immunocompromised patients such as HIV-infected patients [3], acute leukemia [4], bone marrow transplant [5], and other malignancies. Patients infected with this organism often report contact with animals prior to the development of infection [6,7].
In the recent pandemic of COVID-19, patients with underlying diabetes mellitus, obesity, and immunocompromised patients are at an increased risk of developing severe disease. Patients with a history of solid organ transplantation on immunosuppression have been described with significantly higher mortality [8]. The spectrum of clinical disease with COVID-19 varies from a mild respiratory illness to fulminant pneumonia with ARDS requiring mechanical ventilation. Some patients present with a clinical picture as well as radiological appearance similar to bacterial or atypical pneumonia. In hospitalized patients, it is sometimes difficult to distinguish between SARS-CoV-2 pneumonia and hospital or ventilator-associated pneumonia. Many of these patients are therefore started on antibiotic treatment and are worked up for bacterial or atypical pneumonia. In a recent review, Rawson et al. [9] reviewed the current literature on evidence of bacterial/fungal coinfection in hospitalized COVID-19 patients. They found 62/806 (8%) coinfection with bacterial/fungal organisms. Zhou et al. [8] reported a 15% (28/191) secondary bacterial infection, of which 27 patients died. Reports on atypical organisms infecting COVID-19 patients are lacking, and to our knowledge, there is no report of Bordetella pneumonia associated with COVID-19.
Our patient had various risk factors for complicated SARS-CoV-2 infection [10]: he was obese, had diabetes mellitus, hypertension, history of renal transplantation, and was treated with immunosuppressants. Radiographic findings in COVID-19-associated pneumonia include bilateral, multifocal lung lesions, ground-glass opacities, consolidation, and pleural thickening [11]. Similar radiologic findings have been noted in B. bronchiseptica-associated pneumonia [3]. Infections with B. bronchiseptica in renal transplant patients have been uncommonly described. In one case, a patient with a history of renal transplant had bacteremia with B. bronchiseptica three weeks after undergoing a pancreas transplant who had exposure to dogs [12].
It is plausible to assume that our patient had an initial SARS-CoV-2 viral pneumonia, resulting in respiratory failure. B. bronchiseptica was cultured 12 days into his clinical course.
B. bronchiseptica infections in animals are usually treated with doxycycline, quinolones, or macrolides. Infections in humans have been treated with an anti-pseudomonal penicillins, quinolones, aminoglycosides, tetracycline, trimethoprim-sulfamethoxazole, or carbapenems [13]. Response to macrolides has been reported to be variable [14]. The frequency of macrolide resistance among Bordetella isolates in animals is low. In vitro experiments show that resistance to erythromycin develops quickly but that the organisms that developed resistance were unable to colonize mice, suggesting that the drugs may be effective in vivo [14].
Macrolides have not been the drugs of choice for treatment of B. bronchiseptica in humans, but it appears that susceptibility for this organism in vitro does not always predict clinical response [15]. It is therefore possible that this class of drugs may be effective in clinical settings, as happened in our case.
Conclusions
Bacterial coinfection or superinfections should be considered in patients hospitalized with COVID-19-associated pneumonia when the clinical status deteriorates after initial improvement. Severe infection with rare bacterial organisms, especially in transplant recipients, is a concern. An accurate microbiological diagnosis is essential so that patient can be treated appropriately. Clinical response may not coincide with microbiologic in vitro susceptibility results.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33728132 | 19,089,181 | 2021-02-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | A Case of Metastatic Pancreatic Adenocarcinoma in Complete Remission Using Chemotherapy and Immunotherapy.
Among the various types of cancer, pancreatic cancer is considered to have a particularly grim prognosis. Treatment includes surgery, chemotherapy, or both. While the role of immunotherapy is well-studied in many types of cancer, such is not the case with pancreatic cancer. A 49-year-old female presented to the oncology clinic following a biopsy of a pancreatic mass. CT-guided needle biopsy of the mass demonstrated moderately differentiated pancreatic adenocarcinoma. Positive emission tomography-computed tomography (PET-CT) revealed metastases to the liver. She was started on chemotherapy with FOLFIRINOX (leucovorin calcium, 5-fluorouracil, irinotecan hydrochloride, oxaliplatin) and demonstrated over 60% reduction in the size of liver metastases within three months. PET-CT four months after initiation of chemotherapy revealed no focal avid fluorodeoxyglucose (FDG) uptake in the liver, and the pancreatic body mass was stable in size at 3.0 cm with stable standardized uptake value (SUV) max at 2.4, only slightly elevated from 1.9 on the previous scan. Further treatment with chemotherapy was halted after 18 cycles due to side effects. With the patient's tumor being epidermal growth factor receptor (EGFR) negative, mismatch repair (MMR) negative, 3% tumor cells PD-L1 positive with 10% tumor-associated immune cells positive, treatment with pembrolizumab was started. Follow-up PET-CTs over the next several months confirmed the patient was in complete remission from metastatic pancreatic cancer. At the time of the report, the patient had a durable response of three years. We report a rare case of complete remission of metastatic pancreatic adenocarcinoma treated with chemotherapy, followed by immunotherapy. With emerging targets for modification of tumor microenvironment, immunotherapy must be further explored in the treatment of pancreatic cancer.
Introduction
Cancer remains one of the deadliest diseases both within the United States and globally. Among the various types of cancer, pancreatic cancer is considered to have a particularly grim prognosis, with five-year survival rates ranging from 2% to 9% [1]. Risk factors include but are not limited to age, obesity, diabetes, smoking, alcohol, chronic pancreatitis, family history, and prior abdominal radiotherapy [2]. Diagnosis can be made using CT, positive emission tomography-computerized tomography (PET-CT), endoscopic ultrasound, magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and percutaneous biopsy [3]. Significant advances have been made in the treatment of many cancers, particularly with the development of immunotherapy and more targeted radiation. Pancreatic cancer, however, remains difficult to treat, due to its aggressive nature, lack of well-studied screening tools, and limited treatment options. Although ineffective as a screening tool, CA 19-9 is a marker often used to monitor response to treatment [1]. Mainstays for treatment depend on the type of pancreatic cancer, as well as its location and regional involvement, but generally involve surgery, chemotherapy, radiation, or a combination of the three. While the role of immunotherapy is well-studied in many types of cancer, such is not the case with pancreatic cancer. Herein, we present a case of a patient with metastatic pancreatic adenocarcinoma, now in complete remission after treatment with chemotherapy, then pembrolizumab.
Case presentation
A 49-year-old female with a history of alcohol abuse, tobacco abuse, and hypertension, presented to the oncology clinic as a referral following biopsy of a pancreatic mass. She began having right upper quadrant abdominal pain, mid-back pain, changes in bowel habits, and abdominal bloating three months prior, and she noticed a 5-pound weight loss during this time frame. CT scan of the abdomen revealed a 3.3 cm mass in the body of the pancreas, and subsequent CT-guided needle biopsy of the mass demonstrated moderately differentiated pancreatic adenocarcinoma. PET-CT revealed metastases to the liver (Figure 1). She was started on chemotherapy with FOLFIRINOX (leucovorin calcium, 5-fluorouracil, irinotecan hydrochloride, oxaliplatin) and demonstrated over 60% reduction in the size of liver metastases within three months. PET-CT at six months showed hepatic fluorodeoxyglucose (FDG) uptake only mildly increased from the background and stable size of pancreatic mass with FDG uptake below background activity. Baseline CA 19-9 was obtained at nine months and measured 13 (reference range <35 U/mL). One month later, CA 19-9 level was 10. PET-CT revealed no focal avid FDG uptake in the liver, and the pancreatic body mass was stable in size at 3.0 cm with a stable standardized uptake value (SUV) max at 2.4, only slightly elevated from 1.9 on the previous scan. After 18 cycles of chemotherapy, additional treatment options were explored as the patient had received near maximum benefit from adjuvant therapy and was experiencing worsening side effects including progressive peripheral neuropathy. The patient’s tumor was epidermal growth factor receptor (EGFR) negative, mismatch repair (MMR) negative, 3% tumor cells PD-L1 positive with 10% tumor-associated immune cells positive. Given the patient's young age and excellent functional status, approval for treatment with pembrolizumab was obtained and therapy was started. Prior to treatment, CA 19-9 level was nine. Two months later, this level had decreased to six, and CT abdomen one month later after four cycles of pembrolizumab showed no evidence of disease. Follow-up PET-CTs over the next several months confirmed the patient was in complete remission from metastatic pancreatic cancer (Figure 2). At the time of the report, the patient had a durable response of three years.
Figure 1 PET-CT demonstrating pancreatic adenocarcinoma with metastases to the liver, prior to the initiation of treatment
Figure 2 PET-CT demonstrating complete remission two months after starting treatment with pembrolizumab
Discussion
Among the various types of pancreatic cancer, pancreatic adenocarcinoma is the most common, accounting for nearly 85% of all diagnoses [1]. In early-stage cases without local invasion, surgical resection with adjuvant chemotherapy is the treatment of choice. With the local invasion, neo-adjuvant chemotherapy with either FOLFIRINOX or nab-paclitaxel plus gemcitabine has become standard, followed by a re-evaluation for surgical resection. However, more than 50% of cases are identified after metastases, and chemotherapy in these patients confers poor survival rates [4]. Median survival in patients with advanced pancreatic cancer is less than 12 months despite the treatment options available [5].
With such poor outcomes, the need for new therapies is evident. Immunotherapy is being investigated given its success with other forms of cancer, and pembrolizumab was recently approved for the treatment of advanced pancreatic cancers [6]. It has been noted that some forms of cancer will respond to checkpoint inhibitors regardless of whether or not the tumor expresses PD-L1. Furthermore, PD-L1 expression can be variable even within the tissue of a single tumor [7]. PD-L1 expression in pancreatic cancer has been associated with worse clinical outcomes as well, again highlighting this interaction as a potential therapy target [8]. The phase II COMBAT trial showed a potential role for PD-1 blockade in combination with chemokine receptor 4 (CXCR4) blockade [9]. However, many early-phase clinical trials with checkpoint inhibitors have not shown success in treating pancreatic adenocarcinoma, which is suspected to be due to the tumor microenvironment and its relative lack of effector T cells [8]. Modifying the tumor microenvironment to allow for the cytotoxic effect of T cells may be a useful approach towards improving the efficacy of immunotherapy. Pre-clinical studies in mice have shown an improved response of tumors treated concurrently with PD-1/PD-L1 blockade and gemcitabine [10]. Studies of mice models showed that fibroblast activation protein (FAP)-positive stromal cells that were initially depleted were able to respond to treatment with immunotherapy [11]. Furthermore, mice with pancreatic ductal adenocarcinoma and overexpression of the tumor suppressor ETS homologous factor (EHF) were more responsive to anti-PD1 therapy, underscoring the importance of the tumor microenvironment in treatment response [12]. While Ca 19-9 is often used to monitor treatment response, new studies have revealed a role for using leukemia inhibitory factor (LIF) as a protein marker to observe disease progression and response to treatment [13]. Additionally, deletion of the gene for LIF in mouse models showed enhanced chemosensitivity and slowed disease progression [13]. Thus, LIF may be a potential target to modify the pancreatic tumor microenvironment that can improve the response to immunotherapy as well.
Expanding upon the success of pancreatic adenocarcinoma treatment with immunotherapy in mouse trials, this case demonstrates the need for further investigation of immunotherapy as a treatment modality for pancreatic cancer. It is possible the prior treatment with FOLFIRINOX created a favorable tumor microenvironment prior to the initiation of immunotherapy. With emerging targets for modification of tumor microenvironment, including FAP-positive stromal cells and LIF, immunotherapy must be further explored as a treatment option for pancreatic cancer.
Conclusions
This appears to be the only reported case in the literature of complete remission of metastatic pancreatic adenocarcinoma treated with chemotherapy, followed by immunotherapy. Furthermore, the durable response of three years is remarkable in what is widely considered a fatal prognosis. Prior treatment with FOLFIRINOX may have created a favorable tumor microenvironment preceding immunotherapy. With emerging targets for modification of tumor microenvironment, including FAP-positive stromal cells, EHF, and LIF, the role of immunotherapy in the treatment of pancreatic cancer must be further explored.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | FLUOROURACIL, IRINOTECAN, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY | 33728149 | 19,089,454 | 2021-02-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | A Case of Metastatic Pancreatic Adenocarcinoma in Complete Remission Using Chemotherapy and Immunotherapy.
Among the various types of cancer, pancreatic cancer is considered to have a particularly grim prognosis. Treatment includes surgery, chemotherapy, or both. While the role of immunotherapy is well-studied in many types of cancer, such is not the case with pancreatic cancer. A 49-year-old female presented to the oncology clinic following a biopsy of a pancreatic mass. CT-guided needle biopsy of the mass demonstrated moderately differentiated pancreatic adenocarcinoma. Positive emission tomography-computed tomography (PET-CT) revealed metastases to the liver. She was started on chemotherapy with FOLFIRINOX (leucovorin calcium, 5-fluorouracil, irinotecan hydrochloride, oxaliplatin) and demonstrated over 60% reduction in the size of liver metastases within three months. PET-CT four months after initiation of chemotherapy revealed no focal avid fluorodeoxyglucose (FDG) uptake in the liver, and the pancreatic body mass was stable in size at 3.0 cm with stable standardized uptake value (SUV) max at 2.4, only slightly elevated from 1.9 on the previous scan. Further treatment with chemotherapy was halted after 18 cycles due to side effects. With the patient's tumor being epidermal growth factor receptor (EGFR) negative, mismatch repair (MMR) negative, 3% tumor cells PD-L1 positive with 10% tumor-associated immune cells positive, treatment with pembrolizumab was started. Follow-up PET-CTs over the next several months confirmed the patient was in complete remission from metastatic pancreatic cancer. At the time of the report, the patient had a durable response of three years. We report a rare case of complete remission of metastatic pancreatic adenocarcinoma treated with chemotherapy, followed by immunotherapy. With emerging targets for modification of tumor microenvironment, immunotherapy must be further explored in the treatment of pancreatic cancer.
Introduction
Cancer remains one of the deadliest diseases both within the United States and globally. Among the various types of cancer, pancreatic cancer is considered to have a particularly grim prognosis, with five-year survival rates ranging from 2% to 9% [1]. Risk factors include but are not limited to age, obesity, diabetes, smoking, alcohol, chronic pancreatitis, family history, and prior abdominal radiotherapy [2]. Diagnosis can be made using CT, positive emission tomography-computerized tomography (PET-CT), endoscopic ultrasound, magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and percutaneous biopsy [3]. Significant advances have been made in the treatment of many cancers, particularly with the development of immunotherapy and more targeted radiation. Pancreatic cancer, however, remains difficult to treat, due to its aggressive nature, lack of well-studied screening tools, and limited treatment options. Although ineffective as a screening tool, CA 19-9 is a marker often used to monitor response to treatment [1]. Mainstays for treatment depend on the type of pancreatic cancer, as well as its location and regional involvement, but generally involve surgery, chemotherapy, radiation, or a combination of the three. While the role of immunotherapy is well-studied in many types of cancer, such is not the case with pancreatic cancer. Herein, we present a case of a patient with metastatic pancreatic adenocarcinoma, now in complete remission after treatment with chemotherapy, then pembrolizumab.
Case presentation
A 49-year-old female with a history of alcohol abuse, tobacco abuse, and hypertension, presented to the oncology clinic as a referral following biopsy of a pancreatic mass. She began having right upper quadrant abdominal pain, mid-back pain, changes in bowel habits, and abdominal bloating three months prior, and she noticed a 5-pound weight loss during this time frame. CT scan of the abdomen revealed a 3.3 cm mass in the body of the pancreas, and subsequent CT-guided needle biopsy of the mass demonstrated moderately differentiated pancreatic adenocarcinoma. PET-CT revealed metastases to the liver (Figure 1). She was started on chemotherapy with FOLFIRINOX (leucovorin calcium, 5-fluorouracil, irinotecan hydrochloride, oxaliplatin) and demonstrated over 60% reduction in the size of liver metastases within three months. PET-CT at six months showed hepatic fluorodeoxyglucose (FDG) uptake only mildly increased from the background and stable size of pancreatic mass with FDG uptake below background activity. Baseline CA 19-9 was obtained at nine months and measured 13 (reference range <35 U/mL). One month later, CA 19-9 level was 10. PET-CT revealed no focal avid FDG uptake in the liver, and the pancreatic body mass was stable in size at 3.0 cm with a stable standardized uptake value (SUV) max at 2.4, only slightly elevated from 1.9 on the previous scan. After 18 cycles of chemotherapy, additional treatment options were explored as the patient had received near maximum benefit from adjuvant therapy and was experiencing worsening side effects including progressive peripheral neuropathy. The patient’s tumor was epidermal growth factor receptor (EGFR) negative, mismatch repair (MMR) negative, 3% tumor cells PD-L1 positive with 10% tumor-associated immune cells positive. Given the patient's young age and excellent functional status, approval for treatment with pembrolizumab was obtained and therapy was started. Prior to treatment, CA 19-9 level was nine. Two months later, this level had decreased to six, and CT abdomen one month later after four cycles of pembrolizumab showed no evidence of disease. Follow-up PET-CTs over the next several months confirmed the patient was in complete remission from metastatic pancreatic cancer (Figure 2). At the time of the report, the patient had a durable response of three years.
Figure 1 PET-CT demonstrating pancreatic adenocarcinoma with metastases to the liver, prior to the initiation of treatment
Figure 2 PET-CT demonstrating complete remission two months after starting treatment with pembrolizumab
Discussion
Among the various types of pancreatic cancer, pancreatic adenocarcinoma is the most common, accounting for nearly 85% of all diagnoses [1]. In early-stage cases without local invasion, surgical resection with adjuvant chemotherapy is the treatment of choice. With the local invasion, neo-adjuvant chemotherapy with either FOLFIRINOX or nab-paclitaxel plus gemcitabine has become standard, followed by a re-evaluation for surgical resection. However, more than 50% of cases are identified after metastases, and chemotherapy in these patients confers poor survival rates [4]. Median survival in patients with advanced pancreatic cancer is less than 12 months despite the treatment options available [5].
With such poor outcomes, the need for new therapies is evident. Immunotherapy is being investigated given its success with other forms of cancer, and pembrolizumab was recently approved for the treatment of advanced pancreatic cancers [6]. It has been noted that some forms of cancer will respond to checkpoint inhibitors regardless of whether or not the tumor expresses PD-L1. Furthermore, PD-L1 expression can be variable even within the tissue of a single tumor [7]. PD-L1 expression in pancreatic cancer has been associated with worse clinical outcomes as well, again highlighting this interaction as a potential therapy target [8]. The phase II COMBAT trial showed a potential role for PD-1 blockade in combination with chemokine receptor 4 (CXCR4) blockade [9]. However, many early-phase clinical trials with checkpoint inhibitors have not shown success in treating pancreatic adenocarcinoma, which is suspected to be due to the tumor microenvironment and its relative lack of effector T cells [8]. Modifying the tumor microenvironment to allow for the cytotoxic effect of T cells may be a useful approach towards improving the efficacy of immunotherapy. Pre-clinical studies in mice have shown an improved response of tumors treated concurrently with PD-1/PD-L1 blockade and gemcitabine [10]. Studies of mice models showed that fibroblast activation protein (FAP)-positive stromal cells that were initially depleted were able to respond to treatment with immunotherapy [11]. Furthermore, mice with pancreatic ductal adenocarcinoma and overexpression of the tumor suppressor ETS homologous factor (EHF) were more responsive to anti-PD1 therapy, underscoring the importance of the tumor microenvironment in treatment response [12]. While Ca 19-9 is often used to monitor treatment response, new studies have revealed a role for using leukemia inhibitory factor (LIF) as a protein marker to observe disease progression and response to treatment [13]. Additionally, deletion of the gene for LIF in mouse models showed enhanced chemosensitivity and slowed disease progression [13]. Thus, LIF may be a potential target to modify the pancreatic tumor microenvironment that can improve the response to immunotherapy as well.
Expanding upon the success of pancreatic adenocarcinoma treatment with immunotherapy in mouse trials, this case demonstrates the need for further investigation of immunotherapy as a treatment modality for pancreatic cancer. It is possible the prior treatment with FOLFIRINOX created a favorable tumor microenvironment prior to the initiation of immunotherapy. With emerging targets for modification of tumor microenvironment, including FAP-positive stromal cells and LIF, immunotherapy must be further explored as a treatment option for pancreatic cancer.
Conclusions
This appears to be the only reported case in the literature of complete remission of metastatic pancreatic adenocarcinoma treated with chemotherapy, followed by immunotherapy. Furthermore, the durable response of three years is remarkable in what is widely considered a fatal prognosis. Prior treatment with FOLFIRINOX may have created a favorable tumor microenvironment preceding immunotherapy. With emerging targets for modification of tumor microenvironment, including FAP-positive stromal cells, EHF, and LIF, the role of immunotherapy in the treatment of pancreatic cancer must be further explored.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | FLUOROURACIL, IRINOTECAN HYDROCHLORIDE, LEUCOVORIN CALCIUM, OXALIPLATIN | DrugsGivenReaction | CC BY | 33728149 | 19,060,614 | 2021-02-04 |
What was the outcome of reaction 'Product use in unapproved indication'? | A Case of Metastatic Pancreatic Adenocarcinoma in Complete Remission Using Chemotherapy and Immunotherapy.
Among the various types of cancer, pancreatic cancer is considered to have a particularly grim prognosis. Treatment includes surgery, chemotherapy, or both. While the role of immunotherapy is well-studied in many types of cancer, such is not the case with pancreatic cancer. A 49-year-old female presented to the oncology clinic following a biopsy of a pancreatic mass. CT-guided needle biopsy of the mass demonstrated moderately differentiated pancreatic adenocarcinoma. Positive emission tomography-computed tomography (PET-CT) revealed metastases to the liver. She was started on chemotherapy with FOLFIRINOX (leucovorin calcium, 5-fluorouracil, irinotecan hydrochloride, oxaliplatin) and demonstrated over 60% reduction in the size of liver metastases within three months. PET-CT four months after initiation of chemotherapy revealed no focal avid fluorodeoxyglucose (FDG) uptake in the liver, and the pancreatic body mass was stable in size at 3.0 cm with stable standardized uptake value (SUV) max at 2.4, only slightly elevated from 1.9 on the previous scan. Further treatment with chemotherapy was halted after 18 cycles due to side effects. With the patient's tumor being epidermal growth factor receptor (EGFR) negative, mismatch repair (MMR) negative, 3% tumor cells PD-L1 positive with 10% tumor-associated immune cells positive, treatment with pembrolizumab was started. Follow-up PET-CTs over the next several months confirmed the patient was in complete remission from metastatic pancreatic cancer. At the time of the report, the patient had a durable response of three years. We report a rare case of complete remission of metastatic pancreatic adenocarcinoma treated with chemotherapy, followed by immunotherapy. With emerging targets for modification of tumor microenvironment, immunotherapy must be further explored in the treatment of pancreatic cancer.
Introduction
Cancer remains one of the deadliest diseases both within the United States and globally. Among the various types of cancer, pancreatic cancer is considered to have a particularly grim prognosis, with five-year survival rates ranging from 2% to 9% [1]. Risk factors include but are not limited to age, obesity, diabetes, smoking, alcohol, chronic pancreatitis, family history, and prior abdominal radiotherapy [2]. Diagnosis can be made using CT, positive emission tomography-computerized tomography (PET-CT), endoscopic ultrasound, magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and percutaneous biopsy [3]. Significant advances have been made in the treatment of many cancers, particularly with the development of immunotherapy and more targeted radiation. Pancreatic cancer, however, remains difficult to treat, due to its aggressive nature, lack of well-studied screening tools, and limited treatment options. Although ineffective as a screening tool, CA 19-9 is a marker often used to monitor response to treatment [1]. Mainstays for treatment depend on the type of pancreatic cancer, as well as its location and regional involvement, but generally involve surgery, chemotherapy, radiation, or a combination of the three. While the role of immunotherapy is well-studied in many types of cancer, such is not the case with pancreatic cancer. Herein, we present a case of a patient with metastatic pancreatic adenocarcinoma, now in complete remission after treatment with chemotherapy, then pembrolizumab.
Case presentation
A 49-year-old female with a history of alcohol abuse, tobacco abuse, and hypertension, presented to the oncology clinic as a referral following biopsy of a pancreatic mass. She began having right upper quadrant abdominal pain, mid-back pain, changes in bowel habits, and abdominal bloating three months prior, and she noticed a 5-pound weight loss during this time frame. CT scan of the abdomen revealed a 3.3 cm mass in the body of the pancreas, and subsequent CT-guided needle biopsy of the mass demonstrated moderately differentiated pancreatic adenocarcinoma. PET-CT revealed metastases to the liver (Figure 1). She was started on chemotherapy with FOLFIRINOX (leucovorin calcium, 5-fluorouracil, irinotecan hydrochloride, oxaliplatin) and demonstrated over 60% reduction in the size of liver metastases within three months. PET-CT at six months showed hepatic fluorodeoxyglucose (FDG) uptake only mildly increased from the background and stable size of pancreatic mass with FDG uptake below background activity. Baseline CA 19-9 was obtained at nine months and measured 13 (reference range <35 U/mL). One month later, CA 19-9 level was 10. PET-CT revealed no focal avid FDG uptake in the liver, and the pancreatic body mass was stable in size at 3.0 cm with a stable standardized uptake value (SUV) max at 2.4, only slightly elevated from 1.9 on the previous scan. After 18 cycles of chemotherapy, additional treatment options were explored as the patient had received near maximum benefit from adjuvant therapy and was experiencing worsening side effects including progressive peripheral neuropathy. The patient’s tumor was epidermal growth factor receptor (EGFR) negative, mismatch repair (MMR) negative, 3% tumor cells PD-L1 positive with 10% tumor-associated immune cells positive. Given the patient's young age and excellent functional status, approval for treatment with pembrolizumab was obtained and therapy was started. Prior to treatment, CA 19-9 level was nine. Two months later, this level had decreased to six, and CT abdomen one month later after four cycles of pembrolizumab showed no evidence of disease. Follow-up PET-CTs over the next several months confirmed the patient was in complete remission from metastatic pancreatic cancer (Figure 2). At the time of the report, the patient had a durable response of three years.
Figure 1 PET-CT demonstrating pancreatic adenocarcinoma with metastases to the liver, prior to the initiation of treatment
Figure 2 PET-CT demonstrating complete remission two months after starting treatment with pembrolizumab
Discussion
Among the various types of pancreatic cancer, pancreatic adenocarcinoma is the most common, accounting for nearly 85% of all diagnoses [1]. In early-stage cases without local invasion, surgical resection with adjuvant chemotherapy is the treatment of choice. With the local invasion, neo-adjuvant chemotherapy with either FOLFIRINOX or nab-paclitaxel plus gemcitabine has become standard, followed by a re-evaluation for surgical resection. However, more than 50% of cases are identified after metastases, and chemotherapy in these patients confers poor survival rates [4]. Median survival in patients with advanced pancreatic cancer is less than 12 months despite the treatment options available [5].
With such poor outcomes, the need for new therapies is evident. Immunotherapy is being investigated given its success with other forms of cancer, and pembrolizumab was recently approved for the treatment of advanced pancreatic cancers [6]. It has been noted that some forms of cancer will respond to checkpoint inhibitors regardless of whether or not the tumor expresses PD-L1. Furthermore, PD-L1 expression can be variable even within the tissue of a single tumor [7]. PD-L1 expression in pancreatic cancer has been associated with worse clinical outcomes as well, again highlighting this interaction as a potential therapy target [8]. The phase II COMBAT trial showed a potential role for PD-1 blockade in combination with chemokine receptor 4 (CXCR4) blockade [9]. However, many early-phase clinical trials with checkpoint inhibitors have not shown success in treating pancreatic adenocarcinoma, which is suspected to be due to the tumor microenvironment and its relative lack of effector T cells [8]. Modifying the tumor microenvironment to allow for the cytotoxic effect of T cells may be a useful approach towards improving the efficacy of immunotherapy. Pre-clinical studies in mice have shown an improved response of tumors treated concurrently with PD-1/PD-L1 blockade and gemcitabine [10]. Studies of mice models showed that fibroblast activation protein (FAP)-positive stromal cells that were initially depleted were able to respond to treatment with immunotherapy [11]. Furthermore, mice with pancreatic ductal adenocarcinoma and overexpression of the tumor suppressor ETS homologous factor (EHF) were more responsive to anti-PD1 therapy, underscoring the importance of the tumor microenvironment in treatment response [12]. While Ca 19-9 is often used to monitor treatment response, new studies have revealed a role for using leukemia inhibitory factor (LIF) as a protein marker to observe disease progression and response to treatment [13]. Additionally, deletion of the gene for LIF in mouse models showed enhanced chemosensitivity and slowed disease progression [13]. Thus, LIF may be a potential target to modify the pancreatic tumor microenvironment that can improve the response to immunotherapy as well.
Expanding upon the success of pancreatic adenocarcinoma treatment with immunotherapy in mouse trials, this case demonstrates the need for further investigation of immunotherapy as a treatment modality for pancreatic cancer. It is possible the prior treatment with FOLFIRINOX created a favorable tumor microenvironment prior to the initiation of immunotherapy. With emerging targets for modification of tumor microenvironment, including FAP-positive stromal cells and LIF, immunotherapy must be further explored as a treatment option for pancreatic cancer.
Conclusions
This appears to be the only reported case in the literature of complete remission of metastatic pancreatic adenocarcinoma treated with chemotherapy, followed by immunotherapy. Furthermore, the durable response of three years is remarkable in what is widely considered a fatal prognosis. Prior treatment with FOLFIRINOX may have created a favorable tumor microenvironment preceding immunotherapy. With emerging targets for modification of tumor microenvironment, including FAP-positive stromal cells, EHF, and LIF, the role of immunotherapy in the treatment of pancreatic cancer must be further explored.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33728149 | 19,060,614 | 2021-02-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Antineutrophil cytoplasmic antibody'. | A Curious Case of Acute Glomerulonephritis - Staphylococcus vs Lupus: Case Report and Literature Review.
Here we report a case of a 65-year-old female, where we encountered acute glomerulonephritis. The patient initially presented with a hemorrhagic blister involving the second through fourth toes with serosanguinous discharge and was on hydralazine for blood pressure control. Differentials included Staphylococcus-associated/lupus nephritis/anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. Still, detailed history and meticulous clinical approach with supporting labs and imaging helped us to narrow it to Staphylococcus-associated glomerulonephritis, which is rarely encountered in clinical practice and is associated with high mortality. The management of the patient resulted in a positive outcome and she was discharged home.
Introduction
Acute glomerulonephritis is often encountered in clinical practice. The differentials are broad and include lupus nephritis, vasculitis, infection-related, and immunoglobulin A (IgA) nephropathy. Good history, physical and meticulous laboratory investigations help narrow down the differentials, as prompt initiation of management can be critical in preventing morbidity and mortality. Staphylococcus-related glomerulonephritis is rare, and early recognition and eradication of infection can be life-saving.
Case presentation
A 65-year-old female with medical comorbidities of dementia, diabetes (diet controlled), and hypertension (controlled on hydralazine) presented complaining of progressively worsening left foot ulcer for three days. As per the patient, the ulcer started as a blister and since worsened, accompanied by severe pain. On presentation, her blood pressure was 145/78 mmHg, pulse 71/min, respiratory rate 14/min, temperature 98F. On examination, she was at her baseline mental status (alert, oriented to self and place); her left foot was tender with a hemorrhagic blister involving the second through fourth toes with serosanguinous discharge. The rest of the physical examination was normal. Laboratory examination was noted to have acute kidney injury (blood urea nitrogen (BUN) and creatinine 24 mg/l and 2.4 mg/l respectively), baseline renal function was entirely normal six months prior to presentation, hemoglobin/hematocrit of 10 g/dl and 32% respectively, white blood cell 7 k/ul, erythrocyte sedimentation rate (ESR) 120 mm/hr, C-reactive protein 178 mg/l. Urine analysis was significant for large hematuria and trace proteinuria, urine protein 51 (0-31 mg/dl) and urine creatinine 60 (20-200 mg/dl) (Table 1).
Table 1 Autoimmune workup
RPR: rapid plasma reagin, RNP: ribonucleoprotein, anti-Sm: anti-Smith, HCV: hepatitis C virus, EIA: enzyme immunoassay
Labs Patient result Reference range
Anti-peroxidase <1 <1AI
Anti Myeloperoxidase 7.6 <1AI
Anti-RNP <1 <1 AI
Anti-Sm <1 <1AI
Glomerular basement membrane antibody <1 <1AI
Histone antibody 9.6 <1U
Anti-DNA AB 5 <4IU/ml
HIV-1/2Ab (EIA) Negative Non-reactive
RPR screen Non-reactive Non-reactive
Anti-HCV Negative Negative
X-ray chest was negative for any acute process. The patient was suspected of having clinical necrotizing fasciitis, she refused computed tomography (CT) of the lower extremity and underwent incision drainage, and debridement and cultures were sent. The patient was started on daptomycin/meropenem/clindamycin and was transferred to the medical floor. Kidney injury was presumably due to prerenal due to underlying infection, that was managed conservatively without dialysis. Antibiotics were deescalated to cefazolin/metronidazole as the cultures from the foot grew methicillin-sensitive Staphylococcus aureus. Her post-operative course was complicated with poor foot healing, and the patient ended up getting transmetatarsal amputation and then below-knee amputation (BKA) in a matter of days. Histopathology later reported skin and subcutaneous tissue with acute and chronic inflammation, abscess and granulation tissue. Soft tissue margin and bone margin of resection were unremarkable.
The renal function continued to worsen, and the creatinine jumped to 4.4 mg/l. The antinuclear antibody was positive with a titer of 1:320, hypocomplementemia (C3 was 53 mg/dl and C4 was 3 mg/dl). At this point, differentials included post-inflammatory glomerulonephritis versus late-onset systemic lupus nephritis versus drug-induced lupus. Hydralazine was placed on hold. Other pertinent labs revealed positive anti-histone antibodies 9.6 unit (ref <0.1), cardiolipin IgM >150 (normal <20) and myeloperoxidase antibodies 9 units and 7.6 units respectively, creatinine jumped up to 6.6 mg/l, anti-DNA, glomerular basement antibody, and antiphospholipid antibody were negative. Hepatitis panel including hepatitis B and C were negative. She also tested negative for HIV. Another differential of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis was included, Rheumatology was taken on board, the patient was started on a pulsed dose of methylprednisone, and renal biopsy was planned to differentiate between lupus nephritis/pauci-immune glomerulonephritis. The patient's clinical course took a turn for the worse when she became hypoxic on the floor, was placed on the high flow oxygen, and transferred to the critical care unit. CT chest at this point revealed diffuse mixed interstitial and alveolar airspace disease and small pleural effusions (Figure 1). She also had a 1 g drop in hemoglobin from baseline requiring one packed red blood cell transfusion. She tested negative for coronavirus disease 2019 (COVID-19).
Figure 1 CT chest with diffuse mixed interstitial and alveolar airspace disease (red arrows) and small pleural effusion (yellow arrow)
Suspecting diffuse alveolar hemorrhage, the patient was planned for bronchoscopy, which she and the family adamantly refused. Renal biopsy was suggestive of focal glomerulosclerosis with small mesangial and subepithelial deposits suggestive of membranous lupus nephritis, the resolving phase of infection-related included in the differential. Positive multifocal red blood cell (RBC) casts consistent with the pauci-immune focal crescentic glomerulonephritis associated with ANCA (possibly hydralazine-induced).
The patient had an uneventful course in the critical care unit, completed two weeks course of antibiotics, remained on the tapering doses of prednisone (started on prednisone 60 mg and tapering 10 mg every week), was weaned off oxygen, BKA stump healed well, and creatinine dropped down to 4.4 mg/l and plateaued at 4.0 mg/l without dialysis. The patient was planned to be discharged to short term rehab, but the family refused and decided to take her home. The patient was discharged with improving clinical/lab status on tapering doses of prednisone and outpatient follow up with nephrology/rheumatology/surgery.
Our patient's kidney biopsy showed no definitive findings compatible with vasculitis. Our differentials remained the possibility of post-infectious/systemic lupus erythematosus (SLE)/drug-induced lupus. However, SLE remained lower on the differentials as the anti-DNA antibody and anti-Smith antibody were negative. In our clinical assessment and supporting laboratory examination (Table 2), repeat cardiolipin IgM antibody was normal.
Table 2 Improving labs over days
ESR: erythrocyte sedimentation rate. CRP: C-reactive protein, BUN: blood urea nitrogen
labs Day 1 Day 21
ESR (ref 0-30 mmhr) 120 44
CRP (ref <5 mg/l) 178 21
C3 (ref 90-150 mg/dl) 53 92
C4 (ref 16-47 mg/dl) 3 16
BUN (ref 6-20 mg/dl) 105 47
Creatinine (ref 0.5-1.5 mg/dl) 7.2 4.5
We believe that our patient had infectious glomerulonephritis with some element of drug-induced nephritis. Our clinical suspicion was further solidified when the patient showed improvement after below-knee amputation, a continuation of culture-specific antibiotic therapy, and discontinuation of hydralazine.
Discussion
The differential diagnosis encompassing acute glomerulonephritis is lupus nephritis, vasculitis (such as ANCA-associated vasculitis), and IgA nephropathy, to name a few. Thus, it is prudent to include the antinuclear antibodies, anti-double-stranded DNA antibodies, antineutrophil cytoplasmic antibodies (ANCA), cryoglobulins, hepatitis B and C, HIV, and anti-glomerular basement membrane antibodies in the evaluation. The specific patterns of hypocomplementemia can help narrow down the differentials like in Staphylococcus-associated or other bacterial causes of glomerulonephritis, the typical way is low C3 and normal C4 levels, lupus nephritis is usually associated with reduced levels of both C3 and C4, and mixed cryoglobulinemia is frequently associated with low C4 and normal C3 [1].
Hydralazine is known to be associated with both developing lupus and ANCA-positive vasculitis involving the kidney. The risk for the former is estimated to be 13% [2]. In patients taking hydralazine, anti-histone antibodies are present in 95% [3]. Necrotizing glomerulonephritis is mostly implicated in drug-induced lupus with little or no immune complex deposition [4], although immune complex-mediated glomerulonephritis can occur [5]. The patients with necrotizing glomerulonephritis usually have a perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) pattern with anti-myeloperoxidase (MPO) antibodies, plus either anti-lactoferrin or anti-elastase antibodies [4]. This combination of ANCAs is relatively specific for this form of hydralazine-induced vasculitis [6]. The most common symptoms of drug-induced lupus include fever, myalgia, arthralgia, arthritis, rash, and serositis. Hematologic abnormalities, renal disease, and central nervous system involvement, although uncommon, can occur [3].
Staphylococcus-associated glomerulonephritis is rare and occurs more commonly in middle-aged to older adult patients [1]. In one single-center cohort that included 9500 kidney biopsies, the incidence of Staphylococcus-associated glomerulonephritis was found to be 0.8%; the mean age was 55 years, and male to female ratio 3.5:1. Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) were implicated in 59 and 27% of cases [7]. The proposed mechanisms of pathogenesis include firstly, glomerular deposition of preformed circulating immune complexes [8], and secondly, Staphylococcal antigens acting as superantigens, activating T cells, polyclonal B-cell and production of polyclonal immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) [9].
The clinical features in adults with Staphylococcus-associated glomerulonephritis include simultaneous infection with hematuria, proteinuria of varying degrees, a rising serum creatinine, and/or edema [10]. A provisional diagnosis of Staphylococcus-associated glomerulonephritis can be made if the patient has low complement levels, endocapillary proliferation and exudative glomerulonephritis on light microscopy, C3 dominant glomerular staining on immunofluorescence microscopy, and hump-shaped subepithelial deposits on electron microscopy. Kidney biopsy is definitive, which typically shows hump-shaped subepithelial electron-dense deposits [1]. Further confirmatory is the resolution of the disease activity after eradication of the infection.
Eliminating infections is the cornerstone of the management of Staphylococcus-associated glomerulonephritis; rest involves relieving symptoms and controlling hypertension and edema by limiting salt intake and using diuretics. The role of immunosuppressants in treating Staphylococcus-associated glomerulonephritis is not well understood and is controversial in patients with an active infection, as giving high-dose glucocorticoids can lead to worsening of the condition or death [11]. Nasr et al. observed no correlation between glucocorticoid therapy and renal outcomes. In a series of patients with Staphylococcus-associated glomerulonephritis, 24% had complete renal function recovery, 32% had persistent renal dysfunction, and 44% progressed to end-stage renal disease [10].
We introduced steroids in our patient because there was an element of drug-induced lupus, and our experience had a positive outcome. The long-term renal prognosis in patients with Staphylococcus-associated glomerulonephritis is relatively low, which may be related to the fact that affected patients are usually older and have comorbidities such as diabetes.
Conclusions
Clinicians, when faced with acute glomerulonephritis, should keep their eyes open for any possible infection as an inciting factor and, at the same time, rule out other important causes as well. The successful management lies in early recognition, eradicating the inciting element, and prompt initiation of a specific therapy. Where the diagnosis is mixed, like in our case, clinicians must weigh the benefits versus risk of starting immunosuppressive therapy like steroids, as the steroids can act as a double-edged sword, so their judicious use is recommended.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | HYDRALAZINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33728152 | 19,089,276 | 2021-02-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Glomerulonephritis rapidly progressive'. | A Curious Case of Acute Glomerulonephritis - Staphylococcus vs Lupus: Case Report and Literature Review.
Here we report a case of a 65-year-old female, where we encountered acute glomerulonephritis. The patient initially presented with a hemorrhagic blister involving the second through fourth toes with serosanguinous discharge and was on hydralazine for blood pressure control. Differentials included Staphylococcus-associated/lupus nephritis/anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. Still, detailed history and meticulous clinical approach with supporting labs and imaging helped us to narrow it to Staphylococcus-associated glomerulonephritis, which is rarely encountered in clinical practice and is associated with high mortality. The management of the patient resulted in a positive outcome and she was discharged home.
Introduction
Acute glomerulonephritis is often encountered in clinical practice. The differentials are broad and include lupus nephritis, vasculitis, infection-related, and immunoglobulin A (IgA) nephropathy. Good history, physical and meticulous laboratory investigations help narrow down the differentials, as prompt initiation of management can be critical in preventing morbidity and mortality. Staphylococcus-related glomerulonephritis is rare, and early recognition and eradication of infection can be life-saving.
Case presentation
A 65-year-old female with medical comorbidities of dementia, diabetes (diet controlled), and hypertension (controlled on hydralazine) presented complaining of progressively worsening left foot ulcer for three days. As per the patient, the ulcer started as a blister and since worsened, accompanied by severe pain. On presentation, her blood pressure was 145/78 mmHg, pulse 71/min, respiratory rate 14/min, temperature 98F. On examination, she was at her baseline mental status (alert, oriented to self and place); her left foot was tender with a hemorrhagic blister involving the second through fourth toes with serosanguinous discharge. The rest of the physical examination was normal. Laboratory examination was noted to have acute kidney injury (blood urea nitrogen (BUN) and creatinine 24 mg/l and 2.4 mg/l respectively), baseline renal function was entirely normal six months prior to presentation, hemoglobin/hematocrit of 10 g/dl and 32% respectively, white blood cell 7 k/ul, erythrocyte sedimentation rate (ESR) 120 mm/hr, C-reactive protein 178 mg/l. Urine analysis was significant for large hematuria and trace proteinuria, urine protein 51 (0-31 mg/dl) and urine creatinine 60 (20-200 mg/dl) (Table 1).
Table 1 Autoimmune workup
RPR: rapid plasma reagin, RNP: ribonucleoprotein, anti-Sm: anti-Smith, HCV: hepatitis C virus, EIA: enzyme immunoassay
Labs Patient result Reference range
Anti-peroxidase <1 <1AI
Anti Myeloperoxidase 7.6 <1AI
Anti-RNP <1 <1 AI
Anti-Sm <1 <1AI
Glomerular basement membrane antibody <1 <1AI
Histone antibody 9.6 <1U
Anti-DNA AB 5 <4IU/ml
HIV-1/2Ab (EIA) Negative Non-reactive
RPR screen Non-reactive Non-reactive
Anti-HCV Negative Negative
X-ray chest was negative for any acute process. The patient was suspected of having clinical necrotizing fasciitis, she refused computed tomography (CT) of the lower extremity and underwent incision drainage, and debridement and cultures were sent. The patient was started on daptomycin/meropenem/clindamycin and was transferred to the medical floor. Kidney injury was presumably due to prerenal due to underlying infection, that was managed conservatively without dialysis. Antibiotics were deescalated to cefazolin/metronidazole as the cultures from the foot grew methicillin-sensitive Staphylococcus aureus. Her post-operative course was complicated with poor foot healing, and the patient ended up getting transmetatarsal amputation and then below-knee amputation (BKA) in a matter of days. Histopathology later reported skin and subcutaneous tissue with acute and chronic inflammation, abscess and granulation tissue. Soft tissue margin and bone margin of resection were unremarkable.
The renal function continued to worsen, and the creatinine jumped to 4.4 mg/l. The antinuclear antibody was positive with a titer of 1:320, hypocomplementemia (C3 was 53 mg/dl and C4 was 3 mg/dl). At this point, differentials included post-inflammatory glomerulonephritis versus late-onset systemic lupus nephritis versus drug-induced lupus. Hydralazine was placed on hold. Other pertinent labs revealed positive anti-histone antibodies 9.6 unit (ref <0.1), cardiolipin IgM >150 (normal <20) and myeloperoxidase antibodies 9 units and 7.6 units respectively, creatinine jumped up to 6.6 mg/l, anti-DNA, glomerular basement antibody, and antiphospholipid antibody were negative. Hepatitis panel including hepatitis B and C were negative. She also tested negative for HIV. Another differential of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis was included, Rheumatology was taken on board, the patient was started on a pulsed dose of methylprednisone, and renal biopsy was planned to differentiate between lupus nephritis/pauci-immune glomerulonephritis. The patient's clinical course took a turn for the worse when she became hypoxic on the floor, was placed on the high flow oxygen, and transferred to the critical care unit. CT chest at this point revealed diffuse mixed interstitial and alveolar airspace disease and small pleural effusions (Figure 1). She also had a 1 g drop in hemoglobin from baseline requiring one packed red blood cell transfusion. She tested negative for coronavirus disease 2019 (COVID-19).
Figure 1 CT chest with diffuse mixed interstitial and alveolar airspace disease (red arrows) and small pleural effusion (yellow arrow)
Suspecting diffuse alveolar hemorrhage, the patient was planned for bronchoscopy, which she and the family adamantly refused. Renal biopsy was suggestive of focal glomerulosclerosis with small mesangial and subepithelial deposits suggestive of membranous lupus nephritis, the resolving phase of infection-related included in the differential. Positive multifocal red blood cell (RBC) casts consistent with the pauci-immune focal crescentic glomerulonephritis associated with ANCA (possibly hydralazine-induced).
The patient had an uneventful course in the critical care unit, completed two weeks course of antibiotics, remained on the tapering doses of prednisone (started on prednisone 60 mg and tapering 10 mg every week), was weaned off oxygen, BKA stump healed well, and creatinine dropped down to 4.4 mg/l and plateaued at 4.0 mg/l without dialysis. The patient was planned to be discharged to short term rehab, but the family refused and decided to take her home. The patient was discharged with improving clinical/lab status on tapering doses of prednisone and outpatient follow up with nephrology/rheumatology/surgery.
Our patient's kidney biopsy showed no definitive findings compatible with vasculitis. Our differentials remained the possibility of post-infectious/systemic lupus erythematosus (SLE)/drug-induced lupus. However, SLE remained lower on the differentials as the anti-DNA antibody and anti-Smith antibody were negative. In our clinical assessment and supporting laboratory examination (Table 2), repeat cardiolipin IgM antibody was normal.
Table 2 Improving labs over days
ESR: erythrocyte sedimentation rate. CRP: C-reactive protein, BUN: blood urea nitrogen
labs Day 1 Day 21
ESR (ref 0-30 mmhr) 120 44
CRP (ref <5 mg/l) 178 21
C3 (ref 90-150 mg/dl) 53 92
C4 (ref 16-47 mg/dl) 3 16
BUN (ref 6-20 mg/dl) 105 47
Creatinine (ref 0.5-1.5 mg/dl) 7.2 4.5
We believe that our patient had infectious glomerulonephritis with some element of drug-induced nephritis. Our clinical suspicion was further solidified when the patient showed improvement after below-knee amputation, a continuation of culture-specific antibiotic therapy, and discontinuation of hydralazine.
Discussion
The differential diagnosis encompassing acute glomerulonephritis is lupus nephritis, vasculitis (such as ANCA-associated vasculitis), and IgA nephropathy, to name a few. Thus, it is prudent to include the antinuclear antibodies, anti-double-stranded DNA antibodies, antineutrophil cytoplasmic antibodies (ANCA), cryoglobulins, hepatitis B and C, HIV, and anti-glomerular basement membrane antibodies in the evaluation. The specific patterns of hypocomplementemia can help narrow down the differentials like in Staphylococcus-associated or other bacterial causes of glomerulonephritis, the typical way is low C3 and normal C4 levels, lupus nephritis is usually associated with reduced levels of both C3 and C4, and mixed cryoglobulinemia is frequently associated with low C4 and normal C3 [1].
Hydralazine is known to be associated with both developing lupus and ANCA-positive vasculitis involving the kidney. The risk for the former is estimated to be 13% [2]. In patients taking hydralazine, anti-histone antibodies are present in 95% [3]. Necrotizing glomerulonephritis is mostly implicated in drug-induced lupus with little or no immune complex deposition [4], although immune complex-mediated glomerulonephritis can occur [5]. The patients with necrotizing glomerulonephritis usually have a perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) pattern with anti-myeloperoxidase (MPO) antibodies, plus either anti-lactoferrin or anti-elastase antibodies [4]. This combination of ANCAs is relatively specific for this form of hydralazine-induced vasculitis [6]. The most common symptoms of drug-induced lupus include fever, myalgia, arthralgia, arthritis, rash, and serositis. Hematologic abnormalities, renal disease, and central nervous system involvement, although uncommon, can occur [3].
Staphylococcus-associated glomerulonephritis is rare and occurs more commonly in middle-aged to older adult patients [1]. In one single-center cohort that included 9500 kidney biopsies, the incidence of Staphylococcus-associated glomerulonephritis was found to be 0.8%; the mean age was 55 years, and male to female ratio 3.5:1. Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) were implicated in 59 and 27% of cases [7]. The proposed mechanisms of pathogenesis include firstly, glomerular deposition of preformed circulating immune complexes [8], and secondly, Staphylococcal antigens acting as superantigens, activating T cells, polyclonal B-cell and production of polyclonal immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) [9].
The clinical features in adults with Staphylococcus-associated glomerulonephritis include simultaneous infection with hematuria, proteinuria of varying degrees, a rising serum creatinine, and/or edema [10]. A provisional diagnosis of Staphylococcus-associated glomerulonephritis can be made if the patient has low complement levels, endocapillary proliferation and exudative glomerulonephritis on light microscopy, C3 dominant glomerular staining on immunofluorescence microscopy, and hump-shaped subepithelial deposits on electron microscopy. Kidney biopsy is definitive, which typically shows hump-shaped subepithelial electron-dense deposits [1]. Further confirmatory is the resolution of the disease activity after eradication of the infection.
Eliminating infections is the cornerstone of the management of Staphylococcus-associated glomerulonephritis; rest involves relieving symptoms and controlling hypertension and edema by limiting salt intake and using diuretics. The role of immunosuppressants in treating Staphylococcus-associated glomerulonephritis is not well understood and is controversial in patients with an active infection, as giving high-dose glucocorticoids can lead to worsening of the condition or death [11]. Nasr et al. observed no correlation between glucocorticoid therapy and renal outcomes. In a series of patients with Staphylococcus-associated glomerulonephritis, 24% had complete renal function recovery, 32% had persistent renal dysfunction, and 44% progressed to end-stage renal disease [10].
We introduced steroids in our patient because there was an element of drug-induced lupus, and our experience had a positive outcome. The long-term renal prognosis in patients with Staphylococcus-associated glomerulonephritis is relatively low, which may be related to the fact that affected patients are usually older and have comorbidities such as diabetes.
Conclusions
Clinicians, when faced with acute glomerulonephritis, should keep their eyes open for any possible infection as an inciting factor and, at the same time, rule out other important causes as well. The successful management lies in early recognition, eradicating the inciting element, and prompt initiation of a specific therapy. Where the diagnosis is mixed, like in our case, clinicians must weigh the benefits versus risk of starting immunosuppressive therapy like steroids, as the steroids can act as a double-edged sword, so their judicious use is recommended.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | HYDRALAZINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33728152 | 20,117,890 | 2021-02-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nephritis'. | A Curious Case of Acute Glomerulonephritis - Staphylococcus vs Lupus: Case Report and Literature Review.
Here we report a case of a 65-year-old female, where we encountered acute glomerulonephritis. The patient initially presented with a hemorrhagic blister involving the second through fourth toes with serosanguinous discharge and was on hydralazine for blood pressure control. Differentials included Staphylococcus-associated/lupus nephritis/anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. Still, detailed history and meticulous clinical approach with supporting labs and imaging helped us to narrow it to Staphylococcus-associated glomerulonephritis, which is rarely encountered in clinical practice and is associated with high mortality. The management of the patient resulted in a positive outcome and she was discharged home.
Introduction
Acute glomerulonephritis is often encountered in clinical practice. The differentials are broad and include lupus nephritis, vasculitis, infection-related, and immunoglobulin A (IgA) nephropathy. Good history, physical and meticulous laboratory investigations help narrow down the differentials, as prompt initiation of management can be critical in preventing morbidity and mortality. Staphylococcus-related glomerulonephritis is rare, and early recognition and eradication of infection can be life-saving.
Case presentation
A 65-year-old female with medical comorbidities of dementia, diabetes (diet controlled), and hypertension (controlled on hydralazine) presented complaining of progressively worsening left foot ulcer for three days. As per the patient, the ulcer started as a blister and since worsened, accompanied by severe pain. On presentation, her blood pressure was 145/78 mmHg, pulse 71/min, respiratory rate 14/min, temperature 98F. On examination, she was at her baseline mental status (alert, oriented to self and place); her left foot was tender with a hemorrhagic blister involving the second through fourth toes with serosanguinous discharge. The rest of the physical examination was normal. Laboratory examination was noted to have acute kidney injury (blood urea nitrogen (BUN) and creatinine 24 mg/l and 2.4 mg/l respectively), baseline renal function was entirely normal six months prior to presentation, hemoglobin/hematocrit of 10 g/dl and 32% respectively, white blood cell 7 k/ul, erythrocyte sedimentation rate (ESR) 120 mm/hr, C-reactive protein 178 mg/l. Urine analysis was significant for large hematuria and trace proteinuria, urine protein 51 (0-31 mg/dl) and urine creatinine 60 (20-200 mg/dl) (Table 1).
Table 1 Autoimmune workup
RPR: rapid plasma reagin, RNP: ribonucleoprotein, anti-Sm: anti-Smith, HCV: hepatitis C virus, EIA: enzyme immunoassay
Labs Patient result Reference range
Anti-peroxidase <1 <1AI
Anti Myeloperoxidase 7.6 <1AI
Anti-RNP <1 <1 AI
Anti-Sm <1 <1AI
Glomerular basement membrane antibody <1 <1AI
Histone antibody 9.6 <1U
Anti-DNA AB 5 <4IU/ml
HIV-1/2Ab (EIA) Negative Non-reactive
RPR screen Non-reactive Non-reactive
Anti-HCV Negative Negative
X-ray chest was negative for any acute process. The patient was suspected of having clinical necrotizing fasciitis, she refused computed tomography (CT) of the lower extremity and underwent incision drainage, and debridement and cultures were sent. The patient was started on daptomycin/meropenem/clindamycin and was transferred to the medical floor. Kidney injury was presumably due to prerenal due to underlying infection, that was managed conservatively without dialysis. Antibiotics were deescalated to cefazolin/metronidazole as the cultures from the foot grew methicillin-sensitive Staphylococcus aureus. Her post-operative course was complicated with poor foot healing, and the patient ended up getting transmetatarsal amputation and then below-knee amputation (BKA) in a matter of days. Histopathology later reported skin and subcutaneous tissue with acute and chronic inflammation, abscess and granulation tissue. Soft tissue margin and bone margin of resection were unremarkable.
The renal function continued to worsen, and the creatinine jumped to 4.4 mg/l. The antinuclear antibody was positive with a titer of 1:320, hypocomplementemia (C3 was 53 mg/dl and C4 was 3 mg/dl). At this point, differentials included post-inflammatory glomerulonephritis versus late-onset systemic lupus nephritis versus drug-induced lupus. Hydralazine was placed on hold. Other pertinent labs revealed positive anti-histone antibodies 9.6 unit (ref <0.1), cardiolipin IgM >150 (normal <20) and myeloperoxidase antibodies 9 units and 7.6 units respectively, creatinine jumped up to 6.6 mg/l, anti-DNA, glomerular basement antibody, and antiphospholipid antibody were negative. Hepatitis panel including hepatitis B and C were negative. She also tested negative for HIV. Another differential of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis was included, Rheumatology was taken on board, the patient was started on a pulsed dose of methylprednisone, and renal biopsy was planned to differentiate between lupus nephritis/pauci-immune glomerulonephritis. The patient's clinical course took a turn for the worse when she became hypoxic on the floor, was placed on the high flow oxygen, and transferred to the critical care unit. CT chest at this point revealed diffuse mixed interstitial and alveolar airspace disease and small pleural effusions (Figure 1). She also had a 1 g drop in hemoglobin from baseline requiring one packed red blood cell transfusion. She tested negative for coronavirus disease 2019 (COVID-19).
Figure 1 CT chest with diffuse mixed interstitial and alveolar airspace disease (red arrows) and small pleural effusion (yellow arrow)
Suspecting diffuse alveolar hemorrhage, the patient was planned for bronchoscopy, which she and the family adamantly refused. Renal biopsy was suggestive of focal glomerulosclerosis with small mesangial and subepithelial deposits suggestive of membranous lupus nephritis, the resolving phase of infection-related included in the differential. Positive multifocal red blood cell (RBC) casts consistent with the pauci-immune focal crescentic glomerulonephritis associated with ANCA (possibly hydralazine-induced).
The patient had an uneventful course in the critical care unit, completed two weeks course of antibiotics, remained on the tapering doses of prednisone (started on prednisone 60 mg and tapering 10 mg every week), was weaned off oxygen, BKA stump healed well, and creatinine dropped down to 4.4 mg/l and plateaued at 4.0 mg/l without dialysis. The patient was planned to be discharged to short term rehab, but the family refused and decided to take her home. The patient was discharged with improving clinical/lab status on tapering doses of prednisone and outpatient follow up with nephrology/rheumatology/surgery.
Our patient's kidney biopsy showed no definitive findings compatible with vasculitis. Our differentials remained the possibility of post-infectious/systemic lupus erythematosus (SLE)/drug-induced lupus. However, SLE remained lower on the differentials as the anti-DNA antibody and anti-Smith antibody were negative. In our clinical assessment and supporting laboratory examination (Table 2), repeat cardiolipin IgM antibody was normal.
Table 2 Improving labs over days
ESR: erythrocyte sedimentation rate. CRP: C-reactive protein, BUN: blood urea nitrogen
labs Day 1 Day 21
ESR (ref 0-30 mmhr) 120 44
CRP (ref <5 mg/l) 178 21
C3 (ref 90-150 mg/dl) 53 92
C4 (ref 16-47 mg/dl) 3 16
BUN (ref 6-20 mg/dl) 105 47
Creatinine (ref 0.5-1.5 mg/dl) 7.2 4.5
We believe that our patient had infectious glomerulonephritis with some element of drug-induced nephritis. Our clinical suspicion was further solidified when the patient showed improvement after below-knee amputation, a continuation of culture-specific antibiotic therapy, and discontinuation of hydralazine.
Discussion
The differential diagnosis encompassing acute glomerulonephritis is lupus nephritis, vasculitis (such as ANCA-associated vasculitis), and IgA nephropathy, to name a few. Thus, it is prudent to include the antinuclear antibodies, anti-double-stranded DNA antibodies, antineutrophil cytoplasmic antibodies (ANCA), cryoglobulins, hepatitis B and C, HIV, and anti-glomerular basement membrane antibodies in the evaluation. The specific patterns of hypocomplementemia can help narrow down the differentials like in Staphylococcus-associated or other bacterial causes of glomerulonephritis, the typical way is low C3 and normal C4 levels, lupus nephritis is usually associated with reduced levels of both C3 and C4, and mixed cryoglobulinemia is frequently associated with low C4 and normal C3 [1].
Hydralazine is known to be associated with both developing lupus and ANCA-positive vasculitis involving the kidney. The risk for the former is estimated to be 13% [2]. In patients taking hydralazine, anti-histone antibodies are present in 95% [3]. Necrotizing glomerulonephritis is mostly implicated in drug-induced lupus with little or no immune complex deposition [4], although immune complex-mediated glomerulonephritis can occur [5]. The patients with necrotizing glomerulonephritis usually have a perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) pattern with anti-myeloperoxidase (MPO) antibodies, plus either anti-lactoferrin or anti-elastase antibodies [4]. This combination of ANCAs is relatively specific for this form of hydralazine-induced vasculitis [6]. The most common symptoms of drug-induced lupus include fever, myalgia, arthralgia, arthritis, rash, and serositis. Hematologic abnormalities, renal disease, and central nervous system involvement, although uncommon, can occur [3].
Staphylococcus-associated glomerulonephritis is rare and occurs more commonly in middle-aged to older adult patients [1]. In one single-center cohort that included 9500 kidney biopsies, the incidence of Staphylococcus-associated glomerulonephritis was found to be 0.8%; the mean age was 55 years, and male to female ratio 3.5:1. Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) were implicated in 59 and 27% of cases [7]. The proposed mechanisms of pathogenesis include firstly, glomerular deposition of preformed circulating immune complexes [8], and secondly, Staphylococcal antigens acting as superantigens, activating T cells, polyclonal B-cell and production of polyclonal immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) [9].
The clinical features in adults with Staphylococcus-associated glomerulonephritis include simultaneous infection with hematuria, proteinuria of varying degrees, a rising serum creatinine, and/or edema [10]. A provisional diagnosis of Staphylococcus-associated glomerulonephritis can be made if the patient has low complement levels, endocapillary proliferation and exudative glomerulonephritis on light microscopy, C3 dominant glomerular staining on immunofluorescence microscopy, and hump-shaped subepithelial deposits on electron microscopy. Kidney biopsy is definitive, which typically shows hump-shaped subepithelial electron-dense deposits [1]. Further confirmatory is the resolution of the disease activity after eradication of the infection.
Eliminating infections is the cornerstone of the management of Staphylococcus-associated glomerulonephritis; rest involves relieving symptoms and controlling hypertension and edema by limiting salt intake and using diuretics. The role of immunosuppressants in treating Staphylococcus-associated glomerulonephritis is not well understood and is controversial in patients with an active infection, as giving high-dose glucocorticoids can lead to worsening of the condition or death [11]. Nasr et al. observed no correlation between glucocorticoid therapy and renal outcomes. In a series of patients with Staphylococcus-associated glomerulonephritis, 24% had complete renal function recovery, 32% had persistent renal dysfunction, and 44% progressed to end-stage renal disease [10].
We introduced steroids in our patient because there was an element of drug-induced lupus, and our experience had a positive outcome. The long-term renal prognosis in patients with Staphylococcus-associated glomerulonephritis is relatively low, which may be related to the fact that affected patients are usually older and have comorbidities such as diabetes.
Conclusions
Clinicians, when faced with acute glomerulonephritis, should keep their eyes open for any possible infection as an inciting factor and, at the same time, rule out other important causes as well. The successful management lies in early recognition, eradicating the inciting element, and prompt initiation of a specific therapy. Where the diagnosis is mixed, like in our case, clinicians must weigh the benefits versus risk of starting immunosuppressive therapy like steroids, as the steroids can act as a double-edged sword, so their judicious use is recommended.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | HYDRALAZINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33728152 | 19,089,276 | 2021-02-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vasculitis'. | A Curious Case of Acute Glomerulonephritis - Staphylococcus vs Lupus: Case Report and Literature Review.
Here we report a case of a 65-year-old female, where we encountered acute glomerulonephritis. The patient initially presented with a hemorrhagic blister involving the second through fourth toes with serosanguinous discharge and was on hydralazine for blood pressure control. Differentials included Staphylococcus-associated/lupus nephritis/anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. Still, detailed history and meticulous clinical approach with supporting labs and imaging helped us to narrow it to Staphylococcus-associated glomerulonephritis, which is rarely encountered in clinical practice and is associated with high mortality. The management of the patient resulted in a positive outcome and she was discharged home.
Introduction
Acute glomerulonephritis is often encountered in clinical practice. The differentials are broad and include lupus nephritis, vasculitis, infection-related, and immunoglobulin A (IgA) nephropathy. Good history, physical and meticulous laboratory investigations help narrow down the differentials, as prompt initiation of management can be critical in preventing morbidity and mortality. Staphylococcus-related glomerulonephritis is rare, and early recognition and eradication of infection can be life-saving.
Case presentation
A 65-year-old female with medical comorbidities of dementia, diabetes (diet controlled), and hypertension (controlled on hydralazine) presented complaining of progressively worsening left foot ulcer for three days. As per the patient, the ulcer started as a blister and since worsened, accompanied by severe pain. On presentation, her blood pressure was 145/78 mmHg, pulse 71/min, respiratory rate 14/min, temperature 98F. On examination, she was at her baseline mental status (alert, oriented to self and place); her left foot was tender with a hemorrhagic blister involving the second through fourth toes with serosanguinous discharge. The rest of the physical examination was normal. Laboratory examination was noted to have acute kidney injury (blood urea nitrogen (BUN) and creatinine 24 mg/l and 2.4 mg/l respectively), baseline renal function was entirely normal six months prior to presentation, hemoglobin/hematocrit of 10 g/dl and 32% respectively, white blood cell 7 k/ul, erythrocyte sedimentation rate (ESR) 120 mm/hr, C-reactive protein 178 mg/l. Urine analysis was significant for large hematuria and trace proteinuria, urine protein 51 (0-31 mg/dl) and urine creatinine 60 (20-200 mg/dl) (Table 1).
Table 1 Autoimmune workup
RPR: rapid plasma reagin, RNP: ribonucleoprotein, anti-Sm: anti-Smith, HCV: hepatitis C virus, EIA: enzyme immunoassay
Labs Patient result Reference range
Anti-peroxidase <1 <1AI
Anti Myeloperoxidase 7.6 <1AI
Anti-RNP <1 <1 AI
Anti-Sm <1 <1AI
Glomerular basement membrane antibody <1 <1AI
Histone antibody 9.6 <1U
Anti-DNA AB 5 <4IU/ml
HIV-1/2Ab (EIA) Negative Non-reactive
RPR screen Non-reactive Non-reactive
Anti-HCV Negative Negative
X-ray chest was negative for any acute process. The patient was suspected of having clinical necrotizing fasciitis, she refused computed tomography (CT) of the lower extremity and underwent incision drainage, and debridement and cultures were sent. The patient was started on daptomycin/meropenem/clindamycin and was transferred to the medical floor. Kidney injury was presumably due to prerenal due to underlying infection, that was managed conservatively without dialysis. Antibiotics were deescalated to cefazolin/metronidazole as the cultures from the foot grew methicillin-sensitive Staphylococcus aureus. Her post-operative course was complicated with poor foot healing, and the patient ended up getting transmetatarsal amputation and then below-knee amputation (BKA) in a matter of days. Histopathology later reported skin and subcutaneous tissue with acute and chronic inflammation, abscess and granulation tissue. Soft tissue margin and bone margin of resection were unremarkable.
The renal function continued to worsen, and the creatinine jumped to 4.4 mg/l. The antinuclear antibody was positive with a titer of 1:320, hypocomplementemia (C3 was 53 mg/dl and C4 was 3 mg/dl). At this point, differentials included post-inflammatory glomerulonephritis versus late-onset systemic lupus nephritis versus drug-induced lupus. Hydralazine was placed on hold. Other pertinent labs revealed positive anti-histone antibodies 9.6 unit (ref <0.1), cardiolipin IgM >150 (normal <20) and myeloperoxidase antibodies 9 units and 7.6 units respectively, creatinine jumped up to 6.6 mg/l, anti-DNA, glomerular basement antibody, and antiphospholipid antibody were negative. Hepatitis panel including hepatitis B and C were negative. She also tested negative for HIV. Another differential of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis was included, Rheumatology was taken on board, the patient was started on a pulsed dose of methylprednisone, and renal biopsy was planned to differentiate between lupus nephritis/pauci-immune glomerulonephritis. The patient's clinical course took a turn for the worse when she became hypoxic on the floor, was placed on the high flow oxygen, and transferred to the critical care unit. CT chest at this point revealed diffuse mixed interstitial and alveolar airspace disease and small pleural effusions (Figure 1). She also had a 1 g drop in hemoglobin from baseline requiring one packed red blood cell transfusion. She tested negative for coronavirus disease 2019 (COVID-19).
Figure 1 CT chest with diffuse mixed interstitial and alveolar airspace disease (red arrows) and small pleural effusion (yellow arrow)
Suspecting diffuse alveolar hemorrhage, the patient was planned for bronchoscopy, which she and the family adamantly refused. Renal biopsy was suggestive of focal glomerulosclerosis with small mesangial and subepithelial deposits suggestive of membranous lupus nephritis, the resolving phase of infection-related included in the differential. Positive multifocal red blood cell (RBC) casts consistent with the pauci-immune focal crescentic glomerulonephritis associated with ANCA (possibly hydralazine-induced).
The patient had an uneventful course in the critical care unit, completed two weeks course of antibiotics, remained on the tapering doses of prednisone (started on prednisone 60 mg and tapering 10 mg every week), was weaned off oxygen, BKA stump healed well, and creatinine dropped down to 4.4 mg/l and plateaued at 4.0 mg/l without dialysis. The patient was planned to be discharged to short term rehab, but the family refused and decided to take her home. The patient was discharged with improving clinical/lab status on tapering doses of prednisone and outpatient follow up with nephrology/rheumatology/surgery.
Our patient's kidney biopsy showed no definitive findings compatible with vasculitis. Our differentials remained the possibility of post-infectious/systemic lupus erythematosus (SLE)/drug-induced lupus. However, SLE remained lower on the differentials as the anti-DNA antibody and anti-Smith antibody were negative. In our clinical assessment and supporting laboratory examination (Table 2), repeat cardiolipin IgM antibody was normal.
Table 2 Improving labs over days
ESR: erythrocyte sedimentation rate. CRP: C-reactive protein, BUN: blood urea nitrogen
labs Day 1 Day 21
ESR (ref 0-30 mmhr) 120 44
CRP (ref <5 mg/l) 178 21
C3 (ref 90-150 mg/dl) 53 92
C4 (ref 16-47 mg/dl) 3 16
BUN (ref 6-20 mg/dl) 105 47
Creatinine (ref 0.5-1.5 mg/dl) 7.2 4.5
We believe that our patient had infectious glomerulonephritis with some element of drug-induced nephritis. Our clinical suspicion was further solidified when the patient showed improvement after below-knee amputation, a continuation of culture-specific antibiotic therapy, and discontinuation of hydralazine.
Discussion
The differential diagnosis encompassing acute glomerulonephritis is lupus nephritis, vasculitis (such as ANCA-associated vasculitis), and IgA nephropathy, to name a few. Thus, it is prudent to include the antinuclear antibodies, anti-double-stranded DNA antibodies, antineutrophil cytoplasmic antibodies (ANCA), cryoglobulins, hepatitis B and C, HIV, and anti-glomerular basement membrane antibodies in the evaluation. The specific patterns of hypocomplementemia can help narrow down the differentials like in Staphylococcus-associated or other bacterial causes of glomerulonephritis, the typical way is low C3 and normal C4 levels, lupus nephritis is usually associated with reduced levels of both C3 and C4, and mixed cryoglobulinemia is frequently associated with low C4 and normal C3 [1].
Hydralazine is known to be associated with both developing lupus and ANCA-positive vasculitis involving the kidney. The risk for the former is estimated to be 13% [2]. In patients taking hydralazine, anti-histone antibodies are present in 95% [3]. Necrotizing glomerulonephritis is mostly implicated in drug-induced lupus with little or no immune complex deposition [4], although immune complex-mediated glomerulonephritis can occur [5]. The patients with necrotizing glomerulonephritis usually have a perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) pattern with anti-myeloperoxidase (MPO) antibodies, plus either anti-lactoferrin or anti-elastase antibodies [4]. This combination of ANCAs is relatively specific for this form of hydralazine-induced vasculitis [6]. The most common symptoms of drug-induced lupus include fever, myalgia, arthralgia, arthritis, rash, and serositis. Hematologic abnormalities, renal disease, and central nervous system involvement, although uncommon, can occur [3].
Staphylococcus-associated glomerulonephritis is rare and occurs more commonly in middle-aged to older adult patients [1]. In one single-center cohort that included 9500 kidney biopsies, the incidence of Staphylococcus-associated glomerulonephritis was found to be 0.8%; the mean age was 55 years, and male to female ratio 3.5:1. Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) were implicated in 59 and 27% of cases [7]. The proposed mechanisms of pathogenesis include firstly, glomerular deposition of preformed circulating immune complexes [8], and secondly, Staphylococcal antigens acting as superantigens, activating T cells, polyclonal B-cell and production of polyclonal immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) [9].
The clinical features in adults with Staphylococcus-associated glomerulonephritis include simultaneous infection with hematuria, proteinuria of varying degrees, a rising serum creatinine, and/or edema [10]. A provisional diagnosis of Staphylococcus-associated glomerulonephritis can be made if the patient has low complement levels, endocapillary proliferation and exudative glomerulonephritis on light microscopy, C3 dominant glomerular staining on immunofluorescence microscopy, and hump-shaped subepithelial deposits on electron microscopy. Kidney biopsy is definitive, which typically shows hump-shaped subepithelial electron-dense deposits [1]. Further confirmatory is the resolution of the disease activity after eradication of the infection.
Eliminating infections is the cornerstone of the management of Staphylococcus-associated glomerulonephritis; rest involves relieving symptoms and controlling hypertension and edema by limiting salt intake and using diuretics. The role of immunosuppressants in treating Staphylococcus-associated glomerulonephritis is not well understood and is controversial in patients with an active infection, as giving high-dose glucocorticoids can lead to worsening of the condition or death [11]. Nasr et al. observed no correlation between glucocorticoid therapy and renal outcomes. In a series of patients with Staphylococcus-associated glomerulonephritis, 24% had complete renal function recovery, 32% had persistent renal dysfunction, and 44% progressed to end-stage renal disease [10].
We introduced steroids in our patient because there was an element of drug-induced lupus, and our experience had a positive outcome. The long-term renal prognosis in patients with Staphylococcus-associated glomerulonephritis is relatively low, which may be related to the fact that affected patients are usually older and have comorbidities such as diabetes.
Conclusions
Clinicians, when faced with acute glomerulonephritis, should keep their eyes open for any possible infection as an inciting factor and, at the same time, rule out other important causes as well. The successful management lies in early recognition, eradicating the inciting element, and prompt initiation of a specific therapy. Where the diagnosis is mixed, like in our case, clinicians must weigh the benefits versus risk of starting immunosuppressive therapy like steroids, as the steroids can act as a double-edged sword, so their judicious use is recommended.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | HYDRALAZINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33728152 | 19,089,276 | 2021-02-04 |
What was the outcome of reaction 'Antineutrophil cytoplasmic antibody'? | A Curious Case of Acute Glomerulonephritis - Staphylococcus vs Lupus: Case Report and Literature Review.
Here we report a case of a 65-year-old female, where we encountered acute glomerulonephritis. The patient initially presented with a hemorrhagic blister involving the second through fourth toes with serosanguinous discharge and was on hydralazine for blood pressure control. Differentials included Staphylococcus-associated/lupus nephritis/anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. Still, detailed history and meticulous clinical approach with supporting labs and imaging helped us to narrow it to Staphylococcus-associated glomerulonephritis, which is rarely encountered in clinical practice and is associated with high mortality. The management of the patient resulted in a positive outcome and she was discharged home.
Introduction
Acute glomerulonephritis is often encountered in clinical practice. The differentials are broad and include lupus nephritis, vasculitis, infection-related, and immunoglobulin A (IgA) nephropathy. Good history, physical and meticulous laboratory investigations help narrow down the differentials, as prompt initiation of management can be critical in preventing morbidity and mortality. Staphylococcus-related glomerulonephritis is rare, and early recognition and eradication of infection can be life-saving.
Case presentation
A 65-year-old female with medical comorbidities of dementia, diabetes (diet controlled), and hypertension (controlled on hydralazine) presented complaining of progressively worsening left foot ulcer for three days. As per the patient, the ulcer started as a blister and since worsened, accompanied by severe pain. On presentation, her blood pressure was 145/78 mmHg, pulse 71/min, respiratory rate 14/min, temperature 98F. On examination, she was at her baseline mental status (alert, oriented to self and place); her left foot was tender with a hemorrhagic blister involving the second through fourth toes with serosanguinous discharge. The rest of the physical examination was normal. Laboratory examination was noted to have acute kidney injury (blood urea nitrogen (BUN) and creatinine 24 mg/l and 2.4 mg/l respectively), baseline renal function was entirely normal six months prior to presentation, hemoglobin/hematocrit of 10 g/dl and 32% respectively, white blood cell 7 k/ul, erythrocyte sedimentation rate (ESR) 120 mm/hr, C-reactive protein 178 mg/l. Urine analysis was significant for large hematuria and trace proteinuria, urine protein 51 (0-31 mg/dl) and urine creatinine 60 (20-200 mg/dl) (Table 1).
Table 1 Autoimmune workup
RPR: rapid plasma reagin, RNP: ribonucleoprotein, anti-Sm: anti-Smith, HCV: hepatitis C virus, EIA: enzyme immunoassay
Labs Patient result Reference range
Anti-peroxidase <1 <1AI
Anti Myeloperoxidase 7.6 <1AI
Anti-RNP <1 <1 AI
Anti-Sm <1 <1AI
Glomerular basement membrane antibody <1 <1AI
Histone antibody 9.6 <1U
Anti-DNA AB 5 <4IU/ml
HIV-1/2Ab (EIA) Negative Non-reactive
RPR screen Non-reactive Non-reactive
Anti-HCV Negative Negative
X-ray chest was negative for any acute process. The patient was suspected of having clinical necrotizing fasciitis, she refused computed tomography (CT) of the lower extremity and underwent incision drainage, and debridement and cultures were sent. The patient was started on daptomycin/meropenem/clindamycin and was transferred to the medical floor. Kidney injury was presumably due to prerenal due to underlying infection, that was managed conservatively without dialysis. Antibiotics were deescalated to cefazolin/metronidazole as the cultures from the foot grew methicillin-sensitive Staphylococcus aureus. Her post-operative course was complicated with poor foot healing, and the patient ended up getting transmetatarsal amputation and then below-knee amputation (BKA) in a matter of days. Histopathology later reported skin and subcutaneous tissue with acute and chronic inflammation, abscess and granulation tissue. Soft tissue margin and bone margin of resection were unremarkable.
The renal function continued to worsen, and the creatinine jumped to 4.4 mg/l. The antinuclear antibody was positive with a titer of 1:320, hypocomplementemia (C3 was 53 mg/dl and C4 was 3 mg/dl). At this point, differentials included post-inflammatory glomerulonephritis versus late-onset systemic lupus nephritis versus drug-induced lupus. Hydralazine was placed on hold. Other pertinent labs revealed positive anti-histone antibodies 9.6 unit (ref <0.1), cardiolipin IgM >150 (normal <20) and myeloperoxidase antibodies 9 units and 7.6 units respectively, creatinine jumped up to 6.6 mg/l, anti-DNA, glomerular basement antibody, and antiphospholipid antibody were negative. Hepatitis panel including hepatitis B and C were negative. She also tested negative for HIV. Another differential of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis was included, Rheumatology was taken on board, the patient was started on a pulsed dose of methylprednisone, and renal biopsy was planned to differentiate between lupus nephritis/pauci-immune glomerulonephritis. The patient's clinical course took a turn for the worse when she became hypoxic on the floor, was placed on the high flow oxygen, and transferred to the critical care unit. CT chest at this point revealed diffuse mixed interstitial and alveolar airspace disease and small pleural effusions (Figure 1). She also had a 1 g drop in hemoglobin from baseline requiring one packed red blood cell transfusion. She tested negative for coronavirus disease 2019 (COVID-19).
Figure 1 CT chest with diffuse mixed interstitial and alveolar airspace disease (red arrows) and small pleural effusion (yellow arrow)
Suspecting diffuse alveolar hemorrhage, the patient was planned for bronchoscopy, which she and the family adamantly refused. Renal biopsy was suggestive of focal glomerulosclerosis with small mesangial and subepithelial deposits suggestive of membranous lupus nephritis, the resolving phase of infection-related included in the differential. Positive multifocal red blood cell (RBC) casts consistent with the pauci-immune focal crescentic glomerulonephritis associated with ANCA (possibly hydralazine-induced).
The patient had an uneventful course in the critical care unit, completed two weeks course of antibiotics, remained on the tapering doses of prednisone (started on prednisone 60 mg and tapering 10 mg every week), was weaned off oxygen, BKA stump healed well, and creatinine dropped down to 4.4 mg/l and plateaued at 4.0 mg/l without dialysis. The patient was planned to be discharged to short term rehab, but the family refused and decided to take her home. The patient was discharged with improving clinical/lab status on tapering doses of prednisone and outpatient follow up with nephrology/rheumatology/surgery.
Our patient's kidney biopsy showed no definitive findings compatible with vasculitis. Our differentials remained the possibility of post-infectious/systemic lupus erythematosus (SLE)/drug-induced lupus. However, SLE remained lower on the differentials as the anti-DNA antibody and anti-Smith antibody were negative. In our clinical assessment and supporting laboratory examination (Table 2), repeat cardiolipin IgM antibody was normal.
Table 2 Improving labs over days
ESR: erythrocyte sedimentation rate. CRP: C-reactive protein, BUN: blood urea nitrogen
labs Day 1 Day 21
ESR (ref 0-30 mmhr) 120 44
CRP (ref <5 mg/l) 178 21
C3 (ref 90-150 mg/dl) 53 92
C4 (ref 16-47 mg/dl) 3 16
BUN (ref 6-20 mg/dl) 105 47
Creatinine (ref 0.5-1.5 mg/dl) 7.2 4.5
We believe that our patient had infectious glomerulonephritis with some element of drug-induced nephritis. Our clinical suspicion was further solidified when the patient showed improvement after below-knee amputation, a continuation of culture-specific antibiotic therapy, and discontinuation of hydralazine.
Discussion
The differential diagnosis encompassing acute glomerulonephritis is lupus nephritis, vasculitis (such as ANCA-associated vasculitis), and IgA nephropathy, to name a few. Thus, it is prudent to include the antinuclear antibodies, anti-double-stranded DNA antibodies, antineutrophil cytoplasmic antibodies (ANCA), cryoglobulins, hepatitis B and C, HIV, and anti-glomerular basement membrane antibodies in the evaluation. The specific patterns of hypocomplementemia can help narrow down the differentials like in Staphylococcus-associated or other bacterial causes of glomerulonephritis, the typical way is low C3 and normal C4 levels, lupus nephritis is usually associated with reduced levels of both C3 and C4, and mixed cryoglobulinemia is frequently associated with low C4 and normal C3 [1].
Hydralazine is known to be associated with both developing lupus and ANCA-positive vasculitis involving the kidney. The risk for the former is estimated to be 13% [2]. In patients taking hydralazine, anti-histone antibodies are present in 95% [3]. Necrotizing glomerulonephritis is mostly implicated in drug-induced lupus with little or no immune complex deposition [4], although immune complex-mediated glomerulonephritis can occur [5]. The patients with necrotizing glomerulonephritis usually have a perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) pattern with anti-myeloperoxidase (MPO) antibodies, plus either anti-lactoferrin or anti-elastase antibodies [4]. This combination of ANCAs is relatively specific for this form of hydralazine-induced vasculitis [6]. The most common symptoms of drug-induced lupus include fever, myalgia, arthralgia, arthritis, rash, and serositis. Hematologic abnormalities, renal disease, and central nervous system involvement, although uncommon, can occur [3].
Staphylococcus-associated glomerulonephritis is rare and occurs more commonly in middle-aged to older adult patients [1]. In one single-center cohort that included 9500 kidney biopsies, the incidence of Staphylococcus-associated glomerulonephritis was found to be 0.8%; the mean age was 55 years, and male to female ratio 3.5:1. Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) were implicated in 59 and 27% of cases [7]. The proposed mechanisms of pathogenesis include firstly, glomerular deposition of preformed circulating immune complexes [8], and secondly, Staphylococcal antigens acting as superantigens, activating T cells, polyclonal B-cell and production of polyclonal immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) [9].
The clinical features in adults with Staphylococcus-associated glomerulonephritis include simultaneous infection with hematuria, proteinuria of varying degrees, a rising serum creatinine, and/or edema [10]. A provisional diagnosis of Staphylococcus-associated glomerulonephritis can be made if the patient has low complement levels, endocapillary proliferation and exudative glomerulonephritis on light microscopy, C3 dominant glomerular staining on immunofluorescence microscopy, and hump-shaped subepithelial deposits on electron microscopy. Kidney biopsy is definitive, which typically shows hump-shaped subepithelial electron-dense deposits [1]. Further confirmatory is the resolution of the disease activity after eradication of the infection.
Eliminating infections is the cornerstone of the management of Staphylococcus-associated glomerulonephritis; rest involves relieving symptoms and controlling hypertension and edema by limiting salt intake and using diuretics. The role of immunosuppressants in treating Staphylococcus-associated glomerulonephritis is not well understood and is controversial in patients with an active infection, as giving high-dose glucocorticoids can lead to worsening of the condition or death [11]. Nasr et al. observed no correlation between glucocorticoid therapy and renal outcomes. In a series of patients with Staphylococcus-associated glomerulonephritis, 24% had complete renal function recovery, 32% had persistent renal dysfunction, and 44% progressed to end-stage renal disease [10].
We introduced steroids in our patient because there was an element of drug-induced lupus, and our experience had a positive outcome. The long-term renal prognosis in patients with Staphylococcus-associated glomerulonephritis is relatively low, which may be related to the fact that affected patients are usually older and have comorbidities such as diabetes.
Conclusions
Clinicians, when faced with acute glomerulonephritis, should keep their eyes open for any possible infection as an inciting factor and, at the same time, rule out other important causes as well. The successful management lies in early recognition, eradicating the inciting element, and prompt initiation of a specific therapy. Where the diagnosis is mixed, like in our case, clinicians must weigh the benefits versus risk of starting immunosuppressive therapy like steroids, as the steroids can act as a double-edged sword, so their judicious use is recommended.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovering | ReactionOutcome | CC BY | 33728152 | 19,089,276 | 2021-02-04 |
What was the outcome of reaction 'Nephritis'? | A Curious Case of Acute Glomerulonephritis - Staphylococcus vs Lupus: Case Report and Literature Review.
Here we report a case of a 65-year-old female, where we encountered acute glomerulonephritis. The patient initially presented with a hemorrhagic blister involving the second through fourth toes with serosanguinous discharge and was on hydralazine for blood pressure control. Differentials included Staphylococcus-associated/lupus nephritis/anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. Still, detailed history and meticulous clinical approach with supporting labs and imaging helped us to narrow it to Staphylococcus-associated glomerulonephritis, which is rarely encountered in clinical practice and is associated with high mortality. The management of the patient resulted in a positive outcome and she was discharged home.
Introduction
Acute glomerulonephritis is often encountered in clinical practice. The differentials are broad and include lupus nephritis, vasculitis, infection-related, and immunoglobulin A (IgA) nephropathy. Good history, physical and meticulous laboratory investigations help narrow down the differentials, as prompt initiation of management can be critical in preventing morbidity and mortality. Staphylococcus-related glomerulonephritis is rare, and early recognition and eradication of infection can be life-saving.
Case presentation
A 65-year-old female with medical comorbidities of dementia, diabetes (diet controlled), and hypertension (controlled on hydralazine) presented complaining of progressively worsening left foot ulcer for three days. As per the patient, the ulcer started as a blister and since worsened, accompanied by severe pain. On presentation, her blood pressure was 145/78 mmHg, pulse 71/min, respiratory rate 14/min, temperature 98F. On examination, she was at her baseline mental status (alert, oriented to self and place); her left foot was tender with a hemorrhagic blister involving the second through fourth toes with serosanguinous discharge. The rest of the physical examination was normal. Laboratory examination was noted to have acute kidney injury (blood urea nitrogen (BUN) and creatinine 24 mg/l and 2.4 mg/l respectively), baseline renal function was entirely normal six months prior to presentation, hemoglobin/hematocrit of 10 g/dl and 32% respectively, white blood cell 7 k/ul, erythrocyte sedimentation rate (ESR) 120 mm/hr, C-reactive protein 178 mg/l. Urine analysis was significant for large hematuria and trace proteinuria, urine protein 51 (0-31 mg/dl) and urine creatinine 60 (20-200 mg/dl) (Table 1).
Table 1 Autoimmune workup
RPR: rapid plasma reagin, RNP: ribonucleoprotein, anti-Sm: anti-Smith, HCV: hepatitis C virus, EIA: enzyme immunoassay
Labs Patient result Reference range
Anti-peroxidase <1 <1AI
Anti Myeloperoxidase 7.6 <1AI
Anti-RNP <1 <1 AI
Anti-Sm <1 <1AI
Glomerular basement membrane antibody <1 <1AI
Histone antibody 9.6 <1U
Anti-DNA AB 5 <4IU/ml
HIV-1/2Ab (EIA) Negative Non-reactive
RPR screen Non-reactive Non-reactive
Anti-HCV Negative Negative
X-ray chest was negative for any acute process. The patient was suspected of having clinical necrotizing fasciitis, she refused computed tomography (CT) of the lower extremity and underwent incision drainage, and debridement and cultures were sent. The patient was started on daptomycin/meropenem/clindamycin and was transferred to the medical floor. Kidney injury was presumably due to prerenal due to underlying infection, that was managed conservatively without dialysis. Antibiotics were deescalated to cefazolin/metronidazole as the cultures from the foot grew methicillin-sensitive Staphylococcus aureus. Her post-operative course was complicated with poor foot healing, and the patient ended up getting transmetatarsal amputation and then below-knee amputation (BKA) in a matter of days. Histopathology later reported skin and subcutaneous tissue with acute and chronic inflammation, abscess and granulation tissue. Soft tissue margin and bone margin of resection were unremarkable.
The renal function continued to worsen, and the creatinine jumped to 4.4 mg/l. The antinuclear antibody was positive with a titer of 1:320, hypocomplementemia (C3 was 53 mg/dl and C4 was 3 mg/dl). At this point, differentials included post-inflammatory glomerulonephritis versus late-onset systemic lupus nephritis versus drug-induced lupus. Hydralazine was placed on hold. Other pertinent labs revealed positive anti-histone antibodies 9.6 unit (ref <0.1), cardiolipin IgM >150 (normal <20) and myeloperoxidase antibodies 9 units and 7.6 units respectively, creatinine jumped up to 6.6 mg/l, anti-DNA, glomerular basement antibody, and antiphospholipid antibody were negative. Hepatitis panel including hepatitis B and C were negative. She also tested negative for HIV. Another differential of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis was included, Rheumatology was taken on board, the patient was started on a pulsed dose of methylprednisone, and renal biopsy was planned to differentiate between lupus nephritis/pauci-immune glomerulonephritis. The patient's clinical course took a turn for the worse when she became hypoxic on the floor, was placed on the high flow oxygen, and transferred to the critical care unit. CT chest at this point revealed diffuse mixed interstitial and alveolar airspace disease and small pleural effusions (Figure 1). She also had a 1 g drop in hemoglobin from baseline requiring one packed red blood cell transfusion. She tested negative for coronavirus disease 2019 (COVID-19).
Figure 1 CT chest with diffuse mixed interstitial and alveolar airspace disease (red arrows) and small pleural effusion (yellow arrow)
Suspecting diffuse alveolar hemorrhage, the patient was planned for bronchoscopy, which she and the family adamantly refused. Renal biopsy was suggestive of focal glomerulosclerosis with small mesangial and subepithelial deposits suggestive of membranous lupus nephritis, the resolving phase of infection-related included in the differential. Positive multifocal red blood cell (RBC) casts consistent with the pauci-immune focal crescentic glomerulonephritis associated with ANCA (possibly hydralazine-induced).
The patient had an uneventful course in the critical care unit, completed two weeks course of antibiotics, remained on the tapering doses of prednisone (started on prednisone 60 mg and tapering 10 mg every week), was weaned off oxygen, BKA stump healed well, and creatinine dropped down to 4.4 mg/l and plateaued at 4.0 mg/l without dialysis. The patient was planned to be discharged to short term rehab, but the family refused and decided to take her home. The patient was discharged with improving clinical/lab status on tapering doses of prednisone and outpatient follow up with nephrology/rheumatology/surgery.
Our patient's kidney biopsy showed no definitive findings compatible with vasculitis. Our differentials remained the possibility of post-infectious/systemic lupus erythematosus (SLE)/drug-induced lupus. However, SLE remained lower on the differentials as the anti-DNA antibody and anti-Smith antibody were negative. In our clinical assessment and supporting laboratory examination (Table 2), repeat cardiolipin IgM antibody was normal.
Table 2 Improving labs over days
ESR: erythrocyte sedimentation rate. CRP: C-reactive protein, BUN: blood urea nitrogen
labs Day 1 Day 21
ESR (ref 0-30 mmhr) 120 44
CRP (ref <5 mg/l) 178 21
C3 (ref 90-150 mg/dl) 53 92
C4 (ref 16-47 mg/dl) 3 16
BUN (ref 6-20 mg/dl) 105 47
Creatinine (ref 0.5-1.5 mg/dl) 7.2 4.5
We believe that our patient had infectious glomerulonephritis with some element of drug-induced nephritis. Our clinical suspicion was further solidified when the patient showed improvement after below-knee amputation, a continuation of culture-specific antibiotic therapy, and discontinuation of hydralazine.
Discussion
The differential diagnosis encompassing acute glomerulonephritis is lupus nephritis, vasculitis (such as ANCA-associated vasculitis), and IgA nephropathy, to name a few. Thus, it is prudent to include the antinuclear antibodies, anti-double-stranded DNA antibodies, antineutrophil cytoplasmic antibodies (ANCA), cryoglobulins, hepatitis B and C, HIV, and anti-glomerular basement membrane antibodies in the evaluation. The specific patterns of hypocomplementemia can help narrow down the differentials like in Staphylococcus-associated or other bacterial causes of glomerulonephritis, the typical way is low C3 and normal C4 levels, lupus nephritis is usually associated with reduced levels of both C3 and C4, and mixed cryoglobulinemia is frequently associated with low C4 and normal C3 [1].
Hydralazine is known to be associated with both developing lupus and ANCA-positive vasculitis involving the kidney. The risk for the former is estimated to be 13% [2]. In patients taking hydralazine, anti-histone antibodies are present in 95% [3]. Necrotizing glomerulonephritis is mostly implicated in drug-induced lupus with little or no immune complex deposition [4], although immune complex-mediated glomerulonephritis can occur [5]. The patients with necrotizing glomerulonephritis usually have a perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) pattern with anti-myeloperoxidase (MPO) antibodies, plus either anti-lactoferrin or anti-elastase antibodies [4]. This combination of ANCAs is relatively specific for this form of hydralazine-induced vasculitis [6]. The most common symptoms of drug-induced lupus include fever, myalgia, arthralgia, arthritis, rash, and serositis. Hematologic abnormalities, renal disease, and central nervous system involvement, although uncommon, can occur [3].
Staphylococcus-associated glomerulonephritis is rare and occurs more commonly in middle-aged to older adult patients [1]. In one single-center cohort that included 9500 kidney biopsies, the incidence of Staphylococcus-associated glomerulonephritis was found to be 0.8%; the mean age was 55 years, and male to female ratio 3.5:1. Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) were implicated in 59 and 27% of cases [7]. The proposed mechanisms of pathogenesis include firstly, glomerular deposition of preformed circulating immune complexes [8], and secondly, Staphylococcal antigens acting as superantigens, activating T cells, polyclonal B-cell and production of polyclonal immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) [9].
The clinical features in adults with Staphylococcus-associated glomerulonephritis include simultaneous infection with hematuria, proteinuria of varying degrees, a rising serum creatinine, and/or edema [10]. A provisional diagnosis of Staphylococcus-associated glomerulonephritis can be made if the patient has low complement levels, endocapillary proliferation and exudative glomerulonephritis on light microscopy, C3 dominant glomerular staining on immunofluorescence microscopy, and hump-shaped subepithelial deposits on electron microscopy. Kidney biopsy is definitive, which typically shows hump-shaped subepithelial electron-dense deposits [1]. Further confirmatory is the resolution of the disease activity after eradication of the infection.
Eliminating infections is the cornerstone of the management of Staphylococcus-associated glomerulonephritis; rest involves relieving symptoms and controlling hypertension and edema by limiting salt intake and using diuretics. The role of immunosuppressants in treating Staphylococcus-associated glomerulonephritis is not well understood and is controversial in patients with an active infection, as giving high-dose glucocorticoids can lead to worsening of the condition or death [11]. Nasr et al. observed no correlation between glucocorticoid therapy and renal outcomes. In a series of patients with Staphylococcus-associated glomerulonephritis, 24% had complete renal function recovery, 32% had persistent renal dysfunction, and 44% progressed to end-stage renal disease [10].
We introduced steroids in our patient because there was an element of drug-induced lupus, and our experience had a positive outcome. The long-term renal prognosis in patients with Staphylococcus-associated glomerulonephritis is relatively low, which may be related to the fact that affected patients are usually older and have comorbidities such as diabetes.
Conclusions
Clinicians, when faced with acute glomerulonephritis, should keep their eyes open for any possible infection as an inciting factor and, at the same time, rule out other important causes as well. The successful management lies in early recognition, eradicating the inciting element, and prompt initiation of a specific therapy. Where the diagnosis is mixed, like in our case, clinicians must weigh the benefits versus risk of starting immunosuppressive therapy like steroids, as the steroids can act as a double-edged sword, so their judicious use is recommended.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovering | ReactionOutcome | CC BY | 33728152 | 19,089,276 | 2021-02-04 |
What was the outcome of reaction 'Vasculitis'? | A Curious Case of Acute Glomerulonephritis - Staphylococcus vs Lupus: Case Report and Literature Review.
Here we report a case of a 65-year-old female, where we encountered acute glomerulonephritis. The patient initially presented with a hemorrhagic blister involving the second through fourth toes with serosanguinous discharge and was on hydralazine for blood pressure control. Differentials included Staphylococcus-associated/lupus nephritis/anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. Still, detailed history and meticulous clinical approach with supporting labs and imaging helped us to narrow it to Staphylococcus-associated glomerulonephritis, which is rarely encountered in clinical practice and is associated with high mortality. The management of the patient resulted in a positive outcome and she was discharged home.
Introduction
Acute glomerulonephritis is often encountered in clinical practice. The differentials are broad and include lupus nephritis, vasculitis, infection-related, and immunoglobulin A (IgA) nephropathy. Good history, physical and meticulous laboratory investigations help narrow down the differentials, as prompt initiation of management can be critical in preventing morbidity and mortality. Staphylococcus-related glomerulonephritis is rare, and early recognition and eradication of infection can be life-saving.
Case presentation
A 65-year-old female with medical comorbidities of dementia, diabetes (diet controlled), and hypertension (controlled on hydralazine) presented complaining of progressively worsening left foot ulcer for three days. As per the patient, the ulcer started as a blister and since worsened, accompanied by severe pain. On presentation, her blood pressure was 145/78 mmHg, pulse 71/min, respiratory rate 14/min, temperature 98F. On examination, she was at her baseline mental status (alert, oriented to self and place); her left foot was tender with a hemorrhagic blister involving the second through fourth toes with serosanguinous discharge. The rest of the physical examination was normal. Laboratory examination was noted to have acute kidney injury (blood urea nitrogen (BUN) and creatinine 24 mg/l and 2.4 mg/l respectively), baseline renal function was entirely normal six months prior to presentation, hemoglobin/hematocrit of 10 g/dl and 32% respectively, white blood cell 7 k/ul, erythrocyte sedimentation rate (ESR) 120 mm/hr, C-reactive protein 178 mg/l. Urine analysis was significant for large hematuria and trace proteinuria, urine protein 51 (0-31 mg/dl) and urine creatinine 60 (20-200 mg/dl) (Table 1).
Table 1 Autoimmune workup
RPR: rapid plasma reagin, RNP: ribonucleoprotein, anti-Sm: anti-Smith, HCV: hepatitis C virus, EIA: enzyme immunoassay
Labs Patient result Reference range
Anti-peroxidase <1 <1AI
Anti Myeloperoxidase 7.6 <1AI
Anti-RNP <1 <1 AI
Anti-Sm <1 <1AI
Glomerular basement membrane antibody <1 <1AI
Histone antibody 9.6 <1U
Anti-DNA AB 5 <4IU/ml
HIV-1/2Ab (EIA) Negative Non-reactive
RPR screen Non-reactive Non-reactive
Anti-HCV Negative Negative
X-ray chest was negative for any acute process. The patient was suspected of having clinical necrotizing fasciitis, she refused computed tomography (CT) of the lower extremity and underwent incision drainage, and debridement and cultures were sent. The patient was started on daptomycin/meropenem/clindamycin and was transferred to the medical floor. Kidney injury was presumably due to prerenal due to underlying infection, that was managed conservatively without dialysis. Antibiotics were deescalated to cefazolin/metronidazole as the cultures from the foot grew methicillin-sensitive Staphylococcus aureus. Her post-operative course was complicated with poor foot healing, and the patient ended up getting transmetatarsal amputation and then below-knee amputation (BKA) in a matter of days. Histopathology later reported skin and subcutaneous tissue with acute and chronic inflammation, abscess and granulation tissue. Soft tissue margin and bone margin of resection were unremarkable.
The renal function continued to worsen, and the creatinine jumped to 4.4 mg/l. The antinuclear antibody was positive with a titer of 1:320, hypocomplementemia (C3 was 53 mg/dl and C4 was 3 mg/dl). At this point, differentials included post-inflammatory glomerulonephritis versus late-onset systemic lupus nephritis versus drug-induced lupus. Hydralazine was placed on hold. Other pertinent labs revealed positive anti-histone antibodies 9.6 unit (ref <0.1), cardiolipin IgM >150 (normal <20) and myeloperoxidase antibodies 9 units and 7.6 units respectively, creatinine jumped up to 6.6 mg/l, anti-DNA, glomerular basement antibody, and antiphospholipid antibody were negative. Hepatitis panel including hepatitis B and C were negative. She also tested negative for HIV. Another differential of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis was included, Rheumatology was taken on board, the patient was started on a pulsed dose of methylprednisone, and renal biopsy was planned to differentiate between lupus nephritis/pauci-immune glomerulonephritis. The patient's clinical course took a turn for the worse when she became hypoxic on the floor, was placed on the high flow oxygen, and transferred to the critical care unit. CT chest at this point revealed diffuse mixed interstitial and alveolar airspace disease and small pleural effusions (Figure 1). She also had a 1 g drop in hemoglobin from baseline requiring one packed red blood cell transfusion. She tested negative for coronavirus disease 2019 (COVID-19).
Figure 1 CT chest with diffuse mixed interstitial and alveolar airspace disease (red arrows) and small pleural effusion (yellow arrow)
Suspecting diffuse alveolar hemorrhage, the patient was planned for bronchoscopy, which she and the family adamantly refused. Renal biopsy was suggestive of focal glomerulosclerosis with small mesangial and subepithelial deposits suggestive of membranous lupus nephritis, the resolving phase of infection-related included in the differential. Positive multifocal red blood cell (RBC) casts consistent with the pauci-immune focal crescentic glomerulonephritis associated with ANCA (possibly hydralazine-induced).
The patient had an uneventful course in the critical care unit, completed two weeks course of antibiotics, remained on the tapering doses of prednisone (started on prednisone 60 mg and tapering 10 mg every week), was weaned off oxygen, BKA stump healed well, and creatinine dropped down to 4.4 mg/l and plateaued at 4.0 mg/l without dialysis. The patient was planned to be discharged to short term rehab, but the family refused and decided to take her home. The patient was discharged with improving clinical/lab status on tapering doses of prednisone and outpatient follow up with nephrology/rheumatology/surgery.
Our patient's kidney biopsy showed no definitive findings compatible with vasculitis. Our differentials remained the possibility of post-infectious/systemic lupus erythematosus (SLE)/drug-induced lupus. However, SLE remained lower on the differentials as the anti-DNA antibody and anti-Smith antibody were negative. In our clinical assessment and supporting laboratory examination (Table 2), repeat cardiolipin IgM antibody was normal.
Table 2 Improving labs over days
ESR: erythrocyte sedimentation rate. CRP: C-reactive protein, BUN: blood urea nitrogen
labs Day 1 Day 21
ESR (ref 0-30 mmhr) 120 44
CRP (ref <5 mg/l) 178 21
C3 (ref 90-150 mg/dl) 53 92
C4 (ref 16-47 mg/dl) 3 16
BUN (ref 6-20 mg/dl) 105 47
Creatinine (ref 0.5-1.5 mg/dl) 7.2 4.5
We believe that our patient had infectious glomerulonephritis with some element of drug-induced nephritis. Our clinical suspicion was further solidified when the patient showed improvement after below-knee amputation, a continuation of culture-specific antibiotic therapy, and discontinuation of hydralazine.
Discussion
The differential diagnosis encompassing acute glomerulonephritis is lupus nephritis, vasculitis (such as ANCA-associated vasculitis), and IgA nephropathy, to name a few. Thus, it is prudent to include the antinuclear antibodies, anti-double-stranded DNA antibodies, antineutrophil cytoplasmic antibodies (ANCA), cryoglobulins, hepatitis B and C, HIV, and anti-glomerular basement membrane antibodies in the evaluation. The specific patterns of hypocomplementemia can help narrow down the differentials like in Staphylococcus-associated or other bacterial causes of glomerulonephritis, the typical way is low C3 and normal C4 levels, lupus nephritis is usually associated with reduced levels of both C3 and C4, and mixed cryoglobulinemia is frequently associated with low C4 and normal C3 [1].
Hydralazine is known to be associated with both developing lupus and ANCA-positive vasculitis involving the kidney. The risk for the former is estimated to be 13% [2]. In patients taking hydralazine, anti-histone antibodies are present in 95% [3]. Necrotizing glomerulonephritis is mostly implicated in drug-induced lupus with little or no immune complex deposition [4], although immune complex-mediated glomerulonephritis can occur [5]. The patients with necrotizing glomerulonephritis usually have a perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) pattern with anti-myeloperoxidase (MPO) antibodies, plus either anti-lactoferrin or anti-elastase antibodies [4]. This combination of ANCAs is relatively specific for this form of hydralazine-induced vasculitis [6]. The most common symptoms of drug-induced lupus include fever, myalgia, arthralgia, arthritis, rash, and serositis. Hematologic abnormalities, renal disease, and central nervous system involvement, although uncommon, can occur [3].
Staphylococcus-associated glomerulonephritis is rare and occurs more commonly in middle-aged to older adult patients [1]. In one single-center cohort that included 9500 kidney biopsies, the incidence of Staphylococcus-associated glomerulonephritis was found to be 0.8%; the mean age was 55 years, and male to female ratio 3.5:1. Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) were implicated in 59 and 27% of cases [7]. The proposed mechanisms of pathogenesis include firstly, glomerular deposition of preformed circulating immune complexes [8], and secondly, Staphylococcal antigens acting as superantigens, activating T cells, polyclonal B-cell and production of polyclonal immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) [9].
The clinical features in adults with Staphylococcus-associated glomerulonephritis include simultaneous infection with hematuria, proteinuria of varying degrees, a rising serum creatinine, and/or edema [10]. A provisional diagnosis of Staphylococcus-associated glomerulonephritis can be made if the patient has low complement levels, endocapillary proliferation and exudative glomerulonephritis on light microscopy, C3 dominant glomerular staining on immunofluorescence microscopy, and hump-shaped subepithelial deposits on electron microscopy. Kidney biopsy is definitive, which typically shows hump-shaped subepithelial electron-dense deposits [1]. Further confirmatory is the resolution of the disease activity after eradication of the infection.
Eliminating infections is the cornerstone of the management of Staphylococcus-associated glomerulonephritis; rest involves relieving symptoms and controlling hypertension and edema by limiting salt intake and using diuretics. The role of immunosuppressants in treating Staphylococcus-associated glomerulonephritis is not well understood and is controversial in patients with an active infection, as giving high-dose glucocorticoids can lead to worsening of the condition or death [11]. Nasr et al. observed no correlation between glucocorticoid therapy and renal outcomes. In a series of patients with Staphylococcus-associated glomerulonephritis, 24% had complete renal function recovery, 32% had persistent renal dysfunction, and 44% progressed to end-stage renal disease [10].
We introduced steroids in our patient because there was an element of drug-induced lupus, and our experience had a positive outcome. The long-term renal prognosis in patients with Staphylococcus-associated glomerulonephritis is relatively low, which may be related to the fact that affected patients are usually older and have comorbidities such as diabetes.
Conclusions
Clinicians, when faced with acute glomerulonephritis, should keep their eyes open for any possible infection as an inciting factor and, at the same time, rule out other important causes as well. The successful management lies in early recognition, eradicating the inciting element, and prompt initiation of a specific therapy. Where the diagnosis is mixed, like in our case, clinicians must weigh the benefits versus risk of starting immunosuppressive therapy like steroids, as the steroids can act as a double-edged sword, so their judicious use is recommended.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovering | ReactionOutcome | CC BY | 33728152 | 19,089,276 | 2021-02-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neuropathy peripheral'. | Death and Rebirth of the Thalidomide Molecule: A Case of Thalidomide-Induced Sensory Neuropathy.
The thalidomide molecule is a remarkable molecule that exists in a racemic mixture of optical isomers. In the 1950s, due to its teratogenicity, the levorotatory isomer led to its dramatic downfall. However, the molecule with its panoramic mechanisms of action and its uncanny ability to intercalate within the geometry of deoxyribonucleic acid (DNA), led to its remarkable renaissance; thalidomide being United States Food and Drug Administration (FDA)-approved for at least 13 different indications ranging from multiple myeloma to leprosy to glioblastoma. Thalidomide-induced polyneuropathy is usually reversible and is the rate-limiting step in its long-term use. The development of a polyneuropathy is invariably associated with a cumulative dose exceeding 20 grams. However, the polyneuropathy is almost always a sensory neuropathy. Asymmetry, bona fide weakness such as difficulty standing on the heels, a poly-ganglioneuropathy pattern with widespread or patchy numbness and sensory ataxia should raise a red flag and an alternative diagnosis should be considered. We present a typical case of a thalidomide-induced sensory neuropathy in order to highlight the resurgence of thalidomide use in clinical practice. We review the literature and outline the molecular biology of the thalidomide molecule.
Introduction
Thalidomide is a versatile molecule. It is a derivative of glutamic acid and it has a panorama of actions that includes specific and broad antiinflammatory, immune-modulatory actions and inhibition of angiogenesis. On the downside, one of its chiral enantiomers has notoriously been associated with teratogenesis. Thalidomide is a racemic mixture of two enantiomers rectus R- and sinister S- optical isomers. They are readily interchangeable, the R-isomer is a sedative and the S-isomer is a teratogen [1].
As an analogue of glutethimide, it was marketed as a sedative, and as an anti-emetic for morning sickness with catastrophic results. Thalidomide embryopathy was an epidemic of congenital malformations between the years 1957 and 1961. Early exposure during pregnancy, between days 20 and 36 after fertilization, led to ocular, auditory, upper and lower limb and cranial nerve (facial motor nerve) malformations. Autism, epilepsy, and urogenital defects were also reported. Only one-half of the infants exposed to thalidomide survived [2].
Thalidomide's pleomorphic effects on the immune system, anti-proliferative effects and its anti-angiogenesis properties have led to its spectacular renaissance. It is now a United States Food and Drug Administration (FDA)-approved drug for a bewildering variety of at least 13 different diseases or disease states including erythema nodosum leprosum, multiple myeloma, acquired immune deficiency syndrome (AIDS)-wasting syndrome, recurrent aphthous ulcers and stomatitis in the immuno-suppressed, graft-versus-host disease, AIDS-related Kaposi's sarcoma, primary malignant glioma, myelodysplastic syndrome, various systemic lupus erythematosis states, Behcet's syndrome, prurigo, refractory Crohn's disease, and peripheral thymic (T)-cell lymphoma [3].
The polyneuropathy induced by thalidomide is mostly axonal and rarely demyelinating. It is typically a sensory neuropathy and is rarely a sensory-motor polyneuropathy. When sensory, the large fibers (touch, pressure, proprioception) are more affected than the small fibers (pain, temperature) [4]. Serum from patients treated with thalidomide for prurigo and injected into cultured rabbit dorsal root ganglia was associated with a neuronopathy (disease of the dorsal root ganglia) [5]. The cereblon (CRBN) gene codes for the enzyme (E)-3 protein-ligase-complex that mediates the ubiquitination and proteasomal degradation of proteins. This is required as a clearing mechanism of proteins during limb budding and sculpting during embryogenesis. In a study of 82 patients treated with thalidomide for multiple myeloma, carriers of the CRBN cytosine-cytosine (CC)-genotype had a 14-fold higher risk of a polyneuropathy [6].
Case presentation
We present the case of a 64-year-old woman with bone marrow biopsy-proven (30% plasma cells) stage-III immunoglobulin (IgG) lambda multiple myeloma. She had a corresponding anemia but no hypercalcemia or lytic bone lesions. Remission was achieved with a course of decadron, cyclophosphamide and melphalan. Maintenance therapy was with oral thalidomide was done for three years after which she relapsed and developed osteonecrosis of the right maxilla, which was successfully treated with radiotherapy. Remission was subsequently achieved with oral lenalidomide.
One year after starting treatment with thalidomide, initially at 50 milligrams (mg) daily and slowly escalated up to 200 mg daily, she developed numbness, tingling and burning pain of the feet. The neuropathic symptoms were successfully treated with pregabalin at a dose of 150 mg twice daily. After two years of symptomatic treatment with pregabalin for the neuropathic pain, she was successfully weaned off pregabalin with residual but tolerable mild numbness and aching of the feet.
Past medical history was significant for hypertension treated with amlodipine 10 mg daily.
We will list the relevant clinical findings on examination. Gait was steady with normal tandem-walking. Heel and toe-walking were normal. Cranial nerve examination was normal with normal trigeminal nerve sensory testing to touch in all three trigeminal divisions bilaterally.
Power testing of the arms and legs was normal using medical research council (MRC) grading. Cerebellar examination revealed normal heel-to-shin and finger-to-nose testing. Romberg sign was absent with absence of pseudoathetosis of the fingers with the outstretched arms and eyes closed. Deep tendon reflexes were normal except for trace ankle jerks bilaterally. Sensory examination of the feet revealed mild diminished pin-prick testing of the toes with absent vibratory testing of the toes bilaterally. The findings on examination are consistent with a low-grade sensory neuropathy.
A nerve conduction study (NCS) of the feet revealed absent sural and peroneal sensory nerve action potentials bilaterally. Peroneal and tibial motor amplitudes and velocities were normal in both feet. This is consistent with sensory neuropathy (Figure 1).
Figure 1 Sensory nerve action potentials. 1A - absent right sural sensory amplitude; 1B - absent right superficial peroneal sensory amplitude
Nerve Conduction Study
The NCS preserved motor findings are displayed in Figure 2.
Figure 2 Motor compound muscle action potentials. 2A - right peroneal motor nerve; 2B - right tibial motor nerve
Nerve Conduction Study
Our case conforms to the typical profile of a thalidomide-induced polyneuropathy; a cumulative dose of at least 20 grams, predominantly sensory neuropathy and the absence of power loss or a frank sensory ataxia. The latter findings, if present, should prompt the search for an alternate diagnosis. Furthermore, as expected, the discontinuation of drug therapy was associated with a gradual improvement of symptoms.
Due to the recent resurgence of the use of thalidomide, we were propelled to present the typical case and outline the clinical profile and red flags of presentation. Familiarity with the neurotoxicity of this agent should be highlighted.
Discussion
Thalidomide exists as a racemic mixture of two enantiomers that exist as mirror images of each other. These images are non-superimposable, a phenomenon known in physics as parity. This stereochemistry (geometry in physics) gives them optical properties whereby the plane of polarized light is rotated clockwise (+) or dextrorotatory (D), also referred to as rectus (R) and counterclockwise (-) or levorotatory, also known as sinister (S). The chiral center, the part of the molecule that imparts handedness, is usually a carbon molecule (Figure 3).
Figure 3 Thalidomide molecule. 3A - Thalidomide rings resemble the ring of the nucleotide guanine; 3B - The S- and R- stereoisomers
Sinister (S), rectus (R), oxygen (O), nitrogen (N), hydrogen (H)
The bewildering panorama of the molecular biology of thalidomide and its anti-inflammatory, immunomodulatory, and anti-angiogenesis effects, and its subsequent effects on embryogenesis and neuronal functions are listed in Table 1.
Table 1 The molecular biology of the thalidomide molecule and its subsequent pathology
Tumor necrosis factor (TNF), messenger ribonucleic acid (mRNA), fibroblast growth factor (FGF), interleukin (IL), vascular endothelial growth factor (VEGF), polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS), thymic helper cells (Th), insulin growth factor (IGF), deoxyribonucleic acid (DNA), nuclear factor (NF)
Study Molecular biology Effects
Amato RJ, et al. [7] reduces TNF-alpha by accelerated degeneration of mRNA reduces inflammation in TNF-alpha immune mediated diseases
George A, et al. [8] recruits epineural IL-10 macrophages and increases dorsal horn met-enkephalins may reduce neuropathic pain
Kuwabara S, et al. [9] reduces serum VEGF and inhibits angiogenesis clinical and electrophysiological improvement in POEMS
Park SJ, et al. [10] inhibits neointimal hyperplasia reduced FGF and TNF-alfa
McHugh SM, et al. [11] shift from pro-inflammatory Th1 to anti-inflammatory Th2 cytokines broad-spectrum anti-inflammatory action
Mori T, et al. [12] inhibits cereblon - E3 ubiquitine ligase embryopathy
Stephens TD, et al. [13] inhibit binding of IGF-1 and IGF-2 to alpha and beta integrins reduce angiogenesis and bud outgrowth.
Parman T, et al. [14] oxidizes DNA thalidomide molecule similar to guanine nucleotide
Yasui K, et al. [15] inhibits NF-kappa inhibit granulocyte- mediated tissue injury
How does thalidomide induce its toxic effects on neurons? It may lead to dorsal root ganglion toxicity or a length-dependent axonopathy [6]. Inhibition of ubiquitination and reduced clearance of proteins [12] and oxidation of DNA leading to Wallerian degeneration is speculative at this point [14]. There is a need for electron-microscopic studies of sural nerve biopsies of afflicted patients to look for accumulation of deposits (toxic axonopathy) such as axonal spheroids (accumulation of cytoskeletal proteins) and abnormal mitochondria (oxidative phosphorylation abnormalities) or abnormal granular deposits in the endoplasmic reticulum.
The pleomorphic molecular mechanisms of the thalidomide molecule explain its wide-ranging therapeutic effects. From the neurological therapeutic point of view, thalidomide has benefits for two diseases: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS syndrome) and advanced glioblastoma.
The POEMS syndrome is an osteosclerotic myeloma associated with a monoclonal spike of immunoglobulin IgA or IgG and a lambda-chain paraproteinemia. POEMS is an aggressive demyelinating sensory-motor polyneuropathy associated with bilateral lower and upper limb weakness and difficulty walking by two years. One-third of patients have papilledema and testicular atrophy and gynecomastia are not infrequent. POEMS can mimic chronic inflammatory demyelinating polyneuropathy (CIDP) and treatment-resistant CIDP should raise suspicion for POEMS. Treatment for POEMS can include radiotherapy for osteosclerotic lesions, alkylating agents such as cyclophosphamide, and bone marrow transplant. Elevated serum levels of vascular endothelial growth factor (VEGF) are seen in most patients and this has prompted the use of thalidomide in POEMS. Kuwabara et al. treated nine patients who were not candidates for alkylating agents or bone marrow transplant with thalidomide. All patients had elevated serum VEGF. Treatment with thalidomide led to clinical improvements, reduced serum VEGF levels, and improvement in electrophysiological parameters in all patients [8].
The anti-angiogenesis and sedative properties of thalidomide have also been used to treat advanced gliomas. The benefits include prolonged survival and better sleep hygiene [3].
The polyneuropathy of thalidomide is mostly a sensory neuropathy associated with a large fiber neuropathy (numbness, mild unsteadiness) and/or a small fiber neuropathy (tingling, burning pain, aching, shooting pain). The development of a polyneuropathy is related to the duration of treatment and the cumulative dose of drug, with doses exceeding 20 grams increasing the risk to 50%. The polyneuropathy is mostly axonal, rarely demyelinating and is usually reversible with drug discontinuation. Clinically, the ankle-deep tendon reflexes are normal, diminished, or absent. There is usually a length-dependent polyneuropathy to pin-prick. Vibratory sense may be diminished but joint-position sense at the toes is usually preserved. The Romberg sign is usually absent (normal proprioception) and the patient is almost always able to stand on his or her heels (absence of weakness) (Table 2).
Table 2 Thalidomide treated patients - emphasis on predominantly sensory neuropathy and dose-dependent effects on development of a neuropathy
Somatosensory evoked potential (SSEP), dorsal root ganglion (DRG), grams (g)
Study Number of patients treated with thalidomide Sensory findings Sensory-motor findings Noteworthy findings
Lagueny A, et al. [16] 13 13 0 Two patients with prolonged SSEP's - ? dorsal column / DRG involvement
Briana C, et al. [17] 14 7 1 No correlation between cumulative dose of thalidomide and emergence of neuropathy
Cavaletti G, at al. [18] 65 46 0 A cumulative dose greater than 20 g is related to development of a neuropathy
Chaudhry V, et al. [19] 7 7 3 Dose-dependent effect. Sural nerve biopsy demonstrating Wallerian degeneration and loss of myelinated fibers
Bastuji-Garin S, et al. [20] 135 34 no data provided No neuropathy for daily doses of less than 25 g daily. The risk increased with increased daily dosing
If the patient develops a sensory ataxia, Romberg sign, inability to stand on the heels or tip-toes, diffuse numbness (truncal, facial or appendicular), cranial nerve palsy, or an autonomic neuropathy (orthostatic intolerance, dry eyes, dry mouth, urogenital dysfunction) or asymmetric or multi-focal weakness, then this should raise a red flag and an alternate etiology pursued. An alternate etiology may include a hereditary sensory-motor polyneuropathy, other inflammatory neuropathy such as CIDP or a paraneoplastic ganglioneuropathy.
Conclusions
A thalidomide-induced polyneuropathy is mostly a sensory neuropathy. It is a cumulative dose-dependent polyneuropathy that is usually reversible with discontinuation. We listed " red flag " unusual presentations such as difficulty standing on the heels or sensory ataxia, which should prompt a search for an alternate diagnosis. The stereo-chemistry and molecular mechanisms of the thalidomide molecule are manifold and worthy of review as the indications for its clinical applications has exploded over the last two decades.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | AMLODIPINE BESYLATE, CYCLOPHOSPHAMIDE, DEXAMETHASONE, MELPHALAN, THALIDOMIDE | DrugsGivenReaction | CC BY | 33728154 | 19,072,931 | 2021-02-04 |
What was the administration route of drug 'THALIDOMIDE'? | Death and Rebirth of the Thalidomide Molecule: A Case of Thalidomide-Induced Sensory Neuropathy.
The thalidomide molecule is a remarkable molecule that exists in a racemic mixture of optical isomers. In the 1950s, due to its teratogenicity, the levorotatory isomer led to its dramatic downfall. However, the molecule with its panoramic mechanisms of action and its uncanny ability to intercalate within the geometry of deoxyribonucleic acid (DNA), led to its remarkable renaissance; thalidomide being United States Food and Drug Administration (FDA)-approved for at least 13 different indications ranging from multiple myeloma to leprosy to glioblastoma. Thalidomide-induced polyneuropathy is usually reversible and is the rate-limiting step in its long-term use. The development of a polyneuropathy is invariably associated with a cumulative dose exceeding 20 grams. However, the polyneuropathy is almost always a sensory neuropathy. Asymmetry, bona fide weakness such as difficulty standing on the heels, a poly-ganglioneuropathy pattern with widespread or patchy numbness and sensory ataxia should raise a red flag and an alternative diagnosis should be considered. We present a typical case of a thalidomide-induced sensory neuropathy in order to highlight the resurgence of thalidomide use in clinical practice. We review the literature and outline the molecular biology of the thalidomide molecule.
Introduction
Thalidomide is a versatile molecule. It is a derivative of glutamic acid and it has a panorama of actions that includes specific and broad antiinflammatory, immune-modulatory actions and inhibition of angiogenesis. On the downside, one of its chiral enantiomers has notoriously been associated with teratogenesis. Thalidomide is a racemic mixture of two enantiomers rectus R- and sinister S- optical isomers. They are readily interchangeable, the R-isomer is a sedative and the S-isomer is a teratogen [1].
As an analogue of glutethimide, it was marketed as a sedative, and as an anti-emetic for morning sickness with catastrophic results. Thalidomide embryopathy was an epidemic of congenital malformations between the years 1957 and 1961. Early exposure during pregnancy, between days 20 and 36 after fertilization, led to ocular, auditory, upper and lower limb and cranial nerve (facial motor nerve) malformations. Autism, epilepsy, and urogenital defects were also reported. Only one-half of the infants exposed to thalidomide survived [2].
Thalidomide's pleomorphic effects on the immune system, anti-proliferative effects and its anti-angiogenesis properties have led to its spectacular renaissance. It is now a United States Food and Drug Administration (FDA)-approved drug for a bewildering variety of at least 13 different diseases or disease states including erythema nodosum leprosum, multiple myeloma, acquired immune deficiency syndrome (AIDS)-wasting syndrome, recurrent aphthous ulcers and stomatitis in the immuno-suppressed, graft-versus-host disease, AIDS-related Kaposi's sarcoma, primary malignant glioma, myelodysplastic syndrome, various systemic lupus erythematosis states, Behcet's syndrome, prurigo, refractory Crohn's disease, and peripheral thymic (T)-cell lymphoma [3].
The polyneuropathy induced by thalidomide is mostly axonal and rarely demyelinating. It is typically a sensory neuropathy and is rarely a sensory-motor polyneuropathy. When sensory, the large fibers (touch, pressure, proprioception) are more affected than the small fibers (pain, temperature) [4]. Serum from patients treated with thalidomide for prurigo and injected into cultured rabbit dorsal root ganglia was associated with a neuronopathy (disease of the dorsal root ganglia) [5]. The cereblon (CRBN) gene codes for the enzyme (E)-3 protein-ligase-complex that mediates the ubiquitination and proteasomal degradation of proteins. This is required as a clearing mechanism of proteins during limb budding and sculpting during embryogenesis. In a study of 82 patients treated with thalidomide for multiple myeloma, carriers of the CRBN cytosine-cytosine (CC)-genotype had a 14-fold higher risk of a polyneuropathy [6].
Case presentation
We present the case of a 64-year-old woman with bone marrow biopsy-proven (30% plasma cells) stage-III immunoglobulin (IgG) lambda multiple myeloma. She had a corresponding anemia but no hypercalcemia or lytic bone lesions. Remission was achieved with a course of decadron, cyclophosphamide and melphalan. Maintenance therapy was with oral thalidomide was done for three years after which she relapsed and developed osteonecrosis of the right maxilla, which was successfully treated with radiotherapy. Remission was subsequently achieved with oral lenalidomide.
One year after starting treatment with thalidomide, initially at 50 milligrams (mg) daily and slowly escalated up to 200 mg daily, she developed numbness, tingling and burning pain of the feet. The neuropathic symptoms were successfully treated with pregabalin at a dose of 150 mg twice daily. After two years of symptomatic treatment with pregabalin for the neuropathic pain, she was successfully weaned off pregabalin with residual but tolerable mild numbness and aching of the feet.
Past medical history was significant for hypertension treated with amlodipine 10 mg daily.
We will list the relevant clinical findings on examination. Gait was steady with normal tandem-walking. Heel and toe-walking were normal. Cranial nerve examination was normal with normal trigeminal nerve sensory testing to touch in all three trigeminal divisions bilaterally.
Power testing of the arms and legs was normal using medical research council (MRC) grading. Cerebellar examination revealed normal heel-to-shin and finger-to-nose testing. Romberg sign was absent with absence of pseudoathetosis of the fingers with the outstretched arms and eyes closed. Deep tendon reflexes were normal except for trace ankle jerks bilaterally. Sensory examination of the feet revealed mild diminished pin-prick testing of the toes with absent vibratory testing of the toes bilaterally. The findings on examination are consistent with a low-grade sensory neuropathy.
A nerve conduction study (NCS) of the feet revealed absent sural and peroneal sensory nerve action potentials bilaterally. Peroneal and tibial motor amplitudes and velocities were normal in both feet. This is consistent with sensory neuropathy (Figure 1).
Figure 1 Sensory nerve action potentials. 1A - absent right sural sensory amplitude; 1B - absent right superficial peroneal sensory amplitude
Nerve Conduction Study
The NCS preserved motor findings are displayed in Figure 2.
Figure 2 Motor compound muscle action potentials. 2A - right peroneal motor nerve; 2B - right tibial motor nerve
Nerve Conduction Study
Our case conforms to the typical profile of a thalidomide-induced polyneuropathy; a cumulative dose of at least 20 grams, predominantly sensory neuropathy and the absence of power loss or a frank sensory ataxia. The latter findings, if present, should prompt the search for an alternate diagnosis. Furthermore, as expected, the discontinuation of drug therapy was associated with a gradual improvement of symptoms.
Due to the recent resurgence of the use of thalidomide, we were propelled to present the typical case and outline the clinical profile and red flags of presentation. Familiarity with the neurotoxicity of this agent should be highlighted.
Discussion
Thalidomide exists as a racemic mixture of two enantiomers that exist as mirror images of each other. These images are non-superimposable, a phenomenon known in physics as parity. This stereochemistry (geometry in physics) gives them optical properties whereby the plane of polarized light is rotated clockwise (+) or dextrorotatory (D), also referred to as rectus (R) and counterclockwise (-) or levorotatory, also known as sinister (S). The chiral center, the part of the molecule that imparts handedness, is usually a carbon molecule (Figure 3).
Figure 3 Thalidomide molecule. 3A - Thalidomide rings resemble the ring of the nucleotide guanine; 3B - The S- and R- stereoisomers
Sinister (S), rectus (R), oxygen (O), nitrogen (N), hydrogen (H)
The bewildering panorama of the molecular biology of thalidomide and its anti-inflammatory, immunomodulatory, and anti-angiogenesis effects, and its subsequent effects on embryogenesis and neuronal functions are listed in Table 1.
Table 1 The molecular biology of the thalidomide molecule and its subsequent pathology
Tumor necrosis factor (TNF), messenger ribonucleic acid (mRNA), fibroblast growth factor (FGF), interleukin (IL), vascular endothelial growth factor (VEGF), polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS), thymic helper cells (Th), insulin growth factor (IGF), deoxyribonucleic acid (DNA), nuclear factor (NF)
Study Molecular biology Effects
Amato RJ, et al. [7] reduces TNF-alpha by accelerated degeneration of mRNA reduces inflammation in TNF-alpha immune mediated diseases
George A, et al. [8] recruits epineural IL-10 macrophages and increases dorsal horn met-enkephalins may reduce neuropathic pain
Kuwabara S, et al. [9] reduces serum VEGF and inhibits angiogenesis clinical and electrophysiological improvement in POEMS
Park SJ, et al. [10] inhibits neointimal hyperplasia reduced FGF and TNF-alfa
McHugh SM, et al. [11] shift from pro-inflammatory Th1 to anti-inflammatory Th2 cytokines broad-spectrum anti-inflammatory action
Mori T, et al. [12] inhibits cereblon - E3 ubiquitine ligase embryopathy
Stephens TD, et al. [13] inhibit binding of IGF-1 and IGF-2 to alpha and beta integrins reduce angiogenesis and bud outgrowth.
Parman T, et al. [14] oxidizes DNA thalidomide molecule similar to guanine nucleotide
Yasui K, et al. [15] inhibits NF-kappa inhibit granulocyte- mediated tissue injury
How does thalidomide induce its toxic effects on neurons? It may lead to dorsal root ganglion toxicity or a length-dependent axonopathy [6]. Inhibition of ubiquitination and reduced clearance of proteins [12] and oxidation of DNA leading to Wallerian degeneration is speculative at this point [14]. There is a need for electron-microscopic studies of sural nerve biopsies of afflicted patients to look for accumulation of deposits (toxic axonopathy) such as axonal spheroids (accumulation of cytoskeletal proteins) and abnormal mitochondria (oxidative phosphorylation abnormalities) or abnormal granular deposits in the endoplasmic reticulum.
The pleomorphic molecular mechanisms of the thalidomide molecule explain its wide-ranging therapeutic effects. From the neurological therapeutic point of view, thalidomide has benefits for two diseases: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS syndrome) and advanced glioblastoma.
The POEMS syndrome is an osteosclerotic myeloma associated with a monoclonal spike of immunoglobulin IgA or IgG and a lambda-chain paraproteinemia. POEMS is an aggressive demyelinating sensory-motor polyneuropathy associated with bilateral lower and upper limb weakness and difficulty walking by two years. One-third of patients have papilledema and testicular atrophy and gynecomastia are not infrequent. POEMS can mimic chronic inflammatory demyelinating polyneuropathy (CIDP) and treatment-resistant CIDP should raise suspicion for POEMS. Treatment for POEMS can include radiotherapy for osteosclerotic lesions, alkylating agents such as cyclophosphamide, and bone marrow transplant. Elevated serum levels of vascular endothelial growth factor (VEGF) are seen in most patients and this has prompted the use of thalidomide in POEMS. Kuwabara et al. treated nine patients who were not candidates for alkylating agents or bone marrow transplant with thalidomide. All patients had elevated serum VEGF. Treatment with thalidomide led to clinical improvements, reduced serum VEGF levels, and improvement in electrophysiological parameters in all patients [8].
The anti-angiogenesis and sedative properties of thalidomide have also been used to treat advanced gliomas. The benefits include prolonged survival and better sleep hygiene [3].
The polyneuropathy of thalidomide is mostly a sensory neuropathy associated with a large fiber neuropathy (numbness, mild unsteadiness) and/or a small fiber neuropathy (tingling, burning pain, aching, shooting pain). The development of a polyneuropathy is related to the duration of treatment and the cumulative dose of drug, with doses exceeding 20 grams increasing the risk to 50%. The polyneuropathy is mostly axonal, rarely demyelinating and is usually reversible with drug discontinuation. Clinically, the ankle-deep tendon reflexes are normal, diminished, or absent. There is usually a length-dependent polyneuropathy to pin-prick. Vibratory sense may be diminished but joint-position sense at the toes is usually preserved. The Romberg sign is usually absent (normal proprioception) and the patient is almost always able to stand on his or her heels (absence of weakness) (Table 2).
Table 2 Thalidomide treated patients - emphasis on predominantly sensory neuropathy and dose-dependent effects on development of a neuropathy
Somatosensory evoked potential (SSEP), dorsal root ganglion (DRG), grams (g)
Study Number of patients treated with thalidomide Sensory findings Sensory-motor findings Noteworthy findings
Lagueny A, et al. [16] 13 13 0 Two patients with prolonged SSEP's - ? dorsal column / DRG involvement
Briana C, et al. [17] 14 7 1 No correlation between cumulative dose of thalidomide and emergence of neuropathy
Cavaletti G, at al. [18] 65 46 0 A cumulative dose greater than 20 g is related to development of a neuropathy
Chaudhry V, et al. [19] 7 7 3 Dose-dependent effect. Sural nerve biopsy demonstrating Wallerian degeneration and loss of myelinated fibers
Bastuji-Garin S, et al. [20] 135 34 no data provided No neuropathy for daily doses of less than 25 g daily. The risk increased with increased daily dosing
If the patient develops a sensory ataxia, Romberg sign, inability to stand on the heels or tip-toes, diffuse numbness (truncal, facial or appendicular), cranial nerve palsy, or an autonomic neuropathy (orthostatic intolerance, dry eyes, dry mouth, urogenital dysfunction) or asymmetric or multi-focal weakness, then this should raise a red flag and an alternate etiology pursued. An alternate etiology may include a hereditary sensory-motor polyneuropathy, other inflammatory neuropathy such as CIDP or a paraneoplastic ganglioneuropathy.
Conclusions
A thalidomide-induced polyneuropathy is mostly a sensory neuropathy. It is a cumulative dose-dependent polyneuropathy that is usually reversible with discontinuation. We listed " red flag " unusual presentations such as difficulty standing on the heels or sensory ataxia, which should prompt a search for an alternate diagnosis. The stereo-chemistry and molecular mechanisms of the thalidomide molecule are manifold and worthy of review as the indications for its clinical applications has exploded over the last two decades.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33728154 | 19,072,931 | 2021-02-04 |
What was the outcome of reaction 'Neuropathy peripheral'? | Death and Rebirth of the Thalidomide Molecule: A Case of Thalidomide-Induced Sensory Neuropathy.
The thalidomide molecule is a remarkable molecule that exists in a racemic mixture of optical isomers. In the 1950s, due to its teratogenicity, the levorotatory isomer led to its dramatic downfall. However, the molecule with its panoramic mechanisms of action and its uncanny ability to intercalate within the geometry of deoxyribonucleic acid (DNA), led to its remarkable renaissance; thalidomide being United States Food and Drug Administration (FDA)-approved for at least 13 different indications ranging from multiple myeloma to leprosy to glioblastoma. Thalidomide-induced polyneuropathy is usually reversible and is the rate-limiting step in its long-term use. The development of a polyneuropathy is invariably associated with a cumulative dose exceeding 20 grams. However, the polyneuropathy is almost always a sensory neuropathy. Asymmetry, bona fide weakness such as difficulty standing on the heels, a poly-ganglioneuropathy pattern with widespread or patchy numbness and sensory ataxia should raise a red flag and an alternative diagnosis should be considered. We present a typical case of a thalidomide-induced sensory neuropathy in order to highlight the resurgence of thalidomide use in clinical practice. We review the literature and outline the molecular biology of the thalidomide molecule.
Introduction
Thalidomide is a versatile molecule. It is a derivative of glutamic acid and it has a panorama of actions that includes specific and broad antiinflammatory, immune-modulatory actions and inhibition of angiogenesis. On the downside, one of its chiral enantiomers has notoriously been associated with teratogenesis. Thalidomide is a racemic mixture of two enantiomers rectus R- and sinister S- optical isomers. They are readily interchangeable, the R-isomer is a sedative and the S-isomer is a teratogen [1].
As an analogue of glutethimide, it was marketed as a sedative, and as an anti-emetic for morning sickness with catastrophic results. Thalidomide embryopathy was an epidemic of congenital malformations between the years 1957 and 1961. Early exposure during pregnancy, between days 20 and 36 after fertilization, led to ocular, auditory, upper and lower limb and cranial nerve (facial motor nerve) malformations. Autism, epilepsy, and urogenital defects were also reported. Only one-half of the infants exposed to thalidomide survived [2].
Thalidomide's pleomorphic effects on the immune system, anti-proliferative effects and its anti-angiogenesis properties have led to its spectacular renaissance. It is now a United States Food and Drug Administration (FDA)-approved drug for a bewildering variety of at least 13 different diseases or disease states including erythema nodosum leprosum, multiple myeloma, acquired immune deficiency syndrome (AIDS)-wasting syndrome, recurrent aphthous ulcers and stomatitis in the immuno-suppressed, graft-versus-host disease, AIDS-related Kaposi's sarcoma, primary malignant glioma, myelodysplastic syndrome, various systemic lupus erythematosis states, Behcet's syndrome, prurigo, refractory Crohn's disease, and peripheral thymic (T)-cell lymphoma [3].
The polyneuropathy induced by thalidomide is mostly axonal and rarely demyelinating. It is typically a sensory neuropathy and is rarely a sensory-motor polyneuropathy. When sensory, the large fibers (touch, pressure, proprioception) are more affected than the small fibers (pain, temperature) [4]. Serum from patients treated with thalidomide for prurigo and injected into cultured rabbit dorsal root ganglia was associated with a neuronopathy (disease of the dorsal root ganglia) [5]. The cereblon (CRBN) gene codes for the enzyme (E)-3 protein-ligase-complex that mediates the ubiquitination and proteasomal degradation of proteins. This is required as a clearing mechanism of proteins during limb budding and sculpting during embryogenesis. In a study of 82 patients treated with thalidomide for multiple myeloma, carriers of the CRBN cytosine-cytosine (CC)-genotype had a 14-fold higher risk of a polyneuropathy [6].
Case presentation
We present the case of a 64-year-old woman with bone marrow biopsy-proven (30% plasma cells) stage-III immunoglobulin (IgG) lambda multiple myeloma. She had a corresponding anemia but no hypercalcemia or lytic bone lesions. Remission was achieved with a course of decadron, cyclophosphamide and melphalan. Maintenance therapy was with oral thalidomide was done for three years after which she relapsed and developed osteonecrosis of the right maxilla, which was successfully treated with radiotherapy. Remission was subsequently achieved with oral lenalidomide.
One year after starting treatment with thalidomide, initially at 50 milligrams (mg) daily and slowly escalated up to 200 mg daily, she developed numbness, tingling and burning pain of the feet. The neuropathic symptoms were successfully treated with pregabalin at a dose of 150 mg twice daily. After two years of symptomatic treatment with pregabalin for the neuropathic pain, she was successfully weaned off pregabalin with residual but tolerable mild numbness and aching of the feet.
Past medical history was significant for hypertension treated with amlodipine 10 mg daily.
We will list the relevant clinical findings on examination. Gait was steady with normal tandem-walking. Heel and toe-walking were normal. Cranial nerve examination was normal with normal trigeminal nerve sensory testing to touch in all three trigeminal divisions bilaterally.
Power testing of the arms and legs was normal using medical research council (MRC) grading. Cerebellar examination revealed normal heel-to-shin and finger-to-nose testing. Romberg sign was absent with absence of pseudoathetosis of the fingers with the outstretched arms and eyes closed. Deep tendon reflexes were normal except for trace ankle jerks bilaterally. Sensory examination of the feet revealed mild diminished pin-prick testing of the toes with absent vibratory testing of the toes bilaterally. The findings on examination are consistent with a low-grade sensory neuropathy.
A nerve conduction study (NCS) of the feet revealed absent sural and peroneal sensory nerve action potentials bilaterally. Peroneal and tibial motor amplitudes and velocities were normal in both feet. This is consistent with sensory neuropathy (Figure 1).
Figure 1 Sensory nerve action potentials. 1A - absent right sural sensory amplitude; 1B - absent right superficial peroneal sensory amplitude
Nerve Conduction Study
The NCS preserved motor findings are displayed in Figure 2.
Figure 2 Motor compound muscle action potentials. 2A - right peroneal motor nerve; 2B - right tibial motor nerve
Nerve Conduction Study
Our case conforms to the typical profile of a thalidomide-induced polyneuropathy; a cumulative dose of at least 20 grams, predominantly sensory neuropathy and the absence of power loss or a frank sensory ataxia. The latter findings, if present, should prompt the search for an alternate diagnosis. Furthermore, as expected, the discontinuation of drug therapy was associated with a gradual improvement of symptoms.
Due to the recent resurgence of the use of thalidomide, we were propelled to present the typical case and outline the clinical profile and red flags of presentation. Familiarity with the neurotoxicity of this agent should be highlighted.
Discussion
Thalidomide exists as a racemic mixture of two enantiomers that exist as mirror images of each other. These images are non-superimposable, a phenomenon known in physics as parity. This stereochemistry (geometry in physics) gives them optical properties whereby the plane of polarized light is rotated clockwise (+) or dextrorotatory (D), also referred to as rectus (R) and counterclockwise (-) or levorotatory, also known as sinister (S). The chiral center, the part of the molecule that imparts handedness, is usually a carbon molecule (Figure 3).
Figure 3 Thalidomide molecule. 3A - Thalidomide rings resemble the ring of the nucleotide guanine; 3B - The S- and R- stereoisomers
Sinister (S), rectus (R), oxygen (O), nitrogen (N), hydrogen (H)
The bewildering panorama of the molecular biology of thalidomide and its anti-inflammatory, immunomodulatory, and anti-angiogenesis effects, and its subsequent effects on embryogenesis and neuronal functions are listed in Table 1.
Table 1 The molecular biology of the thalidomide molecule and its subsequent pathology
Tumor necrosis factor (TNF), messenger ribonucleic acid (mRNA), fibroblast growth factor (FGF), interleukin (IL), vascular endothelial growth factor (VEGF), polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS), thymic helper cells (Th), insulin growth factor (IGF), deoxyribonucleic acid (DNA), nuclear factor (NF)
Study Molecular biology Effects
Amato RJ, et al. [7] reduces TNF-alpha by accelerated degeneration of mRNA reduces inflammation in TNF-alpha immune mediated diseases
George A, et al. [8] recruits epineural IL-10 macrophages and increases dorsal horn met-enkephalins may reduce neuropathic pain
Kuwabara S, et al. [9] reduces serum VEGF and inhibits angiogenesis clinical and electrophysiological improvement in POEMS
Park SJ, et al. [10] inhibits neointimal hyperplasia reduced FGF and TNF-alfa
McHugh SM, et al. [11] shift from pro-inflammatory Th1 to anti-inflammatory Th2 cytokines broad-spectrum anti-inflammatory action
Mori T, et al. [12] inhibits cereblon - E3 ubiquitine ligase embryopathy
Stephens TD, et al. [13] inhibit binding of IGF-1 and IGF-2 to alpha and beta integrins reduce angiogenesis and bud outgrowth.
Parman T, et al. [14] oxidizes DNA thalidomide molecule similar to guanine nucleotide
Yasui K, et al. [15] inhibits NF-kappa inhibit granulocyte- mediated tissue injury
How does thalidomide induce its toxic effects on neurons? It may lead to dorsal root ganglion toxicity or a length-dependent axonopathy [6]. Inhibition of ubiquitination and reduced clearance of proteins [12] and oxidation of DNA leading to Wallerian degeneration is speculative at this point [14]. There is a need for electron-microscopic studies of sural nerve biopsies of afflicted patients to look for accumulation of deposits (toxic axonopathy) such as axonal spheroids (accumulation of cytoskeletal proteins) and abnormal mitochondria (oxidative phosphorylation abnormalities) or abnormal granular deposits in the endoplasmic reticulum.
The pleomorphic molecular mechanisms of the thalidomide molecule explain its wide-ranging therapeutic effects. From the neurological therapeutic point of view, thalidomide has benefits for two diseases: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS syndrome) and advanced glioblastoma.
The POEMS syndrome is an osteosclerotic myeloma associated with a monoclonal spike of immunoglobulin IgA or IgG and a lambda-chain paraproteinemia. POEMS is an aggressive demyelinating sensory-motor polyneuropathy associated with bilateral lower and upper limb weakness and difficulty walking by two years. One-third of patients have papilledema and testicular atrophy and gynecomastia are not infrequent. POEMS can mimic chronic inflammatory demyelinating polyneuropathy (CIDP) and treatment-resistant CIDP should raise suspicion for POEMS. Treatment for POEMS can include radiotherapy for osteosclerotic lesions, alkylating agents such as cyclophosphamide, and bone marrow transplant. Elevated serum levels of vascular endothelial growth factor (VEGF) are seen in most patients and this has prompted the use of thalidomide in POEMS. Kuwabara et al. treated nine patients who were not candidates for alkylating agents or bone marrow transplant with thalidomide. All patients had elevated serum VEGF. Treatment with thalidomide led to clinical improvements, reduced serum VEGF levels, and improvement in electrophysiological parameters in all patients [8].
The anti-angiogenesis and sedative properties of thalidomide have also been used to treat advanced gliomas. The benefits include prolonged survival and better sleep hygiene [3].
The polyneuropathy of thalidomide is mostly a sensory neuropathy associated with a large fiber neuropathy (numbness, mild unsteadiness) and/or a small fiber neuropathy (tingling, burning pain, aching, shooting pain). The development of a polyneuropathy is related to the duration of treatment and the cumulative dose of drug, with doses exceeding 20 grams increasing the risk to 50%. The polyneuropathy is mostly axonal, rarely demyelinating and is usually reversible with drug discontinuation. Clinically, the ankle-deep tendon reflexes are normal, diminished, or absent. There is usually a length-dependent polyneuropathy to pin-prick. Vibratory sense may be diminished but joint-position sense at the toes is usually preserved. The Romberg sign is usually absent (normal proprioception) and the patient is almost always able to stand on his or her heels (absence of weakness) (Table 2).
Table 2 Thalidomide treated patients - emphasis on predominantly sensory neuropathy and dose-dependent effects on development of a neuropathy
Somatosensory evoked potential (SSEP), dorsal root ganglion (DRG), grams (g)
Study Number of patients treated with thalidomide Sensory findings Sensory-motor findings Noteworthy findings
Lagueny A, et al. [16] 13 13 0 Two patients with prolonged SSEP's - ? dorsal column / DRG involvement
Briana C, et al. [17] 14 7 1 No correlation between cumulative dose of thalidomide and emergence of neuropathy
Cavaletti G, at al. [18] 65 46 0 A cumulative dose greater than 20 g is related to development of a neuropathy
Chaudhry V, et al. [19] 7 7 3 Dose-dependent effect. Sural nerve biopsy demonstrating Wallerian degeneration and loss of myelinated fibers
Bastuji-Garin S, et al. [20] 135 34 no data provided No neuropathy for daily doses of less than 25 g daily. The risk increased with increased daily dosing
If the patient develops a sensory ataxia, Romberg sign, inability to stand on the heels or tip-toes, diffuse numbness (truncal, facial or appendicular), cranial nerve palsy, or an autonomic neuropathy (orthostatic intolerance, dry eyes, dry mouth, urogenital dysfunction) or asymmetric or multi-focal weakness, then this should raise a red flag and an alternate etiology pursued. An alternate etiology may include a hereditary sensory-motor polyneuropathy, other inflammatory neuropathy such as CIDP or a paraneoplastic ganglioneuropathy.
Conclusions
A thalidomide-induced polyneuropathy is mostly a sensory neuropathy. It is a cumulative dose-dependent polyneuropathy that is usually reversible with discontinuation. We listed " red flag " unusual presentations such as difficulty standing on the heels or sensory ataxia, which should prompt a search for an alternate diagnosis. The stereo-chemistry and molecular mechanisms of the thalidomide molecule are manifold and worthy of review as the indications for its clinical applications has exploded over the last two decades.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovering | ReactionOutcome | CC BY | 33728154 | 19,072,931 | 2021-02-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Relapsing Candida parapsilosis Endocarditis With Septic Embolization: A Case Report.
Candida endocarditis is a rare infection that is becoming an emerging and growing health concern, especially among risk groups such as the elderly and the immunosuppressed. It is associated with high morbidity and mortality. Dilemmas about Candida endocarditis treatment are still around, particularly about the treatment options and their duration. We report a case of Candida parapsilosis prosthetic valve endocarditis with septic embolisms. An elderly male patient with a biological prosthetic valve presented with fever and constitutional symptoms. Abdominal computed tomography (CT) showed an area suggestive of splenic emboli. Transesophageal echocardiography showed a vegetation attaching to the prosthetic valve. Due to several comorbidities, he was not considered a candidate for surgical treatment. He was treated with antifungal drugs (liposomal amphotericin B and caspofungin) and was discharged with per os fluconazole. Later he presented with evidence of lumbar spondylodiscitis due to septic embolization and relapsing fungemia with multidrug-resistant isolates was documented. Unfortunately, the patient outcome was ill-fated and he died in hospital due to sepsis-related to the candidemia and also nosocomial urinary sepsis. Here, we illustrate the complexity of diagnosing and managing fungal endocarditis due to its complications and poor prognosis.
Introduction
Disseminated fungal infections are rare conditions and fungal endocarditis (FE) is even more unique. FE represents only 2%-4% of all endocarditis [1,2]. The incidence of Candida endocarditis has been increasing simultaneously with the increase in the general number of fungal infections. Most common known risk factors for FE include intravenous (IV) drug users, patients with prosthetic heart valves, immunocompromised hosts (namely transplant recipients), cancer patients receiving chemotherapy, prolonged use of a central venous catheter (CVC), human immunodeficiency virus infection, and a previous episode of bacterial endocarditis [1,3]. Recent series confirm that Candida endocarditis is becoming a predominantly healthcare-associated infection (87%) [3,4].
FE has a remarkably high number of complications and burden of disease [5]. The mortality rate is between 30% to 50% [6,7]. Contributing factors include the host immune state, often delayed or missed diagnosis, and lack of efficient antifungal agents in the absence of surgery. Also worth noting, FE is associated with significant recurrence rates and relapses have been documented months to years later [1,8,9].
Case presentation
We present the case of an 81-year-old male with a previous medical history of arterial hypertension, peripheral arterial disease (for which he had received aorto-bifemoral bypass six years before). Three years earlier he had also undergone a biological aortic valve replacement surgery due to aortic stenosis.
A recent medical history included a prolonged hospitalization early that year when he was diagnosed with gastric adenocarcinoma - staging pT1N0M0. He underwent a subtotal gastrectomy with Billroth type II anastomosis. In the postoperative period, he developed a stricture of the gastrojejunostomy. It was managed conservatively and he received long-term parenteral nutrition (PN) through CVC. He scored 0 points in the Eastern Cooperative Oncology Group (ECOG) performance status but needed no systemic therapy.
Six months later, he presented to our Emergency Department (ED) complaining of vespertine fever, anorexia, and asthenia. The symptoms had been present for one month. On physical examination, we noted an excellent general appearance, pallor, new-onset grade II/VI aortic systolic murmur, a tender abdomen on palpation, and splenomegaly. The laboratory workup showed microcytic hypochromic anemia (Hg 11.2 g/dL), normal leukocyte count with relative lymphocytosis, altered liver panel, thrombocytopenia, and elevated C reactive protein (CRP) (Table 1). An abdominal CT scan was performed and showed an enlarged spleen with a 32x22mm peripheral, wedge-shaped hypo-enhancing area on its posterior aspect, which was highly suggestive of a splenic infarct (Figure 1). No other signs of peripheral emboli were noted.
Table 1 Laboratory workup
MCHC: mean corpuscular hemoglobin concentration, MCV: mean corpuscular volume, CRP: C-reactive protein, Hct: hematocrit
Tests Reference values Results
Haemoglobin (g/dL) 11.8 - 15.8 11.2
Hct (%) 36 - 46 36
MCV (fL) 80.4 - 96.4 74.8
MCHC (g/dL) 31,7 - 35,7 31.1
Leucocytes (μL) 4.0 - 10.0 5480
Neutrophils 1800–7700 2.049
Lymphocytes 800–4000 2.619
Platelets (10^9/uL) 150 - 400 32
Glucose (mg/dL) 70 - 110 99
Urea (mg/dL) 17 - 43 26
Creatinine (mg/dL) 0.6 - 1.0 0,83
Sodium (mmol/L) 136 - 145 139
Potassium (mmol/L) 3.5 - 5.1 4,4
CRP (mg/dL) 0.01-0.82 7,2
Total / direct bilirubin (mg/dL) 0.3 - 1.2 1.19 / 0.6
Alkaline phosphatase (UI/L) 30 - 120 255
Gamma-glutamyl Transferase (UI/L) <55 110
Aspartate Transaminase (UI/L) 8 - 35 93
Alanine Transaminase (UI/L) 10 - 45 26
Figure 1 Abdominal CT scan showing an area of spleen infarct (black arrow)
The patient was admitted to the Internal Medicine ward with a presumptive diagnosis of infective endocarditis with splenic emboli. He met three minor clinical criteria from the Modified Duke Criteria for the Clinical Diagnosis of Infective Endocarditis [10] - fever, a predisposing heart condition, and systemic arterial emboli. Empirical antibiotic therapy with vancomycin and gentamicin was started - considering it might be healthcare-associated endocarditis due to recent hospitalization and abdominal surgery. Rifampicin was added three days later, as advocated for prosthetic valve (PV) infective endocarditis (IE) by The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC) [11].
A transthoracic echocardiogram (TTE) was performed and no changes suggestive of endocarditis were noted. Due to a high suspicion index, a transesophageal echocardiogram (TEE) was performed: it revealed a 7x7mm vegetation attached to the right coronary cusp of the prosthetic aortic valve; no perivalvular abscess, leaks, or prosthetic dysfunction were present (Video 1, 2).
Video 1 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve long axis-view. TEE, transesophageal echocardiogram.
Video 2 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve short-view. TEE, transesophageal echocardiogram
Blood cultures were negative for bacterial agents and yielded colonies of Candida parapsilosis. After this result, the patient was started on antifungal therapy with liposomal amphotericin B (5mg/kg daily), as recommended on current guidelines [8]. He developed a severe adverse anaphylactic reaction and treatment had to be suspended. An alternative regimen with high-dose echinocandin (caspofungin 150mg daily) was initiated, also according to latest recommendations [8]. The antibiotic susceptibility testing (AST) was only available two weeks later: it documented sensitivity to flucytosine, amphotericin B, fluconazole, and voriconazole but resistance to caspofungin. Accordingly, the patient was started on fluconazole therapy (12mg/kg/day).
Surgery was discussed between practitioners from several medical specialties (an ad hoc Endocarditis Team) but the patient was not considered for aortic replacement surgery, considering his comorbidities and very high anesthetic risk with a EuroSCORE II of 15.59% and a Society of Thoracic Surgeons (STS) score of 16.76%. A decision was made for lifelong suppressive therapy with fluconazole, as per current guidelines [8,11]. The patient was discharged from hospital once clinically stable and after two sets of negative blood cultures (over 24 hours apart).
Two months after discharge, he was admitted to our ED complaining of severe lower back pain, fever, and vomiting. By this time, the patient's ECOG performance status had declined significantly from 0 to 3. He underwent lumbar magnetic resonance imaging (MRI), which showed high signal in adjacent endplates and thickening of paravertebral soft tissues (T2 sequences) surrounding the L3-L4 intervertebral disk (Figure 2). These changes were compatible with an indolent manifestation of lumbar spondylodiscitis due to septic embolization. Microbiological relapse was documented. Blood cultures grew the same agent, but de novo resistance to fluconazole was reported in AST.
Figure 2 MRI T2 sequences showing L3-L4 spondylodiscitis (black circle).
MRI, magnetic resonance imaging
The patient developed urinary sepsis with multiorgan failure due to extended-spectrum beta-lactamases (ESBL) Klebsiella pneumonia with documented bacteriemia. Unrelenting clinical deterioration culminated with the patient’s death in-hospital approximately three months after the diagnosis of FE. The final diagnosis was Candida parapsilosis endocarditis with septic embolization (splenic infarct and spondylodiscitis).
Discussion
FE is an uncommon but dangerous and devastating infection. Candida species are the most frequent agents involved in FE: C. albicans cause approximately 25% of cases, non-Candida albicans Candida (NCAC) strains cause ~25% and other fungi such as Aspergillus are responsible for the remaining percentage [3].
C. parapsilosis was originally considered non-pathological until 1940 when it was identified as the causative agent of an FE that caused the death of an IV drug user [12]. Nowadays, C. parapsilosis is the second most common strain to be isolated from blood culture and is associated with nosocomial infections. It is mostly related to vascular devices [3], due to biofilm production on foreign bodies and indwelling catheters. [13]. The biofilm structures form pseudo-hyphae (called "giant cells") that are morphologically distinct from those of C. albicans [5,13]. They also show increased appetence and growing capacity on CVC used with parenteral hyper-alimentation solutions [5].
Predisposing risk factors for C. parapsilosis include the prosthetic heart valves or devices (57.4%), IV drug use (20%), PN (6.9%), immunosuppression (6.4%), treatment with broad-spectrum antibiotics (5.6%) and previous valvular disease (4.8%) [13]. When compared to C. albicans, C. parapsilosis FE has a more frequent history of valvular disease and prior parenteral nutrition [13]. C. parapsilosis has also been linked to indwelling CVCs, cardiac devices, transcatheter aortic valve replacement (TAVR), long-term glucocorticoid therapy and transplant recipients [5,6,8]. All these risk factors seem to have a cumulative behaviour [6,14].
Endocarditis presenting symptoms and signs include fever (in 90% of patients), which is usually protracted (>two weeks) and accompanied by chills, sweating, and malaise [15]. Dyspnea, heart failure (HF), and peripheral embolisms might be present [16]. New-onset murmur or changes in a previously known murmur (in 75% of patients) should also be considered [6]. Presentation can be acute or subacute, with nonspecific symptoms over weeks or months. Microembolic or immunologic phenomena (as splinter hemorrhages, conjunctival hemorrhages, Osler nodes, Janeway lesions, and Roth spots) can be seen in 5-10% of patients [15].
FE signs and symptoms are generally comparable to those of bacterial etiology, but FE has some distinctive features [8,13]. FE is characterized by (i) larger (‘bulky’) vegetations, responsible for an increased risk of drastic embolic events (such as massive stroke [6] or member ischaemia [17] ) and valvular destruction or chordae rupture leading to acute mitral insufficiency; (ii) more ophthalmological complications, with typical findings on fundoscopy; and (iii) specific dermatological conditions unique to fungal pathogens - macronodules or maculopapules in candidaemia and black hemorrhagic lesions in Aspergillus endocarditis have been reported [18].
One should suspect FE in cases of recurrent fever in patients with a past history of fungaemia [9], especially in patients with blood culture-negative IE (BCNIE) - i.e. IE in which no causative microorganism can be grown using the usual blood culture methods [11]. Despite vegetations seen on echocardiography, blood cultures are negative in over 50% of cases [6].
Diagnosis is based mainly on two aspects: microbiologic tests and echocardiogram (other imaging modalities are also available). A positive blood culture result is highly desirable. Susceptibility testing and determination of fungicidal minimum inhibitory concentrations (MICs) are mandatory [3]. However, the sensitivity for the diagnosis of FE has been estimated at 50-75% or lower [18]. Explanted valves and tissue should also be cultured for fungi/bacteria.
New testing alternatives are also emerging. The mannan antigen and antibody tests for candidaemia detect circulating Candida antigens, antibodies, or other metabolites and have a combined sensitivity and specificity of 83% and 86% respectively for diagnosing fungaemia. This represents an estimated accuracy of 50-70% [18]. Polymerase chain reaction (PCR) molecular methods are also available in blood or in explanted valves and are 3-fold more sensitive than Gram staining and culture [6,15]. However, there is currently no evidence to support the use of these tests in diagnosis of FE and treatment decisions should not be made based on these results alone [3].
TEE has higher sensitivity compared to TTE in detecting vegetations (95% vs. 60%) [18]. Other organ involvement must also be excluded (due the high embolic rate of events) and fundoscopy should be performed as well as an active search for a thrombus elsewhere [7].
Treatment options contemplate a multimodal approach including combined antifungal agents and surgery for the successful management of FE. Early as possible and aggressive surgical treatment is recommended (class I indication, level of evidence B) due to the high mortality and morbidity among patients with medical treatment alone [6,7].
Native or prosthetic valve FE, is considered a standalone indication for surgery by most society guidelines - including the American College of Cardiology (ACC), the American Heart Association (AHA), and the Infectious Diseases Society of America (IDSA) [13,18]. Surgery should be performed as soon as possible, ideally in the first week [7]. Paradoxically, some studies did not find differences in mortality between those undergoing surgical therapy and those receiving only medical therapy [4]. Rare cases of successful treatments with medical therapy alone have been described [19]. Due to lack of randomized studies, there is no consensus on the optimal medical treatment nor its duration [7,20].
Therapeutic recommendations for initial therapy of native valve endocarditis include lipid formulation amphotericin B, 3-5 mg/kg daily, with or without flucytosine, 25 mg/kg four times daily, OR a high-dose echinocandin (caspofungin 150 mg daily, micafungin 100-150 mg daily, or anidulafungin 100-200 mg daily) [7,8,18]. Azoles are only fungistatic in yeasts and therefore cannot be used as primary treatment of Candida endocarditis [18].
Step-down therapy to fluconazole - 400-800 mg (6-12 mg/kg) daily - is recommended for patients who have susceptible Candida isolates, clinical stability, and evidence fungaemia clearance [8]. A minimum of 14 days after the end of candidaemia (determined by one blood culture per day until negativity) is recommended and switching to oral treatment after 10 days of intravenous therapy is proved safe in clinically stable patients with susceptible species [7]. Some authors suggest courses of six weeks or longer in patients with perivalvular abscesses and other complications [8]. When valve replacement is NOT an option after the initial treatment long-term, suppression with fluconazole - 400-800 mg (6-12 mg/kg) daily - is a reasonable option if the isolate is susceptible [6-8,11]. The same antifungal regimens are recommended for prosthetic valve endocarditis. Some authors also advocate chronic suppressive antifungal therapy with fluconazole - 400-800 mg (6-12 mg/kg) daily - to prevent recurrence [8].
Echinocandin and azole resistance in Candida spp. are becoming a particular concern [13]. Persistent fungaemia after one week of treatment should raise suspicion of resistance and susceptibility should be tested, as resistance may emerge on therapy [3]. C. parapsilosis is usually susceptible to amphotericin B, flucytosine, and azoles. Echinocandin-resistant strains (as in this case report) are infrequent and have only been described in case reports [8,20]. One explanation is that C. parapsilosis demonstrates intrinsically higher MICs to the echinocandins than other Candida spp. However there have been no clinical studies proving fluconazole superiority over the echinocandins for C. parapsilosis infections [8].
Despite progress in antifungal therapy and surgical techniques, prognosis is poor and one-year mortality rate remains as high as 50% [7,8,11]. Baseline characteristics associated with high mortality are: older age, previous HF, and nosocomial acquisition of FE [4,9]. Higher mortality was also associated with clinical development of new-onset congestive HF and refractory candidemia [4]. Relapsing FE is a complication seen in as many as 30 to 40%.
Treatment failure causes include relapses due to Candida species ability to form biofilms, which reduce action of anti-fungal agents [5]. Surgical technical difficulties also play a role: homograft appears to be the most appropriate choice by allowing complete debridement of infected tissue with low risk of valve dehiscence and better antibiotic penetration [19]. Other challenges to consider in treating Candida endocarditis include geographic variations, virulence, and reduced susceptibility to antifungal medications [5].
Conclusions
FE is rare, but it carries a high mortality and incidence has been increasing over the last decades. Candida endocarditis clinical spectrum ranges from native or prosthetic valve endocarditis to infection of cardiac devices. Treatment options include combined antifungal agents and surgery.
This case report reminds us of the importance of raising awareness for fungal disease. Management must be made on a case-by-case personalized basis, considering multiple variables such as antifungal agents, surgical options as well as disease severity, prognosis, and patient’s status.
New evidence and recommendations will surely provide more guidelines to improve clinical medicine and contribute to more successful management of FE. Areas of intervention should include policies aiming at reducing FE in select populations (e.g. needle exchange programs, prophylactic usage of fluconazole in selected patients), innovative diagnostic tests, and expert or society consensus on the definition of clinical or microbiological criteria to guide diagnosis and treatment options for these patients.
Human Ethics
The authors would like to acknowledge Dr. Rui Lima (Cardiology) for his contribution to data and image selection.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | CASPOFUNGIN, FLUCONAZOLE, GENTAMICIN, RIFAMPIN, VANCOMYCIN | DrugsGivenReaction | CC BY | 33728162 | 15,739,818 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | Relapsing Candida parapsilosis Endocarditis With Septic Embolization: A Case Report.
Candida endocarditis is a rare infection that is becoming an emerging and growing health concern, especially among risk groups such as the elderly and the immunosuppressed. It is associated with high morbidity and mortality. Dilemmas about Candida endocarditis treatment are still around, particularly about the treatment options and their duration. We report a case of Candida parapsilosis prosthetic valve endocarditis with septic embolisms. An elderly male patient with a biological prosthetic valve presented with fever and constitutional symptoms. Abdominal computed tomography (CT) showed an area suggestive of splenic emboli. Transesophageal echocardiography showed a vegetation attaching to the prosthetic valve. Due to several comorbidities, he was not considered a candidate for surgical treatment. He was treated with antifungal drugs (liposomal amphotericin B and caspofungin) and was discharged with per os fluconazole. Later he presented with evidence of lumbar spondylodiscitis due to septic embolization and relapsing fungemia with multidrug-resistant isolates was documented. Unfortunately, the patient outcome was ill-fated and he died in hospital due to sepsis-related to the candidemia and also nosocomial urinary sepsis. Here, we illustrate the complexity of diagnosing and managing fungal endocarditis due to its complications and poor prognosis.
Introduction
Disseminated fungal infections are rare conditions and fungal endocarditis (FE) is even more unique. FE represents only 2%-4% of all endocarditis [1,2]. The incidence of Candida endocarditis has been increasing simultaneously with the increase in the general number of fungal infections. Most common known risk factors for FE include intravenous (IV) drug users, patients with prosthetic heart valves, immunocompromised hosts (namely transplant recipients), cancer patients receiving chemotherapy, prolonged use of a central venous catheter (CVC), human immunodeficiency virus infection, and a previous episode of bacterial endocarditis [1,3]. Recent series confirm that Candida endocarditis is becoming a predominantly healthcare-associated infection (87%) [3,4].
FE has a remarkably high number of complications and burden of disease [5]. The mortality rate is between 30% to 50% [6,7]. Contributing factors include the host immune state, often delayed or missed diagnosis, and lack of efficient antifungal agents in the absence of surgery. Also worth noting, FE is associated with significant recurrence rates and relapses have been documented months to years later [1,8,9].
Case presentation
We present the case of an 81-year-old male with a previous medical history of arterial hypertension, peripheral arterial disease (for which he had received aorto-bifemoral bypass six years before). Three years earlier he had also undergone a biological aortic valve replacement surgery due to aortic stenosis.
A recent medical history included a prolonged hospitalization early that year when he was diagnosed with gastric adenocarcinoma - staging pT1N0M0. He underwent a subtotal gastrectomy with Billroth type II anastomosis. In the postoperative period, he developed a stricture of the gastrojejunostomy. It was managed conservatively and he received long-term parenteral nutrition (PN) through CVC. He scored 0 points in the Eastern Cooperative Oncology Group (ECOG) performance status but needed no systemic therapy.
Six months later, he presented to our Emergency Department (ED) complaining of vespertine fever, anorexia, and asthenia. The symptoms had been present for one month. On physical examination, we noted an excellent general appearance, pallor, new-onset grade II/VI aortic systolic murmur, a tender abdomen on palpation, and splenomegaly. The laboratory workup showed microcytic hypochromic anemia (Hg 11.2 g/dL), normal leukocyte count with relative lymphocytosis, altered liver panel, thrombocytopenia, and elevated C reactive protein (CRP) (Table 1). An abdominal CT scan was performed and showed an enlarged spleen with a 32x22mm peripheral, wedge-shaped hypo-enhancing area on its posterior aspect, which was highly suggestive of a splenic infarct (Figure 1). No other signs of peripheral emboli were noted.
Table 1 Laboratory workup
MCHC: mean corpuscular hemoglobin concentration, MCV: mean corpuscular volume, CRP: C-reactive protein, Hct: hematocrit
Tests Reference values Results
Haemoglobin (g/dL) 11.8 - 15.8 11.2
Hct (%) 36 - 46 36
MCV (fL) 80.4 - 96.4 74.8
MCHC (g/dL) 31,7 - 35,7 31.1
Leucocytes (μL) 4.0 - 10.0 5480
Neutrophils 1800–7700 2.049
Lymphocytes 800–4000 2.619
Platelets (10^9/uL) 150 - 400 32
Glucose (mg/dL) 70 - 110 99
Urea (mg/dL) 17 - 43 26
Creatinine (mg/dL) 0.6 - 1.0 0,83
Sodium (mmol/L) 136 - 145 139
Potassium (mmol/L) 3.5 - 5.1 4,4
CRP (mg/dL) 0.01-0.82 7,2
Total / direct bilirubin (mg/dL) 0.3 - 1.2 1.19 / 0.6
Alkaline phosphatase (UI/L) 30 - 120 255
Gamma-glutamyl Transferase (UI/L) <55 110
Aspartate Transaminase (UI/L) 8 - 35 93
Alanine Transaminase (UI/L) 10 - 45 26
Figure 1 Abdominal CT scan showing an area of spleen infarct (black arrow)
The patient was admitted to the Internal Medicine ward with a presumptive diagnosis of infective endocarditis with splenic emboli. He met three minor clinical criteria from the Modified Duke Criteria for the Clinical Diagnosis of Infective Endocarditis [10] - fever, a predisposing heart condition, and systemic arterial emboli. Empirical antibiotic therapy with vancomycin and gentamicin was started - considering it might be healthcare-associated endocarditis due to recent hospitalization and abdominal surgery. Rifampicin was added three days later, as advocated for prosthetic valve (PV) infective endocarditis (IE) by The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC) [11].
A transthoracic echocardiogram (TTE) was performed and no changes suggestive of endocarditis were noted. Due to a high suspicion index, a transesophageal echocardiogram (TEE) was performed: it revealed a 7x7mm vegetation attached to the right coronary cusp of the prosthetic aortic valve; no perivalvular abscess, leaks, or prosthetic dysfunction were present (Video 1, 2).
Video 1 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve long axis-view. TEE, transesophageal echocardiogram.
Video 2 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve short-view. TEE, transesophageal echocardiogram
Blood cultures were negative for bacterial agents and yielded colonies of Candida parapsilosis. After this result, the patient was started on antifungal therapy with liposomal amphotericin B (5mg/kg daily), as recommended on current guidelines [8]. He developed a severe adverse anaphylactic reaction and treatment had to be suspended. An alternative regimen with high-dose echinocandin (caspofungin 150mg daily) was initiated, also according to latest recommendations [8]. The antibiotic susceptibility testing (AST) was only available two weeks later: it documented sensitivity to flucytosine, amphotericin B, fluconazole, and voriconazole but resistance to caspofungin. Accordingly, the patient was started on fluconazole therapy (12mg/kg/day).
Surgery was discussed between practitioners from several medical specialties (an ad hoc Endocarditis Team) but the patient was not considered for aortic replacement surgery, considering his comorbidities and very high anesthetic risk with a EuroSCORE II of 15.59% and a Society of Thoracic Surgeons (STS) score of 16.76%. A decision was made for lifelong suppressive therapy with fluconazole, as per current guidelines [8,11]. The patient was discharged from hospital once clinically stable and after two sets of negative blood cultures (over 24 hours apart).
Two months after discharge, he was admitted to our ED complaining of severe lower back pain, fever, and vomiting. By this time, the patient's ECOG performance status had declined significantly from 0 to 3. He underwent lumbar magnetic resonance imaging (MRI), which showed high signal in adjacent endplates and thickening of paravertebral soft tissues (T2 sequences) surrounding the L3-L4 intervertebral disk (Figure 2). These changes were compatible with an indolent manifestation of lumbar spondylodiscitis due to septic embolization. Microbiological relapse was documented. Blood cultures grew the same agent, but de novo resistance to fluconazole was reported in AST.
Figure 2 MRI T2 sequences showing L3-L4 spondylodiscitis (black circle).
MRI, magnetic resonance imaging
The patient developed urinary sepsis with multiorgan failure due to extended-spectrum beta-lactamases (ESBL) Klebsiella pneumonia with documented bacteriemia. Unrelenting clinical deterioration culminated with the patient’s death in-hospital approximately three months after the diagnosis of FE. The final diagnosis was Candida parapsilosis endocarditis with septic embolization (splenic infarct and spondylodiscitis).
Discussion
FE is an uncommon but dangerous and devastating infection. Candida species are the most frequent agents involved in FE: C. albicans cause approximately 25% of cases, non-Candida albicans Candida (NCAC) strains cause ~25% and other fungi such as Aspergillus are responsible for the remaining percentage [3].
C. parapsilosis was originally considered non-pathological until 1940 when it was identified as the causative agent of an FE that caused the death of an IV drug user [12]. Nowadays, C. parapsilosis is the second most common strain to be isolated from blood culture and is associated with nosocomial infections. It is mostly related to vascular devices [3], due to biofilm production on foreign bodies and indwelling catheters. [13]. The biofilm structures form pseudo-hyphae (called "giant cells") that are morphologically distinct from those of C. albicans [5,13]. They also show increased appetence and growing capacity on CVC used with parenteral hyper-alimentation solutions [5].
Predisposing risk factors for C. parapsilosis include the prosthetic heart valves or devices (57.4%), IV drug use (20%), PN (6.9%), immunosuppression (6.4%), treatment with broad-spectrum antibiotics (5.6%) and previous valvular disease (4.8%) [13]. When compared to C. albicans, C. parapsilosis FE has a more frequent history of valvular disease and prior parenteral nutrition [13]. C. parapsilosis has also been linked to indwelling CVCs, cardiac devices, transcatheter aortic valve replacement (TAVR), long-term glucocorticoid therapy and transplant recipients [5,6,8]. All these risk factors seem to have a cumulative behaviour [6,14].
Endocarditis presenting symptoms and signs include fever (in 90% of patients), which is usually protracted (>two weeks) and accompanied by chills, sweating, and malaise [15]. Dyspnea, heart failure (HF), and peripheral embolisms might be present [16]. New-onset murmur or changes in a previously known murmur (in 75% of patients) should also be considered [6]. Presentation can be acute or subacute, with nonspecific symptoms over weeks or months. Microembolic or immunologic phenomena (as splinter hemorrhages, conjunctival hemorrhages, Osler nodes, Janeway lesions, and Roth spots) can be seen in 5-10% of patients [15].
FE signs and symptoms are generally comparable to those of bacterial etiology, but FE has some distinctive features [8,13]. FE is characterized by (i) larger (‘bulky’) vegetations, responsible for an increased risk of drastic embolic events (such as massive stroke [6] or member ischaemia [17] ) and valvular destruction or chordae rupture leading to acute mitral insufficiency; (ii) more ophthalmological complications, with typical findings on fundoscopy; and (iii) specific dermatological conditions unique to fungal pathogens - macronodules or maculopapules in candidaemia and black hemorrhagic lesions in Aspergillus endocarditis have been reported [18].
One should suspect FE in cases of recurrent fever in patients with a past history of fungaemia [9], especially in patients with blood culture-negative IE (BCNIE) - i.e. IE in which no causative microorganism can be grown using the usual blood culture methods [11]. Despite vegetations seen on echocardiography, blood cultures are negative in over 50% of cases [6].
Diagnosis is based mainly on two aspects: microbiologic tests and echocardiogram (other imaging modalities are also available). A positive blood culture result is highly desirable. Susceptibility testing and determination of fungicidal minimum inhibitory concentrations (MICs) are mandatory [3]. However, the sensitivity for the diagnosis of FE has been estimated at 50-75% or lower [18]. Explanted valves and tissue should also be cultured for fungi/bacteria.
New testing alternatives are also emerging. The mannan antigen and antibody tests for candidaemia detect circulating Candida antigens, antibodies, or other metabolites and have a combined sensitivity and specificity of 83% and 86% respectively for diagnosing fungaemia. This represents an estimated accuracy of 50-70% [18]. Polymerase chain reaction (PCR) molecular methods are also available in blood or in explanted valves and are 3-fold more sensitive than Gram staining and culture [6,15]. However, there is currently no evidence to support the use of these tests in diagnosis of FE and treatment decisions should not be made based on these results alone [3].
TEE has higher sensitivity compared to TTE in detecting vegetations (95% vs. 60%) [18]. Other organ involvement must also be excluded (due the high embolic rate of events) and fundoscopy should be performed as well as an active search for a thrombus elsewhere [7].
Treatment options contemplate a multimodal approach including combined antifungal agents and surgery for the successful management of FE. Early as possible and aggressive surgical treatment is recommended (class I indication, level of evidence B) due to the high mortality and morbidity among patients with medical treatment alone [6,7].
Native or prosthetic valve FE, is considered a standalone indication for surgery by most society guidelines - including the American College of Cardiology (ACC), the American Heart Association (AHA), and the Infectious Diseases Society of America (IDSA) [13,18]. Surgery should be performed as soon as possible, ideally in the first week [7]. Paradoxically, some studies did not find differences in mortality between those undergoing surgical therapy and those receiving only medical therapy [4]. Rare cases of successful treatments with medical therapy alone have been described [19]. Due to lack of randomized studies, there is no consensus on the optimal medical treatment nor its duration [7,20].
Therapeutic recommendations for initial therapy of native valve endocarditis include lipid formulation amphotericin B, 3-5 mg/kg daily, with or without flucytosine, 25 mg/kg four times daily, OR a high-dose echinocandin (caspofungin 150 mg daily, micafungin 100-150 mg daily, or anidulafungin 100-200 mg daily) [7,8,18]. Azoles are only fungistatic in yeasts and therefore cannot be used as primary treatment of Candida endocarditis [18].
Step-down therapy to fluconazole - 400-800 mg (6-12 mg/kg) daily - is recommended for patients who have susceptible Candida isolates, clinical stability, and evidence fungaemia clearance [8]. A minimum of 14 days after the end of candidaemia (determined by one blood culture per day until negativity) is recommended and switching to oral treatment after 10 days of intravenous therapy is proved safe in clinically stable patients with susceptible species [7]. Some authors suggest courses of six weeks or longer in patients with perivalvular abscesses and other complications [8]. When valve replacement is NOT an option after the initial treatment long-term, suppression with fluconazole - 400-800 mg (6-12 mg/kg) daily - is a reasonable option if the isolate is susceptible [6-8,11]. The same antifungal regimens are recommended for prosthetic valve endocarditis. Some authors also advocate chronic suppressive antifungal therapy with fluconazole - 400-800 mg (6-12 mg/kg) daily - to prevent recurrence [8].
Echinocandin and azole resistance in Candida spp. are becoming a particular concern [13]. Persistent fungaemia after one week of treatment should raise suspicion of resistance and susceptibility should be tested, as resistance may emerge on therapy [3]. C. parapsilosis is usually susceptible to amphotericin B, flucytosine, and azoles. Echinocandin-resistant strains (as in this case report) are infrequent and have only been described in case reports [8,20]. One explanation is that C. parapsilosis demonstrates intrinsically higher MICs to the echinocandins than other Candida spp. However there have been no clinical studies proving fluconazole superiority over the echinocandins for C. parapsilosis infections [8].
Despite progress in antifungal therapy and surgical techniques, prognosis is poor and one-year mortality rate remains as high as 50% [7,8,11]. Baseline characteristics associated with high mortality are: older age, previous HF, and nosocomial acquisition of FE [4,9]. Higher mortality was also associated with clinical development of new-onset congestive HF and refractory candidemia [4]. Relapsing FE is a complication seen in as many as 30 to 40%.
Treatment failure causes include relapses due to Candida species ability to form biofilms, which reduce action of anti-fungal agents [5]. Surgical technical difficulties also play a role: homograft appears to be the most appropriate choice by allowing complete debridement of infected tissue with low risk of valve dehiscence and better antibiotic penetration [19]. Other challenges to consider in treating Candida endocarditis include geographic variations, virulence, and reduced susceptibility to antifungal medications [5].
Conclusions
FE is rare, but it carries a high mortality and incidence has been increasing over the last decades. Candida endocarditis clinical spectrum ranges from native or prosthetic valve endocarditis to infection of cardiac devices. Treatment options include combined antifungal agents and surgery.
This case report reminds us of the importance of raising awareness for fungal disease. Management must be made on a case-by-case personalized basis, considering multiple variables such as antifungal agents, surgical options as well as disease severity, prognosis, and patient’s status.
New evidence and recommendations will surely provide more guidelines to improve clinical medicine and contribute to more successful management of FE. Areas of intervention should include policies aiming at reducing FE in select populations (e.g. needle exchange programs, prophylactic usage of fluconazole in selected patients), innovative diagnostic tests, and expert or society consensus on the definition of clinical or microbiological criteria to guide diagnosis and treatment options for these patients.
Human Ethics
The authors would like to acknowledge Dr. Rui Lima (Cardiology) for his contribution to data and image selection.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | CASPOFUNGIN, FLUCONAZOLE, GENTAMICIN, RIFAMPIN, VANCOMYCIN | DrugsGivenReaction | CC BY | 33728162 | 15,739,818 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pathogen resistance'. | Relapsing Candida parapsilosis Endocarditis With Septic Embolization: A Case Report.
Candida endocarditis is a rare infection that is becoming an emerging and growing health concern, especially among risk groups such as the elderly and the immunosuppressed. It is associated with high morbidity and mortality. Dilemmas about Candida endocarditis treatment are still around, particularly about the treatment options and their duration. We report a case of Candida parapsilosis prosthetic valve endocarditis with septic embolisms. An elderly male patient with a biological prosthetic valve presented with fever and constitutional symptoms. Abdominal computed tomography (CT) showed an area suggestive of splenic emboli. Transesophageal echocardiography showed a vegetation attaching to the prosthetic valve. Due to several comorbidities, he was not considered a candidate for surgical treatment. He was treated with antifungal drugs (liposomal amphotericin B and caspofungin) and was discharged with per os fluconazole. Later he presented with evidence of lumbar spondylodiscitis due to septic embolization and relapsing fungemia with multidrug-resistant isolates was documented. Unfortunately, the patient outcome was ill-fated and he died in hospital due to sepsis-related to the candidemia and also nosocomial urinary sepsis. Here, we illustrate the complexity of diagnosing and managing fungal endocarditis due to its complications and poor prognosis.
Introduction
Disseminated fungal infections are rare conditions and fungal endocarditis (FE) is even more unique. FE represents only 2%-4% of all endocarditis [1,2]. The incidence of Candida endocarditis has been increasing simultaneously with the increase in the general number of fungal infections. Most common known risk factors for FE include intravenous (IV) drug users, patients with prosthetic heart valves, immunocompromised hosts (namely transplant recipients), cancer patients receiving chemotherapy, prolonged use of a central venous catheter (CVC), human immunodeficiency virus infection, and a previous episode of bacterial endocarditis [1,3]. Recent series confirm that Candida endocarditis is becoming a predominantly healthcare-associated infection (87%) [3,4].
FE has a remarkably high number of complications and burden of disease [5]. The mortality rate is between 30% to 50% [6,7]. Contributing factors include the host immune state, often delayed or missed diagnosis, and lack of efficient antifungal agents in the absence of surgery. Also worth noting, FE is associated with significant recurrence rates and relapses have been documented months to years later [1,8,9].
Case presentation
We present the case of an 81-year-old male with a previous medical history of arterial hypertension, peripheral arterial disease (for which he had received aorto-bifemoral bypass six years before). Three years earlier he had also undergone a biological aortic valve replacement surgery due to aortic stenosis.
A recent medical history included a prolonged hospitalization early that year when he was diagnosed with gastric adenocarcinoma - staging pT1N0M0. He underwent a subtotal gastrectomy with Billroth type II anastomosis. In the postoperative period, he developed a stricture of the gastrojejunostomy. It was managed conservatively and he received long-term parenteral nutrition (PN) through CVC. He scored 0 points in the Eastern Cooperative Oncology Group (ECOG) performance status but needed no systemic therapy.
Six months later, he presented to our Emergency Department (ED) complaining of vespertine fever, anorexia, and asthenia. The symptoms had been present for one month. On physical examination, we noted an excellent general appearance, pallor, new-onset grade II/VI aortic systolic murmur, a tender abdomen on palpation, and splenomegaly. The laboratory workup showed microcytic hypochromic anemia (Hg 11.2 g/dL), normal leukocyte count with relative lymphocytosis, altered liver panel, thrombocytopenia, and elevated C reactive protein (CRP) (Table 1). An abdominal CT scan was performed and showed an enlarged spleen with a 32x22mm peripheral, wedge-shaped hypo-enhancing area on its posterior aspect, which was highly suggestive of a splenic infarct (Figure 1). No other signs of peripheral emboli were noted.
Table 1 Laboratory workup
MCHC: mean corpuscular hemoglobin concentration, MCV: mean corpuscular volume, CRP: C-reactive protein, Hct: hematocrit
Tests Reference values Results
Haemoglobin (g/dL) 11.8 - 15.8 11.2
Hct (%) 36 - 46 36
MCV (fL) 80.4 - 96.4 74.8
MCHC (g/dL) 31,7 - 35,7 31.1
Leucocytes (μL) 4.0 - 10.0 5480
Neutrophils 1800–7700 2.049
Lymphocytes 800–4000 2.619
Platelets (10^9/uL) 150 - 400 32
Glucose (mg/dL) 70 - 110 99
Urea (mg/dL) 17 - 43 26
Creatinine (mg/dL) 0.6 - 1.0 0,83
Sodium (mmol/L) 136 - 145 139
Potassium (mmol/L) 3.5 - 5.1 4,4
CRP (mg/dL) 0.01-0.82 7,2
Total / direct bilirubin (mg/dL) 0.3 - 1.2 1.19 / 0.6
Alkaline phosphatase (UI/L) 30 - 120 255
Gamma-glutamyl Transferase (UI/L) <55 110
Aspartate Transaminase (UI/L) 8 - 35 93
Alanine Transaminase (UI/L) 10 - 45 26
Figure 1 Abdominal CT scan showing an area of spleen infarct (black arrow)
The patient was admitted to the Internal Medicine ward with a presumptive diagnosis of infective endocarditis with splenic emboli. He met three minor clinical criteria from the Modified Duke Criteria for the Clinical Diagnosis of Infective Endocarditis [10] - fever, a predisposing heart condition, and systemic arterial emboli. Empirical antibiotic therapy with vancomycin and gentamicin was started - considering it might be healthcare-associated endocarditis due to recent hospitalization and abdominal surgery. Rifampicin was added three days later, as advocated for prosthetic valve (PV) infective endocarditis (IE) by The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC) [11].
A transthoracic echocardiogram (TTE) was performed and no changes suggestive of endocarditis were noted. Due to a high suspicion index, a transesophageal echocardiogram (TEE) was performed: it revealed a 7x7mm vegetation attached to the right coronary cusp of the prosthetic aortic valve; no perivalvular abscess, leaks, or prosthetic dysfunction were present (Video 1, 2).
Video 1 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve long axis-view. TEE, transesophageal echocardiogram.
Video 2 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve short-view. TEE, transesophageal echocardiogram
Blood cultures were negative for bacterial agents and yielded colonies of Candida parapsilosis. After this result, the patient was started on antifungal therapy with liposomal amphotericin B (5mg/kg daily), as recommended on current guidelines [8]. He developed a severe adverse anaphylactic reaction and treatment had to be suspended. An alternative regimen with high-dose echinocandin (caspofungin 150mg daily) was initiated, also according to latest recommendations [8]. The antibiotic susceptibility testing (AST) was only available two weeks later: it documented sensitivity to flucytosine, amphotericin B, fluconazole, and voriconazole but resistance to caspofungin. Accordingly, the patient was started on fluconazole therapy (12mg/kg/day).
Surgery was discussed between practitioners from several medical specialties (an ad hoc Endocarditis Team) but the patient was not considered for aortic replacement surgery, considering his comorbidities and very high anesthetic risk with a EuroSCORE II of 15.59% and a Society of Thoracic Surgeons (STS) score of 16.76%. A decision was made for lifelong suppressive therapy with fluconazole, as per current guidelines [8,11]. The patient was discharged from hospital once clinically stable and after two sets of negative blood cultures (over 24 hours apart).
Two months after discharge, he was admitted to our ED complaining of severe lower back pain, fever, and vomiting. By this time, the patient's ECOG performance status had declined significantly from 0 to 3. He underwent lumbar magnetic resonance imaging (MRI), which showed high signal in adjacent endplates and thickening of paravertebral soft tissues (T2 sequences) surrounding the L3-L4 intervertebral disk (Figure 2). These changes were compatible with an indolent manifestation of lumbar spondylodiscitis due to septic embolization. Microbiological relapse was documented. Blood cultures grew the same agent, but de novo resistance to fluconazole was reported in AST.
Figure 2 MRI T2 sequences showing L3-L4 spondylodiscitis (black circle).
MRI, magnetic resonance imaging
The patient developed urinary sepsis with multiorgan failure due to extended-spectrum beta-lactamases (ESBL) Klebsiella pneumonia with documented bacteriemia. Unrelenting clinical deterioration culminated with the patient’s death in-hospital approximately three months after the diagnosis of FE. The final diagnosis was Candida parapsilosis endocarditis with septic embolization (splenic infarct and spondylodiscitis).
Discussion
FE is an uncommon but dangerous and devastating infection. Candida species are the most frequent agents involved in FE: C. albicans cause approximately 25% of cases, non-Candida albicans Candida (NCAC) strains cause ~25% and other fungi such as Aspergillus are responsible for the remaining percentage [3].
C. parapsilosis was originally considered non-pathological until 1940 when it was identified as the causative agent of an FE that caused the death of an IV drug user [12]. Nowadays, C. parapsilosis is the second most common strain to be isolated from blood culture and is associated with nosocomial infections. It is mostly related to vascular devices [3], due to biofilm production on foreign bodies and indwelling catheters. [13]. The biofilm structures form pseudo-hyphae (called "giant cells") that are morphologically distinct from those of C. albicans [5,13]. They also show increased appetence and growing capacity on CVC used with parenteral hyper-alimentation solutions [5].
Predisposing risk factors for C. parapsilosis include the prosthetic heart valves or devices (57.4%), IV drug use (20%), PN (6.9%), immunosuppression (6.4%), treatment with broad-spectrum antibiotics (5.6%) and previous valvular disease (4.8%) [13]. When compared to C. albicans, C. parapsilosis FE has a more frequent history of valvular disease and prior parenteral nutrition [13]. C. parapsilosis has also been linked to indwelling CVCs, cardiac devices, transcatheter aortic valve replacement (TAVR), long-term glucocorticoid therapy and transplant recipients [5,6,8]. All these risk factors seem to have a cumulative behaviour [6,14].
Endocarditis presenting symptoms and signs include fever (in 90% of patients), which is usually protracted (>two weeks) and accompanied by chills, sweating, and malaise [15]. Dyspnea, heart failure (HF), and peripheral embolisms might be present [16]. New-onset murmur or changes in a previously known murmur (in 75% of patients) should also be considered [6]. Presentation can be acute or subacute, with nonspecific symptoms over weeks or months. Microembolic or immunologic phenomena (as splinter hemorrhages, conjunctival hemorrhages, Osler nodes, Janeway lesions, and Roth spots) can be seen in 5-10% of patients [15].
FE signs and symptoms are generally comparable to those of bacterial etiology, but FE has some distinctive features [8,13]. FE is characterized by (i) larger (‘bulky’) vegetations, responsible for an increased risk of drastic embolic events (such as massive stroke [6] or member ischaemia [17] ) and valvular destruction or chordae rupture leading to acute mitral insufficiency; (ii) more ophthalmological complications, with typical findings on fundoscopy; and (iii) specific dermatological conditions unique to fungal pathogens - macronodules or maculopapules in candidaemia and black hemorrhagic lesions in Aspergillus endocarditis have been reported [18].
One should suspect FE in cases of recurrent fever in patients with a past history of fungaemia [9], especially in patients with blood culture-negative IE (BCNIE) - i.e. IE in which no causative microorganism can be grown using the usual blood culture methods [11]. Despite vegetations seen on echocardiography, blood cultures are negative in over 50% of cases [6].
Diagnosis is based mainly on two aspects: microbiologic tests and echocardiogram (other imaging modalities are also available). A positive blood culture result is highly desirable. Susceptibility testing and determination of fungicidal minimum inhibitory concentrations (MICs) are mandatory [3]. However, the sensitivity for the diagnosis of FE has been estimated at 50-75% or lower [18]. Explanted valves and tissue should also be cultured for fungi/bacteria.
New testing alternatives are also emerging. The mannan antigen and antibody tests for candidaemia detect circulating Candida antigens, antibodies, or other metabolites and have a combined sensitivity and specificity of 83% and 86% respectively for diagnosing fungaemia. This represents an estimated accuracy of 50-70% [18]. Polymerase chain reaction (PCR) molecular methods are also available in blood or in explanted valves and are 3-fold more sensitive than Gram staining and culture [6,15]. However, there is currently no evidence to support the use of these tests in diagnosis of FE and treatment decisions should not be made based on these results alone [3].
TEE has higher sensitivity compared to TTE in detecting vegetations (95% vs. 60%) [18]. Other organ involvement must also be excluded (due the high embolic rate of events) and fundoscopy should be performed as well as an active search for a thrombus elsewhere [7].
Treatment options contemplate a multimodal approach including combined antifungal agents and surgery for the successful management of FE. Early as possible and aggressive surgical treatment is recommended (class I indication, level of evidence B) due to the high mortality and morbidity among patients with medical treatment alone [6,7].
Native or prosthetic valve FE, is considered a standalone indication for surgery by most society guidelines - including the American College of Cardiology (ACC), the American Heart Association (AHA), and the Infectious Diseases Society of America (IDSA) [13,18]. Surgery should be performed as soon as possible, ideally in the first week [7]. Paradoxically, some studies did not find differences in mortality between those undergoing surgical therapy and those receiving only medical therapy [4]. Rare cases of successful treatments with medical therapy alone have been described [19]. Due to lack of randomized studies, there is no consensus on the optimal medical treatment nor its duration [7,20].
Therapeutic recommendations for initial therapy of native valve endocarditis include lipid formulation amphotericin B, 3-5 mg/kg daily, with or without flucytosine, 25 mg/kg four times daily, OR a high-dose echinocandin (caspofungin 150 mg daily, micafungin 100-150 mg daily, or anidulafungin 100-200 mg daily) [7,8,18]. Azoles are only fungistatic in yeasts and therefore cannot be used as primary treatment of Candida endocarditis [18].
Step-down therapy to fluconazole - 400-800 mg (6-12 mg/kg) daily - is recommended for patients who have susceptible Candida isolates, clinical stability, and evidence fungaemia clearance [8]. A minimum of 14 days after the end of candidaemia (determined by one blood culture per day until negativity) is recommended and switching to oral treatment after 10 days of intravenous therapy is proved safe in clinically stable patients with susceptible species [7]. Some authors suggest courses of six weeks or longer in patients with perivalvular abscesses and other complications [8]. When valve replacement is NOT an option after the initial treatment long-term, suppression with fluconazole - 400-800 mg (6-12 mg/kg) daily - is a reasonable option if the isolate is susceptible [6-8,11]. The same antifungal regimens are recommended for prosthetic valve endocarditis. Some authors also advocate chronic suppressive antifungal therapy with fluconazole - 400-800 mg (6-12 mg/kg) daily - to prevent recurrence [8].
Echinocandin and azole resistance in Candida spp. are becoming a particular concern [13]. Persistent fungaemia after one week of treatment should raise suspicion of resistance and susceptibility should be tested, as resistance may emerge on therapy [3]. C. parapsilosis is usually susceptible to amphotericin B, flucytosine, and azoles. Echinocandin-resistant strains (as in this case report) are infrequent and have only been described in case reports [8,20]. One explanation is that C. parapsilosis demonstrates intrinsically higher MICs to the echinocandins than other Candida spp. However there have been no clinical studies proving fluconazole superiority over the echinocandins for C. parapsilosis infections [8].
Despite progress in antifungal therapy and surgical techniques, prognosis is poor and one-year mortality rate remains as high as 50% [7,8,11]. Baseline characteristics associated with high mortality are: older age, previous HF, and nosocomial acquisition of FE [4,9]. Higher mortality was also associated with clinical development of new-onset congestive HF and refractory candidemia [4]. Relapsing FE is a complication seen in as many as 30 to 40%.
Treatment failure causes include relapses due to Candida species ability to form biofilms, which reduce action of anti-fungal agents [5]. Surgical technical difficulties also play a role: homograft appears to be the most appropriate choice by allowing complete debridement of infected tissue with low risk of valve dehiscence and better antibiotic penetration [19]. Other challenges to consider in treating Candida endocarditis include geographic variations, virulence, and reduced susceptibility to antifungal medications [5].
Conclusions
FE is rare, but it carries a high mortality and incidence has been increasing over the last decades. Candida endocarditis clinical spectrum ranges from native or prosthetic valve endocarditis to infection of cardiac devices. Treatment options include combined antifungal agents and surgery.
This case report reminds us of the importance of raising awareness for fungal disease. Management must be made on a case-by-case personalized basis, considering multiple variables such as antifungal agents, surgical options as well as disease severity, prognosis, and patient’s status.
New evidence and recommendations will surely provide more guidelines to improve clinical medicine and contribute to more successful management of FE. Areas of intervention should include policies aiming at reducing FE in select populations (e.g. needle exchange programs, prophylactic usage of fluconazole in selected patients), innovative diagnostic tests, and expert or society consensus on the definition of clinical or microbiological criteria to guide diagnosis and treatment options for these patients.
Human Ethics
The authors would like to acknowledge Dr. Rui Lima (Cardiology) for his contribution to data and image selection.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | CASPOFUNGIN, FLUCONAZOLE, GENTAMICIN, RIFAMPIN, VANCOMYCIN | DrugsGivenReaction | CC BY | 33728162 | 15,739,818 | 2021-02-05 |
What was the administration route of drug 'FLUCONAZOLE'? | Relapsing Candida parapsilosis Endocarditis With Septic Embolization: A Case Report.
Candida endocarditis is a rare infection that is becoming an emerging and growing health concern, especially among risk groups such as the elderly and the immunosuppressed. It is associated with high morbidity and mortality. Dilemmas about Candida endocarditis treatment are still around, particularly about the treatment options and their duration. We report a case of Candida parapsilosis prosthetic valve endocarditis with septic embolisms. An elderly male patient with a biological prosthetic valve presented with fever and constitutional symptoms. Abdominal computed tomography (CT) showed an area suggestive of splenic emboli. Transesophageal echocardiography showed a vegetation attaching to the prosthetic valve. Due to several comorbidities, he was not considered a candidate for surgical treatment. He was treated with antifungal drugs (liposomal amphotericin B and caspofungin) and was discharged with per os fluconazole. Later he presented with evidence of lumbar spondylodiscitis due to septic embolization and relapsing fungemia with multidrug-resistant isolates was documented. Unfortunately, the patient outcome was ill-fated and he died in hospital due to sepsis-related to the candidemia and also nosocomial urinary sepsis. Here, we illustrate the complexity of diagnosing and managing fungal endocarditis due to its complications and poor prognosis.
Introduction
Disseminated fungal infections are rare conditions and fungal endocarditis (FE) is even more unique. FE represents only 2%-4% of all endocarditis [1,2]. The incidence of Candida endocarditis has been increasing simultaneously with the increase in the general number of fungal infections. Most common known risk factors for FE include intravenous (IV) drug users, patients with prosthetic heart valves, immunocompromised hosts (namely transplant recipients), cancer patients receiving chemotherapy, prolonged use of a central venous catheter (CVC), human immunodeficiency virus infection, and a previous episode of bacterial endocarditis [1,3]. Recent series confirm that Candida endocarditis is becoming a predominantly healthcare-associated infection (87%) [3,4].
FE has a remarkably high number of complications and burden of disease [5]. The mortality rate is between 30% to 50% [6,7]. Contributing factors include the host immune state, often delayed or missed diagnosis, and lack of efficient antifungal agents in the absence of surgery. Also worth noting, FE is associated with significant recurrence rates and relapses have been documented months to years later [1,8,9].
Case presentation
We present the case of an 81-year-old male with a previous medical history of arterial hypertension, peripheral arterial disease (for which he had received aorto-bifemoral bypass six years before). Three years earlier he had also undergone a biological aortic valve replacement surgery due to aortic stenosis.
A recent medical history included a prolonged hospitalization early that year when he was diagnosed with gastric adenocarcinoma - staging pT1N0M0. He underwent a subtotal gastrectomy with Billroth type II anastomosis. In the postoperative period, he developed a stricture of the gastrojejunostomy. It was managed conservatively and he received long-term parenteral nutrition (PN) through CVC. He scored 0 points in the Eastern Cooperative Oncology Group (ECOG) performance status but needed no systemic therapy.
Six months later, he presented to our Emergency Department (ED) complaining of vespertine fever, anorexia, and asthenia. The symptoms had been present for one month. On physical examination, we noted an excellent general appearance, pallor, new-onset grade II/VI aortic systolic murmur, a tender abdomen on palpation, and splenomegaly. The laboratory workup showed microcytic hypochromic anemia (Hg 11.2 g/dL), normal leukocyte count with relative lymphocytosis, altered liver panel, thrombocytopenia, and elevated C reactive protein (CRP) (Table 1). An abdominal CT scan was performed and showed an enlarged spleen with a 32x22mm peripheral, wedge-shaped hypo-enhancing area on its posterior aspect, which was highly suggestive of a splenic infarct (Figure 1). No other signs of peripheral emboli were noted.
Table 1 Laboratory workup
MCHC: mean corpuscular hemoglobin concentration, MCV: mean corpuscular volume, CRP: C-reactive protein, Hct: hematocrit
Tests Reference values Results
Haemoglobin (g/dL) 11.8 - 15.8 11.2
Hct (%) 36 - 46 36
MCV (fL) 80.4 - 96.4 74.8
MCHC (g/dL) 31,7 - 35,7 31.1
Leucocytes (μL) 4.0 - 10.0 5480
Neutrophils 1800–7700 2.049
Lymphocytes 800–4000 2.619
Platelets (10^9/uL) 150 - 400 32
Glucose (mg/dL) 70 - 110 99
Urea (mg/dL) 17 - 43 26
Creatinine (mg/dL) 0.6 - 1.0 0,83
Sodium (mmol/L) 136 - 145 139
Potassium (mmol/L) 3.5 - 5.1 4,4
CRP (mg/dL) 0.01-0.82 7,2
Total / direct bilirubin (mg/dL) 0.3 - 1.2 1.19 / 0.6
Alkaline phosphatase (UI/L) 30 - 120 255
Gamma-glutamyl Transferase (UI/L) <55 110
Aspartate Transaminase (UI/L) 8 - 35 93
Alanine Transaminase (UI/L) 10 - 45 26
Figure 1 Abdominal CT scan showing an area of spleen infarct (black arrow)
The patient was admitted to the Internal Medicine ward with a presumptive diagnosis of infective endocarditis with splenic emboli. He met three minor clinical criteria from the Modified Duke Criteria for the Clinical Diagnosis of Infective Endocarditis [10] - fever, a predisposing heart condition, and systemic arterial emboli. Empirical antibiotic therapy with vancomycin and gentamicin was started - considering it might be healthcare-associated endocarditis due to recent hospitalization and abdominal surgery. Rifampicin was added three days later, as advocated for prosthetic valve (PV) infective endocarditis (IE) by The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC) [11].
A transthoracic echocardiogram (TTE) was performed and no changes suggestive of endocarditis were noted. Due to a high suspicion index, a transesophageal echocardiogram (TEE) was performed: it revealed a 7x7mm vegetation attached to the right coronary cusp of the prosthetic aortic valve; no perivalvular abscess, leaks, or prosthetic dysfunction were present (Video 1, 2).
Video 1 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve long axis-view. TEE, transesophageal echocardiogram.
Video 2 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve short-view. TEE, transesophageal echocardiogram
Blood cultures were negative for bacterial agents and yielded colonies of Candida parapsilosis. After this result, the patient was started on antifungal therapy with liposomal amphotericin B (5mg/kg daily), as recommended on current guidelines [8]. He developed a severe adverse anaphylactic reaction and treatment had to be suspended. An alternative regimen with high-dose echinocandin (caspofungin 150mg daily) was initiated, also according to latest recommendations [8]. The antibiotic susceptibility testing (AST) was only available two weeks later: it documented sensitivity to flucytosine, amphotericin B, fluconazole, and voriconazole but resistance to caspofungin. Accordingly, the patient was started on fluconazole therapy (12mg/kg/day).
Surgery was discussed between practitioners from several medical specialties (an ad hoc Endocarditis Team) but the patient was not considered for aortic replacement surgery, considering his comorbidities and very high anesthetic risk with a EuroSCORE II of 15.59% and a Society of Thoracic Surgeons (STS) score of 16.76%. A decision was made for lifelong suppressive therapy with fluconazole, as per current guidelines [8,11]. The patient was discharged from hospital once clinically stable and after two sets of negative blood cultures (over 24 hours apart).
Two months after discharge, he was admitted to our ED complaining of severe lower back pain, fever, and vomiting. By this time, the patient's ECOG performance status had declined significantly from 0 to 3. He underwent lumbar magnetic resonance imaging (MRI), which showed high signal in adjacent endplates and thickening of paravertebral soft tissues (T2 sequences) surrounding the L3-L4 intervertebral disk (Figure 2). These changes were compatible with an indolent manifestation of lumbar spondylodiscitis due to septic embolization. Microbiological relapse was documented. Blood cultures grew the same agent, but de novo resistance to fluconazole was reported in AST.
Figure 2 MRI T2 sequences showing L3-L4 spondylodiscitis (black circle).
MRI, magnetic resonance imaging
The patient developed urinary sepsis with multiorgan failure due to extended-spectrum beta-lactamases (ESBL) Klebsiella pneumonia with documented bacteriemia. Unrelenting clinical deterioration culminated with the patient’s death in-hospital approximately three months after the diagnosis of FE. The final diagnosis was Candida parapsilosis endocarditis with septic embolization (splenic infarct and spondylodiscitis).
Discussion
FE is an uncommon but dangerous and devastating infection. Candida species are the most frequent agents involved in FE: C. albicans cause approximately 25% of cases, non-Candida albicans Candida (NCAC) strains cause ~25% and other fungi such as Aspergillus are responsible for the remaining percentage [3].
C. parapsilosis was originally considered non-pathological until 1940 when it was identified as the causative agent of an FE that caused the death of an IV drug user [12]. Nowadays, C. parapsilosis is the second most common strain to be isolated from blood culture and is associated with nosocomial infections. It is mostly related to vascular devices [3], due to biofilm production on foreign bodies and indwelling catheters. [13]. The biofilm structures form pseudo-hyphae (called "giant cells") that are morphologically distinct from those of C. albicans [5,13]. They also show increased appetence and growing capacity on CVC used with parenteral hyper-alimentation solutions [5].
Predisposing risk factors for C. parapsilosis include the prosthetic heart valves or devices (57.4%), IV drug use (20%), PN (6.9%), immunosuppression (6.4%), treatment with broad-spectrum antibiotics (5.6%) and previous valvular disease (4.8%) [13]. When compared to C. albicans, C. parapsilosis FE has a more frequent history of valvular disease and prior parenteral nutrition [13]. C. parapsilosis has also been linked to indwelling CVCs, cardiac devices, transcatheter aortic valve replacement (TAVR), long-term glucocorticoid therapy and transplant recipients [5,6,8]. All these risk factors seem to have a cumulative behaviour [6,14].
Endocarditis presenting symptoms and signs include fever (in 90% of patients), which is usually protracted (>two weeks) and accompanied by chills, sweating, and malaise [15]. Dyspnea, heart failure (HF), and peripheral embolisms might be present [16]. New-onset murmur or changes in a previously known murmur (in 75% of patients) should also be considered [6]. Presentation can be acute or subacute, with nonspecific symptoms over weeks or months. Microembolic or immunologic phenomena (as splinter hemorrhages, conjunctival hemorrhages, Osler nodes, Janeway lesions, and Roth spots) can be seen in 5-10% of patients [15].
FE signs and symptoms are generally comparable to those of bacterial etiology, but FE has some distinctive features [8,13]. FE is characterized by (i) larger (‘bulky’) vegetations, responsible for an increased risk of drastic embolic events (such as massive stroke [6] or member ischaemia [17] ) and valvular destruction or chordae rupture leading to acute mitral insufficiency; (ii) more ophthalmological complications, with typical findings on fundoscopy; and (iii) specific dermatological conditions unique to fungal pathogens - macronodules or maculopapules in candidaemia and black hemorrhagic lesions in Aspergillus endocarditis have been reported [18].
One should suspect FE in cases of recurrent fever in patients with a past history of fungaemia [9], especially in patients with blood culture-negative IE (BCNIE) - i.e. IE in which no causative microorganism can be grown using the usual blood culture methods [11]. Despite vegetations seen on echocardiography, blood cultures are negative in over 50% of cases [6].
Diagnosis is based mainly on two aspects: microbiologic tests and echocardiogram (other imaging modalities are also available). A positive blood culture result is highly desirable. Susceptibility testing and determination of fungicidal minimum inhibitory concentrations (MICs) are mandatory [3]. However, the sensitivity for the diagnosis of FE has been estimated at 50-75% or lower [18]. Explanted valves and tissue should also be cultured for fungi/bacteria.
New testing alternatives are also emerging. The mannan antigen and antibody tests for candidaemia detect circulating Candida antigens, antibodies, or other metabolites and have a combined sensitivity and specificity of 83% and 86% respectively for diagnosing fungaemia. This represents an estimated accuracy of 50-70% [18]. Polymerase chain reaction (PCR) molecular methods are also available in blood or in explanted valves and are 3-fold more sensitive than Gram staining and culture [6,15]. However, there is currently no evidence to support the use of these tests in diagnosis of FE and treatment decisions should not be made based on these results alone [3].
TEE has higher sensitivity compared to TTE in detecting vegetations (95% vs. 60%) [18]. Other organ involvement must also be excluded (due the high embolic rate of events) and fundoscopy should be performed as well as an active search for a thrombus elsewhere [7].
Treatment options contemplate a multimodal approach including combined antifungal agents and surgery for the successful management of FE. Early as possible and aggressive surgical treatment is recommended (class I indication, level of evidence B) due to the high mortality and morbidity among patients with medical treatment alone [6,7].
Native or prosthetic valve FE, is considered a standalone indication for surgery by most society guidelines - including the American College of Cardiology (ACC), the American Heart Association (AHA), and the Infectious Diseases Society of America (IDSA) [13,18]. Surgery should be performed as soon as possible, ideally in the first week [7]. Paradoxically, some studies did not find differences in mortality between those undergoing surgical therapy and those receiving only medical therapy [4]. Rare cases of successful treatments with medical therapy alone have been described [19]. Due to lack of randomized studies, there is no consensus on the optimal medical treatment nor its duration [7,20].
Therapeutic recommendations for initial therapy of native valve endocarditis include lipid formulation amphotericin B, 3-5 mg/kg daily, with or without flucytosine, 25 mg/kg four times daily, OR a high-dose echinocandin (caspofungin 150 mg daily, micafungin 100-150 mg daily, or anidulafungin 100-200 mg daily) [7,8,18]. Azoles are only fungistatic in yeasts and therefore cannot be used as primary treatment of Candida endocarditis [18].
Step-down therapy to fluconazole - 400-800 mg (6-12 mg/kg) daily - is recommended for patients who have susceptible Candida isolates, clinical stability, and evidence fungaemia clearance [8]. A minimum of 14 days after the end of candidaemia (determined by one blood culture per day until negativity) is recommended and switching to oral treatment after 10 days of intravenous therapy is proved safe in clinically stable patients with susceptible species [7]. Some authors suggest courses of six weeks or longer in patients with perivalvular abscesses and other complications [8]. When valve replacement is NOT an option after the initial treatment long-term, suppression with fluconazole - 400-800 mg (6-12 mg/kg) daily - is a reasonable option if the isolate is susceptible [6-8,11]. The same antifungal regimens are recommended for prosthetic valve endocarditis. Some authors also advocate chronic suppressive antifungal therapy with fluconazole - 400-800 mg (6-12 mg/kg) daily - to prevent recurrence [8].
Echinocandin and azole resistance in Candida spp. are becoming a particular concern [13]. Persistent fungaemia after one week of treatment should raise suspicion of resistance and susceptibility should be tested, as resistance may emerge on therapy [3]. C. parapsilosis is usually susceptible to amphotericin B, flucytosine, and azoles. Echinocandin-resistant strains (as in this case report) are infrequent and have only been described in case reports [8,20]. One explanation is that C. parapsilosis demonstrates intrinsically higher MICs to the echinocandins than other Candida spp. However there have been no clinical studies proving fluconazole superiority over the echinocandins for C. parapsilosis infections [8].
Despite progress in antifungal therapy and surgical techniques, prognosis is poor and one-year mortality rate remains as high as 50% [7,8,11]. Baseline characteristics associated with high mortality are: older age, previous HF, and nosocomial acquisition of FE [4,9]. Higher mortality was also associated with clinical development of new-onset congestive HF and refractory candidemia [4]. Relapsing FE is a complication seen in as many as 30 to 40%.
Treatment failure causes include relapses due to Candida species ability to form biofilms, which reduce action of anti-fungal agents [5]. Surgical technical difficulties also play a role: homograft appears to be the most appropriate choice by allowing complete debridement of infected tissue with low risk of valve dehiscence and better antibiotic penetration [19]. Other challenges to consider in treating Candida endocarditis include geographic variations, virulence, and reduced susceptibility to antifungal medications [5].
Conclusions
FE is rare, but it carries a high mortality and incidence has been increasing over the last decades. Candida endocarditis clinical spectrum ranges from native or prosthetic valve endocarditis to infection of cardiac devices. Treatment options include combined antifungal agents and surgery.
This case report reminds us of the importance of raising awareness for fungal disease. Management must be made on a case-by-case personalized basis, considering multiple variables such as antifungal agents, surgical options as well as disease severity, prognosis, and patient’s status.
New evidence and recommendations will surely provide more guidelines to improve clinical medicine and contribute to more successful management of FE. Areas of intervention should include policies aiming at reducing FE in select populations (e.g. needle exchange programs, prophylactic usage of fluconazole in selected patients), innovative diagnostic tests, and expert or society consensus on the definition of clinical or microbiological criteria to guide diagnosis and treatment options for these patients.
Human Ethics
The authors would like to acknowledge Dr. Rui Lima (Cardiology) for his contribution to data and image selection.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33728162 | 15,739,818 | 2021-02-05 |
What was the dosage of drug 'FLUCONAZOLE'? | Relapsing Candida parapsilosis Endocarditis With Septic Embolization: A Case Report.
Candida endocarditis is a rare infection that is becoming an emerging and growing health concern, especially among risk groups such as the elderly and the immunosuppressed. It is associated with high morbidity and mortality. Dilemmas about Candida endocarditis treatment are still around, particularly about the treatment options and their duration. We report a case of Candida parapsilosis prosthetic valve endocarditis with septic embolisms. An elderly male patient with a biological prosthetic valve presented with fever and constitutional symptoms. Abdominal computed tomography (CT) showed an area suggestive of splenic emboli. Transesophageal echocardiography showed a vegetation attaching to the prosthetic valve. Due to several comorbidities, he was not considered a candidate for surgical treatment. He was treated with antifungal drugs (liposomal amphotericin B and caspofungin) and was discharged with per os fluconazole. Later he presented with evidence of lumbar spondylodiscitis due to septic embolization and relapsing fungemia with multidrug-resistant isolates was documented. Unfortunately, the patient outcome was ill-fated and he died in hospital due to sepsis-related to the candidemia and also nosocomial urinary sepsis. Here, we illustrate the complexity of diagnosing and managing fungal endocarditis due to its complications and poor prognosis.
Introduction
Disseminated fungal infections are rare conditions and fungal endocarditis (FE) is even more unique. FE represents only 2%-4% of all endocarditis [1,2]. The incidence of Candida endocarditis has been increasing simultaneously with the increase in the general number of fungal infections. Most common known risk factors for FE include intravenous (IV) drug users, patients with prosthetic heart valves, immunocompromised hosts (namely transplant recipients), cancer patients receiving chemotherapy, prolonged use of a central venous catheter (CVC), human immunodeficiency virus infection, and a previous episode of bacterial endocarditis [1,3]. Recent series confirm that Candida endocarditis is becoming a predominantly healthcare-associated infection (87%) [3,4].
FE has a remarkably high number of complications and burden of disease [5]. The mortality rate is between 30% to 50% [6,7]. Contributing factors include the host immune state, often delayed or missed diagnosis, and lack of efficient antifungal agents in the absence of surgery. Also worth noting, FE is associated with significant recurrence rates and relapses have been documented months to years later [1,8,9].
Case presentation
We present the case of an 81-year-old male with a previous medical history of arterial hypertension, peripheral arterial disease (for which he had received aorto-bifemoral bypass six years before). Three years earlier he had also undergone a biological aortic valve replacement surgery due to aortic stenosis.
A recent medical history included a prolonged hospitalization early that year when he was diagnosed with gastric adenocarcinoma - staging pT1N0M0. He underwent a subtotal gastrectomy with Billroth type II anastomosis. In the postoperative period, he developed a stricture of the gastrojejunostomy. It was managed conservatively and he received long-term parenteral nutrition (PN) through CVC. He scored 0 points in the Eastern Cooperative Oncology Group (ECOG) performance status but needed no systemic therapy.
Six months later, he presented to our Emergency Department (ED) complaining of vespertine fever, anorexia, and asthenia. The symptoms had been present for one month. On physical examination, we noted an excellent general appearance, pallor, new-onset grade II/VI aortic systolic murmur, a tender abdomen on palpation, and splenomegaly. The laboratory workup showed microcytic hypochromic anemia (Hg 11.2 g/dL), normal leukocyte count with relative lymphocytosis, altered liver panel, thrombocytopenia, and elevated C reactive protein (CRP) (Table 1). An abdominal CT scan was performed and showed an enlarged spleen with a 32x22mm peripheral, wedge-shaped hypo-enhancing area on its posterior aspect, which was highly suggestive of a splenic infarct (Figure 1). No other signs of peripheral emboli were noted.
Table 1 Laboratory workup
MCHC: mean corpuscular hemoglobin concentration, MCV: mean corpuscular volume, CRP: C-reactive protein, Hct: hematocrit
Tests Reference values Results
Haemoglobin (g/dL) 11.8 - 15.8 11.2
Hct (%) 36 - 46 36
MCV (fL) 80.4 - 96.4 74.8
MCHC (g/dL) 31,7 - 35,7 31.1
Leucocytes (μL) 4.0 - 10.0 5480
Neutrophils 1800–7700 2.049
Lymphocytes 800–4000 2.619
Platelets (10^9/uL) 150 - 400 32
Glucose (mg/dL) 70 - 110 99
Urea (mg/dL) 17 - 43 26
Creatinine (mg/dL) 0.6 - 1.0 0,83
Sodium (mmol/L) 136 - 145 139
Potassium (mmol/L) 3.5 - 5.1 4,4
CRP (mg/dL) 0.01-0.82 7,2
Total / direct bilirubin (mg/dL) 0.3 - 1.2 1.19 / 0.6
Alkaline phosphatase (UI/L) 30 - 120 255
Gamma-glutamyl Transferase (UI/L) <55 110
Aspartate Transaminase (UI/L) 8 - 35 93
Alanine Transaminase (UI/L) 10 - 45 26
Figure 1 Abdominal CT scan showing an area of spleen infarct (black arrow)
The patient was admitted to the Internal Medicine ward with a presumptive diagnosis of infective endocarditis with splenic emboli. He met three minor clinical criteria from the Modified Duke Criteria for the Clinical Diagnosis of Infective Endocarditis [10] - fever, a predisposing heart condition, and systemic arterial emboli. Empirical antibiotic therapy with vancomycin and gentamicin was started - considering it might be healthcare-associated endocarditis due to recent hospitalization and abdominal surgery. Rifampicin was added three days later, as advocated for prosthetic valve (PV) infective endocarditis (IE) by The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC) [11].
A transthoracic echocardiogram (TTE) was performed and no changes suggestive of endocarditis were noted. Due to a high suspicion index, a transesophageal echocardiogram (TEE) was performed: it revealed a 7x7mm vegetation attached to the right coronary cusp of the prosthetic aortic valve; no perivalvular abscess, leaks, or prosthetic dysfunction were present (Video 1, 2).
Video 1 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve long axis-view. TEE, transesophageal echocardiogram.
Video 2 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve short-view. TEE, transesophageal echocardiogram
Blood cultures were negative for bacterial agents and yielded colonies of Candida parapsilosis. After this result, the patient was started on antifungal therapy with liposomal amphotericin B (5mg/kg daily), as recommended on current guidelines [8]. He developed a severe adverse anaphylactic reaction and treatment had to be suspended. An alternative regimen with high-dose echinocandin (caspofungin 150mg daily) was initiated, also according to latest recommendations [8]. The antibiotic susceptibility testing (AST) was only available two weeks later: it documented sensitivity to flucytosine, amphotericin B, fluconazole, and voriconazole but resistance to caspofungin. Accordingly, the patient was started on fluconazole therapy (12mg/kg/day).
Surgery was discussed between practitioners from several medical specialties (an ad hoc Endocarditis Team) but the patient was not considered for aortic replacement surgery, considering his comorbidities and very high anesthetic risk with a EuroSCORE II of 15.59% and a Society of Thoracic Surgeons (STS) score of 16.76%. A decision was made for lifelong suppressive therapy with fluconazole, as per current guidelines [8,11]. The patient was discharged from hospital once clinically stable and after two sets of negative blood cultures (over 24 hours apart).
Two months after discharge, he was admitted to our ED complaining of severe lower back pain, fever, and vomiting. By this time, the patient's ECOG performance status had declined significantly from 0 to 3. He underwent lumbar magnetic resonance imaging (MRI), which showed high signal in adjacent endplates and thickening of paravertebral soft tissues (T2 sequences) surrounding the L3-L4 intervertebral disk (Figure 2). These changes were compatible with an indolent manifestation of lumbar spondylodiscitis due to septic embolization. Microbiological relapse was documented. Blood cultures grew the same agent, but de novo resistance to fluconazole was reported in AST.
Figure 2 MRI T2 sequences showing L3-L4 spondylodiscitis (black circle).
MRI, magnetic resonance imaging
The patient developed urinary sepsis with multiorgan failure due to extended-spectrum beta-lactamases (ESBL) Klebsiella pneumonia with documented bacteriemia. Unrelenting clinical deterioration culminated with the patient’s death in-hospital approximately three months after the diagnosis of FE. The final diagnosis was Candida parapsilosis endocarditis with septic embolization (splenic infarct and spondylodiscitis).
Discussion
FE is an uncommon but dangerous and devastating infection. Candida species are the most frequent agents involved in FE: C. albicans cause approximately 25% of cases, non-Candida albicans Candida (NCAC) strains cause ~25% and other fungi such as Aspergillus are responsible for the remaining percentage [3].
C. parapsilosis was originally considered non-pathological until 1940 when it was identified as the causative agent of an FE that caused the death of an IV drug user [12]. Nowadays, C. parapsilosis is the second most common strain to be isolated from blood culture and is associated with nosocomial infections. It is mostly related to vascular devices [3], due to biofilm production on foreign bodies and indwelling catheters. [13]. The biofilm structures form pseudo-hyphae (called "giant cells") that are morphologically distinct from those of C. albicans [5,13]. They also show increased appetence and growing capacity on CVC used with parenteral hyper-alimentation solutions [5].
Predisposing risk factors for C. parapsilosis include the prosthetic heart valves or devices (57.4%), IV drug use (20%), PN (6.9%), immunosuppression (6.4%), treatment with broad-spectrum antibiotics (5.6%) and previous valvular disease (4.8%) [13]. When compared to C. albicans, C. parapsilosis FE has a more frequent history of valvular disease and prior parenteral nutrition [13]. C. parapsilosis has also been linked to indwelling CVCs, cardiac devices, transcatheter aortic valve replacement (TAVR), long-term glucocorticoid therapy and transplant recipients [5,6,8]. All these risk factors seem to have a cumulative behaviour [6,14].
Endocarditis presenting symptoms and signs include fever (in 90% of patients), which is usually protracted (>two weeks) and accompanied by chills, sweating, and malaise [15]. Dyspnea, heart failure (HF), and peripheral embolisms might be present [16]. New-onset murmur or changes in a previously known murmur (in 75% of patients) should also be considered [6]. Presentation can be acute or subacute, with nonspecific symptoms over weeks or months. Microembolic or immunologic phenomena (as splinter hemorrhages, conjunctival hemorrhages, Osler nodes, Janeway lesions, and Roth spots) can be seen in 5-10% of patients [15].
FE signs and symptoms are generally comparable to those of bacterial etiology, but FE has some distinctive features [8,13]. FE is characterized by (i) larger (‘bulky’) vegetations, responsible for an increased risk of drastic embolic events (such as massive stroke [6] or member ischaemia [17] ) and valvular destruction or chordae rupture leading to acute mitral insufficiency; (ii) more ophthalmological complications, with typical findings on fundoscopy; and (iii) specific dermatological conditions unique to fungal pathogens - macronodules or maculopapules in candidaemia and black hemorrhagic lesions in Aspergillus endocarditis have been reported [18].
One should suspect FE in cases of recurrent fever in patients with a past history of fungaemia [9], especially in patients with blood culture-negative IE (BCNIE) - i.e. IE in which no causative microorganism can be grown using the usual blood culture methods [11]. Despite vegetations seen on echocardiography, blood cultures are negative in over 50% of cases [6].
Diagnosis is based mainly on two aspects: microbiologic tests and echocardiogram (other imaging modalities are also available). A positive blood culture result is highly desirable. Susceptibility testing and determination of fungicidal minimum inhibitory concentrations (MICs) are mandatory [3]. However, the sensitivity for the diagnosis of FE has been estimated at 50-75% or lower [18]. Explanted valves and tissue should also be cultured for fungi/bacteria.
New testing alternatives are also emerging. The mannan antigen and antibody tests for candidaemia detect circulating Candida antigens, antibodies, or other metabolites and have a combined sensitivity and specificity of 83% and 86% respectively for diagnosing fungaemia. This represents an estimated accuracy of 50-70% [18]. Polymerase chain reaction (PCR) molecular methods are also available in blood or in explanted valves and are 3-fold more sensitive than Gram staining and culture [6,15]. However, there is currently no evidence to support the use of these tests in diagnosis of FE and treatment decisions should not be made based on these results alone [3].
TEE has higher sensitivity compared to TTE in detecting vegetations (95% vs. 60%) [18]. Other organ involvement must also be excluded (due the high embolic rate of events) and fundoscopy should be performed as well as an active search for a thrombus elsewhere [7].
Treatment options contemplate a multimodal approach including combined antifungal agents and surgery for the successful management of FE. Early as possible and aggressive surgical treatment is recommended (class I indication, level of evidence B) due to the high mortality and morbidity among patients with medical treatment alone [6,7].
Native or prosthetic valve FE, is considered a standalone indication for surgery by most society guidelines - including the American College of Cardiology (ACC), the American Heart Association (AHA), and the Infectious Diseases Society of America (IDSA) [13,18]. Surgery should be performed as soon as possible, ideally in the first week [7]. Paradoxically, some studies did not find differences in mortality between those undergoing surgical therapy and those receiving only medical therapy [4]. Rare cases of successful treatments with medical therapy alone have been described [19]. Due to lack of randomized studies, there is no consensus on the optimal medical treatment nor its duration [7,20].
Therapeutic recommendations for initial therapy of native valve endocarditis include lipid formulation amphotericin B, 3-5 mg/kg daily, with or without flucytosine, 25 mg/kg four times daily, OR a high-dose echinocandin (caspofungin 150 mg daily, micafungin 100-150 mg daily, or anidulafungin 100-200 mg daily) [7,8,18]. Azoles are only fungistatic in yeasts and therefore cannot be used as primary treatment of Candida endocarditis [18].
Step-down therapy to fluconazole - 400-800 mg (6-12 mg/kg) daily - is recommended for patients who have susceptible Candida isolates, clinical stability, and evidence fungaemia clearance [8]. A minimum of 14 days after the end of candidaemia (determined by one blood culture per day until negativity) is recommended and switching to oral treatment after 10 days of intravenous therapy is proved safe in clinically stable patients with susceptible species [7]. Some authors suggest courses of six weeks or longer in patients with perivalvular abscesses and other complications [8]. When valve replacement is NOT an option after the initial treatment long-term, suppression with fluconazole - 400-800 mg (6-12 mg/kg) daily - is a reasonable option if the isolate is susceptible [6-8,11]. The same antifungal regimens are recommended for prosthetic valve endocarditis. Some authors also advocate chronic suppressive antifungal therapy with fluconazole - 400-800 mg (6-12 mg/kg) daily - to prevent recurrence [8].
Echinocandin and azole resistance in Candida spp. are becoming a particular concern [13]. Persistent fungaemia after one week of treatment should raise suspicion of resistance and susceptibility should be tested, as resistance may emerge on therapy [3]. C. parapsilosis is usually susceptible to amphotericin B, flucytosine, and azoles. Echinocandin-resistant strains (as in this case report) are infrequent and have only been described in case reports [8,20]. One explanation is that C. parapsilosis demonstrates intrinsically higher MICs to the echinocandins than other Candida spp. However there have been no clinical studies proving fluconazole superiority over the echinocandins for C. parapsilosis infections [8].
Despite progress in antifungal therapy and surgical techniques, prognosis is poor and one-year mortality rate remains as high as 50% [7,8,11]. Baseline characteristics associated with high mortality are: older age, previous HF, and nosocomial acquisition of FE [4,9]. Higher mortality was also associated with clinical development of new-onset congestive HF and refractory candidemia [4]. Relapsing FE is a complication seen in as many as 30 to 40%.
Treatment failure causes include relapses due to Candida species ability to form biofilms, which reduce action of anti-fungal agents [5]. Surgical technical difficulties also play a role: homograft appears to be the most appropriate choice by allowing complete debridement of infected tissue with low risk of valve dehiscence and better antibiotic penetration [19]. Other challenges to consider in treating Candida endocarditis include geographic variations, virulence, and reduced susceptibility to antifungal medications [5].
Conclusions
FE is rare, but it carries a high mortality and incidence has been increasing over the last decades. Candida endocarditis clinical spectrum ranges from native or prosthetic valve endocarditis to infection of cardiac devices. Treatment options include combined antifungal agents and surgery.
This case report reminds us of the importance of raising awareness for fungal disease. Management must be made on a case-by-case personalized basis, considering multiple variables such as antifungal agents, surgical options as well as disease severity, prognosis, and patient’s status.
New evidence and recommendations will surely provide more guidelines to improve clinical medicine and contribute to more successful management of FE. Areas of intervention should include policies aiming at reducing FE in select populations (e.g. needle exchange programs, prophylactic usage of fluconazole in selected patients), innovative diagnostic tests, and expert or society consensus on the definition of clinical or microbiological criteria to guide diagnosis and treatment options for these patients.
Human Ethics
The authors would like to acknowledge Dr. Rui Lima (Cardiology) for his contribution to data and image selection.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | 12 MG/KG, DAILY | DrugDosageText | CC BY | 33728162 | 15,739,818 | 2021-02-05 |
What was the outcome of reaction 'Drug ineffective'? | Relapsing Candida parapsilosis Endocarditis With Septic Embolization: A Case Report.
Candida endocarditis is a rare infection that is becoming an emerging and growing health concern, especially among risk groups such as the elderly and the immunosuppressed. It is associated with high morbidity and mortality. Dilemmas about Candida endocarditis treatment are still around, particularly about the treatment options and their duration. We report a case of Candida parapsilosis prosthetic valve endocarditis with septic embolisms. An elderly male patient with a biological prosthetic valve presented with fever and constitutional symptoms. Abdominal computed tomography (CT) showed an area suggestive of splenic emboli. Transesophageal echocardiography showed a vegetation attaching to the prosthetic valve. Due to several comorbidities, he was not considered a candidate for surgical treatment. He was treated with antifungal drugs (liposomal amphotericin B and caspofungin) and was discharged with per os fluconazole. Later he presented with evidence of lumbar spondylodiscitis due to septic embolization and relapsing fungemia with multidrug-resistant isolates was documented. Unfortunately, the patient outcome was ill-fated and he died in hospital due to sepsis-related to the candidemia and also nosocomial urinary sepsis. Here, we illustrate the complexity of diagnosing and managing fungal endocarditis due to its complications and poor prognosis.
Introduction
Disseminated fungal infections are rare conditions and fungal endocarditis (FE) is even more unique. FE represents only 2%-4% of all endocarditis [1,2]. The incidence of Candida endocarditis has been increasing simultaneously with the increase in the general number of fungal infections. Most common known risk factors for FE include intravenous (IV) drug users, patients with prosthetic heart valves, immunocompromised hosts (namely transplant recipients), cancer patients receiving chemotherapy, prolonged use of a central venous catheter (CVC), human immunodeficiency virus infection, and a previous episode of bacterial endocarditis [1,3]. Recent series confirm that Candida endocarditis is becoming a predominantly healthcare-associated infection (87%) [3,4].
FE has a remarkably high number of complications and burden of disease [5]. The mortality rate is between 30% to 50% [6,7]. Contributing factors include the host immune state, often delayed or missed diagnosis, and lack of efficient antifungal agents in the absence of surgery. Also worth noting, FE is associated with significant recurrence rates and relapses have been documented months to years later [1,8,9].
Case presentation
We present the case of an 81-year-old male with a previous medical history of arterial hypertension, peripheral arterial disease (for which he had received aorto-bifemoral bypass six years before). Three years earlier he had also undergone a biological aortic valve replacement surgery due to aortic stenosis.
A recent medical history included a prolonged hospitalization early that year when he was diagnosed with gastric adenocarcinoma - staging pT1N0M0. He underwent a subtotal gastrectomy with Billroth type II anastomosis. In the postoperative period, he developed a stricture of the gastrojejunostomy. It was managed conservatively and he received long-term parenteral nutrition (PN) through CVC. He scored 0 points in the Eastern Cooperative Oncology Group (ECOG) performance status but needed no systemic therapy.
Six months later, he presented to our Emergency Department (ED) complaining of vespertine fever, anorexia, and asthenia. The symptoms had been present for one month. On physical examination, we noted an excellent general appearance, pallor, new-onset grade II/VI aortic systolic murmur, a tender abdomen on palpation, and splenomegaly. The laboratory workup showed microcytic hypochromic anemia (Hg 11.2 g/dL), normal leukocyte count with relative lymphocytosis, altered liver panel, thrombocytopenia, and elevated C reactive protein (CRP) (Table 1). An abdominal CT scan was performed and showed an enlarged spleen with a 32x22mm peripheral, wedge-shaped hypo-enhancing area on its posterior aspect, which was highly suggestive of a splenic infarct (Figure 1). No other signs of peripheral emboli were noted.
Table 1 Laboratory workup
MCHC: mean corpuscular hemoglobin concentration, MCV: mean corpuscular volume, CRP: C-reactive protein, Hct: hematocrit
Tests Reference values Results
Haemoglobin (g/dL) 11.8 - 15.8 11.2
Hct (%) 36 - 46 36
MCV (fL) 80.4 - 96.4 74.8
MCHC (g/dL) 31,7 - 35,7 31.1
Leucocytes (μL) 4.0 - 10.0 5480
Neutrophils 1800–7700 2.049
Lymphocytes 800–4000 2.619
Platelets (10^9/uL) 150 - 400 32
Glucose (mg/dL) 70 - 110 99
Urea (mg/dL) 17 - 43 26
Creatinine (mg/dL) 0.6 - 1.0 0,83
Sodium (mmol/L) 136 - 145 139
Potassium (mmol/L) 3.5 - 5.1 4,4
CRP (mg/dL) 0.01-0.82 7,2
Total / direct bilirubin (mg/dL) 0.3 - 1.2 1.19 / 0.6
Alkaline phosphatase (UI/L) 30 - 120 255
Gamma-glutamyl Transferase (UI/L) <55 110
Aspartate Transaminase (UI/L) 8 - 35 93
Alanine Transaminase (UI/L) 10 - 45 26
Figure 1 Abdominal CT scan showing an area of spleen infarct (black arrow)
The patient was admitted to the Internal Medicine ward with a presumptive diagnosis of infective endocarditis with splenic emboli. He met three minor clinical criteria from the Modified Duke Criteria for the Clinical Diagnosis of Infective Endocarditis [10] - fever, a predisposing heart condition, and systemic arterial emboli. Empirical antibiotic therapy with vancomycin and gentamicin was started - considering it might be healthcare-associated endocarditis due to recent hospitalization and abdominal surgery. Rifampicin was added three days later, as advocated for prosthetic valve (PV) infective endocarditis (IE) by The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC) [11].
A transthoracic echocardiogram (TTE) was performed and no changes suggestive of endocarditis were noted. Due to a high suspicion index, a transesophageal echocardiogram (TEE) was performed: it revealed a 7x7mm vegetation attached to the right coronary cusp of the prosthetic aortic valve; no perivalvular abscess, leaks, or prosthetic dysfunction were present (Video 1, 2).
Video 1 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve long axis-view. TEE, transesophageal echocardiogram.
Video 2 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve short-view. TEE, transesophageal echocardiogram
Blood cultures were negative for bacterial agents and yielded colonies of Candida parapsilosis. After this result, the patient was started on antifungal therapy with liposomal amphotericin B (5mg/kg daily), as recommended on current guidelines [8]. He developed a severe adverse anaphylactic reaction and treatment had to be suspended. An alternative regimen with high-dose echinocandin (caspofungin 150mg daily) was initiated, also according to latest recommendations [8]. The antibiotic susceptibility testing (AST) was only available two weeks later: it documented sensitivity to flucytosine, amphotericin B, fluconazole, and voriconazole but resistance to caspofungin. Accordingly, the patient was started on fluconazole therapy (12mg/kg/day).
Surgery was discussed between practitioners from several medical specialties (an ad hoc Endocarditis Team) but the patient was not considered for aortic replacement surgery, considering his comorbidities and very high anesthetic risk with a EuroSCORE II of 15.59% and a Society of Thoracic Surgeons (STS) score of 16.76%. A decision was made for lifelong suppressive therapy with fluconazole, as per current guidelines [8,11]. The patient was discharged from hospital once clinically stable and after two sets of negative blood cultures (over 24 hours apart).
Two months after discharge, he was admitted to our ED complaining of severe lower back pain, fever, and vomiting. By this time, the patient's ECOG performance status had declined significantly from 0 to 3. He underwent lumbar magnetic resonance imaging (MRI), which showed high signal in adjacent endplates and thickening of paravertebral soft tissues (T2 sequences) surrounding the L3-L4 intervertebral disk (Figure 2). These changes were compatible with an indolent manifestation of lumbar spondylodiscitis due to septic embolization. Microbiological relapse was documented. Blood cultures grew the same agent, but de novo resistance to fluconazole was reported in AST.
Figure 2 MRI T2 sequences showing L3-L4 spondylodiscitis (black circle).
MRI, magnetic resonance imaging
The patient developed urinary sepsis with multiorgan failure due to extended-spectrum beta-lactamases (ESBL) Klebsiella pneumonia with documented bacteriemia. Unrelenting clinical deterioration culminated with the patient’s death in-hospital approximately three months after the diagnosis of FE. The final diagnosis was Candida parapsilosis endocarditis with septic embolization (splenic infarct and spondylodiscitis).
Discussion
FE is an uncommon but dangerous and devastating infection. Candida species are the most frequent agents involved in FE: C. albicans cause approximately 25% of cases, non-Candida albicans Candida (NCAC) strains cause ~25% and other fungi such as Aspergillus are responsible for the remaining percentage [3].
C. parapsilosis was originally considered non-pathological until 1940 when it was identified as the causative agent of an FE that caused the death of an IV drug user [12]. Nowadays, C. parapsilosis is the second most common strain to be isolated from blood culture and is associated with nosocomial infections. It is mostly related to vascular devices [3], due to biofilm production on foreign bodies and indwelling catheters. [13]. The biofilm structures form pseudo-hyphae (called "giant cells") that are morphologically distinct from those of C. albicans [5,13]. They also show increased appetence and growing capacity on CVC used with parenteral hyper-alimentation solutions [5].
Predisposing risk factors for C. parapsilosis include the prosthetic heart valves or devices (57.4%), IV drug use (20%), PN (6.9%), immunosuppression (6.4%), treatment with broad-spectrum antibiotics (5.6%) and previous valvular disease (4.8%) [13]. When compared to C. albicans, C. parapsilosis FE has a more frequent history of valvular disease and prior parenteral nutrition [13]. C. parapsilosis has also been linked to indwelling CVCs, cardiac devices, transcatheter aortic valve replacement (TAVR), long-term glucocorticoid therapy and transplant recipients [5,6,8]. All these risk factors seem to have a cumulative behaviour [6,14].
Endocarditis presenting symptoms and signs include fever (in 90% of patients), which is usually protracted (>two weeks) and accompanied by chills, sweating, and malaise [15]. Dyspnea, heart failure (HF), and peripheral embolisms might be present [16]. New-onset murmur or changes in a previously known murmur (in 75% of patients) should also be considered [6]. Presentation can be acute or subacute, with nonspecific symptoms over weeks or months. Microembolic or immunologic phenomena (as splinter hemorrhages, conjunctival hemorrhages, Osler nodes, Janeway lesions, and Roth spots) can be seen in 5-10% of patients [15].
FE signs and symptoms are generally comparable to those of bacterial etiology, but FE has some distinctive features [8,13]. FE is characterized by (i) larger (‘bulky’) vegetations, responsible for an increased risk of drastic embolic events (such as massive stroke [6] or member ischaemia [17] ) and valvular destruction or chordae rupture leading to acute mitral insufficiency; (ii) more ophthalmological complications, with typical findings on fundoscopy; and (iii) specific dermatological conditions unique to fungal pathogens - macronodules or maculopapules in candidaemia and black hemorrhagic lesions in Aspergillus endocarditis have been reported [18].
One should suspect FE in cases of recurrent fever in patients with a past history of fungaemia [9], especially in patients with blood culture-negative IE (BCNIE) - i.e. IE in which no causative microorganism can be grown using the usual blood culture methods [11]. Despite vegetations seen on echocardiography, blood cultures are negative in over 50% of cases [6].
Diagnosis is based mainly on two aspects: microbiologic tests and echocardiogram (other imaging modalities are also available). A positive blood culture result is highly desirable. Susceptibility testing and determination of fungicidal minimum inhibitory concentrations (MICs) are mandatory [3]. However, the sensitivity for the diagnosis of FE has been estimated at 50-75% or lower [18]. Explanted valves and tissue should also be cultured for fungi/bacteria.
New testing alternatives are also emerging. The mannan antigen and antibody tests for candidaemia detect circulating Candida antigens, antibodies, or other metabolites and have a combined sensitivity and specificity of 83% and 86% respectively for diagnosing fungaemia. This represents an estimated accuracy of 50-70% [18]. Polymerase chain reaction (PCR) molecular methods are also available in blood or in explanted valves and are 3-fold more sensitive than Gram staining and culture [6,15]. However, there is currently no evidence to support the use of these tests in diagnosis of FE and treatment decisions should not be made based on these results alone [3].
TEE has higher sensitivity compared to TTE in detecting vegetations (95% vs. 60%) [18]. Other organ involvement must also be excluded (due the high embolic rate of events) and fundoscopy should be performed as well as an active search for a thrombus elsewhere [7].
Treatment options contemplate a multimodal approach including combined antifungal agents and surgery for the successful management of FE. Early as possible and aggressive surgical treatment is recommended (class I indication, level of evidence B) due to the high mortality and morbidity among patients with medical treatment alone [6,7].
Native or prosthetic valve FE, is considered a standalone indication for surgery by most society guidelines - including the American College of Cardiology (ACC), the American Heart Association (AHA), and the Infectious Diseases Society of America (IDSA) [13,18]. Surgery should be performed as soon as possible, ideally in the first week [7]. Paradoxically, some studies did not find differences in mortality between those undergoing surgical therapy and those receiving only medical therapy [4]. Rare cases of successful treatments with medical therapy alone have been described [19]. Due to lack of randomized studies, there is no consensus on the optimal medical treatment nor its duration [7,20].
Therapeutic recommendations for initial therapy of native valve endocarditis include lipid formulation amphotericin B, 3-5 mg/kg daily, with or without flucytosine, 25 mg/kg four times daily, OR a high-dose echinocandin (caspofungin 150 mg daily, micafungin 100-150 mg daily, or anidulafungin 100-200 mg daily) [7,8,18]. Azoles are only fungistatic in yeasts and therefore cannot be used as primary treatment of Candida endocarditis [18].
Step-down therapy to fluconazole - 400-800 mg (6-12 mg/kg) daily - is recommended for patients who have susceptible Candida isolates, clinical stability, and evidence fungaemia clearance [8]. A minimum of 14 days after the end of candidaemia (determined by one blood culture per day until negativity) is recommended and switching to oral treatment after 10 days of intravenous therapy is proved safe in clinically stable patients with susceptible species [7]. Some authors suggest courses of six weeks or longer in patients with perivalvular abscesses and other complications [8]. When valve replacement is NOT an option after the initial treatment long-term, suppression with fluconazole - 400-800 mg (6-12 mg/kg) daily - is a reasonable option if the isolate is susceptible [6-8,11]. The same antifungal regimens are recommended for prosthetic valve endocarditis. Some authors also advocate chronic suppressive antifungal therapy with fluconazole - 400-800 mg (6-12 mg/kg) daily - to prevent recurrence [8].
Echinocandin and azole resistance in Candida spp. are becoming a particular concern [13]. Persistent fungaemia after one week of treatment should raise suspicion of resistance and susceptibility should be tested, as resistance may emerge on therapy [3]. C. parapsilosis is usually susceptible to amphotericin B, flucytosine, and azoles. Echinocandin-resistant strains (as in this case report) are infrequent and have only been described in case reports [8,20]. One explanation is that C. parapsilosis demonstrates intrinsically higher MICs to the echinocandins than other Candida spp. However there have been no clinical studies proving fluconazole superiority over the echinocandins for C. parapsilosis infections [8].
Despite progress in antifungal therapy and surgical techniques, prognosis is poor and one-year mortality rate remains as high as 50% [7,8,11]. Baseline characteristics associated with high mortality are: older age, previous HF, and nosocomial acquisition of FE [4,9]. Higher mortality was also associated with clinical development of new-onset congestive HF and refractory candidemia [4]. Relapsing FE is a complication seen in as many as 30 to 40%.
Treatment failure causes include relapses due to Candida species ability to form biofilms, which reduce action of anti-fungal agents [5]. Surgical technical difficulties also play a role: homograft appears to be the most appropriate choice by allowing complete debridement of infected tissue with low risk of valve dehiscence and better antibiotic penetration [19]. Other challenges to consider in treating Candida endocarditis include geographic variations, virulence, and reduced susceptibility to antifungal medications [5].
Conclusions
FE is rare, but it carries a high mortality and incidence has been increasing over the last decades. Candida endocarditis clinical spectrum ranges from native or prosthetic valve endocarditis to infection of cardiac devices. Treatment options include combined antifungal agents and surgery.
This case report reminds us of the importance of raising awareness for fungal disease. Management must be made on a case-by-case personalized basis, considering multiple variables such as antifungal agents, surgical options as well as disease severity, prognosis, and patient’s status.
New evidence and recommendations will surely provide more guidelines to improve clinical medicine and contribute to more successful management of FE. Areas of intervention should include policies aiming at reducing FE in select populations (e.g. needle exchange programs, prophylactic usage of fluconazole in selected patients), innovative diagnostic tests, and expert or society consensus on the definition of clinical or microbiological criteria to guide diagnosis and treatment options for these patients.
Human Ethics
The authors would like to acknowledge Dr. Rui Lima (Cardiology) for his contribution to data and image selection.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Fatal | ReactionOutcome | CC BY | 33728162 | 15,739,818 | 2021-02-05 |
What was the outcome of reaction 'Drug resistance'? | Relapsing Candida parapsilosis Endocarditis With Septic Embolization: A Case Report.
Candida endocarditis is a rare infection that is becoming an emerging and growing health concern, especially among risk groups such as the elderly and the immunosuppressed. It is associated with high morbidity and mortality. Dilemmas about Candida endocarditis treatment are still around, particularly about the treatment options and their duration. We report a case of Candida parapsilosis prosthetic valve endocarditis with septic embolisms. An elderly male patient with a biological prosthetic valve presented with fever and constitutional symptoms. Abdominal computed tomography (CT) showed an area suggestive of splenic emboli. Transesophageal echocardiography showed a vegetation attaching to the prosthetic valve. Due to several comorbidities, he was not considered a candidate for surgical treatment. He was treated with antifungal drugs (liposomal amphotericin B and caspofungin) and was discharged with per os fluconazole. Later he presented with evidence of lumbar spondylodiscitis due to septic embolization and relapsing fungemia with multidrug-resistant isolates was documented. Unfortunately, the patient outcome was ill-fated and he died in hospital due to sepsis-related to the candidemia and also nosocomial urinary sepsis. Here, we illustrate the complexity of diagnosing and managing fungal endocarditis due to its complications and poor prognosis.
Introduction
Disseminated fungal infections are rare conditions and fungal endocarditis (FE) is even more unique. FE represents only 2%-4% of all endocarditis [1,2]. The incidence of Candida endocarditis has been increasing simultaneously with the increase in the general number of fungal infections. Most common known risk factors for FE include intravenous (IV) drug users, patients with prosthetic heart valves, immunocompromised hosts (namely transplant recipients), cancer patients receiving chemotherapy, prolonged use of a central venous catheter (CVC), human immunodeficiency virus infection, and a previous episode of bacterial endocarditis [1,3]. Recent series confirm that Candida endocarditis is becoming a predominantly healthcare-associated infection (87%) [3,4].
FE has a remarkably high number of complications and burden of disease [5]. The mortality rate is between 30% to 50% [6,7]. Contributing factors include the host immune state, often delayed or missed diagnosis, and lack of efficient antifungal agents in the absence of surgery. Also worth noting, FE is associated with significant recurrence rates and relapses have been documented months to years later [1,8,9].
Case presentation
We present the case of an 81-year-old male with a previous medical history of arterial hypertension, peripheral arterial disease (for which he had received aorto-bifemoral bypass six years before). Three years earlier he had also undergone a biological aortic valve replacement surgery due to aortic stenosis.
A recent medical history included a prolonged hospitalization early that year when he was diagnosed with gastric adenocarcinoma - staging pT1N0M0. He underwent a subtotal gastrectomy with Billroth type II anastomosis. In the postoperative period, he developed a stricture of the gastrojejunostomy. It was managed conservatively and he received long-term parenteral nutrition (PN) through CVC. He scored 0 points in the Eastern Cooperative Oncology Group (ECOG) performance status but needed no systemic therapy.
Six months later, he presented to our Emergency Department (ED) complaining of vespertine fever, anorexia, and asthenia. The symptoms had been present for one month. On physical examination, we noted an excellent general appearance, pallor, new-onset grade II/VI aortic systolic murmur, a tender abdomen on palpation, and splenomegaly. The laboratory workup showed microcytic hypochromic anemia (Hg 11.2 g/dL), normal leukocyte count with relative lymphocytosis, altered liver panel, thrombocytopenia, and elevated C reactive protein (CRP) (Table 1). An abdominal CT scan was performed and showed an enlarged spleen with a 32x22mm peripheral, wedge-shaped hypo-enhancing area on its posterior aspect, which was highly suggestive of a splenic infarct (Figure 1). No other signs of peripheral emboli were noted.
Table 1 Laboratory workup
MCHC: mean corpuscular hemoglobin concentration, MCV: mean corpuscular volume, CRP: C-reactive protein, Hct: hematocrit
Tests Reference values Results
Haemoglobin (g/dL) 11.8 - 15.8 11.2
Hct (%) 36 - 46 36
MCV (fL) 80.4 - 96.4 74.8
MCHC (g/dL) 31,7 - 35,7 31.1
Leucocytes (μL) 4.0 - 10.0 5480
Neutrophils 1800–7700 2.049
Lymphocytes 800–4000 2.619
Platelets (10^9/uL) 150 - 400 32
Glucose (mg/dL) 70 - 110 99
Urea (mg/dL) 17 - 43 26
Creatinine (mg/dL) 0.6 - 1.0 0,83
Sodium (mmol/L) 136 - 145 139
Potassium (mmol/L) 3.5 - 5.1 4,4
CRP (mg/dL) 0.01-0.82 7,2
Total / direct bilirubin (mg/dL) 0.3 - 1.2 1.19 / 0.6
Alkaline phosphatase (UI/L) 30 - 120 255
Gamma-glutamyl Transferase (UI/L) <55 110
Aspartate Transaminase (UI/L) 8 - 35 93
Alanine Transaminase (UI/L) 10 - 45 26
Figure 1 Abdominal CT scan showing an area of spleen infarct (black arrow)
The patient was admitted to the Internal Medicine ward with a presumptive diagnosis of infective endocarditis with splenic emboli. He met three minor clinical criteria from the Modified Duke Criteria for the Clinical Diagnosis of Infective Endocarditis [10] - fever, a predisposing heart condition, and systemic arterial emboli. Empirical antibiotic therapy with vancomycin and gentamicin was started - considering it might be healthcare-associated endocarditis due to recent hospitalization and abdominal surgery. Rifampicin was added three days later, as advocated for prosthetic valve (PV) infective endocarditis (IE) by The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC) [11].
A transthoracic echocardiogram (TTE) was performed and no changes suggestive of endocarditis were noted. Due to a high suspicion index, a transesophageal echocardiogram (TEE) was performed: it revealed a 7x7mm vegetation attached to the right coronary cusp of the prosthetic aortic valve; no perivalvular abscess, leaks, or prosthetic dysfunction were present (Video 1, 2).
Video 1 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve long axis-view. TEE, transesophageal echocardiogram.
Video 2 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve short-view. TEE, transesophageal echocardiogram
Blood cultures were negative for bacterial agents and yielded colonies of Candida parapsilosis. After this result, the patient was started on antifungal therapy with liposomal amphotericin B (5mg/kg daily), as recommended on current guidelines [8]. He developed a severe adverse anaphylactic reaction and treatment had to be suspended. An alternative regimen with high-dose echinocandin (caspofungin 150mg daily) was initiated, also according to latest recommendations [8]. The antibiotic susceptibility testing (AST) was only available two weeks later: it documented sensitivity to flucytosine, amphotericin B, fluconazole, and voriconazole but resistance to caspofungin. Accordingly, the patient was started on fluconazole therapy (12mg/kg/day).
Surgery was discussed between practitioners from several medical specialties (an ad hoc Endocarditis Team) but the patient was not considered for aortic replacement surgery, considering his comorbidities and very high anesthetic risk with a EuroSCORE II of 15.59% and a Society of Thoracic Surgeons (STS) score of 16.76%. A decision was made for lifelong suppressive therapy with fluconazole, as per current guidelines [8,11]. The patient was discharged from hospital once clinically stable and after two sets of negative blood cultures (over 24 hours apart).
Two months after discharge, he was admitted to our ED complaining of severe lower back pain, fever, and vomiting. By this time, the patient's ECOG performance status had declined significantly from 0 to 3. He underwent lumbar magnetic resonance imaging (MRI), which showed high signal in adjacent endplates and thickening of paravertebral soft tissues (T2 sequences) surrounding the L3-L4 intervertebral disk (Figure 2). These changes were compatible with an indolent manifestation of lumbar spondylodiscitis due to septic embolization. Microbiological relapse was documented. Blood cultures grew the same agent, but de novo resistance to fluconazole was reported in AST.
Figure 2 MRI T2 sequences showing L3-L4 spondylodiscitis (black circle).
MRI, magnetic resonance imaging
The patient developed urinary sepsis with multiorgan failure due to extended-spectrum beta-lactamases (ESBL) Klebsiella pneumonia with documented bacteriemia. Unrelenting clinical deterioration culminated with the patient’s death in-hospital approximately three months after the diagnosis of FE. The final diagnosis was Candida parapsilosis endocarditis with septic embolization (splenic infarct and spondylodiscitis).
Discussion
FE is an uncommon but dangerous and devastating infection. Candida species are the most frequent agents involved in FE: C. albicans cause approximately 25% of cases, non-Candida albicans Candida (NCAC) strains cause ~25% and other fungi such as Aspergillus are responsible for the remaining percentage [3].
C. parapsilosis was originally considered non-pathological until 1940 when it was identified as the causative agent of an FE that caused the death of an IV drug user [12]. Nowadays, C. parapsilosis is the second most common strain to be isolated from blood culture and is associated with nosocomial infections. It is mostly related to vascular devices [3], due to biofilm production on foreign bodies and indwelling catheters. [13]. The biofilm structures form pseudo-hyphae (called "giant cells") that are morphologically distinct from those of C. albicans [5,13]. They also show increased appetence and growing capacity on CVC used with parenteral hyper-alimentation solutions [5].
Predisposing risk factors for C. parapsilosis include the prosthetic heart valves or devices (57.4%), IV drug use (20%), PN (6.9%), immunosuppression (6.4%), treatment with broad-spectrum antibiotics (5.6%) and previous valvular disease (4.8%) [13]. When compared to C. albicans, C. parapsilosis FE has a more frequent history of valvular disease and prior parenteral nutrition [13]. C. parapsilosis has also been linked to indwelling CVCs, cardiac devices, transcatheter aortic valve replacement (TAVR), long-term glucocorticoid therapy and transplant recipients [5,6,8]. All these risk factors seem to have a cumulative behaviour [6,14].
Endocarditis presenting symptoms and signs include fever (in 90% of patients), which is usually protracted (>two weeks) and accompanied by chills, sweating, and malaise [15]. Dyspnea, heart failure (HF), and peripheral embolisms might be present [16]. New-onset murmur or changes in a previously known murmur (in 75% of patients) should also be considered [6]. Presentation can be acute or subacute, with nonspecific symptoms over weeks or months. Microembolic or immunologic phenomena (as splinter hemorrhages, conjunctival hemorrhages, Osler nodes, Janeway lesions, and Roth spots) can be seen in 5-10% of patients [15].
FE signs and symptoms are generally comparable to those of bacterial etiology, but FE has some distinctive features [8,13]. FE is characterized by (i) larger (‘bulky’) vegetations, responsible for an increased risk of drastic embolic events (such as massive stroke [6] or member ischaemia [17] ) and valvular destruction or chordae rupture leading to acute mitral insufficiency; (ii) more ophthalmological complications, with typical findings on fundoscopy; and (iii) specific dermatological conditions unique to fungal pathogens - macronodules or maculopapules in candidaemia and black hemorrhagic lesions in Aspergillus endocarditis have been reported [18].
One should suspect FE in cases of recurrent fever in patients with a past history of fungaemia [9], especially in patients with blood culture-negative IE (BCNIE) - i.e. IE in which no causative microorganism can be grown using the usual blood culture methods [11]. Despite vegetations seen on echocardiography, blood cultures are negative in over 50% of cases [6].
Diagnosis is based mainly on two aspects: microbiologic tests and echocardiogram (other imaging modalities are also available). A positive blood culture result is highly desirable. Susceptibility testing and determination of fungicidal minimum inhibitory concentrations (MICs) are mandatory [3]. However, the sensitivity for the diagnosis of FE has been estimated at 50-75% or lower [18]. Explanted valves and tissue should also be cultured for fungi/bacteria.
New testing alternatives are also emerging. The mannan antigen and antibody tests for candidaemia detect circulating Candida antigens, antibodies, or other metabolites and have a combined sensitivity and specificity of 83% and 86% respectively for diagnosing fungaemia. This represents an estimated accuracy of 50-70% [18]. Polymerase chain reaction (PCR) molecular methods are also available in blood or in explanted valves and are 3-fold more sensitive than Gram staining and culture [6,15]. However, there is currently no evidence to support the use of these tests in diagnosis of FE and treatment decisions should not be made based on these results alone [3].
TEE has higher sensitivity compared to TTE in detecting vegetations (95% vs. 60%) [18]. Other organ involvement must also be excluded (due the high embolic rate of events) and fundoscopy should be performed as well as an active search for a thrombus elsewhere [7].
Treatment options contemplate a multimodal approach including combined antifungal agents and surgery for the successful management of FE. Early as possible and aggressive surgical treatment is recommended (class I indication, level of evidence B) due to the high mortality and morbidity among patients with medical treatment alone [6,7].
Native or prosthetic valve FE, is considered a standalone indication for surgery by most society guidelines - including the American College of Cardiology (ACC), the American Heart Association (AHA), and the Infectious Diseases Society of America (IDSA) [13,18]. Surgery should be performed as soon as possible, ideally in the first week [7]. Paradoxically, some studies did not find differences in mortality between those undergoing surgical therapy and those receiving only medical therapy [4]. Rare cases of successful treatments with medical therapy alone have been described [19]. Due to lack of randomized studies, there is no consensus on the optimal medical treatment nor its duration [7,20].
Therapeutic recommendations for initial therapy of native valve endocarditis include lipid formulation amphotericin B, 3-5 mg/kg daily, with or without flucytosine, 25 mg/kg four times daily, OR a high-dose echinocandin (caspofungin 150 mg daily, micafungin 100-150 mg daily, or anidulafungin 100-200 mg daily) [7,8,18]. Azoles are only fungistatic in yeasts and therefore cannot be used as primary treatment of Candida endocarditis [18].
Step-down therapy to fluconazole - 400-800 mg (6-12 mg/kg) daily - is recommended for patients who have susceptible Candida isolates, clinical stability, and evidence fungaemia clearance [8]. A minimum of 14 days after the end of candidaemia (determined by one blood culture per day until negativity) is recommended and switching to oral treatment after 10 days of intravenous therapy is proved safe in clinically stable patients with susceptible species [7]. Some authors suggest courses of six weeks or longer in patients with perivalvular abscesses and other complications [8]. When valve replacement is NOT an option after the initial treatment long-term, suppression with fluconazole - 400-800 mg (6-12 mg/kg) daily - is a reasonable option if the isolate is susceptible [6-8,11]. The same antifungal regimens are recommended for prosthetic valve endocarditis. Some authors also advocate chronic suppressive antifungal therapy with fluconazole - 400-800 mg (6-12 mg/kg) daily - to prevent recurrence [8].
Echinocandin and azole resistance in Candida spp. are becoming a particular concern [13]. Persistent fungaemia after one week of treatment should raise suspicion of resistance and susceptibility should be tested, as resistance may emerge on therapy [3]. C. parapsilosis is usually susceptible to amphotericin B, flucytosine, and azoles. Echinocandin-resistant strains (as in this case report) are infrequent and have only been described in case reports [8,20]. One explanation is that C. parapsilosis demonstrates intrinsically higher MICs to the echinocandins than other Candida spp. However there have been no clinical studies proving fluconazole superiority over the echinocandins for C. parapsilosis infections [8].
Despite progress in antifungal therapy and surgical techniques, prognosis is poor and one-year mortality rate remains as high as 50% [7,8,11]. Baseline characteristics associated with high mortality are: older age, previous HF, and nosocomial acquisition of FE [4,9]. Higher mortality was also associated with clinical development of new-onset congestive HF and refractory candidemia [4]. Relapsing FE is a complication seen in as many as 30 to 40%.
Treatment failure causes include relapses due to Candida species ability to form biofilms, which reduce action of anti-fungal agents [5]. Surgical technical difficulties also play a role: homograft appears to be the most appropriate choice by allowing complete debridement of infected tissue with low risk of valve dehiscence and better antibiotic penetration [19]. Other challenges to consider in treating Candida endocarditis include geographic variations, virulence, and reduced susceptibility to antifungal medications [5].
Conclusions
FE is rare, but it carries a high mortality and incidence has been increasing over the last decades. Candida endocarditis clinical spectrum ranges from native or prosthetic valve endocarditis to infection of cardiac devices. Treatment options include combined antifungal agents and surgery.
This case report reminds us of the importance of raising awareness for fungal disease. Management must be made on a case-by-case personalized basis, considering multiple variables such as antifungal agents, surgical options as well as disease severity, prognosis, and patient’s status.
New evidence and recommendations will surely provide more guidelines to improve clinical medicine and contribute to more successful management of FE. Areas of intervention should include policies aiming at reducing FE in select populations (e.g. needle exchange programs, prophylactic usage of fluconazole in selected patients), innovative diagnostic tests, and expert or society consensus on the definition of clinical or microbiological criteria to guide diagnosis and treatment options for these patients.
Human Ethics
The authors would like to acknowledge Dr. Rui Lima (Cardiology) for his contribution to data and image selection.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Fatal | ReactionOutcome | CC BY | 33728162 | 15,739,818 | 2021-02-05 |
What was the outcome of reaction 'Pathogen resistance'? | Relapsing Candida parapsilosis Endocarditis With Septic Embolization: A Case Report.
Candida endocarditis is a rare infection that is becoming an emerging and growing health concern, especially among risk groups such as the elderly and the immunosuppressed. It is associated with high morbidity and mortality. Dilemmas about Candida endocarditis treatment are still around, particularly about the treatment options and their duration. We report a case of Candida parapsilosis prosthetic valve endocarditis with septic embolisms. An elderly male patient with a biological prosthetic valve presented with fever and constitutional symptoms. Abdominal computed tomography (CT) showed an area suggestive of splenic emboli. Transesophageal echocardiography showed a vegetation attaching to the prosthetic valve. Due to several comorbidities, he was not considered a candidate for surgical treatment. He was treated with antifungal drugs (liposomal amphotericin B and caspofungin) and was discharged with per os fluconazole. Later he presented with evidence of lumbar spondylodiscitis due to septic embolization and relapsing fungemia with multidrug-resistant isolates was documented. Unfortunately, the patient outcome was ill-fated and he died in hospital due to sepsis-related to the candidemia and also nosocomial urinary sepsis. Here, we illustrate the complexity of diagnosing and managing fungal endocarditis due to its complications and poor prognosis.
Introduction
Disseminated fungal infections are rare conditions and fungal endocarditis (FE) is even more unique. FE represents only 2%-4% of all endocarditis [1,2]. The incidence of Candida endocarditis has been increasing simultaneously with the increase in the general number of fungal infections. Most common known risk factors for FE include intravenous (IV) drug users, patients with prosthetic heart valves, immunocompromised hosts (namely transplant recipients), cancer patients receiving chemotherapy, prolonged use of a central venous catheter (CVC), human immunodeficiency virus infection, and a previous episode of bacterial endocarditis [1,3]. Recent series confirm that Candida endocarditis is becoming a predominantly healthcare-associated infection (87%) [3,4].
FE has a remarkably high number of complications and burden of disease [5]. The mortality rate is between 30% to 50% [6,7]. Contributing factors include the host immune state, often delayed or missed diagnosis, and lack of efficient antifungal agents in the absence of surgery. Also worth noting, FE is associated with significant recurrence rates and relapses have been documented months to years later [1,8,9].
Case presentation
We present the case of an 81-year-old male with a previous medical history of arterial hypertension, peripheral arterial disease (for which he had received aorto-bifemoral bypass six years before). Three years earlier he had also undergone a biological aortic valve replacement surgery due to aortic stenosis.
A recent medical history included a prolonged hospitalization early that year when he was diagnosed with gastric adenocarcinoma - staging pT1N0M0. He underwent a subtotal gastrectomy with Billroth type II anastomosis. In the postoperative period, he developed a stricture of the gastrojejunostomy. It was managed conservatively and he received long-term parenteral nutrition (PN) through CVC. He scored 0 points in the Eastern Cooperative Oncology Group (ECOG) performance status but needed no systemic therapy.
Six months later, he presented to our Emergency Department (ED) complaining of vespertine fever, anorexia, and asthenia. The symptoms had been present for one month. On physical examination, we noted an excellent general appearance, pallor, new-onset grade II/VI aortic systolic murmur, a tender abdomen on palpation, and splenomegaly. The laboratory workup showed microcytic hypochromic anemia (Hg 11.2 g/dL), normal leukocyte count with relative lymphocytosis, altered liver panel, thrombocytopenia, and elevated C reactive protein (CRP) (Table 1). An abdominal CT scan was performed and showed an enlarged spleen with a 32x22mm peripheral, wedge-shaped hypo-enhancing area on its posterior aspect, which was highly suggestive of a splenic infarct (Figure 1). No other signs of peripheral emboli were noted.
Table 1 Laboratory workup
MCHC: mean corpuscular hemoglobin concentration, MCV: mean corpuscular volume, CRP: C-reactive protein, Hct: hematocrit
Tests Reference values Results
Haemoglobin (g/dL) 11.8 - 15.8 11.2
Hct (%) 36 - 46 36
MCV (fL) 80.4 - 96.4 74.8
MCHC (g/dL) 31,7 - 35,7 31.1
Leucocytes (μL) 4.0 - 10.0 5480
Neutrophils 1800–7700 2.049
Lymphocytes 800–4000 2.619
Platelets (10^9/uL) 150 - 400 32
Glucose (mg/dL) 70 - 110 99
Urea (mg/dL) 17 - 43 26
Creatinine (mg/dL) 0.6 - 1.0 0,83
Sodium (mmol/L) 136 - 145 139
Potassium (mmol/L) 3.5 - 5.1 4,4
CRP (mg/dL) 0.01-0.82 7,2
Total / direct bilirubin (mg/dL) 0.3 - 1.2 1.19 / 0.6
Alkaline phosphatase (UI/L) 30 - 120 255
Gamma-glutamyl Transferase (UI/L) <55 110
Aspartate Transaminase (UI/L) 8 - 35 93
Alanine Transaminase (UI/L) 10 - 45 26
Figure 1 Abdominal CT scan showing an area of spleen infarct (black arrow)
The patient was admitted to the Internal Medicine ward with a presumptive diagnosis of infective endocarditis with splenic emboli. He met three minor clinical criteria from the Modified Duke Criteria for the Clinical Diagnosis of Infective Endocarditis [10] - fever, a predisposing heart condition, and systemic arterial emboli. Empirical antibiotic therapy with vancomycin and gentamicin was started - considering it might be healthcare-associated endocarditis due to recent hospitalization and abdominal surgery. Rifampicin was added three days later, as advocated for prosthetic valve (PV) infective endocarditis (IE) by The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC) [11].
A transthoracic echocardiogram (TTE) was performed and no changes suggestive of endocarditis were noted. Due to a high suspicion index, a transesophageal echocardiogram (TEE) was performed: it revealed a 7x7mm vegetation attached to the right coronary cusp of the prosthetic aortic valve; no perivalvular abscess, leaks, or prosthetic dysfunction were present (Video 1, 2).
Video 1 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve long axis-view. TEE, transesophageal echocardiogram.
Video 2 TEE showing vegetation attached to the right coronary cusp of the prosthetic aortic valve.
Upper esophageal probe position - Aortic valve short-view. TEE, transesophageal echocardiogram
Blood cultures were negative for bacterial agents and yielded colonies of Candida parapsilosis. After this result, the patient was started on antifungal therapy with liposomal amphotericin B (5mg/kg daily), as recommended on current guidelines [8]. He developed a severe adverse anaphylactic reaction and treatment had to be suspended. An alternative regimen with high-dose echinocandin (caspofungin 150mg daily) was initiated, also according to latest recommendations [8]. The antibiotic susceptibility testing (AST) was only available two weeks later: it documented sensitivity to flucytosine, amphotericin B, fluconazole, and voriconazole but resistance to caspofungin. Accordingly, the patient was started on fluconazole therapy (12mg/kg/day).
Surgery was discussed between practitioners from several medical specialties (an ad hoc Endocarditis Team) but the patient was not considered for aortic replacement surgery, considering his comorbidities and very high anesthetic risk with a EuroSCORE II of 15.59% and a Society of Thoracic Surgeons (STS) score of 16.76%. A decision was made for lifelong suppressive therapy with fluconazole, as per current guidelines [8,11]. The patient was discharged from hospital once clinically stable and after two sets of negative blood cultures (over 24 hours apart).
Two months after discharge, he was admitted to our ED complaining of severe lower back pain, fever, and vomiting. By this time, the patient's ECOG performance status had declined significantly from 0 to 3. He underwent lumbar magnetic resonance imaging (MRI), which showed high signal in adjacent endplates and thickening of paravertebral soft tissues (T2 sequences) surrounding the L3-L4 intervertebral disk (Figure 2). These changes were compatible with an indolent manifestation of lumbar spondylodiscitis due to septic embolization. Microbiological relapse was documented. Blood cultures grew the same agent, but de novo resistance to fluconazole was reported in AST.
Figure 2 MRI T2 sequences showing L3-L4 spondylodiscitis (black circle).
MRI, magnetic resonance imaging
The patient developed urinary sepsis with multiorgan failure due to extended-spectrum beta-lactamases (ESBL) Klebsiella pneumonia with documented bacteriemia. Unrelenting clinical deterioration culminated with the patient’s death in-hospital approximately three months after the diagnosis of FE. The final diagnosis was Candida parapsilosis endocarditis with septic embolization (splenic infarct and spondylodiscitis).
Discussion
FE is an uncommon but dangerous and devastating infection. Candida species are the most frequent agents involved in FE: C. albicans cause approximately 25% of cases, non-Candida albicans Candida (NCAC) strains cause ~25% and other fungi such as Aspergillus are responsible for the remaining percentage [3].
C. parapsilosis was originally considered non-pathological until 1940 when it was identified as the causative agent of an FE that caused the death of an IV drug user [12]. Nowadays, C. parapsilosis is the second most common strain to be isolated from blood culture and is associated with nosocomial infections. It is mostly related to vascular devices [3], due to biofilm production on foreign bodies and indwelling catheters. [13]. The biofilm structures form pseudo-hyphae (called "giant cells") that are morphologically distinct from those of C. albicans [5,13]. They also show increased appetence and growing capacity on CVC used with parenteral hyper-alimentation solutions [5].
Predisposing risk factors for C. parapsilosis include the prosthetic heart valves or devices (57.4%), IV drug use (20%), PN (6.9%), immunosuppression (6.4%), treatment with broad-spectrum antibiotics (5.6%) and previous valvular disease (4.8%) [13]. When compared to C. albicans, C. parapsilosis FE has a more frequent history of valvular disease and prior parenteral nutrition [13]. C. parapsilosis has also been linked to indwelling CVCs, cardiac devices, transcatheter aortic valve replacement (TAVR), long-term glucocorticoid therapy and transplant recipients [5,6,8]. All these risk factors seem to have a cumulative behaviour [6,14].
Endocarditis presenting symptoms and signs include fever (in 90% of patients), which is usually protracted (>two weeks) and accompanied by chills, sweating, and malaise [15]. Dyspnea, heart failure (HF), and peripheral embolisms might be present [16]. New-onset murmur or changes in a previously known murmur (in 75% of patients) should also be considered [6]. Presentation can be acute or subacute, with nonspecific symptoms over weeks or months. Microembolic or immunologic phenomena (as splinter hemorrhages, conjunctival hemorrhages, Osler nodes, Janeway lesions, and Roth spots) can be seen in 5-10% of patients [15].
FE signs and symptoms are generally comparable to those of bacterial etiology, but FE has some distinctive features [8,13]. FE is characterized by (i) larger (‘bulky’) vegetations, responsible for an increased risk of drastic embolic events (such as massive stroke [6] or member ischaemia [17] ) and valvular destruction or chordae rupture leading to acute mitral insufficiency; (ii) more ophthalmological complications, with typical findings on fundoscopy; and (iii) specific dermatological conditions unique to fungal pathogens - macronodules or maculopapules in candidaemia and black hemorrhagic lesions in Aspergillus endocarditis have been reported [18].
One should suspect FE in cases of recurrent fever in patients with a past history of fungaemia [9], especially in patients with blood culture-negative IE (BCNIE) - i.e. IE in which no causative microorganism can be grown using the usual blood culture methods [11]. Despite vegetations seen on echocardiography, blood cultures are negative in over 50% of cases [6].
Diagnosis is based mainly on two aspects: microbiologic tests and echocardiogram (other imaging modalities are also available). A positive blood culture result is highly desirable. Susceptibility testing and determination of fungicidal minimum inhibitory concentrations (MICs) are mandatory [3]. However, the sensitivity for the diagnosis of FE has been estimated at 50-75% or lower [18]. Explanted valves and tissue should also be cultured for fungi/bacteria.
New testing alternatives are also emerging. The mannan antigen and antibody tests for candidaemia detect circulating Candida antigens, antibodies, or other metabolites and have a combined sensitivity and specificity of 83% and 86% respectively for diagnosing fungaemia. This represents an estimated accuracy of 50-70% [18]. Polymerase chain reaction (PCR) molecular methods are also available in blood or in explanted valves and are 3-fold more sensitive than Gram staining and culture [6,15]. However, there is currently no evidence to support the use of these tests in diagnosis of FE and treatment decisions should not be made based on these results alone [3].
TEE has higher sensitivity compared to TTE in detecting vegetations (95% vs. 60%) [18]. Other organ involvement must also be excluded (due the high embolic rate of events) and fundoscopy should be performed as well as an active search for a thrombus elsewhere [7].
Treatment options contemplate a multimodal approach including combined antifungal agents and surgery for the successful management of FE. Early as possible and aggressive surgical treatment is recommended (class I indication, level of evidence B) due to the high mortality and morbidity among patients with medical treatment alone [6,7].
Native or prosthetic valve FE, is considered a standalone indication for surgery by most society guidelines - including the American College of Cardiology (ACC), the American Heart Association (AHA), and the Infectious Diseases Society of America (IDSA) [13,18]. Surgery should be performed as soon as possible, ideally in the first week [7]. Paradoxically, some studies did not find differences in mortality between those undergoing surgical therapy and those receiving only medical therapy [4]. Rare cases of successful treatments with medical therapy alone have been described [19]. Due to lack of randomized studies, there is no consensus on the optimal medical treatment nor its duration [7,20].
Therapeutic recommendations for initial therapy of native valve endocarditis include lipid formulation amphotericin B, 3-5 mg/kg daily, with or without flucytosine, 25 mg/kg four times daily, OR a high-dose echinocandin (caspofungin 150 mg daily, micafungin 100-150 mg daily, or anidulafungin 100-200 mg daily) [7,8,18]. Azoles are only fungistatic in yeasts and therefore cannot be used as primary treatment of Candida endocarditis [18].
Step-down therapy to fluconazole - 400-800 mg (6-12 mg/kg) daily - is recommended for patients who have susceptible Candida isolates, clinical stability, and evidence fungaemia clearance [8]. A minimum of 14 days after the end of candidaemia (determined by one blood culture per day until negativity) is recommended and switching to oral treatment after 10 days of intravenous therapy is proved safe in clinically stable patients with susceptible species [7]. Some authors suggest courses of six weeks or longer in patients with perivalvular abscesses and other complications [8]. When valve replacement is NOT an option after the initial treatment long-term, suppression with fluconazole - 400-800 mg (6-12 mg/kg) daily - is a reasonable option if the isolate is susceptible [6-8,11]. The same antifungal regimens are recommended for prosthetic valve endocarditis. Some authors also advocate chronic suppressive antifungal therapy with fluconazole - 400-800 mg (6-12 mg/kg) daily - to prevent recurrence [8].
Echinocandin and azole resistance in Candida spp. are becoming a particular concern [13]. Persistent fungaemia after one week of treatment should raise suspicion of resistance and susceptibility should be tested, as resistance may emerge on therapy [3]. C. parapsilosis is usually susceptible to amphotericin B, flucytosine, and azoles. Echinocandin-resistant strains (as in this case report) are infrequent and have only been described in case reports [8,20]. One explanation is that C. parapsilosis demonstrates intrinsically higher MICs to the echinocandins than other Candida spp. However there have been no clinical studies proving fluconazole superiority over the echinocandins for C. parapsilosis infections [8].
Despite progress in antifungal therapy and surgical techniques, prognosis is poor and one-year mortality rate remains as high as 50% [7,8,11]. Baseline characteristics associated with high mortality are: older age, previous HF, and nosocomial acquisition of FE [4,9]. Higher mortality was also associated with clinical development of new-onset congestive HF and refractory candidemia [4]. Relapsing FE is a complication seen in as many as 30 to 40%.
Treatment failure causes include relapses due to Candida species ability to form biofilms, which reduce action of anti-fungal agents [5]. Surgical technical difficulties also play a role: homograft appears to be the most appropriate choice by allowing complete debridement of infected tissue with low risk of valve dehiscence and better antibiotic penetration [19]. Other challenges to consider in treating Candida endocarditis include geographic variations, virulence, and reduced susceptibility to antifungal medications [5].
Conclusions
FE is rare, but it carries a high mortality and incidence has been increasing over the last decades. Candida endocarditis clinical spectrum ranges from native or prosthetic valve endocarditis to infection of cardiac devices. Treatment options include combined antifungal agents and surgery.
This case report reminds us of the importance of raising awareness for fungal disease. Management must be made on a case-by-case personalized basis, considering multiple variables such as antifungal agents, surgical options as well as disease severity, prognosis, and patient’s status.
New evidence and recommendations will surely provide more guidelines to improve clinical medicine and contribute to more successful management of FE. Areas of intervention should include policies aiming at reducing FE in select populations (e.g. needle exchange programs, prophylactic usage of fluconazole in selected patients), innovative diagnostic tests, and expert or society consensus on the definition of clinical or microbiological criteria to guide diagnosis and treatment options for these patients.
Human Ethics
The authors would like to acknowledge Dr. Rui Lima (Cardiology) for his contribution to data and image selection.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Fatal | ReactionOutcome | CC BY | 33728162 | 15,739,818 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myelosuppression'. | Metastatic thymic-enteric adenocarcinoma responding to chemoradiation plus anti-angiogenic therapy: A case report.
BACKGROUND
Thymic-enteric adenocarcinoma with positive expression of CDX2 and CK20 is rare in adults, with only 16 reported cases. However, standard treatment options for this type of thymic adenocarcinoma has not yet been established. Therefore, we report a case of stage IV thymic-enteric adenocarcinoma treated with radiotherapy, chemotherapy, and anti-angiogenesis therapy.
METHODS
We report a case of thymic-enteric adenocarcinoma occurring in a 44-year-old woman. The tumor was considered unresectable owing to its invasiveness. The patient was treated with six cycles of oxaliplatin (130 mg/m2, day 1) and capecitabine (1000 mg/m2 BID, days 1-14). During the first three cycles of chemotherapy, concurrent radiotherapy (60 Gy/30 fractions) and anti-angiogenic therapy using apatinib were recommended. The primary tumor achieved partial remission based on the Response Evaluation Criteria in Solid Tumors. During follow-up, there was no evidence of disease relapse, except a high serum CA19-9 level. The patient is alive and regularly followed. Based on the previous literature and the present case, we believe that early diagnosis of thymic-enteric adenocarcinoma is important.
CONCLUSIONS
XELOX (capecitabine plus oxaliplatin) combined with radiotherapy is an optional therapy for inoperable thymic-enteric adenocarcinoma.
Core Tip: This report introduces the diagnosis and treatment of a metastatic thymic-enteric adenocarcinoma with positive expression of CDX2 and CK20. For the first time, radiotherapy and chemotherapy combined with anti-angiogenesis therapy were used. The tumor was partially remitted, and there was no sign of recurrence. XELOX (capecitabine plus oxaliplatin) combined with radiotherapy is an alternative treatment for inoperable metastatic thymic-enteric adenocarcinoma.
INTRODUCTION
Thymic cancer is rare, accounting for only 0.06% of all thymic neoplasms[1]. It may be asymptomatic or associated with an intermittent cough, chest pain, or dyspnea. According to the 2015 World Health Organization thymic cancer classification, its histological types include squamous cell carcinoma, lymphoid epithelioid carcinoma, or basal-like carcinoma. However, the enteric type was first identified in 2003[2]. To date, a total of 16 cases of thymic adenocarcinoma with positive expression of CDX2 and CK20 have been reported (Table 1). However, standard treatment options for this type of thymic adenocarcinoma have not yet been established. We report a case of stage IV thymic-enteric adenocarcinoma treated with radiotherapy, chemotherapy, and anti-angiogenesis therapy. Our primary result demonstrated the effectiveness of a comprehensive approach.
Table 1 Clinicopathologic features of 16 patients with thymic adenocarcinoma as reported in the literature
Case No. Age Gender Ki-67 Treatment Outcome Ref.
1 70 Male 20%-30% Surgery AWD, 7 mo [2]
2 59 Female NA Surgery + chemoradiotherapy + radiotherapy Alive with disease, 11 mo (bone and lung metastasis) [8]
3 41 Female 90% Surgery AWD, 18 mo [9]
4 39 Female NA Surgery AWD, 159 mo (recurrence +) [9]
5 28 Female NA Surgery + chemotherapy (GEMOX) + radiotherapy AWD, 30 mo (2 times recurrence) [10]
6 55 Male NA Surgery + radiotherapy AWD, 14 mo [11]
7 36 Female NA Surgery + chemotherapy (Taxol/CDDP) + radiotherapy DOD, 15 mo [12]
8 66 Female NA Surgery AWD, 5 yr [13]
9 NA NA NA Surgery NA [14]
10 52 Female NA Surgery + chemotherapy (cisplatin + etoposide/carboplatin + paclitaxel) + radiotherapy Alive with disease, 11 mo (lung and lymph node metastasis) [15]
11 38 Male NA Surgery + radiotherapy + chemotherapy (carboplatin + docetaxel) DOD, 12 mo (bone metastasis) [15]
12 55 Male NA Surgery + chemotherapy (carboplatin + docetaxel/paclitaxel) DOD, 24 mo (bone, liver, lung, adrenal gland metastases) [15]
13 41 Male NA Surgery AWD, 43 mo (lung metastasis+) [16]
14 34 Male NA Surgery + chemotherapy (carboplatin, Adriamycin, cyclophosphamide, and vincristine) + radiotherapy DOD, 20 mo [17]
15 15 Male NA Surgery + radiotherapy DOD, 26 mo [18]
16 29 Female NA Surgery AWD, 8 mo [19]
Present case 44 Female 70% Concurrent chemoradiotherapy + antiangiogenic therapy AWD
AWD: Alive without disease; DOD: Died of disease; NA: Not available; NOS: Not otherwise specified.
CASE PRESENTATION
Chief complaints
A 44-year-old woman was admitted to our hospital for dyspnea with chest pain in April 2018.
History of present illness
The patient had no history of present illness.
History of past illness
The patient had no history of past illness.
Personal and family history
The patient had no personal and family history.
Physical examination
No obvious abnormalities were found on physical examination.
Laboratory examinations
Laboratory tests showed elevated levels of several serum tumor markers (CA19-9, 483.98 U/mL; CA125, 111.44 IU/mL; CA242, 138.50 IU/mL; cytokeratin-19 fragment, 5.34 ng/mL; and carcinoembryonic antigen, 20.07 ng/mL). Liver and kidney function tests were normal. The pericardial effusion was bloody, and tumor cells were detected. Mediastinal mass biopsy showed pathological adenocarcinoma infiltration (Figure 1A). Immunohistochemical staining showed that the tumor cells were positive for CK20 (Figure 1B), CDX2 (Figure 1C), villin, and EGFR; partially positive for CA15-3; and negative for lung cancer markers, including CK7, TTF-1, and Napsin A. The Ki-67 index was 70%. Moreover, wild types of KRAS, NRAS, and BRAF were detected. The pathological results suggested intestinal metastatic adenocarcinoma. However, no other primary tumor was found on systemic examination.
Figure 1 Pathological and immunohistochemical features of puncture tissue of the mediastinal tumor (× 100). A: The tissue was infiltrated by adenocarcinoma cells; B: Neoplastic cells were positive for cytokeratin; C: CDX-2 20 (× 100).
Imaging examinations
Whole-body positron emission computed tomography (CT) (Figure 2A) showed an anterior calcified mediastinal mass measuring approximately 43 mm × 38 mm with an increased edge radioactivity uptake [maximum standardized uptake value (SUV) of 6.4; CT value of 41.8 HU]; increased pericardial radioactive uptake and a fluid density shadow; and increased sternal spot-like radioactivity uptake (maximum SUV value of 3.4).
Figure 2 Serial high-resolution computed tomography scans of the chest. A: The computed tomography (CT) scan on July 31, 2018 showing an anterior mediastinal mass with calcification; B: The CT scan on August 28, 2018 showing that the anterior mediastinal mass was improved during the treatment; C: The CT scan on September 26, 2018 showing that the anterior mediastinal mass decreased during the treatment; D: The CT scan on December 4, 2018 showing that the anterior mediastinal mass was stable after treatment.
FINAL DIAGNOSIS
After consultation with histopathologists in our institution, the tumor was diagnosed as a thymic adenocarcinoma (enteric type T4N0M1b stage IVb) with pericardial and sternal metastases according to the American Joint Committee on Cancer Staging Manual Eight Edition (2017).
TREATMENT
A comprehensive therapeutic regimen was administered. First, the patient underwent six cycles of oxaliplatin (130 mg/m2, day 1) and capecitabine (1000 mg/m2, BID, days 1-14) therapy. During the first three cycles of chemotherapy, concurrent radiotherapy (60 Gy/30 fractions) targeting the thymic mass was planned. Meanwhile, anti-angiogenic therapy using apatinib, a VEGFR2 inhibitor (Jiangsu Hengrui Pharmaceutical Company Limited, Jiangsu Province, China), was omitted. This elicited grade II myelosuppression and grade II radioactive esophagitis during the concurrent chemoradiotherapy.
OUTCOME AND FOLLOW-UP
The patient’s chest pain and dyspnea were significantly relieved after chemo-radiotherapy. The thymus mass size was reduced after radiotherapy (30 Gy/15 fractions), but the patient occasionally experienced tachycardia. To reduce heart toxicity, we narrowed the irradiation field. During treatment, the tumor continued to shrink, as shown in Figure 2B and C. After six cycles of XELOX, chest CT showed that the tumor was approximately 37 mm × 20 mm (Figure 2D). Laboratory tests showed that only one serum tumor marker (CA19-9, 60.70 U/mL) remained elevated. The patient refused physical examination during her long-term follow-up; however, she was alive without recurrence for 16 mo when this paper was written.
DISCUSSION
During embryogenesis, the thymus and gut originate from the same arch endoderm. Intriguingly, tuft cells were found to be present in the adult thymus[3]. In fact, tuft cells are functional intestinal epithelial cells[3]. Moreover, mutations in tuft cells elicit gut carcinogenesis in humans. In this regard, thymic tuft cells' role as potential sources for thymic carcinogenesis should be investigated.
To the best of our knowledge, there is no standard of care for the thymic-enteric adenocarcinoma. Previously, patients were mainly treated surgically because the disease was localized. In this case, tumor resection was challenging because of pericardial involvement. Initially, the Ki-67 index was 70%, suggesting that the tumor cells expanded in number. Proliferative cells are sensitive to ionizing irradiation[4]. Therefore, we chose radiotherapy for controlling the primary tumor, thereby alleviating the patient’s symptoms. Meanwhile, systematic chemotherapy plus anti-angiogenic therapy was used as the main treatment. Based on the similarities between thymic-enteric adenocarcinoma and colorectal cancer in histologic phenotype, the XELOX regimen was selected. Capecitabine inhibits DNA synthesis[5], while oxaliplatin induces immunogenic cell death. Moreover, angiogenic factors such as VEGF were detected in the malignant effusion[6]. Secreted by tumor cells, VEGF is a potent inducer of angiogenesis[6]. In this process, VEGF can significantly increase vascular permeability. Inhibition of angiogenesis in tumors limits pericardial effusion[7]. Thus, apatinib was selected for this patient.
CONCLUSION
In this case, the primary tumor achieved partial remission according to the Response Evaluation Criteria in Solid Tumors, and there was no evidence of relapse during follow-up, except for high serum CA19-9 levels. In addition, treatment-related toxicity was manageable. Only grade II myelosuppression and grade II radioactive esophagitis occurred during treatment, thus demonstrating that our treatment was effective in this patient.
Informed consent statement: Informed written consent was obtained from the patient for publishing this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest related to this manuscript.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: September 23, 2020
First decision: December 14, 2020
Article in press: January 6, 2021
Specialty type: Oncology
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): 0
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Mohamed SY S-Editor: Zhang H L-Editor: Wang TQ P-Editor: Yuan YY | APATINIB, CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33728312 | 19,075,475 | 2021-03-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Oesophagitis'. | Metastatic thymic-enteric adenocarcinoma responding to chemoradiation plus anti-angiogenic therapy: A case report.
BACKGROUND
Thymic-enteric adenocarcinoma with positive expression of CDX2 and CK20 is rare in adults, with only 16 reported cases. However, standard treatment options for this type of thymic adenocarcinoma has not yet been established. Therefore, we report a case of stage IV thymic-enteric adenocarcinoma treated with radiotherapy, chemotherapy, and anti-angiogenesis therapy.
METHODS
We report a case of thymic-enteric adenocarcinoma occurring in a 44-year-old woman. The tumor was considered unresectable owing to its invasiveness. The patient was treated with six cycles of oxaliplatin (130 mg/m2, day 1) and capecitabine (1000 mg/m2 BID, days 1-14). During the first three cycles of chemotherapy, concurrent radiotherapy (60 Gy/30 fractions) and anti-angiogenic therapy using apatinib were recommended. The primary tumor achieved partial remission based on the Response Evaluation Criteria in Solid Tumors. During follow-up, there was no evidence of disease relapse, except a high serum CA19-9 level. The patient is alive and regularly followed. Based on the previous literature and the present case, we believe that early diagnosis of thymic-enteric adenocarcinoma is important.
CONCLUSIONS
XELOX (capecitabine plus oxaliplatin) combined with radiotherapy is an optional therapy for inoperable thymic-enteric adenocarcinoma.
Core Tip: This report introduces the diagnosis and treatment of a metastatic thymic-enteric adenocarcinoma with positive expression of CDX2 and CK20. For the first time, radiotherapy and chemotherapy combined with anti-angiogenesis therapy were used. The tumor was partially remitted, and there was no sign of recurrence. XELOX (capecitabine plus oxaliplatin) combined with radiotherapy is an alternative treatment for inoperable metastatic thymic-enteric adenocarcinoma.
INTRODUCTION
Thymic cancer is rare, accounting for only 0.06% of all thymic neoplasms[1]. It may be asymptomatic or associated with an intermittent cough, chest pain, or dyspnea. According to the 2015 World Health Organization thymic cancer classification, its histological types include squamous cell carcinoma, lymphoid epithelioid carcinoma, or basal-like carcinoma. However, the enteric type was first identified in 2003[2]. To date, a total of 16 cases of thymic adenocarcinoma with positive expression of CDX2 and CK20 have been reported (Table 1). However, standard treatment options for this type of thymic adenocarcinoma have not yet been established. We report a case of stage IV thymic-enteric adenocarcinoma treated with radiotherapy, chemotherapy, and anti-angiogenesis therapy. Our primary result demonstrated the effectiveness of a comprehensive approach.
Table 1 Clinicopathologic features of 16 patients with thymic adenocarcinoma as reported in the literature
Case No. Age Gender Ki-67 Treatment Outcome Ref.
1 70 Male 20%-30% Surgery AWD, 7 mo [2]
2 59 Female NA Surgery + chemoradiotherapy + radiotherapy Alive with disease, 11 mo (bone and lung metastasis) [8]
3 41 Female 90% Surgery AWD, 18 mo [9]
4 39 Female NA Surgery AWD, 159 mo (recurrence +) [9]
5 28 Female NA Surgery + chemotherapy (GEMOX) + radiotherapy AWD, 30 mo (2 times recurrence) [10]
6 55 Male NA Surgery + radiotherapy AWD, 14 mo [11]
7 36 Female NA Surgery + chemotherapy (Taxol/CDDP) + radiotherapy DOD, 15 mo [12]
8 66 Female NA Surgery AWD, 5 yr [13]
9 NA NA NA Surgery NA [14]
10 52 Female NA Surgery + chemotherapy (cisplatin + etoposide/carboplatin + paclitaxel) + radiotherapy Alive with disease, 11 mo (lung and lymph node metastasis) [15]
11 38 Male NA Surgery + radiotherapy + chemotherapy (carboplatin + docetaxel) DOD, 12 mo (bone metastasis) [15]
12 55 Male NA Surgery + chemotherapy (carboplatin + docetaxel/paclitaxel) DOD, 24 mo (bone, liver, lung, adrenal gland metastases) [15]
13 41 Male NA Surgery AWD, 43 mo (lung metastasis+) [16]
14 34 Male NA Surgery + chemotherapy (carboplatin, Adriamycin, cyclophosphamide, and vincristine) + radiotherapy DOD, 20 mo [17]
15 15 Male NA Surgery + radiotherapy DOD, 26 mo [18]
16 29 Female NA Surgery AWD, 8 mo [19]
Present case 44 Female 70% Concurrent chemoradiotherapy + antiangiogenic therapy AWD
AWD: Alive without disease; DOD: Died of disease; NA: Not available; NOS: Not otherwise specified.
CASE PRESENTATION
Chief complaints
A 44-year-old woman was admitted to our hospital for dyspnea with chest pain in April 2018.
History of present illness
The patient had no history of present illness.
History of past illness
The patient had no history of past illness.
Personal and family history
The patient had no personal and family history.
Physical examination
No obvious abnormalities were found on physical examination.
Laboratory examinations
Laboratory tests showed elevated levels of several serum tumor markers (CA19-9, 483.98 U/mL; CA125, 111.44 IU/mL; CA242, 138.50 IU/mL; cytokeratin-19 fragment, 5.34 ng/mL; and carcinoembryonic antigen, 20.07 ng/mL). Liver and kidney function tests were normal. The pericardial effusion was bloody, and tumor cells were detected. Mediastinal mass biopsy showed pathological adenocarcinoma infiltration (Figure 1A). Immunohistochemical staining showed that the tumor cells were positive for CK20 (Figure 1B), CDX2 (Figure 1C), villin, and EGFR; partially positive for CA15-3; and negative for lung cancer markers, including CK7, TTF-1, and Napsin A. The Ki-67 index was 70%. Moreover, wild types of KRAS, NRAS, and BRAF were detected. The pathological results suggested intestinal metastatic adenocarcinoma. However, no other primary tumor was found on systemic examination.
Figure 1 Pathological and immunohistochemical features of puncture tissue of the mediastinal tumor (× 100). A: The tissue was infiltrated by adenocarcinoma cells; B: Neoplastic cells were positive for cytokeratin; C: CDX-2 20 (× 100).
Imaging examinations
Whole-body positron emission computed tomography (CT) (Figure 2A) showed an anterior calcified mediastinal mass measuring approximately 43 mm × 38 mm with an increased edge radioactivity uptake [maximum standardized uptake value (SUV) of 6.4; CT value of 41.8 HU]; increased pericardial radioactive uptake and a fluid density shadow; and increased sternal spot-like radioactivity uptake (maximum SUV value of 3.4).
Figure 2 Serial high-resolution computed tomography scans of the chest. A: The computed tomography (CT) scan on July 31, 2018 showing an anterior mediastinal mass with calcification; B: The CT scan on August 28, 2018 showing that the anterior mediastinal mass was improved during the treatment; C: The CT scan on September 26, 2018 showing that the anterior mediastinal mass decreased during the treatment; D: The CT scan on December 4, 2018 showing that the anterior mediastinal mass was stable after treatment.
FINAL DIAGNOSIS
After consultation with histopathologists in our institution, the tumor was diagnosed as a thymic adenocarcinoma (enteric type T4N0M1b stage IVb) with pericardial and sternal metastases according to the American Joint Committee on Cancer Staging Manual Eight Edition (2017).
TREATMENT
A comprehensive therapeutic regimen was administered. First, the patient underwent six cycles of oxaliplatin (130 mg/m2, day 1) and capecitabine (1000 mg/m2, BID, days 1-14) therapy. During the first three cycles of chemotherapy, concurrent radiotherapy (60 Gy/30 fractions) targeting the thymic mass was planned. Meanwhile, anti-angiogenic therapy using apatinib, a VEGFR2 inhibitor (Jiangsu Hengrui Pharmaceutical Company Limited, Jiangsu Province, China), was omitted. This elicited grade II myelosuppression and grade II radioactive esophagitis during the concurrent chemoradiotherapy.
OUTCOME AND FOLLOW-UP
The patient’s chest pain and dyspnea were significantly relieved after chemo-radiotherapy. The thymus mass size was reduced after radiotherapy (30 Gy/15 fractions), but the patient occasionally experienced tachycardia. To reduce heart toxicity, we narrowed the irradiation field. During treatment, the tumor continued to shrink, as shown in Figure 2B and C. After six cycles of XELOX, chest CT showed that the tumor was approximately 37 mm × 20 mm (Figure 2D). Laboratory tests showed that only one serum tumor marker (CA19-9, 60.70 U/mL) remained elevated. The patient refused physical examination during her long-term follow-up; however, she was alive without recurrence for 16 mo when this paper was written.
DISCUSSION
During embryogenesis, the thymus and gut originate from the same arch endoderm. Intriguingly, tuft cells were found to be present in the adult thymus[3]. In fact, tuft cells are functional intestinal epithelial cells[3]. Moreover, mutations in tuft cells elicit gut carcinogenesis in humans. In this regard, thymic tuft cells' role as potential sources for thymic carcinogenesis should be investigated.
To the best of our knowledge, there is no standard of care for the thymic-enteric adenocarcinoma. Previously, patients were mainly treated surgically because the disease was localized. In this case, tumor resection was challenging because of pericardial involvement. Initially, the Ki-67 index was 70%, suggesting that the tumor cells expanded in number. Proliferative cells are sensitive to ionizing irradiation[4]. Therefore, we chose radiotherapy for controlling the primary tumor, thereby alleviating the patient’s symptoms. Meanwhile, systematic chemotherapy plus anti-angiogenic therapy was used as the main treatment. Based on the similarities between thymic-enteric adenocarcinoma and colorectal cancer in histologic phenotype, the XELOX regimen was selected. Capecitabine inhibits DNA synthesis[5], while oxaliplatin induces immunogenic cell death. Moreover, angiogenic factors such as VEGF were detected in the malignant effusion[6]. Secreted by tumor cells, VEGF is a potent inducer of angiogenesis[6]. In this process, VEGF can significantly increase vascular permeability. Inhibition of angiogenesis in tumors limits pericardial effusion[7]. Thus, apatinib was selected for this patient.
CONCLUSION
In this case, the primary tumor achieved partial remission according to the Response Evaluation Criteria in Solid Tumors, and there was no evidence of relapse during follow-up, except for high serum CA19-9 levels. In addition, treatment-related toxicity was manageable. Only grade II myelosuppression and grade II radioactive esophagitis occurred during treatment, thus demonstrating that our treatment was effective in this patient.
Informed consent statement: Informed written consent was obtained from the patient for publishing this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest related to this manuscript.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: September 23, 2020
First decision: December 14, 2020
Article in press: January 6, 2021
Specialty type: Oncology
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): 0
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Mohamed SY S-Editor: Zhang H L-Editor: Wang TQ P-Editor: Yuan YY | APATINIB, CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33728312 | 19,075,475 | 2021-03-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Radiation oesophagitis'. | Metastatic thymic-enteric adenocarcinoma responding to chemoradiation plus anti-angiogenic therapy: A case report.
BACKGROUND
Thymic-enteric adenocarcinoma with positive expression of CDX2 and CK20 is rare in adults, with only 16 reported cases. However, standard treatment options for this type of thymic adenocarcinoma has not yet been established. Therefore, we report a case of stage IV thymic-enteric adenocarcinoma treated with radiotherapy, chemotherapy, and anti-angiogenesis therapy.
METHODS
We report a case of thymic-enteric adenocarcinoma occurring in a 44-year-old woman. The tumor was considered unresectable owing to its invasiveness. The patient was treated with six cycles of oxaliplatin (130 mg/m2, day 1) and capecitabine (1000 mg/m2 BID, days 1-14). During the first three cycles of chemotherapy, concurrent radiotherapy (60 Gy/30 fractions) and anti-angiogenic therapy using apatinib were recommended. The primary tumor achieved partial remission based on the Response Evaluation Criteria in Solid Tumors. During follow-up, there was no evidence of disease relapse, except a high serum CA19-9 level. The patient is alive and regularly followed. Based on the previous literature and the present case, we believe that early diagnosis of thymic-enteric adenocarcinoma is important.
CONCLUSIONS
XELOX (capecitabine plus oxaliplatin) combined with radiotherapy is an optional therapy for inoperable thymic-enteric adenocarcinoma.
Core Tip: This report introduces the diagnosis and treatment of a metastatic thymic-enteric adenocarcinoma with positive expression of CDX2 and CK20. For the first time, radiotherapy and chemotherapy combined with anti-angiogenesis therapy were used. The tumor was partially remitted, and there was no sign of recurrence. XELOX (capecitabine plus oxaliplatin) combined with radiotherapy is an alternative treatment for inoperable metastatic thymic-enteric adenocarcinoma.
INTRODUCTION
Thymic cancer is rare, accounting for only 0.06% of all thymic neoplasms[1]. It may be asymptomatic or associated with an intermittent cough, chest pain, or dyspnea. According to the 2015 World Health Organization thymic cancer classification, its histological types include squamous cell carcinoma, lymphoid epithelioid carcinoma, or basal-like carcinoma. However, the enteric type was first identified in 2003[2]. To date, a total of 16 cases of thymic adenocarcinoma with positive expression of CDX2 and CK20 have been reported (Table 1). However, standard treatment options for this type of thymic adenocarcinoma have not yet been established. We report a case of stage IV thymic-enteric adenocarcinoma treated with radiotherapy, chemotherapy, and anti-angiogenesis therapy. Our primary result demonstrated the effectiveness of a comprehensive approach.
Table 1 Clinicopathologic features of 16 patients with thymic adenocarcinoma as reported in the literature
Case No. Age Gender Ki-67 Treatment Outcome Ref.
1 70 Male 20%-30% Surgery AWD, 7 mo [2]
2 59 Female NA Surgery + chemoradiotherapy + radiotherapy Alive with disease, 11 mo (bone and lung metastasis) [8]
3 41 Female 90% Surgery AWD, 18 mo [9]
4 39 Female NA Surgery AWD, 159 mo (recurrence +) [9]
5 28 Female NA Surgery + chemotherapy (GEMOX) + radiotherapy AWD, 30 mo (2 times recurrence) [10]
6 55 Male NA Surgery + radiotherapy AWD, 14 mo [11]
7 36 Female NA Surgery + chemotherapy (Taxol/CDDP) + radiotherapy DOD, 15 mo [12]
8 66 Female NA Surgery AWD, 5 yr [13]
9 NA NA NA Surgery NA [14]
10 52 Female NA Surgery + chemotherapy (cisplatin + etoposide/carboplatin + paclitaxel) + radiotherapy Alive with disease, 11 mo (lung and lymph node metastasis) [15]
11 38 Male NA Surgery + radiotherapy + chemotherapy (carboplatin + docetaxel) DOD, 12 mo (bone metastasis) [15]
12 55 Male NA Surgery + chemotherapy (carboplatin + docetaxel/paclitaxel) DOD, 24 mo (bone, liver, lung, adrenal gland metastases) [15]
13 41 Male NA Surgery AWD, 43 mo (lung metastasis+) [16]
14 34 Male NA Surgery + chemotherapy (carboplatin, Adriamycin, cyclophosphamide, and vincristine) + radiotherapy DOD, 20 mo [17]
15 15 Male NA Surgery + radiotherapy DOD, 26 mo [18]
16 29 Female NA Surgery AWD, 8 mo [19]
Present case 44 Female 70% Concurrent chemoradiotherapy + antiangiogenic therapy AWD
AWD: Alive without disease; DOD: Died of disease; NA: Not available; NOS: Not otherwise specified.
CASE PRESENTATION
Chief complaints
A 44-year-old woman was admitted to our hospital for dyspnea with chest pain in April 2018.
History of present illness
The patient had no history of present illness.
History of past illness
The patient had no history of past illness.
Personal and family history
The patient had no personal and family history.
Physical examination
No obvious abnormalities were found on physical examination.
Laboratory examinations
Laboratory tests showed elevated levels of several serum tumor markers (CA19-9, 483.98 U/mL; CA125, 111.44 IU/mL; CA242, 138.50 IU/mL; cytokeratin-19 fragment, 5.34 ng/mL; and carcinoembryonic antigen, 20.07 ng/mL). Liver and kidney function tests were normal. The pericardial effusion was bloody, and tumor cells were detected. Mediastinal mass biopsy showed pathological adenocarcinoma infiltration (Figure 1A). Immunohistochemical staining showed that the tumor cells were positive for CK20 (Figure 1B), CDX2 (Figure 1C), villin, and EGFR; partially positive for CA15-3; and negative for lung cancer markers, including CK7, TTF-1, and Napsin A. The Ki-67 index was 70%. Moreover, wild types of KRAS, NRAS, and BRAF were detected. The pathological results suggested intestinal metastatic adenocarcinoma. However, no other primary tumor was found on systemic examination.
Figure 1 Pathological and immunohistochemical features of puncture tissue of the mediastinal tumor (× 100). A: The tissue was infiltrated by adenocarcinoma cells; B: Neoplastic cells were positive for cytokeratin; C: CDX-2 20 (× 100).
Imaging examinations
Whole-body positron emission computed tomography (CT) (Figure 2A) showed an anterior calcified mediastinal mass measuring approximately 43 mm × 38 mm with an increased edge radioactivity uptake [maximum standardized uptake value (SUV) of 6.4; CT value of 41.8 HU]; increased pericardial radioactive uptake and a fluid density shadow; and increased sternal spot-like radioactivity uptake (maximum SUV value of 3.4).
Figure 2 Serial high-resolution computed tomography scans of the chest. A: The computed tomography (CT) scan on July 31, 2018 showing an anterior mediastinal mass with calcification; B: The CT scan on August 28, 2018 showing that the anterior mediastinal mass was improved during the treatment; C: The CT scan on September 26, 2018 showing that the anterior mediastinal mass decreased during the treatment; D: The CT scan on December 4, 2018 showing that the anterior mediastinal mass was stable after treatment.
FINAL DIAGNOSIS
After consultation with histopathologists in our institution, the tumor was diagnosed as a thymic adenocarcinoma (enteric type T4N0M1b stage IVb) with pericardial and sternal metastases according to the American Joint Committee on Cancer Staging Manual Eight Edition (2017).
TREATMENT
A comprehensive therapeutic regimen was administered. First, the patient underwent six cycles of oxaliplatin (130 mg/m2, day 1) and capecitabine (1000 mg/m2, BID, days 1-14) therapy. During the first three cycles of chemotherapy, concurrent radiotherapy (60 Gy/30 fractions) targeting the thymic mass was planned. Meanwhile, anti-angiogenic therapy using apatinib, a VEGFR2 inhibitor (Jiangsu Hengrui Pharmaceutical Company Limited, Jiangsu Province, China), was omitted. This elicited grade II myelosuppression and grade II radioactive esophagitis during the concurrent chemoradiotherapy.
OUTCOME AND FOLLOW-UP
The patient’s chest pain and dyspnea were significantly relieved after chemo-radiotherapy. The thymus mass size was reduced after radiotherapy (30 Gy/15 fractions), but the patient occasionally experienced tachycardia. To reduce heart toxicity, we narrowed the irradiation field. During treatment, the tumor continued to shrink, as shown in Figure 2B and C. After six cycles of XELOX, chest CT showed that the tumor was approximately 37 mm × 20 mm (Figure 2D). Laboratory tests showed that only one serum tumor marker (CA19-9, 60.70 U/mL) remained elevated. The patient refused physical examination during her long-term follow-up; however, she was alive without recurrence for 16 mo when this paper was written.
DISCUSSION
During embryogenesis, the thymus and gut originate from the same arch endoderm. Intriguingly, tuft cells were found to be present in the adult thymus[3]. In fact, tuft cells are functional intestinal epithelial cells[3]. Moreover, mutations in tuft cells elicit gut carcinogenesis in humans. In this regard, thymic tuft cells' role as potential sources for thymic carcinogenesis should be investigated.
To the best of our knowledge, there is no standard of care for the thymic-enteric adenocarcinoma. Previously, patients were mainly treated surgically because the disease was localized. In this case, tumor resection was challenging because of pericardial involvement. Initially, the Ki-67 index was 70%, suggesting that the tumor cells expanded in number. Proliferative cells are sensitive to ionizing irradiation[4]. Therefore, we chose radiotherapy for controlling the primary tumor, thereby alleviating the patient’s symptoms. Meanwhile, systematic chemotherapy plus anti-angiogenic therapy was used as the main treatment. Based on the similarities between thymic-enteric adenocarcinoma and colorectal cancer in histologic phenotype, the XELOX regimen was selected. Capecitabine inhibits DNA synthesis[5], while oxaliplatin induces immunogenic cell death. Moreover, angiogenic factors such as VEGF were detected in the malignant effusion[6]. Secreted by tumor cells, VEGF is a potent inducer of angiogenesis[6]. In this process, VEGF can significantly increase vascular permeability. Inhibition of angiogenesis in tumors limits pericardial effusion[7]. Thus, apatinib was selected for this patient.
CONCLUSION
In this case, the primary tumor achieved partial remission according to the Response Evaluation Criteria in Solid Tumors, and there was no evidence of relapse during follow-up, except for high serum CA19-9 levels. In addition, treatment-related toxicity was manageable. Only grade II myelosuppression and grade II radioactive esophagitis occurred during treatment, thus demonstrating that our treatment was effective in this patient.
Informed consent statement: Informed written consent was obtained from the patient for publishing this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest related to this manuscript.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: September 23, 2020
First decision: December 14, 2020
Article in press: January 6, 2021
Specialty type: Oncology
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): 0
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Mohamed SY S-Editor: Zhang H L-Editor: Wang TQ P-Editor: Yuan YY | APATINIB, CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33728312 | 19,055,703 | 2021-03-06 |
What was the dosage of drug 'OXALIPLATIN'? | Metastatic thymic-enteric adenocarcinoma responding to chemoradiation plus anti-angiogenic therapy: A case report.
BACKGROUND
Thymic-enteric adenocarcinoma with positive expression of CDX2 and CK20 is rare in adults, with only 16 reported cases. However, standard treatment options for this type of thymic adenocarcinoma has not yet been established. Therefore, we report a case of stage IV thymic-enteric adenocarcinoma treated with radiotherapy, chemotherapy, and anti-angiogenesis therapy.
METHODS
We report a case of thymic-enteric adenocarcinoma occurring in a 44-year-old woman. The tumor was considered unresectable owing to its invasiveness. The patient was treated with six cycles of oxaliplatin (130 mg/m2, day 1) and capecitabine (1000 mg/m2 BID, days 1-14). During the first three cycles of chemotherapy, concurrent radiotherapy (60 Gy/30 fractions) and anti-angiogenic therapy using apatinib were recommended. The primary tumor achieved partial remission based on the Response Evaluation Criteria in Solid Tumors. During follow-up, there was no evidence of disease relapse, except a high serum CA19-9 level. The patient is alive and regularly followed. Based on the previous literature and the present case, we believe that early diagnosis of thymic-enteric adenocarcinoma is important.
CONCLUSIONS
XELOX (capecitabine plus oxaliplatin) combined with radiotherapy is an optional therapy for inoperable thymic-enteric adenocarcinoma.
Core Tip: This report introduces the diagnosis and treatment of a metastatic thymic-enteric adenocarcinoma with positive expression of CDX2 and CK20. For the first time, radiotherapy and chemotherapy combined with anti-angiogenesis therapy were used. The tumor was partially remitted, and there was no sign of recurrence. XELOX (capecitabine plus oxaliplatin) combined with radiotherapy is an alternative treatment for inoperable metastatic thymic-enteric adenocarcinoma.
INTRODUCTION
Thymic cancer is rare, accounting for only 0.06% of all thymic neoplasms[1]. It may be asymptomatic or associated with an intermittent cough, chest pain, or dyspnea. According to the 2015 World Health Organization thymic cancer classification, its histological types include squamous cell carcinoma, lymphoid epithelioid carcinoma, or basal-like carcinoma. However, the enteric type was first identified in 2003[2]. To date, a total of 16 cases of thymic adenocarcinoma with positive expression of CDX2 and CK20 have been reported (Table 1). However, standard treatment options for this type of thymic adenocarcinoma have not yet been established. We report a case of stage IV thymic-enteric adenocarcinoma treated with radiotherapy, chemotherapy, and anti-angiogenesis therapy. Our primary result demonstrated the effectiveness of a comprehensive approach.
Table 1 Clinicopathologic features of 16 patients with thymic adenocarcinoma as reported in the literature
Case No. Age Gender Ki-67 Treatment Outcome Ref.
1 70 Male 20%-30% Surgery AWD, 7 mo [2]
2 59 Female NA Surgery + chemoradiotherapy + radiotherapy Alive with disease, 11 mo (bone and lung metastasis) [8]
3 41 Female 90% Surgery AWD, 18 mo [9]
4 39 Female NA Surgery AWD, 159 mo (recurrence +) [9]
5 28 Female NA Surgery + chemotherapy (GEMOX) + radiotherapy AWD, 30 mo (2 times recurrence) [10]
6 55 Male NA Surgery + radiotherapy AWD, 14 mo [11]
7 36 Female NA Surgery + chemotherapy (Taxol/CDDP) + radiotherapy DOD, 15 mo [12]
8 66 Female NA Surgery AWD, 5 yr [13]
9 NA NA NA Surgery NA [14]
10 52 Female NA Surgery + chemotherapy (cisplatin + etoposide/carboplatin + paclitaxel) + radiotherapy Alive with disease, 11 mo (lung and lymph node metastasis) [15]
11 38 Male NA Surgery + radiotherapy + chemotherapy (carboplatin + docetaxel) DOD, 12 mo (bone metastasis) [15]
12 55 Male NA Surgery + chemotherapy (carboplatin + docetaxel/paclitaxel) DOD, 24 mo (bone, liver, lung, adrenal gland metastases) [15]
13 41 Male NA Surgery AWD, 43 mo (lung metastasis+) [16]
14 34 Male NA Surgery + chemotherapy (carboplatin, Adriamycin, cyclophosphamide, and vincristine) + radiotherapy DOD, 20 mo [17]
15 15 Male NA Surgery + radiotherapy DOD, 26 mo [18]
16 29 Female NA Surgery AWD, 8 mo [19]
Present case 44 Female 70% Concurrent chemoradiotherapy + antiangiogenic therapy AWD
AWD: Alive without disease; DOD: Died of disease; NA: Not available; NOS: Not otherwise specified.
CASE PRESENTATION
Chief complaints
A 44-year-old woman was admitted to our hospital for dyspnea with chest pain in April 2018.
History of present illness
The patient had no history of present illness.
History of past illness
The patient had no history of past illness.
Personal and family history
The patient had no personal and family history.
Physical examination
No obvious abnormalities were found on physical examination.
Laboratory examinations
Laboratory tests showed elevated levels of several serum tumor markers (CA19-9, 483.98 U/mL; CA125, 111.44 IU/mL; CA242, 138.50 IU/mL; cytokeratin-19 fragment, 5.34 ng/mL; and carcinoembryonic antigen, 20.07 ng/mL). Liver and kidney function tests were normal. The pericardial effusion was bloody, and tumor cells were detected. Mediastinal mass biopsy showed pathological adenocarcinoma infiltration (Figure 1A). Immunohistochemical staining showed that the tumor cells were positive for CK20 (Figure 1B), CDX2 (Figure 1C), villin, and EGFR; partially positive for CA15-3; and negative for lung cancer markers, including CK7, TTF-1, and Napsin A. The Ki-67 index was 70%. Moreover, wild types of KRAS, NRAS, and BRAF were detected. The pathological results suggested intestinal metastatic adenocarcinoma. However, no other primary tumor was found on systemic examination.
Figure 1 Pathological and immunohistochemical features of puncture tissue of the mediastinal tumor (× 100). A: The tissue was infiltrated by adenocarcinoma cells; B: Neoplastic cells were positive for cytokeratin; C: CDX-2 20 (× 100).
Imaging examinations
Whole-body positron emission computed tomography (CT) (Figure 2A) showed an anterior calcified mediastinal mass measuring approximately 43 mm × 38 mm with an increased edge radioactivity uptake [maximum standardized uptake value (SUV) of 6.4; CT value of 41.8 HU]; increased pericardial radioactive uptake and a fluid density shadow; and increased sternal spot-like radioactivity uptake (maximum SUV value of 3.4).
Figure 2 Serial high-resolution computed tomography scans of the chest. A: The computed tomography (CT) scan on July 31, 2018 showing an anterior mediastinal mass with calcification; B: The CT scan on August 28, 2018 showing that the anterior mediastinal mass was improved during the treatment; C: The CT scan on September 26, 2018 showing that the anterior mediastinal mass decreased during the treatment; D: The CT scan on December 4, 2018 showing that the anterior mediastinal mass was stable after treatment.
FINAL DIAGNOSIS
After consultation with histopathologists in our institution, the tumor was diagnosed as a thymic adenocarcinoma (enteric type T4N0M1b stage IVb) with pericardial and sternal metastases according to the American Joint Committee on Cancer Staging Manual Eight Edition (2017).
TREATMENT
A comprehensive therapeutic regimen was administered. First, the patient underwent six cycles of oxaliplatin (130 mg/m2, day 1) and capecitabine (1000 mg/m2, BID, days 1-14) therapy. During the first three cycles of chemotherapy, concurrent radiotherapy (60 Gy/30 fractions) targeting the thymic mass was planned. Meanwhile, anti-angiogenic therapy using apatinib, a VEGFR2 inhibitor (Jiangsu Hengrui Pharmaceutical Company Limited, Jiangsu Province, China), was omitted. This elicited grade II myelosuppression and grade II radioactive esophagitis during the concurrent chemoradiotherapy.
OUTCOME AND FOLLOW-UP
The patient’s chest pain and dyspnea were significantly relieved after chemo-radiotherapy. The thymus mass size was reduced after radiotherapy (30 Gy/15 fractions), but the patient occasionally experienced tachycardia. To reduce heart toxicity, we narrowed the irradiation field. During treatment, the tumor continued to shrink, as shown in Figure 2B and C. After six cycles of XELOX, chest CT showed that the tumor was approximately 37 mm × 20 mm (Figure 2D). Laboratory tests showed that only one serum tumor marker (CA19-9, 60.70 U/mL) remained elevated. The patient refused physical examination during her long-term follow-up; however, she was alive without recurrence for 16 mo when this paper was written.
DISCUSSION
During embryogenesis, the thymus and gut originate from the same arch endoderm. Intriguingly, tuft cells were found to be present in the adult thymus[3]. In fact, tuft cells are functional intestinal epithelial cells[3]. Moreover, mutations in tuft cells elicit gut carcinogenesis in humans. In this regard, thymic tuft cells' role as potential sources for thymic carcinogenesis should be investigated.
To the best of our knowledge, there is no standard of care for the thymic-enteric adenocarcinoma. Previously, patients were mainly treated surgically because the disease was localized. In this case, tumor resection was challenging because of pericardial involvement. Initially, the Ki-67 index was 70%, suggesting that the tumor cells expanded in number. Proliferative cells are sensitive to ionizing irradiation[4]. Therefore, we chose radiotherapy for controlling the primary tumor, thereby alleviating the patient’s symptoms. Meanwhile, systematic chemotherapy plus anti-angiogenic therapy was used as the main treatment. Based on the similarities between thymic-enteric adenocarcinoma and colorectal cancer in histologic phenotype, the XELOX regimen was selected. Capecitabine inhibits DNA synthesis[5], while oxaliplatin induces immunogenic cell death. Moreover, angiogenic factors such as VEGF were detected in the malignant effusion[6]. Secreted by tumor cells, VEGF is a potent inducer of angiogenesis[6]. In this process, VEGF can significantly increase vascular permeability. Inhibition of angiogenesis in tumors limits pericardial effusion[7]. Thus, apatinib was selected for this patient.
CONCLUSION
In this case, the primary tumor achieved partial remission according to the Response Evaluation Criteria in Solid Tumors, and there was no evidence of relapse during follow-up, except for high serum CA19-9 levels. In addition, treatment-related toxicity was manageable. Only grade II myelosuppression and grade II radioactive esophagitis occurred during treatment, thus demonstrating that our treatment was effective in this patient.
Informed consent statement: Informed written consent was obtained from the patient for publishing this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest related to this manuscript.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: September 23, 2020
First decision: December 14, 2020
Article in press: January 6, 2021
Specialty type: Oncology
Country/Territory of origin: China
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P-Reviewer: Mohamed SY S-Editor: Zhang H L-Editor: Wang TQ P-Editor: Yuan YY | DAY 1 | DrugDosageText | CC BY-NC | 33728312 | 19,075,475 | 2021-03-06 |
What was the administration route of drug 'PENICILLIN G'? | Vancomycin-induced thrombocytopenia in endocarditis: A case report and review of literature.
BACKGROUND
Thrombocytopenia is a serious complication in the medical practice of numerous drugs. Vancomycin is frequently used for the prophylaxis and treatment of suspected or identified methicillin-resistant positive infections. Several cases with vancomycin-induced thrombocytopenia (VIT) have been reported. However, these have rarely been extensively reviewed. The present report describes a case of VIT in endocarditis, and reviews all VIT cases reported in the literature.
METHODS
A 26-year-old male diagnosed with infective endocarditis was admitted. The patient was treated with multiple drugs, including vancomycin, which was initially intravenously given at 1000 mg every 12 h and subsequently at 500 mg every 8 h on day 3. On day 11, the platelet count decreased to 51 × 109/L, vancomycin was switched to 500 mg every 12 h, and platelet transfusion was given. On day 17, the platelet count dropped to 27 × 109/L, and platelet transfusion was administered again. On day 23, vancomycin was adjusted to 500 mg every 8 h as the trough concentration dropped to the minimum effective concentration. On day 33, the platelet count declined to approximately 40 × 109/L. After platelet transfusion, the platelet count rebounded to 90 × 109/L on day 35 but dropped again to 42 × 109/L on day 43. Based on the time-to-platelet count curve and Naranjo's Adverse Drug Reaction Probability Scale score, VIT was suspected. After vancomycin discontinuation and platelet transfusion, the platelet count gradually normalized.
CONCLUSIONS
The diagnosis of VIT can be achieved through the time-to-platelet count curve and Naranjo's Adverse Drug Reaction Probability Scale score. The platelet count cannot be normalized simply by platelet transfusion alone, and vancomycin discontinuation is essential.
Core Tip: The present report describes a case of vancomycin-induced thrombocytopenia (VIT) in endocarditis and reviews all VIT cases reported in the literature, in terms of indications, diagnosis, management, and potential molecular mechanisms. The present case highlights the importance of accurate diagnosis of VIT in endocarditis, which can be achieved through the time-to-platelet count curve and the Naranjo’s Adverse Drug Reaction Probability Scale score. The platelet count cannot be normalized simply by platelet transfusion alone, and the discontinuation of vancomycin is essential. Due to the anamnestic response to vancomycin re-exposure and the formation of vancomycin-dependent antiplatelet antibodies, the re-administration of vancomycin should be avoided.
INTRODUCTION
Thrombocytopenia, which is generally defined as a platelet count of less than 100 × 109/L of blood or a decrease in the platelet count of 20%-50% from baseline[1,2], has been considered as an adverse reaction correlated to drugs used in the treatment of various diseases[3]. Drug-induced thrombocytopenia is mostly caused by immune-mediated platelet degradation and is always drug dependent, indicating that the platelet count can return to baseline levels after the discontinuation of medications[4]. Although it has been reported that approximately 10 million persons per year are suspected to suffer from drug-induced thrombocytopenia[5], its incidence has not been well-defined[4].
Antibiotic-induced thrombocytopenia has been documented[3]. The commonly reported antibiotics that induce thrombocytopenia are β-lactam antibiotics agents (such as penicillin, nafcillin, ticarcillin, cefazolin, cefuroxime, ceftriaxone, and piperacillin) and linezolid[6]. Vancomycin is a first-generation glycopeptide antibiotic that is often used for the prophylaxis and treatment of suspected or identified methicillin-resistant infections, such as Staphylococcus aureus infection[7], and has been considered as an uncommon cause of thrombocytopenia[6]. Several clinical observational studies have suggested that the incidence of vancomycin-induced thrombocytopenia (VIT) might be higher than that induced by linezolid[1]. However, the incidence of VIT may have been overestimated, because the definition for thrombocytopenia used among these studies vary. A platelet count of less than 150 × 109/L was used in two studies[8,9], and a decrease in platelet count of at least 50% from baseline was used in another study[1]. In addition, the clinical manifestations, diagnosis, and management of VIT have not been well-established, and the underlying molecular mechanisms by which vancomycin induces thrombocytopenia needs to be further elucidated[10]. Over the past two decades, cases with VIT have been continuously reported[11]. However, these cases have rarely been extensively reviewed.
In June 2019, a young male patient with endocarditis was admitted to our hospital, and he developed VIT after vancomycin therapy during the treatment for endocarditis. The present report describes this case and extensively reviews all VIT cases reported in the literature, in terms of indications, diagnosis, management, and potential molecular mechanisms.
CASE PRESENTATION
Chief complaints
A 26-year-old Chinese male presented with dyspnea, fatigue, arrhythmias, fever, and cough.
History of present illness
The patient was admitted to the hospital on June 6, 2019 and diagnosed with infective endocarditis, heart failure, and ventricular septal defect, with a series of manifestations of inflammatory response syndrome.
History of past illness
He had a medical history of uncontrolled hypotension and rheumatic heart disease.
Personal and family history
He denied any family history.
Physical examination
He had a body temperature of 39.1 °C and a heart rate of 100 beats per min.
Laboratory examinations
Initial laboratory testing showed no abnormality.
Imaging examinations
The electrocardiosignal data revealed a high echo of the tricuspid valve, suggesting a neoplasm.
FINAL DIAGNOSIS
Infective endocarditis, heart failure, and ventricular septal defect.
TREATMENT
During hospitalization, the patient was treated with multiple courses of drug therapy, which included vancomycin, omeprazole (40 mg q.d. for 10 d), ceftazidime (2 g t.i.d. for 9 d) and metoprolol (50 mg q.d. for 11 d). Based on the bacterial culture and drug susceptibility test, methicillin-resistant Staphylococcus aureus was identified with the minimum inhibitory concentration of less than 2 mg/L. Therefore, according to The Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children[12], vancomycin was prescribed for the patient with infective endocarditis. Initially, the patient was intravenously treated with 1000 mg of vancomycin every 12 h and 960 mg of benzylpenicillin every 8 h on day 2 for suspected gram-positive infections. The blood cultures were negative for two consecutive tests. Then, the intravenous administration of vancomycin was changed to 500 mg for every 8 h on day 3, for a trough concentration of 25.87 µg/mL beyond the upper limit of 20 µg/mL, and the platelet count was maintained within 100-110 × 109/L for 7 d. On day 11, the administration of vancomycin was switched to 500 mg every 12 h, because the platelet count decreased to 51 × 109/L and the peak concentration of vancomycin reached 57.2 µg/mL. Platelet transfusion (1 U) was given on day 11, and the platelet count slightly increased to 64 × 109/L on day 14, but dramatically dropped afterwards to 27 × 109/L on day 17. Then, platelet transfusion (1 U) was given again on day 17, and the platelet count steadily increased up to 67 × 109/L on day 31. The dose of vancomycin was adjusted to 500 mg every 8 h on day 23 when the trough concentration of vancomycin dropped to 8.86 µg/mL in order to ensure the minimal effective treatment concentration (10 µg/mL). However, on day 33, the hemoglobin level sharply dropped from 101 g/L to 54 g/L, the platelet count continuously declined to approximately 40 × 109/L, and platelet transfusion (1 U) was given. The platelet count rebounded to 90 × 109/L on day 35 but dropped to 42 × 109/L again on day 43. Based on these above observations, and along with the time-to-platelet count curve that illustrated the decline in platelet level after the administration of vancomycin (Figure 1), VIT was suspected, vancomycin was discontinued and replaced with daptomycin, and platelet transfusion (1 U) was given on the same day. The platelet count level increased and reached up to 120 × 109/L on day 50 and remained stable thereafter.
Figure 1 Time-to-platelet count curve during hospitalization. Vancomycin was initiated on day 2 and continued on day 43, as indicated by the downward arrows. Platelet transfusion was given on day 11, 17, 33, and 43, as indicated by the upward arrows.
The concurrent antibiotic, benzylpenicillin, was continuously used during the period with little effect on the platelet count. The respiratory rate, white blood cell count, and hemodynamic variables remained stable, and the microbiological cultures from the sputum and urine revealed negative results, implying that no infection was correlated with thrombocytopenia for the present patient. The other causes of thrombocytopenia, including thrombotic thrombocytopenic purpura, hemolytic anemia, disseminated intravascular coagulation, and platelet-clumping pseudothrombocytopenia, were also excluded, because the results of the blood smear, bilirubin, and hemoglobin were normal. There have been no reports on the occurrence of drug-induced thrombocytopenia caused by other medications during treatment, including omeprazole, ceftazidime, and metoprolol. Therefore, a diagnosis of VIT was initially established using the time-to-platelet count curve. In addition, the Naranjo’s Adverse Drug Reaction Probability Scale score (Naranjo score) for vancomycin was 8, indicating the probable correlation between thrombocytopenia and vancomycin.
OUTCOME AND FOLLOW-UP
The patient was discharged from the hospital.
DISCUSSION
A literature search for all case reports on VIT published in English from April 1985 to June 2020 was performed on PMC/PubMed, Scopus, and Web of Science. Keywords, which included vancomycin and thrombocytopenia, were used to search the titles and abstracts. References of relevant case reports, according to the brief research, were also carefully checked. The demographic data (e.g., age and gender), platelet count, diagnosis, and treatment were recorded and analyzed.
A total of 36 articles that reported 37 cases with VIT were identified in the literature. Thus, the data of 38 cases, which included the case described in the present report, were reviewed and are summarized in Table 1. Among these cases, 14 cases were females and 24 cases were males. The mean age of these cases was 51.19 ± 26.98 years-old (range: 3 mo to 81-years-old). Furthermore, four children were under 2-years-old, and 36 cases were adults 26-81 years-old. The most common indications for the treatment with vancomycin were endocarditis (n = 6), sepsis (n = 6), pneumonia (n = 5), and cellulitis (n = 2). These were followed by other various indications, such as prosthetic infection, hemodialysis, bone graft, acute pancreatitis, etc. The diagnosis of VIT mainly relied on the platelet count, with or without the Naranjo score[13]. The test results for the vancomycin-dependent antibodies were available for 19 patients, and all except three were positive. Among the 27 patients with available bleeding information, 21 patients exhibited bleeding signs. The treatments for these cases comprised of platelet transfusion, prednisone, dexamethasone, immunoglobulin, and daptomycin, and the discontinuation of vancomycin. For the six cases with endocarditis, VIT was diagnosed as probable by the Naranjo score. The information on bleeding signs was available for four cases, and three of these cases presented with bleeding signs. The presence of vancomycin-dependent antibodies was examined only in two patients, and positive results were obtained in one of them. After vancomycin discontinuation, VIT was generally resolved for all patients within 4-15 d. Despite clinical significance revealed by the present literature review, it must be clearly stated that this is only a narrative review, which possesses all the limitations of the selection of papers. Thus, a methodologically acceptable systematic review should be carried out when more data with high quality are available in order to draw a firm conclusion.
Table 1 Summary of case reports of vancomycin-induced thrombocytopenia
Author (publication year) Age (yr) Gender Indication Platelet count (109/L)1 Naranjo Score Treatment Time for resolution (d)2 Vancomycin-dependentantibodies Bleeding sign
Present case 26 M Endocarditis 27 Probable Platelet transfusion and daptomycin 12 NA +
MacDougall et al[14] (2020) 81 M Prosthetic infection 2 NA Prednisone, immunoglobulin, and daptomycin 10 + -
Ajit et al[27] (2019) 61 M Hemodialysis < 10 NA Prednisone, immunoglobulin, eltrombopag and plasma exchange 15 + +
Getz et al[18] (2019) 71 M Transverse myelitis 8.6 Definite Dexamethasone and immunoglobulin 8 + +
Chen et al[16] (2018) 0 F Purulent meningitis 8 Probable Methylprednisolone 4 + +
Danieletto et al[17] (2017) 57 F Bone graft 9 Probable Tigecycline 7 - -
Kalra et al[28] (2016) 0.7 M Sepsis 30 NA Platelet transfusion 3 NA -
Schueler et al[15] (2016) 55 M Purpura 1 NA Prednisone and immunoglobulin 3 NA +
Yamanouchi et al[29] (2016) 72 F Sepsis 2 NA Steroid therapy and carbapenem 7 + +
Lobo et al[13] (2015) 67 M Pneumonia 2 Probable Platelet transfusion, methylprednisolone and immunoglobulin 3 + +
Ahmed et al[30] (2015) 63 M Diabetic foot 2 Probable Daptomycin 10 + -
Candemir et al[10] (2013) 54 F Hematoma 42 Probable Platelet transfusion and daptomycin 4 NA NA
Wetzel et al[31] (2013) 64 F Sepsis 7 Probable Prednisone and immunoglobulin 8 NA +
Ruggero et al[32] (2012) 41 M Pneumonia 15 Definite Daptomycin 5 NA +
Arnold et al[23] (2013) 66 F Endocarditis 4 Probable Platelet transfusion and immunoglobulin 5 + +
Rowland et al[33] (2013) 51 M Acute pancreatitis 9 Probable Only vancomycin discontinuation 5 NA +
Anand et al[34] (2011) 54 M Cellulitis 1 Possible Corticosteroids and daptomycin 2 + +
Ganly et al[22] (2011) 67 M Sepsis 2 NA Platelet transfusion and immunoglobulin 8 NA +
Shah et al[11] (2009) 60 M Shoulder infection 9 Possible Platelet transfusion 3 + +
Lee et al[35] (2009) 76 M Diabetic foot < 15 Possible Platelet transfusion and teicoplanin. 5 + -
Apiwattanakul et al[36] (2008) 16 F Endocarditis 123 Possible Prednisone and cefotaxime 5 NA -
Kenney et al[20] (2008) 61 M Gangrene and bacteremia 3 Probable Platelet transfusion and immunoglobulin 4 + +
Pauldine et al[37] (2008) 60 M Pneumonia 10 Possible Platelet transfusion 12 + +
Dilli et al[38] (2008) 0.6 M Neonatal respiratory distress 41 NA Only vancomycin discontinuation 3 - NA
O’Donnell et al[21] (2007) 56 F Prosthetic infection 2 Possible Immunoglobulin 7 + +
Bay et al[39] (2006) 2 M Pneumonia 11 NA Only vancomycin discontinuation 4 NA NA
Winteroll et al[24] (2004) 72 M Sepsis 3 Probable Platelet transfusion 10 + +
Peel et al[40] (2003) 45 M Peritonitis 5 Probable Platelet transfusion and prednisone 4 NA +
Marraffa et al[41] (2003) 50 M Endocarditis 10 Probable Clindamycin and methylprednisolone 5 NA +
Rocha et al[42] (2002) 38 F Prosthetic infection 68 Possible Only vancomycin discontinuation 4 NA NA
Shahar et al[43] (2000) 43 F Surgery-site infection 118 Probable Only vancomycin discontinuation 3 NA NA
Govindarajan et al[44] (1999) 72 M Epidural abscess 13 Probable Trimethoprim/sulfmethoxazole 10 NA NA
Kuruppu et al[45] (1999) 72 F Endocarditis 14 Possible Only vancomycin discontinuation 5 - NA
Mizon et al[46] (1997) 71 F Sepsis < 10 Probable Antibiotics withdrawn 4 + +
Zenon et al[47] (1991) 54 M Cellulitis 17 Probable Antibiotics withdrawn 7 NA NA
Christie et al[48] (1990) 73 F Pneumonia 14 Probable Platelet transfusion 2 + NA
Christie et al[48] (1990) 31 M Fever < 10 Possible Platelet transfusion 11 (not continued) + NA
Carmichael et al[49] (1986) 42 F Endocarditis 82 Possible NA 9 NA NA
1 The lowest value during the vancomycin treatment.
2 The time from vancomycin discontinuation to the resolution of vancomycin-induced thrombocytopenia. +: A positive result; -: A negative result. F: Female; M: Male; NA: Not available or not tested.
The present patient with infective endocarditis was diagnosed with VIT, which rapidly progressed. The early diagnosis of VIT was performed using the time-to-platelet count curve and Naranjo score. During treatment, the repeated platelet transfusions failed to increase the platelet levels. Subsequently, simply switching vancomycin to daptomycin returned the platelet count close to the baseline level.
The early diagnosis of VIT is quite difficult due to many suspected causes, such as severe infection, disseminated intravascular coagulation, heparin, and other medications. The correct diagnosis can be masked by the simultaneous administration of medications, which can cause drug-induced immune thrombocytopenia[14] or a complicating disease, such as primary idiopathic thrombocytopenic purpura or chronic hepatitis C[15]. Therefore, the early recognition of VIT was of key importance for the following treatment. According to previous studies[6], the investigators used the platelet count at different time points as the initial diagnosis of VIT, which can reveal a definite time-independent relationship with drug administration. All other causes of thrombocytopenia were excluded. Furthermore, the Naranjo score, which has been applied to help with the diagnosis of VIT[16-18], also indicated a probable correlation between thrombocytopenia and vancomycin. Noticeably, endocarditis represents the most common indication that is associated with VIT. The probable correlation between thrombocytopenia and vancomycin can be made through the Naranjo score for all cases, indicating that the Naranjo score is a useful tool to initially diagnose VIT in patients with endocarditis. A bleeding sign is also a useful clinical manifestation to which attention should be given in order to make a definite diagnosis, since most cases would present bleeding signs when VIT occurs. This is particularly true in patents with endocarditis, based on the analyzed data. However, the value of the detection of vancomycin-dependent antibodies in the diagnosis of VIT in patients with endocarditis remains to be elucidated due to the very limited data available.
The critical management after suspicions of VIT is to determine whether to continue or discontinue the vancomycin therapy. The seriousness of the bleeding and the dropping trend of the platelet count should be carefully considered and closely monitored when continuing the vancomycin therapy. However, once VIT is diagnosed, the vancomycin must be stopped, and the platelet transfusion should be taken into consideration as a supplemental treatment for some patients with various success rates, although there are still some transfusion-resistant patients[10,13,19,20]. If vancomycin is not stopped, the survival time of the transfused platelets would be obviously reduced, and the platelet transfusion will not always expectedly increase the platelet count of affected patients[3]. In any of these circumstances, platelet transfusion should be considered for severe thrombocytopenia with a platelet count of below 20 × 109/L and bleeding[19]. In addition to platelet transfusion, therapies with intravenous corticosteroids, intravenous immunoglobulins, rituximab, and plasma exchange have been shown to be beneficial in some cases after vancomycin discontinuation[3,21-23]. However, these medical approaches may not always be effective. In the present case, VIT was effectively resolved by platelet transfusion with the switching of vancomycin to daptomycin.
The mechanisms of VIT remains unclear. The formation of different drug-dependent platelet antibodies, including hapten-dependent, quinine-type, fiban-type and drug-specific antibodies, and other platelet destruction antibodies, are the widely documented mechanisms for VIT[11,21,24]. In contrast, naturally occurring antibodies may not contribute to VIT[25]. It has been postulated that vancomycin can bind to platelet glycoproteins and induce the generation of antibodies, which can attach to the drug-platelet complex, resulting in cell lysis[26]. In the present case, the platelet count gradually dropped after the administration of vancomycin (1000 mg per day) for 7 d. Although the vancomycin was changed to a low-dose (500 mg per day), the platelet count continued to drop. It was postulated that the persistent thrombocytopenia might be due to the anamnestic response for vancomycin re-exposure, and vancomycin-dependent antiplatelet antibodies were formed once vancomycin was re-used.
CONCLUSION
The present case highlights the importance of the accurate diagnosis of VIT in patients with endocarditis. The time-to-platelet count curve and Naranjo score are useful tools for the diagnosis of VIT. The platelet count cannot be normalized simply by platelet transfusion alone. Instead, the discontinuation of vancomycin or switching vancomycin to other antibiotics, such as daptomycin, is essential for effectively treating VIT. Due to the anamnestic response to vancomycin re-exposure and the formation of vancomycin-dependent antiplatelet antibodies, the re-administration of vancomycin should be avoided.
Informed consent statement: An informed written consent was obtained from the patient for the publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: October 13, 2020
First decision: December 13, 2020
Article in press: January 22, 2021
Specialty type: Pharmacology and pharmacy
Country/Territory of origin: China
Peer-review report’s scientific quality classification
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Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
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P-Reviewer: Momčilović S S-Editor: Zhang H L-Editor: Filipodia P-Editor: Xing YX | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33728314 | 19,048,518 | 2021-03-06 |
What was the administration route of drug 'VANCOMYCIN HYDROCHLORIDE'? | Vancomycin-induced thrombocytopenia in endocarditis: A case report and review of literature.
BACKGROUND
Thrombocytopenia is a serious complication in the medical practice of numerous drugs. Vancomycin is frequently used for the prophylaxis and treatment of suspected or identified methicillin-resistant positive infections. Several cases with vancomycin-induced thrombocytopenia (VIT) have been reported. However, these have rarely been extensively reviewed. The present report describes a case of VIT in endocarditis, and reviews all VIT cases reported in the literature.
METHODS
A 26-year-old male diagnosed with infective endocarditis was admitted. The patient was treated with multiple drugs, including vancomycin, which was initially intravenously given at 1000 mg every 12 h and subsequently at 500 mg every 8 h on day 3. On day 11, the platelet count decreased to 51 × 109/L, vancomycin was switched to 500 mg every 12 h, and platelet transfusion was given. On day 17, the platelet count dropped to 27 × 109/L, and platelet transfusion was administered again. On day 23, vancomycin was adjusted to 500 mg every 8 h as the trough concentration dropped to the minimum effective concentration. On day 33, the platelet count declined to approximately 40 × 109/L. After platelet transfusion, the platelet count rebounded to 90 × 109/L on day 35 but dropped again to 42 × 109/L on day 43. Based on the time-to-platelet count curve and Naranjo's Adverse Drug Reaction Probability Scale score, VIT was suspected. After vancomycin discontinuation and platelet transfusion, the platelet count gradually normalized.
CONCLUSIONS
The diagnosis of VIT can be achieved through the time-to-platelet count curve and Naranjo's Adverse Drug Reaction Probability Scale score. The platelet count cannot be normalized simply by platelet transfusion alone, and vancomycin discontinuation is essential.
Core Tip: The present report describes a case of vancomycin-induced thrombocytopenia (VIT) in endocarditis and reviews all VIT cases reported in the literature, in terms of indications, diagnosis, management, and potential molecular mechanisms. The present case highlights the importance of accurate diagnosis of VIT in endocarditis, which can be achieved through the time-to-platelet count curve and the Naranjo’s Adverse Drug Reaction Probability Scale score. The platelet count cannot be normalized simply by platelet transfusion alone, and the discontinuation of vancomycin is essential. Due to the anamnestic response to vancomycin re-exposure and the formation of vancomycin-dependent antiplatelet antibodies, the re-administration of vancomycin should be avoided.
INTRODUCTION
Thrombocytopenia, which is generally defined as a platelet count of less than 100 × 109/L of blood or a decrease in the platelet count of 20%-50% from baseline[1,2], has been considered as an adverse reaction correlated to drugs used in the treatment of various diseases[3]. Drug-induced thrombocytopenia is mostly caused by immune-mediated platelet degradation and is always drug dependent, indicating that the platelet count can return to baseline levels after the discontinuation of medications[4]. Although it has been reported that approximately 10 million persons per year are suspected to suffer from drug-induced thrombocytopenia[5], its incidence has not been well-defined[4].
Antibiotic-induced thrombocytopenia has been documented[3]. The commonly reported antibiotics that induce thrombocytopenia are β-lactam antibiotics agents (such as penicillin, nafcillin, ticarcillin, cefazolin, cefuroxime, ceftriaxone, and piperacillin) and linezolid[6]. Vancomycin is a first-generation glycopeptide antibiotic that is often used for the prophylaxis and treatment of suspected or identified methicillin-resistant infections, such as Staphylococcus aureus infection[7], and has been considered as an uncommon cause of thrombocytopenia[6]. Several clinical observational studies have suggested that the incidence of vancomycin-induced thrombocytopenia (VIT) might be higher than that induced by linezolid[1]. However, the incidence of VIT may have been overestimated, because the definition for thrombocytopenia used among these studies vary. A platelet count of less than 150 × 109/L was used in two studies[8,9], and a decrease in platelet count of at least 50% from baseline was used in another study[1]. In addition, the clinical manifestations, diagnosis, and management of VIT have not been well-established, and the underlying molecular mechanisms by which vancomycin induces thrombocytopenia needs to be further elucidated[10]. Over the past two decades, cases with VIT have been continuously reported[11]. However, these cases have rarely been extensively reviewed.
In June 2019, a young male patient with endocarditis was admitted to our hospital, and he developed VIT after vancomycin therapy during the treatment for endocarditis. The present report describes this case and extensively reviews all VIT cases reported in the literature, in terms of indications, diagnosis, management, and potential molecular mechanisms.
CASE PRESENTATION
Chief complaints
A 26-year-old Chinese male presented with dyspnea, fatigue, arrhythmias, fever, and cough.
History of present illness
The patient was admitted to the hospital on June 6, 2019 and diagnosed with infective endocarditis, heart failure, and ventricular septal defect, with a series of manifestations of inflammatory response syndrome.
History of past illness
He had a medical history of uncontrolled hypotension and rheumatic heart disease.
Personal and family history
He denied any family history.
Physical examination
He had a body temperature of 39.1 °C and a heart rate of 100 beats per min.
Laboratory examinations
Initial laboratory testing showed no abnormality.
Imaging examinations
The electrocardiosignal data revealed a high echo of the tricuspid valve, suggesting a neoplasm.
FINAL DIAGNOSIS
Infective endocarditis, heart failure, and ventricular septal defect.
TREATMENT
During hospitalization, the patient was treated with multiple courses of drug therapy, which included vancomycin, omeprazole (40 mg q.d. for 10 d), ceftazidime (2 g t.i.d. for 9 d) and metoprolol (50 mg q.d. for 11 d). Based on the bacterial culture and drug susceptibility test, methicillin-resistant Staphylococcus aureus was identified with the minimum inhibitory concentration of less than 2 mg/L. Therefore, according to The Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children[12], vancomycin was prescribed for the patient with infective endocarditis. Initially, the patient was intravenously treated with 1000 mg of vancomycin every 12 h and 960 mg of benzylpenicillin every 8 h on day 2 for suspected gram-positive infections. The blood cultures were negative for two consecutive tests. Then, the intravenous administration of vancomycin was changed to 500 mg for every 8 h on day 3, for a trough concentration of 25.87 µg/mL beyond the upper limit of 20 µg/mL, and the platelet count was maintained within 100-110 × 109/L for 7 d. On day 11, the administration of vancomycin was switched to 500 mg every 12 h, because the platelet count decreased to 51 × 109/L and the peak concentration of vancomycin reached 57.2 µg/mL. Platelet transfusion (1 U) was given on day 11, and the platelet count slightly increased to 64 × 109/L on day 14, but dramatically dropped afterwards to 27 × 109/L on day 17. Then, platelet transfusion (1 U) was given again on day 17, and the platelet count steadily increased up to 67 × 109/L on day 31. The dose of vancomycin was adjusted to 500 mg every 8 h on day 23 when the trough concentration of vancomycin dropped to 8.86 µg/mL in order to ensure the minimal effective treatment concentration (10 µg/mL). However, on day 33, the hemoglobin level sharply dropped from 101 g/L to 54 g/L, the platelet count continuously declined to approximately 40 × 109/L, and platelet transfusion (1 U) was given. The platelet count rebounded to 90 × 109/L on day 35 but dropped to 42 × 109/L again on day 43. Based on these above observations, and along with the time-to-platelet count curve that illustrated the decline in platelet level after the administration of vancomycin (Figure 1), VIT was suspected, vancomycin was discontinued and replaced with daptomycin, and platelet transfusion (1 U) was given on the same day. The platelet count level increased and reached up to 120 × 109/L on day 50 and remained stable thereafter.
Figure 1 Time-to-platelet count curve during hospitalization. Vancomycin was initiated on day 2 and continued on day 43, as indicated by the downward arrows. Platelet transfusion was given on day 11, 17, 33, and 43, as indicated by the upward arrows.
The concurrent antibiotic, benzylpenicillin, was continuously used during the period with little effect on the platelet count. The respiratory rate, white blood cell count, and hemodynamic variables remained stable, and the microbiological cultures from the sputum and urine revealed negative results, implying that no infection was correlated with thrombocytopenia for the present patient. The other causes of thrombocytopenia, including thrombotic thrombocytopenic purpura, hemolytic anemia, disseminated intravascular coagulation, and platelet-clumping pseudothrombocytopenia, were also excluded, because the results of the blood smear, bilirubin, and hemoglobin were normal. There have been no reports on the occurrence of drug-induced thrombocytopenia caused by other medications during treatment, including omeprazole, ceftazidime, and metoprolol. Therefore, a diagnosis of VIT was initially established using the time-to-platelet count curve. In addition, the Naranjo’s Adverse Drug Reaction Probability Scale score (Naranjo score) for vancomycin was 8, indicating the probable correlation between thrombocytopenia and vancomycin.
OUTCOME AND FOLLOW-UP
The patient was discharged from the hospital.
DISCUSSION
A literature search for all case reports on VIT published in English from April 1985 to June 2020 was performed on PMC/PubMed, Scopus, and Web of Science. Keywords, which included vancomycin and thrombocytopenia, were used to search the titles and abstracts. References of relevant case reports, according to the brief research, were also carefully checked. The demographic data (e.g., age and gender), platelet count, diagnosis, and treatment were recorded and analyzed.
A total of 36 articles that reported 37 cases with VIT were identified in the literature. Thus, the data of 38 cases, which included the case described in the present report, were reviewed and are summarized in Table 1. Among these cases, 14 cases were females and 24 cases were males. The mean age of these cases was 51.19 ± 26.98 years-old (range: 3 mo to 81-years-old). Furthermore, four children were under 2-years-old, and 36 cases were adults 26-81 years-old. The most common indications for the treatment with vancomycin were endocarditis (n = 6), sepsis (n = 6), pneumonia (n = 5), and cellulitis (n = 2). These were followed by other various indications, such as prosthetic infection, hemodialysis, bone graft, acute pancreatitis, etc. The diagnosis of VIT mainly relied on the platelet count, with or without the Naranjo score[13]. The test results for the vancomycin-dependent antibodies were available for 19 patients, and all except three were positive. Among the 27 patients with available bleeding information, 21 patients exhibited bleeding signs. The treatments for these cases comprised of platelet transfusion, prednisone, dexamethasone, immunoglobulin, and daptomycin, and the discontinuation of vancomycin. For the six cases with endocarditis, VIT was diagnosed as probable by the Naranjo score. The information on bleeding signs was available for four cases, and three of these cases presented with bleeding signs. The presence of vancomycin-dependent antibodies was examined only in two patients, and positive results were obtained in one of them. After vancomycin discontinuation, VIT was generally resolved for all patients within 4-15 d. Despite clinical significance revealed by the present literature review, it must be clearly stated that this is only a narrative review, which possesses all the limitations of the selection of papers. Thus, a methodologically acceptable systematic review should be carried out when more data with high quality are available in order to draw a firm conclusion.
Table 1 Summary of case reports of vancomycin-induced thrombocytopenia
Author (publication year) Age (yr) Gender Indication Platelet count (109/L)1 Naranjo Score Treatment Time for resolution (d)2 Vancomycin-dependentantibodies Bleeding sign
Present case 26 M Endocarditis 27 Probable Platelet transfusion and daptomycin 12 NA +
MacDougall et al[14] (2020) 81 M Prosthetic infection 2 NA Prednisone, immunoglobulin, and daptomycin 10 + -
Ajit et al[27] (2019) 61 M Hemodialysis < 10 NA Prednisone, immunoglobulin, eltrombopag and plasma exchange 15 + +
Getz et al[18] (2019) 71 M Transverse myelitis 8.6 Definite Dexamethasone and immunoglobulin 8 + +
Chen et al[16] (2018) 0 F Purulent meningitis 8 Probable Methylprednisolone 4 + +
Danieletto et al[17] (2017) 57 F Bone graft 9 Probable Tigecycline 7 - -
Kalra et al[28] (2016) 0.7 M Sepsis 30 NA Platelet transfusion 3 NA -
Schueler et al[15] (2016) 55 M Purpura 1 NA Prednisone and immunoglobulin 3 NA +
Yamanouchi et al[29] (2016) 72 F Sepsis 2 NA Steroid therapy and carbapenem 7 + +
Lobo et al[13] (2015) 67 M Pneumonia 2 Probable Platelet transfusion, methylprednisolone and immunoglobulin 3 + +
Ahmed et al[30] (2015) 63 M Diabetic foot 2 Probable Daptomycin 10 + -
Candemir et al[10] (2013) 54 F Hematoma 42 Probable Platelet transfusion and daptomycin 4 NA NA
Wetzel et al[31] (2013) 64 F Sepsis 7 Probable Prednisone and immunoglobulin 8 NA +
Ruggero et al[32] (2012) 41 M Pneumonia 15 Definite Daptomycin 5 NA +
Arnold et al[23] (2013) 66 F Endocarditis 4 Probable Platelet transfusion and immunoglobulin 5 + +
Rowland et al[33] (2013) 51 M Acute pancreatitis 9 Probable Only vancomycin discontinuation 5 NA +
Anand et al[34] (2011) 54 M Cellulitis 1 Possible Corticosteroids and daptomycin 2 + +
Ganly et al[22] (2011) 67 M Sepsis 2 NA Platelet transfusion and immunoglobulin 8 NA +
Shah et al[11] (2009) 60 M Shoulder infection 9 Possible Platelet transfusion 3 + +
Lee et al[35] (2009) 76 M Diabetic foot < 15 Possible Platelet transfusion and teicoplanin. 5 + -
Apiwattanakul et al[36] (2008) 16 F Endocarditis 123 Possible Prednisone and cefotaxime 5 NA -
Kenney et al[20] (2008) 61 M Gangrene and bacteremia 3 Probable Platelet transfusion and immunoglobulin 4 + +
Pauldine et al[37] (2008) 60 M Pneumonia 10 Possible Platelet transfusion 12 + +
Dilli et al[38] (2008) 0.6 M Neonatal respiratory distress 41 NA Only vancomycin discontinuation 3 - NA
O’Donnell et al[21] (2007) 56 F Prosthetic infection 2 Possible Immunoglobulin 7 + +
Bay et al[39] (2006) 2 M Pneumonia 11 NA Only vancomycin discontinuation 4 NA NA
Winteroll et al[24] (2004) 72 M Sepsis 3 Probable Platelet transfusion 10 + +
Peel et al[40] (2003) 45 M Peritonitis 5 Probable Platelet transfusion and prednisone 4 NA +
Marraffa et al[41] (2003) 50 M Endocarditis 10 Probable Clindamycin and methylprednisolone 5 NA +
Rocha et al[42] (2002) 38 F Prosthetic infection 68 Possible Only vancomycin discontinuation 4 NA NA
Shahar et al[43] (2000) 43 F Surgery-site infection 118 Probable Only vancomycin discontinuation 3 NA NA
Govindarajan et al[44] (1999) 72 M Epidural abscess 13 Probable Trimethoprim/sulfmethoxazole 10 NA NA
Kuruppu et al[45] (1999) 72 F Endocarditis 14 Possible Only vancomycin discontinuation 5 - NA
Mizon et al[46] (1997) 71 F Sepsis < 10 Probable Antibiotics withdrawn 4 + +
Zenon et al[47] (1991) 54 M Cellulitis 17 Probable Antibiotics withdrawn 7 NA NA
Christie et al[48] (1990) 73 F Pneumonia 14 Probable Platelet transfusion 2 + NA
Christie et al[48] (1990) 31 M Fever < 10 Possible Platelet transfusion 11 (not continued) + NA
Carmichael et al[49] (1986) 42 F Endocarditis 82 Possible NA 9 NA NA
1 The lowest value during the vancomycin treatment.
2 The time from vancomycin discontinuation to the resolution of vancomycin-induced thrombocytopenia. +: A positive result; -: A negative result. F: Female; M: Male; NA: Not available or not tested.
The present patient with infective endocarditis was diagnosed with VIT, which rapidly progressed. The early diagnosis of VIT was performed using the time-to-platelet count curve and Naranjo score. During treatment, the repeated platelet transfusions failed to increase the platelet levels. Subsequently, simply switching vancomycin to daptomycin returned the platelet count close to the baseline level.
The early diagnosis of VIT is quite difficult due to many suspected causes, such as severe infection, disseminated intravascular coagulation, heparin, and other medications. The correct diagnosis can be masked by the simultaneous administration of medications, which can cause drug-induced immune thrombocytopenia[14] or a complicating disease, such as primary idiopathic thrombocytopenic purpura or chronic hepatitis C[15]. Therefore, the early recognition of VIT was of key importance for the following treatment. According to previous studies[6], the investigators used the platelet count at different time points as the initial diagnosis of VIT, which can reveal a definite time-independent relationship with drug administration. All other causes of thrombocytopenia were excluded. Furthermore, the Naranjo score, which has been applied to help with the diagnosis of VIT[16-18], also indicated a probable correlation between thrombocytopenia and vancomycin. Noticeably, endocarditis represents the most common indication that is associated with VIT. The probable correlation between thrombocytopenia and vancomycin can be made through the Naranjo score for all cases, indicating that the Naranjo score is a useful tool to initially diagnose VIT in patients with endocarditis. A bleeding sign is also a useful clinical manifestation to which attention should be given in order to make a definite diagnosis, since most cases would present bleeding signs when VIT occurs. This is particularly true in patents with endocarditis, based on the analyzed data. However, the value of the detection of vancomycin-dependent antibodies in the diagnosis of VIT in patients with endocarditis remains to be elucidated due to the very limited data available.
The critical management after suspicions of VIT is to determine whether to continue or discontinue the vancomycin therapy. The seriousness of the bleeding and the dropping trend of the platelet count should be carefully considered and closely monitored when continuing the vancomycin therapy. However, once VIT is diagnosed, the vancomycin must be stopped, and the platelet transfusion should be taken into consideration as a supplemental treatment for some patients with various success rates, although there are still some transfusion-resistant patients[10,13,19,20]. If vancomycin is not stopped, the survival time of the transfused platelets would be obviously reduced, and the platelet transfusion will not always expectedly increase the platelet count of affected patients[3]. In any of these circumstances, platelet transfusion should be considered for severe thrombocytopenia with a platelet count of below 20 × 109/L and bleeding[19]. In addition to platelet transfusion, therapies with intravenous corticosteroids, intravenous immunoglobulins, rituximab, and plasma exchange have been shown to be beneficial in some cases after vancomycin discontinuation[3,21-23]. However, these medical approaches may not always be effective. In the present case, VIT was effectively resolved by platelet transfusion with the switching of vancomycin to daptomycin.
The mechanisms of VIT remains unclear. The formation of different drug-dependent platelet antibodies, including hapten-dependent, quinine-type, fiban-type and drug-specific antibodies, and other platelet destruction antibodies, are the widely documented mechanisms for VIT[11,21,24]. In contrast, naturally occurring antibodies may not contribute to VIT[25]. It has been postulated that vancomycin can bind to platelet glycoproteins and induce the generation of antibodies, which can attach to the drug-platelet complex, resulting in cell lysis[26]. In the present case, the platelet count gradually dropped after the administration of vancomycin (1000 mg per day) for 7 d. Although the vancomycin was changed to a low-dose (500 mg per day), the platelet count continued to drop. It was postulated that the persistent thrombocytopenia might be due to the anamnestic response for vancomycin re-exposure, and vancomycin-dependent antiplatelet antibodies were formed once vancomycin was re-used.
CONCLUSION
The present case highlights the importance of the accurate diagnosis of VIT in patients with endocarditis. The time-to-platelet count curve and Naranjo score are useful tools for the diagnosis of VIT. The platelet count cannot be normalized simply by platelet transfusion alone. Instead, the discontinuation of vancomycin or switching vancomycin to other antibiotics, such as daptomycin, is essential for effectively treating VIT. Due to the anamnestic response to vancomycin re-exposure and the formation of vancomycin-dependent antiplatelet antibodies, the re-administration of vancomycin should be avoided.
Informed consent statement: An informed written consent was obtained from the patient for the publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: October 13, 2020
First decision: December 13, 2020
Article in press: January 22, 2021
Specialty type: Pharmacology and pharmacy
Country/Territory of origin: China
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P-Reviewer: Momčilović S S-Editor: Zhang H L-Editor: Filipodia P-Editor: Xing YX | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33728314 | 19,048,518 | 2021-03-06 |
What was the administration route of drug 'VANCOMYCIN'? | Vancomycin-induced thrombocytopenia in endocarditis: A case report and review of literature.
BACKGROUND
Thrombocytopenia is a serious complication in the medical practice of numerous drugs. Vancomycin is frequently used for the prophylaxis and treatment of suspected or identified methicillin-resistant positive infections. Several cases with vancomycin-induced thrombocytopenia (VIT) have been reported. However, these have rarely been extensively reviewed. The present report describes a case of VIT in endocarditis, and reviews all VIT cases reported in the literature.
METHODS
A 26-year-old male diagnosed with infective endocarditis was admitted. The patient was treated with multiple drugs, including vancomycin, which was initially intravenously given at 1000 mg every 12 h and subsequently at 500 mg every 8 h on day 3. On day 11, the platelet count decreased to 51 × 109/L, vancomycin was switched to 500 mg every 12 h, and platelet transfusion was given. On day 17, the platelet count dropped to 27 × 109/L, and platelet transfusion was administered again. On day 23, vancomycin was adjusted to 500 mg every 8 h as the trough concentration dropped to the minimum effective concentration. On day 33, the platelet count declined to approximately 40 × 109/L. After platelet transfusion, the platelet count rebounded to 90 × 109/L on day 35 but dropped again to 42 × 109/L on day 43. Based on the time-to-platelet count curve and Naranjo's Adverse Drug Reaction Probability Scale score, VIT was suspected. After vancomycin discontinuation and platelet transfusion, the platelet count gradually normalized.
CONCLUSIONS
The diagnosis of VIT can be achieved through the time-to-platelet count curve and Naranjo's Adverse Drug Reaction Probability Scale score. The platelet count cannot be normalized simply by platelet transfusion alone, and vancomycin discontinuation is essential.
Core Tip: The present report describes a case of vancomycin-induced thrombocytopenia (VIT) in endocarditis and reviews all VIT cases reported in the literature, in terms of indications, diagnosis, management, and potential molecular mechanisms. The present case highlights the importance of accurate diagnosis of VIT in endocarditis, which can be achieved through the time-to-platelet count curve and the Naranjo’s Adverse Drug Reaction Probability Scale score. The platelet count cannot be normalized simply by platelet transfusion alone, and the discontinuation of vancomycin is essential. Due to the anamnestic response to vancomycin re-exposure and the formation of vancomycin-dependent antiplatelet antibodies, the re-administration of vancomycin should be avoided.
INTRODUCTION
Thrombocytopenia, which is generally defined as a platelet count of less than 100 × 109/L of blood or a decrease in the platelet count of 20%-50% from baseline[1,2], has been considered as an adverse reaction correlated to drugs used in the treatment of various diseases[3]. Drug-induced thrombocytopenia is mostly caused by immune-mediated platelet degradation and is always drug dependent, indicating that the platelet count can return to baseline levels after the discontinuation of medications[4]. Although it has been reported that approximately 10 million persons per year are suspected to suffer from drug-induced thrombocytopenia[5], its incidence has not been well-defined[4].
Antibiotic-induced thrombocytopenia has been documented[3]. The commonly reported antibiotics that induce thrombocytopenia are β-lactam antibiotics agents (such as penicillin, nafcillin, ticarcillin, cefazolin, cefuroxime, ceftriaxone, and piperacillin) and linezolid[6]. Vancomycin is a first-generation glycopeptide antibiotic that is often used for the prophylaxis and treatment of suspected or identified methicillin-resistant infections, such as Staphylococcus aureus infection[7], and has been considered as an uncommon cause of thrombocytopenia[6]. Several clinical observational studies have suggested that the incidence of vancomycin-induced thrombocytopenia (VIT) might be higher than that induced by linezolid[1]. However, the incidence of VIT may have been overestimated, because the definition for thrombocytopenia used among these studies vary. A platelet count of less than 150 × 109/L was used in two studies[8,9], and a decrease in platelet count of at least 50% from baseline was used in another study[1]. In addition, the clinical manifestations, diagnosis, and management of VIT have not been well-established, and the underlying molecular mechanisms by which vancomycin induces thrombocytopenia needs to be further elucidated[10]. Over the past two decades, cases with VIT have been continuously reported[11]. However, these cases have rarely been extensively reviewed.
In June 2019, a young male patient with endocarditis was admitted to our hospital, and he developed VIT after vancomycin therapy during the treatment for endocarditis. The present report describes this case and extensively reviews all VIT cases reported in the literature, in terms of indications, diagnosis, management, and potential molecular mechanisms.
CASE PRESENTATION
Chief complaints
A 26-year-old Chinese male presented with dyspnea, fatigue, arrhythmias, fever, and cough.
History of present illness
The patient was admitted to the hospital on June 6, 2019 and diagnosed with infective endocarditis, heart failure, and ventricular septal defect, with a series of manifestations of inflammatory response syndrome.
History of past illness
He had a medical history of uncontrolled hypotension and rheumatic heart disease.
Personal and family history
He denied any family history.
Physical examination
He had a body temperature of 39.1 °C and a heart rate of 100 beats per min.
Laboratory examinations
Initial laboratory testing showed no abnormality.
Imaging examinations
The electrocardiosignal data revealed a high echo of the tricuspid valve, suggesting a neoplasm.
FINAL DIAGNOSIS
Infective endocarditis, heart failure, and ventricular septal defect.
TREATMENT
During hospitalization, the patient was treated with multiple courses of drug therapy, which included vancomycin, omeprazole (40 mg q.d. for 10 d), ceftazidime (2 g t.i.d. for 9 d) and metoprolol (50 mg q.d. for 11 d). Based on the bacterial culture and drug susceptibility test, methicillin-resistant Staphylococcus aureus was identified with the minimum inhibitory concentration of less than 2 mg/L. Therefore, according to The Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children[12], vancomycin was prescribed for the patient with infective endocarditis. Initially, the patient was intravenously treated with 1000 mg of vancomycin every 12 h and 960 mg of benzylpenicillin every 8 h on day 2 for suspected gram-positive infections. The blood cultures were negative for two consecutive tests. Then, the intravenous administration of vancomycin was changed to 500 mg for every 8 h on day 3, for a trough concentration of 25.87 µg/mL beyond the upper limit of 20 µg/mL, and the platelet count was maintained within 100-110 × 109/L for 7 d. On day 11, the administration of vancomycin was switched to 500 mg every 12 h, because the platelet count decreased to 51 × 109/L and the peak concentration of vancomycin reached 57.2 µg/mL. Platelet transfusion (1 U) was given on day 11, and the platelet count slightly increased to 64 × 109/L on day 14, but dramatically dropped afterwards to 27 × 109/L on day 17. Then, platelet transfusion (1 U) was given again on day 17, and the platelet count steadily increased up to 67 × 109/L on day 31. The dose of vancomycin was adjusted to 500 mg every 8 h on day 23 when the trough concentration of vancomycin dropped to 8.86 µg/mL in order to ensure the minimal effective treatment concentration (10 µg/mL). However, on day 33, the hemoglobin level sharply dropped from 101 g/L to 54 g/L, the platelet count continuously declined to approximately 40 × 109/L, and platelet transfusion (1 U) was given. The platelet count rebounded to 90 × 109/L on day 35 but dropped to 42 × 109/L again on day 43. Based on these above observations, and along with the time-to-platelet count curve that illustrated the decline in platelet level after the administration of vancomycin (Figure 1), VIT was suspected, vancomycin was discontinued and replaced with daptomycin, and platelet transfusion (1 U) was given on the same day. The platelet count level increased and reached up to 120 × 109/L on day 50 and remained stable thereafter.
Figure 1 Time-to-platelet count curve during hospitalization. Vancomycin was initiated on day 2 and continued on day 43, as indicated by the downward arrows. Platelet transfusion was given on day 11, 17, 33, and 43, as indicated by the upward arrows.
The concurrent antibiotic, benzylpenicillin, was continuously used during the period with little effect on the platelet count. The respiratory rate, white blood cell count, and hemodynamic variables remained stable, and the microbiological cultures from the sputum and urine revealed negative results, implying that no infection was correlated with thrombocytopenia for the present patient. The other causes of thrombocytopenia, including thrombotic thrombocytopenic purpura, hemolytic anemia, disseminated intravascular coagulation, and platelet-clumping pseudothrombocytopenia, were also excluded, because the results of the blood smear, bilirubin, and hemoglobin were normal. There have been no reports on the occurrence of drug-induced thrombocytopenia caused by other medications during treatment, including omeprazole, ceftazidime, and metoprolol. Therefore, a diagnosis of VIT was initially established using the time-to-platelet count curve. In addition, the Naranjo’s Adverse Drug Reaction Probability Scale score (Naranjo score) for vancomycin was 8, indicating the probable correlation between thrombocytopenia and vancomycin.
OUTCOME AND FOLLOW-UP
The patient was discharged from the hospital.
DISCUSSION
A literature search for all case reports on VIT published in English from April 1985 to June 2020 was performed on PMC/PubMed, Scopus, and Web of Science. Keywords, which included vancomycin and thrombocytopenia, were used to search the titles and abstracts. References of relevant case reports, according to the brief research, were also carefully checked. The demographic data (e.g., age and gender), platelet count, diagnosis, and treatment were recorded and analyzed.
A total of 36 articles that reported 37 cases with VIT were identified in the literature. Thus, the data of 38 cases, which included the case described in the present report, were reviewed and are summarized in Table 1. Among these cases, 14 cases were females and 24 cases were males. The mean age of these cases was 51.19 ± 26.98 years-old (range: 3 mo to 81-years-old). Furthermore, four children were under 2-years-old, and 36 cases were adults 26-81 years-old. The most common indications for the treatment with vancomycin were endocarditis (n = 6), sepsis (n = 6), pneumonia (n = 5), and cellulitis (n = 2). These were followed by other various indications, such as prosthetic infection, hemodialysis, bone graft, acute pancreatitis, etc. The diagnosis of VIT mainly relied on the platelet count, with or without the Naranjo score[13]. The test results for the vancomycin-dependent antibodies were available for 19 patients, and all except three were positive. Among the 27 patients with available bleeding information, 21 patients exhibited bleeding signs. The treatments for these cases comprised of platelet transfusion, prednisone, dexamethasone, immunoglobulin, and daptomycin, and the discontinuation of vancomycin. For the six cases with endocarditis, VIT was diagnosed as probable by the Naranjo score. The information on bleeding signs was available for four cases, and three of these cases presented with bleeding signs. The presence of vancomycin-dependent antibodies was examined only in two patients, and positive results were obtained in one of them. After vancomycin discontinuation, VIT was generally resolved for all patients within 4-15 d. Despite clinical significance revealed by the present literature review, it must be clearly stated that this is only a narrative review, which possesses all the limitations of the selection of papers. Thus, a methodologically acceptable systematic review should be carried out when more data with high quality are available in order to draw a firm conclusion.
Table 1 Summary of case reports of vancomycin-induced thrombocytopenia
Author (publication year) Age (yr) Gender Indication Platelet count (109/L)1 Naranjo Score Treatment Time for resolution (d)2 Vancomycin-dependentantibodies Bleeding sign
Present case 26 M Endocarditis 27 Probable Platelet transfusion and daptomycin 12 NA +
MacDougall et al[14] (2020) 81 M Prosthetic infection 2 NA Prednisone, immunoglobulin, and daptomycin 10 + -
Ajit et al[27] (2019) 61 M Hemodialysis < 10 NA Prednisone, immunoglobulin, eltrombopag and plasma exchange 15 + +
Getz et al[18] (2019) 71 M Transverse myelitis 8.6 Definite Dexamethasone and immunoglobulin 8 + +
Chen et al[16] (2018) 0 F Purulent meningitis 8 Probable Methylprednisolone 4 + +
Danieletto et al[17] (2017) 57 F Bone graft 9 Probable Tigecycline 7 - -
Kalra et al[28] (2016) 0.7 M Sepsis 30 NA Platelet transfusion 3 NA -
Schueler et al[15] (2016) 55 M Purpura 1 NA Prednisone and immunoglobulin 3 NA +
Yamanouchi et al[29] (2016) 72 F Sepsis 2 NA Steroid therapy and carbapenem 7 + +
Lobo et al[13] (2015) 67 M Pneumonia 2 Probable Platelet transfusion, methylprednisolone and immunoglobulin 3 + +
Ahmed et al[30] (2015) 63 M Diabetic foot 2 Probable Daptomycin 10 + -
Candemir et al[10] (2013) 54 F Hematoma 42 Probable Platelet transfusion and daptomycin 4 NA NA
Wetzel et al[31] (2013) 64 F Sepsis 7 Probable Prednisone and immunoglobulin 8 NA +
Ruggero et al[32] (2012) 41 M Pneumonia 15 Definite Daptomycin 5 NA +
Arnold et al[23] (2013) 66 F Endocarditis 4 Probable Platelet transfusion and immunoglobulin 5 + +
Rowland et al[33] (2013) 51 M Acute pancreatitis 9 Probable Only vancomycin discontinuation 5 NA +
Anand et al[34] (2011) 54 M Cellulitis 1 Possible Corticosteroids and daptomycin 2 + +
Ganly et al[22] (2011) 67 M Sepsis 2 NA Platelet transfusion and immunoglobulin 8 NA +
Shah et al[11] (2009) 60 M Shoulder infection 9 Possible Platelet transfusion 3 + +
Lee et al[35] (2009) 76 M Diabetic foot < 15 Possible Platelet transfusion and teicoplanin. 5 + -
Apiwattanakul et al[36] (2008) 16 F Endocarditis 123 Possible Prednisone and cefotaxime 5 NA -
Kenney et al[20] (2008) 61 M Gangrene and bacteremia 3 Probable Platelet transfusion and immunoglobulin 4 + +
Pauldine et al[37] (2008) 60 M Pneumonia 10 Possible Platelet transfusion 12 + +
Dilli et al[38] (2008) 0.6 M Neonatal respiratory distress 41 NA Only vancomycin discontinuation 3 - NA
O’Donnell et al[21] (2007) 56 F Prosthetic infection 2 Possible Immunoglobulin 7 + +
Bay et al[39] (2006) 2 M Pneumonia 11 NA Only vancomycin discontinuation 4 NA NA
Winteroll et al[24] (2004) 72 M Sepsis 3 Probable Platelet transfusion 10 + +
Peel et al[40] (2003) 45 M Peritonitis 5 Probable Platelet transfusion and prednisone 4 NA +
Marraffa et al[41] (2003) 50 M Endocarditis 10 Probable Clindamycin and methylprednisolone 5 NA +
Rocha et al[42] (2002) 38 F Prosthetic infection 68 Possible Only vancomycin discontinuation 4 NA NA
Shahar et al[43] (2000) 43 F Surgery-site infection 118 Probable Only vancomycin discontinuation 3 NA NA
Govindarajan et al[44] (1999) 72 M Epidural abscess 13 Probable Trimethoprim/sulfmethoxazole 10 NA NA
Kuruppu et al[45] (1999) 72 F Endocarditis 14 Possible Only vancomycin discontinuation 5 - NA
Mizon et al[46] (1997) 71 F Sepsis < 10 Probable Antibiotics withdrawn 4 + +
Zenon et al[47] (1991) 54 M Cellulitis 17 Probable Antibiotics withdrawn 7 NA NA
Christie et al[48] (1990) 73 F Pneumonia 14 Probable Platelet transfusion 2 + NA
Christie et al[48] (1990) 31 M Fever < 10 Possible Platelet transfusion 11 (not continued) + NA
Carmichael et al[49] (1986) 42 F Endocarditis 82 Possible NA 9 NA NA
1 The lowest value during the vancomycin treatment.
2 The time from vancomycin discontinuation to the resolution of vancomycin-induced thrombocytopenia. +: A positive result; -: A negative result. F: Female; M: Male; NA: Not available or not tested.
The present patient with infective endocarditis was diagnosed with VIT, which rapidly progressed. The early diagnosis of VIT was performed using the time-to-platelet count curve and Naranjo score. During treatment, the repeated platelet transfusions failed to increase the platelet levels. Subsequently, simply switching vancomycin to daptomycin returned the platelet count close to the baseline level.
The early diagnosis of VIT is quite difficult due to many suspected causes, such as severe infection, disseminated intravascular coagulation, heparin, and other medications. The correct diagnosis can be masked by the simultaneous administration of medications, which can cause drug-induced immune thrombocytopenia[14] or a complicating disease, such as primary idiopathic thrombocytopenic purpura or chronic hepatitis C[15]. Therefore, the early recognition of VIT was of key importance for the following treatment. According to previous studies[6], the investigators used the platelet count at different time points as the initial diagnosis of VIT, which can reveal a definite time-independent relationship with drug administration. All other causes of thrombocytopenia were excluded. Furthermore, the Naranjo score, which has been applied to help with the diagnosis of VIT[16-18], also indicated a probable correlation between thrombocytopenia and vancomycin. Noticeably, endocarditis represents the most common indication that is associated with VIT. The probable correlation between thrombocytopenia and vancomycin can be made through the Naranjo score for all cases, indicating that the Naranjo score is a useful tool to initially diagnose VIT in patients with endocarditis. A bleeding sign is also a useful clinical manifestation to which attention should be given in order to make a definite diagnosis, since most cases would present bleeding signs when VIT occurs. This is particularly true in patents with endocarditis, based on the analyzed data. However, the value of the detection of vancomycin-dependent antibodies in the diagnosis of VIT in patients with endocarditis remains to be elucidated due to the very limited data available.
The critical management after suspicions of VIT is to determine whether to continue or discontinue the vancomycin therapy. The seriousness of the bleeding and the dropping trend of the platelet count should be carefully considered and closely monitored when continuing the vancomycin therapy. However, once VIT is diagnosed, the vancomycin must be stopped, and the platelet transfusion should be taken into consideration as a supplemental treatment for some patients with various success rates, although there are still some transfusion-resistant patients[10,13,19,20]. If vancomycin is not stopped, the survival time of the transfused platelets would be obviously reduced, and the platelet transfusion will not always expectedly increase the platelet count of affected patients[3]. In any of these circumstances, platelet transfusion should be considered for severe thrombocytopenia with a platelet count of below 20 × 109/L and bleeding[19]. In addition to platelet transfusion, therapies with intravenous corticosteroids, intravenous immunoglobulins, rituximab, and plasma exchange have been shown to be beneficial in some cases after vancomycin discontinuation[3,21-23]. However, these medical approaches may not always be effective. In the present case, VIT was effectively resolved by platelet transfusion with the switching of vancomycin to daptomycin.
The mechanisms of VIT remains unclear. The formation of different drug-dependent platelet antibodies, including hapten-dependent, quinine-type, fiban-type and drug-specific antibodies, and other platelet destruction antibodies, are the widely documented mechanisms for VIT[11,21,24]. In contrast, naturally occurring antibodies may not contribute to VIT[25]. It has been postulated that vancomycin can bind to platelet glycoproteins and induce the generation of antibodies, which can attach to the drug-platelet complex, resulting in cell lysis[26]. In the present case, the platelet count gradually dropped after the administration of vancomycin (1000 mg per day) for 7 d. Although the vancomycin was changed to a low-dose (500 mg per day), the platelet count continued to drop. It was postulated that the persistent thrombocytopenia might be due to the anamnestic response for vancomycin re-exposure, and vancomycin-dependent antiplatelet antibodies were formed once vancomycin was re-used.
CONCLUSION
The present case highlights the importance of the accurate diagnosis of VIT in patients with endocarditis. The time-to-platelet count curve and Naranjo score are useful tools for the diagnosis of VIT. The platelet count cannot be normalized simply by platelet transfusion alone. Instead, the discontinuation of vancomycin or switching vancomycin to other antibiotics, such as daptomycin, is essential for effectively treating VIT. Due to the anamnestic response to vancomycin re-exposure and the formation of vancomycin-dependent antiplatelet antibodies, the re-administration of vancomycin should be avoided.
Informed consent statement: An informed written consent was obtained from the patient for the publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: October 13, 2020
First decision: December 13, 2020
Article in press: January 22, 2021
Specialty type: Pharmacology and pharmacy
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Momčilović S S-Editor: Zhang H L-Editor: Filipodia P-Editor: Xing YX | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33728314 | 19,089,446 | 2021-03-06 |
What was the outcome of reaction 'Haemoglobin decreased'? | Vancomycin-induced thrombocytopenia in endocarditis: A case report and review of literature.
BACKGROUND
Thrombocytopenia is a serious complication in the medical practice of numerous drugs. Vancomycin is frequently used for the prophylaxis and treatment of suspected or identified methicillin-resistant positive infections. Several cases with vancomycin-induced thrombocytopenia (VIT) have been reported. However, these have rarely been extensively reviewed. The present report describes a case of VIT in endocarditis, and reviews all VIT cases reported in the literature.
METHODS
A 26-year-old male diagnosed with infective endocarditis was admitted. The patient was treated with multiple drugs, including vancomycin, which was initially intravenously given at 1000 mg every 12 h and subsequently at 500 mg every 8 h on day 3. On day 11, the platelet count decreased to 51 × 109/L, vancomycin was switched to 500 mg every 12 h, and platelet transfusion was given. On day 17, the platelet count dropped to 27 × 109/L, and platelet transfusion was administered again. On day 23, vancomycin was adjusted to 500 mg every 8 h as the trough concentration dropped to the minimum effective concentration. On day 33, the platelet count declined to approximately 40 × 109/L. After platelet transfusion, the platelet count rebounded to 90 × 109/L on day 35 but dropped again to 42 × 109/L on day 43. Based on the time-to-platelet count curve and Naranjo's Adverse Drug Reaction Probability Scale score, VIT was suspected. After vancomycin discontinuation and platelet transfusion, the platelet count gradually normalized.
CONCLUSIONS
The diagnosis of VIT can be achieved through the time-to-platelet count curve and Naranjo's Adverse Drug Reaction Probability Scale score. The platelet count cannot be normalized simply by platelet transfusion alone, and vancomycin discontinuation is essential.
Core Tip: The present report describes a case of vancomycin-induced thrombocytopenia (VIT) in endocarditis and reviews all VIT cases reported in the literature, in terms of indications, diagnosis, management, and potential molecular mechanisms. The present case highlights the importance of accurate diagnosis of VIT in endocarditis, which can be achieved through the time-to-platelet count curve and the Naranjo’s Adverse Drug Reaction Probability Scale score. The platelet count cannot be normalized simply by platelet transfusion alone, and the discontinuation of vancomycin is essential. Due to the anamnestic response to vancomycin re-exposure and the formation of vancomycin-dependent antiplatelet antibodies, the re-administration of vancomycin should be avoided.
INTRODUCTION
Thrombocytopenia, which is generally defined as a platelet count of less than 100 × 109/L of blood or a decrease in the platelet count of 20%-50% from baseline[1,2], has been considered as an adverse reaction correlated to drugs used in the treatment of various diseases[3]. Drug-induced thrombocytopenia is mostly caused by immune-mediated platelet degradation and is always drug dependent, indicating that the platelet count can return to baseline levels after the discontinuation of medications[4]. Although it has been reported that approximately 10 million persons per year are suspected to suffer from drug-induced thrombocytopenia[5], its incidence has not been well-defined[4].
Antibiotic-induced thrombocytopenia has been documented[3]. The commonly reported antibiotics that induce thrombocytopenia are β-lactam antibiotics agents (such as penicillin, nafcillin, ticarcillin, cefazolin, cefuroxime, ceftriaxone, and piperacillin) and linezolid[6]. Vancomycin is a first-generation glycopeptide antibiotic that is often used for the prophylaxis and treatment of suspected or identified methicillin-resistant infections, such as Staphylococcus aureus infection[7], and has been considered as an uncommon cause of thrombocytopenia[6]. Several clinical observational studies have suggested that the incidence of vancomycin-induced thrombocytopenia (VIT) might be higher than that induced by linezolid[1]. However, the incidence of VIT may have been overestimated, because the definition for thrombocytopenia used among these studies vary. A platelet count of less than 150 × 109/L was used in two studies[8,9], and a decrease in platelet count of at least 50% from baseline was used in another study[1]. In addition, the clinical manifestations, diagnosis, and management of VIT have not been well-established, and the underlying molecular mechanisms by which vancomycin induces thrombocytopenia needs to be further elucidated[10]. Over the past two decades, cases with VIT have been continuously reported[11]. However, these cases have rarely been extensively reviewed.
In June 2019, a young male patient with endocarditis was admitted to our hospital, and he developed VIT after vancomycin therapy during the treatment for endocarditis. The present report describes this case and extensively reviews all VIT cases reported in the literature, in terms of indications, diagnosis, management, and potential molecular mechanisms.
CASE PRESENTATION
Chief complaints
A 26-year-old Chinese male presented with dyspnea, fatigue, arrhythmias, fever, and cough.
History of present illness
The patient was admitted to the hospital on June 6, 2019 and diagnosed with infective endocarditis, heart failure, and ventricular septal defect, with a series of manifestations of inflammatory response syndrome.
History of past illness
He had a medical history of uncontrolled hypotension and rheumatic heart disease.
Personal and family history
He denied any family history.
Physical examination
He had a body temperature of 39.1 °C and a heart rate of 100 beats per min.
Laboratory examinations
Initial laboratory testing showed no abnormality.
Imaging examinations
The electrocardiosignal data revealed a high echo of the tricuspid valve, suggesting a neoplasm.
FINAL DIAGNOSIS
Infective endocarditis, heart failure, and ventricular septal defect.
TREATMENT
During hospitalization, the patient was treated with multiple courses of drug therapy, which included vancomycin, omeprazole (40 mg q.d. for 10 d), ceftazidime (2 g t.i.d. for 9 d) and metoprolol (50 mg q.d. for 11 d). Based on the bacterial culture and drug susceptibility test, methicillin-resistant Staphylococcus aureus was identified with the minimum inhibitory concentration of less than 2 mg/L. Therefore, according to The Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children[12], vancomycin was prescribed for the patient with infective endocarditis. Initially, the patient was intravenously treated with 1000 mg of vancomycin every 12 h and 960 mg of benzylpenicillin every 8 h on day 2 for suspected gram-positive infections. The blood cultures were negative for two consecutive tests. Then, the intravenous administration of vancomycin was changed to 500 mg for every 8 h on day 3, for a trough concentration of 25.87 µg/mL beyond the upper limit of 20 µg/mL, and the platelet count was maintained within 100-110 × 109/L for 7 d. On day 11, the administration of vancomycin was switched to 500 mg every 12 h, because the platelet count decreased to 51 × 109/L and the peak concentration of vancomycin reached 57.2 µg/mL. Platelet transfusion (1 U) was given on day 11, and the platelet count slightly increased to 64 × 109/L on day 14, but dramatically dropped afterwards to 27 × 109/L on day 17. Then, platelet transfusion (1 U) was given again on day 17, and the platelet count steadily increased up to 67 × 109/L on day 31. The dose of vancomycin was adjusted to 500 mg every 8 h on day 23 when the trough concentration of vancomycin dropped to 8.86 µg/mL in order to ensure the minimal effective treatment concentration (10 µg/mL). However, on day 33, the hemoglobin level sharply dropped from 101 g/L to 54 g/L, the platelet count continuously declined to approximately 40 × 109/L, and platelet transfusion (1 U) was given. The platelet count rebounded to 90 × 109/L on day 35 but dropped to 42 × 109/L again on day 43. Based on these above observations, and along with the time-to-platelet count curve that illustrated the decline in platelet level after the administration of vancomycin (Figure 1), VIT was suspected, vancomycin was discontinued and replaced with daptomycin, and platelet transfusion (1 U) was given on the same day. The platelet count level increased and reached up to 120 × 109/L on day 50 and remained stable thereafter.
Figure 1 Time-to-platelet count curve during hospitalization. Vancomycin was initiated on day 2 and continued on day 43, as indicated by the downward arrows. Platelet transfusion was given on day 11, 17, 33, and 43, as indicated by the upward arrows.
The concurrent antibiotic, benzylpenicillin, was continuously used during the period with little effect on the platelet count. The respiratory rate, white blood cell count, and hemodynamic variables remained stable, and the microbiological cultures from the sputum and urine revealed negative results, implying that no infection was correlated with thrombocytopenia for the present patient. The other causes of thrombocytopenia, including thrombotic thrombocytopenic purpura, hemolytic anemia, disseminated intravascular coagulation, and platelet-clumping pseudothrombocytopenia, were also excluded, because the results of the blood smear, bilirubin, and hemoglobin were normal. There have been no reports on the occurrence of drug-induced thrombocytopenia caused by other medications during treatment, including omeprazole, ceftazidime, and metoprolol. Therefore, a diagnosis of VIT was initially established using the time-to-platelet count curve. In addition, the Naranjo’s Adverse Drug Reaction Probability Scale score (Naranjo score) for vancomycin was 8, indicating the probable correlation between thrombocytopenia and vancomycin.
OUTCOME AND FOLLOW-UP
The patient was discharged from the hospital.
DISCUSSION
A literature search for all case reports on VIT published in English from April 1985 to June 2020 was performed on PMC/PubMed, Scopus, and Web of Science. Keywords, which included vancomycin and thrombocytopenia, were used to search the titles and abstracts. References of relevant case reports, according to the brief research, were also carefully checked. The demographic data (e.g., age and gender), platelet count, diagnosis, and treatment were recorded and analyzed.
A total of 36 articles that reported 37 cases with VIT were identified in the literature. Thus, the data of 38 cases, which included the case described in the present report, were reviewed and are summarized in Table 1. Among these cases, 14 cases were females and 24 cases were males. The mean age of these cases was 51.19 ± 26.98 years-old (range: 3 mo to 81-years-old). Furthermore, four children were under 2-years-old, and 36 cases were adults 26-81 years-old. The most common indications for the treatment with vancomycin were endocarditis (n = 6), sepsis (n = 6), pneumonia (n = 5), and cellulitis (n = 2). These were followed by other various indications, such as prosthetic infection, hemodialysis, bone graft, acute pancreatitis, etc. The diagnosis of VIT mainly relied on the platelet count, with or without the Naranjo score[13]. The test results for the vancomycin-dependent antibodies were available for 19 patients, and all except three were positive. Among the 27 patients with available bleeding information, 21 patients exhibited bleeding signs. The treatments for these cases comprised of platelet transfusion, prednisone, dexamethasone, immunoglobulin, and daptomycin, and the discontinuation of vancomycin. For the six cases with endocarditis, VIT was diagnosed as probable by the Naranjo score. The information on bleeding signs was available for four cases, and three of these cases presented with bleeding signs. The presence of vancomycin-dependent antibodies was examined only in two patients, and positive results were obtained in one of them. After vancomycin discontinuation, VIT was generally resolved for all patients within 4-15 d. Despite clinical significance revealed by the present literature review, it must be clearly stated that this is only a narrative review, which possesses all the limitations of the selection of papers. Thus, a methodologically acceptable systematic review should be carried out when more data with high quality are available in order to draw a firm conclusion.
Table 1 Summary of case reports of vancomycin-induced thrombocytopenia
Author (publication year) Age (yr) Gender Indication Platelet count (109/L)1 Naranjo Score Treatment Time for resolution (d)2 Vancomycin-dependentantibodies Bleeding sign
Present case 26 M Endocarditis 27 Probable Platelet transfusion and daptomycin 12 NA +
MacDougall et al[14] (2020) 81 M Prosthetic infection 2 NA Prednisone, immunoglobulin, and daptomycin 10 + -
Ajit et al[27] (2019) 61 M Hemodialysis < 10 NA Prednisone, immunoglobulin, eltrombopag and plasma exchange 15 + +
Getz et al[18] (2019) 71 M Transverse myelitis 8.6 Definite Dexamethasone and immunoglobulin 8 + +
Chen et al[16] (2018) 0 F Purulent meningitis 8 Probable Methylprednisolone 4 + +
Danieletto et al[17] (2017) 57 F Bone graft 9 Probable Tigecycline 7 - -
Kalra et al[28] (2016) 0.7 M Sepsis 30 NA Platelet transfusion 3 NA -
Schueler et al[15] (2016) 55 M Purpura 1 NA Prednisone and immunoglobulin 3 NA +
Yamanouchi et al[29] (2016) 72 F Sepsis 2 NA Steroid therapy and carbapenem 7 + +
Lobo et al[13] (2015) 67 M Pneumonia 2 Probable Platelet transfusion, methylprednisolone and immunoglobulin 3 + +
Ahmed et al[30] (2015) 63 M Diabetic foot 2 Probable Daptomycin 10 + -
Candemir et al[10] (2013) 54 F Hematoma 42 Probable Platelet transfusion and daptomycin 4 NA NA
Wetzel et al[31] (2013) 64 F Sepsis 7 Probable Prednisone and immunoglobulin 8 NA +
Ruggero et al[32] (2012) 41 M Pneumonia 15 Definite Daptomycin 5 NA +
Arnold et al[23] (2013) 66 F Endocarditis 4 Probable Platelet transfusion and immunoglobulin 5 + +
Rowland et al[33] (2013) 51 M Acute pancreatitis 9 Probable Only vancomycin discontinuation 5 NA +
Anand et al[34] (2011) 54 M Cellulitis 1 Possible Corticosteroids and daptomycin 2 + +
Ganly et al[22] (2011) 67 M Sepsis 2 NA Platelet transfusion and immunoglobulin 8 NA +
Shah et al[11] (2009) 60 M Shoulder infection 9 Possible Platelet transfusion 3 + +
Lee et al[35] (2009) 76 M Diabetic foot < 15 Possible Platelet transfusion and teicoplanin. 5 + -
Apiwattanakul et al[36] (2008) 16 F Endocarditis 123 Possible Prednisone and cefotaxime 5 NA -
Kenney et al[20] (2008) 61 M Gangrene and bacteremia 3 Probable Platelet transfusion and immunoglobulin 4 + +
Pauldine et al[37] (2008) 60 M Pneumonia 10 Possible Platelet transfusion 12 + +
Dilli et al[38] (2008) 0.6 M Neonatal respiratory distress 41 NA Only vancomycin discontinuation 3 - NA
O’Donnell et al[21] (2007) 56 F Prosthetic infection 2 Possible Immunoglobulin 7 + +
Bay et al[39] (2006) 2 M Pneumonia 11 NA Only vancomycin discontinuation 4 NA NA
Winteroll et al[24] (2004) 72 M Sepsis 3 Probable Platelet transfusion 10 + +
Peel et al[40] (2003) 45 M Peritonitis 5 Probable Platelet transfusion and prednisone 4 NA +
Marraffa et al[41] (2003) 50 M Endocarditis 10 Probable Clindamycin and methylprednisolone 5 NA +
Rocha et al[42] (2002) 38 F Prosthetic infection 68 Possible Only vancomycin discontinuation 4 NA NA
Shahar et al[43] (2000) 43 F Surgery-site infection 118 Probable Only vancomycin discontinuation 3 NA NA
Govindarajan et al[44] (1999) 72 M Epidural abscess 13 Probable Trimethoprim/sulfmethoxazole 10 NA NA
Kuruppu et al[45] (1999) 72 F Endocarditis 14 Possible Only vancomycin discontinuation 5 - NA
Mizon et al[46] (1997) 71 F Sepsis < 10 Probable Antibiotics withdrawn 4 + +
Zenon et al[47] (1991) 54 M Cellulitis 17 Probable Antibiotics withdrawn 7 NA NA
Christie et al[48] (1990) 73 F Pneumonia 14 Probable Platelet transfusion 2 + NA
Christie et al[48] (1990) 31 M Fever < 10 Possible Platelet transfusion 11 (not continued) + NA
Carmichael et al[49] (1986) 42 F Endocarditis 82 Possible NA 9 NA NA
1 The lowest value during the vancomycin treatment.
2 The time from vancomycin discontinuation to the resolution of vancomycin-induced thrombocytopenia. +: A positive result; -: A negative result. F: Female; M: Male; NA: Not available or not tested.
The present patient with infective endocarditis was diagnosed with VIT, which rapidly progressed. The early diagnosis of VIT was performed using the time-to-platelet count curve and Naranjo score. During treatment, the repeated platelet transfusions failed to increase the platelet levels. Subsequently, simply switching vancomycin to daptomycin returned the platelet count close to the baseline level.
The early diagnosis of VIT is quite difficult due to many suspected causes, such as severe infection, disseminated intravascular coagulation, heparin, and other medications. The correct diagnosis can be masked by the simultaneous administration of medications, which can cause drug-induced immune thrombocytopenia[14] or a complicating disease, such as primary idiopathic thrombocytopenic purpura or chronic hepatitis C[15]. Therefore, the early recognition of VIT was of key importance for the following treatment. According to previous studies[6], the investigators used the platelet count at different time points as the initial diagnosis of VIT, which can reveal a definite time-independent relationship with drug administration. All other causes of thrombocytopenia were excluded. Furthermore, the Naranjo score, which has been applied to help with the diagnosis of VIT[16-18], also indicated a probable correlation between thrombocytopenia and vancomycin. Noticeably, endocarditis represents the most common indication that is associated with VIT. The probable correlation between thrombocytopenia and vancomycin can be made through the Naranjo score for all cases, indicating that the Naranjo score is a useful tool to initially diagnose VIT in patients with endocarditis. A bleeding sign is also a useful clinical manifestation to which attention should be given in order to make a definite diagnosis, since most cases would present bleeding signs when VIT occurs. This is particularly true in patents with endocarditis, based on the analyzed data. However, the value of the detection of vancomycin-dependent antibodies in the diagnosis of VIT in patients with endocarditis remains to be elucidated due to the very limited data available.
The critical management after suspicions of VIT is to determine whether to continue or discontinue the vancomycin therapy. The seriousness of the bleeding and the dropping trend of the platelet count should be carefully considered and closely monitored when continuing the vancomycin therapy. However, once VIT is diagnosed, the vancomycin must be stopped, and the platelet transfusion should be taken into consideration as a supplemental treatment for some patients with various success rates, although there are still some transfusion-resistant patients[10,13,19,20]. If vancomycin is not stopped, the survival time of the transfused platelets would be obviously reduced, and the platelet transfusion will not always expectedly increase the platelet count of affected patients[3]. In any of these circumstances, platelet transfusion should be considered for severe thrombocytopenia with a platelet count of below 20 × 109/L and bleeding[19]. In addition to platelet transfusion, therapies with intravenous corticosteroids, intravenous immunoglobulins, rituximab, and plasma exchange have been shown to be beneficial in some cases after vancomycin discontinuation[3,21-23]. However, these medical approaches may not always be effective. In the present case, VIT was effectively resolved by platelet transfusion with the switching of vancomycin to daptomycin.
The mechanisms of VIT remains unclear. The formation of different drug-dependent platelet antibodies, including hapten-dependent, quinine-type, fiban-type and drug-specific antibodies, and other platelet destruction antibodies, are the widely documented mechanisms for VIT[11,21,24]. In contrast, naturally occurring antibodies may not contribute to VIT[25]. It has been postulated that vancomycin can bind to platelet glycoproteins and induce the generation of antibodies, which can attach to the drug-platelet complex, resulting in cell lysis[26]. In the present case, the platelet count gradually dropped after the administration of vancomycin (1000 mg per day) for 7 d. Although the vancomycin was changed to a low-dose (500 mg per day), the platelet count continued to drop. It was postulated that the persistent thrombocytopenia might be due to the anamnestic response for vancomycin re-exposure, and vancomycin-dependent antiplatelet antibodies were formed once vancomycin was re-used.
CONCLUSION
The present case highlights the importance of the accurate diagnosis of VIT in patients with endocarditis. The time-to-platelet count curve and Naranjo score are useful tools for the diagnosis of VIT. The platelet count cannot be normalized simply by platelet transfusion alone. Instead, the discontinuation of vancomycin or switching vancomycin to other antibiotics, such as daptomycin, is essential for effectively treating VIT. Due to the anamnestic response to vancomycin re-exposure and the formation of vancomycin-dependent antiplatelet antibodies, the re-administration of vancomycin should be avoided.
Informed consent statement: An informed written consent was obtained from the patient for the publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: October 13, 2020
First decision: December 13, 2020
Article in press: January 22, 2021
Specialty type: Pharmacology and pharmacy
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Momčilović S S-Editor: Zhang H L-Editor: Filipodia P-Editor: Xing YX | Recovered | ReactionOutcome | CC BY-NC | 33728314 | 19,048,518 | 2021-03-06 |
What was the outcome of reaction 'Thrombocytopenia'? | Vancomycin-induced thrombocytopenia in endocarditis: A case report and review of literature.
BACKGROUND
Thrombocytopenia is a serious complication in the medical practice of numerous drugs. Vancomycin is frequently used for the prophylaxis and treatment of suspected or identified methicillin-resistant positive infections. Several cases with vancomycin-induced thrombocytopenia (VIT) have been reported. However, these have rarely been extensively reviewed. The present report describes a case of VIT in endocarditis, and reviews all VIT cases reported in the literature.
METHODS
A 26-year-old male diagnosed with infective endocarditis was admitted. The patient was treated with multiple drugs, including vancomycin, which was initially intravenously given at 1000 mg every 12 h and subsequently at 500 mg every 8 h on day 3. On day 11, the platelet count decreased to 51 × 109/L, vancomycin was switched to 500 mg every 12 h, and platelet transfusion was given. On day 17, the platelet count dropped to 27 × 109/L, and platelet transfusion was administered again. On day 23, vancomycin was adjusted to 500 mg every 8 h as the trough concentration dropped to the minimum effective concentration. On day 33, the platelet count declined to approximately 40 × 109/L. After platelet transfusion, the platelet count rebounded to 90 × 109/L on day 35 but dropped again to 42 × 109/L on day 43. Based on the time-to-platelet count curve and Naranjo's Adverse Drug Reaction Probability Scale score, VIT was suspected. After vancomycin discontinuation and platelet transfusion, the platelet count gradually normalized.
CONCLUSIONS
The diagnosis of VIT can be achieved through the time-to-platelet count curve and Naranjo's Adverse Drug Reaction Probability Scale score. The platelet count cannot be normalized simply by platelet transfusion alone, and vancomycin discontinuation is essential.
Core Tip: The present report describes a case of vancomycin-induced thrombocytopenia (VIT) in endocarditis and reviews all VIT cases reported in the literature, in terms of indications, diagnosis, management, and potential molecular mechanisms. The present case highlights the importance of accurate diagnosis of VIT in endocarditis, which can be achieved through the time-to-platelet count curve and the Naranjo’s Adverse Drug Reaction Probability Scale score. The platelet count cannot be normalized simply by platelet transfusion alone, and the discontinuation of vancomycin is essential. Due to the anamnestic response to vancomycin re-exposure and the formation of vancomycin-dependent antiplatelet antibodies, the re-administration of vancomycin should be avoided.
INTRODUCTION
Thrombocytopenia, which is generally defined as a platelet count of less than 100 × 109/L of blood or a decrease in the platelet count of 20%-50% from baseline[1,2], has been considered as an adverse reaction correlated to drugs used in the treatment of various diseases[3]. Drug-induced thrombocytopenia is mostly caused by immune-mediated platelet degradation and is always drug dependent, indicating that the platelet count can return to baseline levels after the discontinuation of medications[4]. Although it has been reported that approximately 10 million persons per year are suspected to suffer from drug-induced thrombocytopenia[5], its incidence has not been well-defined[4].
Antibiotic-induced thrombocytopenia has been documented[3]. The commonly reported antibiotics that induce thrombocytopenia are β-lactam antibiotics agents (such as penicillin, nafcillin, ticarcillin, cefazolin, cefuroxime, ceftriaxone, and piperacillin) and linezolid[6]. Vancomycin is a first-generation glycopeptide antibiotic that is often used for the prophylaxis and treatment of suspected or identified methicillin-resistant infections, such as Staphylococcus aureus infection[7], and has been considered as an uncommon cause of thrombocytopenia[6]. Several clinical observational studies have suggested that the incidence of vancomycin-induced thrombocytopenia (VIT) might be higher than that induced by linezolid[1]. However, the incidence of VIT may have been overestimated, because the definition for thrombocytopenia used among these studies vary. A platelet count of less than 150 × 109/L was used in two studies[8,9], and a decrease in platelet count of at least 50% from baseline was used in another study[1]. In addition, the clinical manifestations, diagnosis, and management of VIT have not been well-established, and the underlying molecular mechanisms by which vancomycin induces thrombocytopenia needs to be further elucidated[10]. Over the past two decades, cases with VIT have been continuously reported[11]. However, these cases have rarely been extensively reviewed.
In June 2019, a young male patient with endocarditis was admitted to our hospital, and he developed VIT after vancomycin therapy during the treatment for endocarditis. The present report describes this case and extensively reviews all VIT cases reported in the literature, in terms of indications, diagnosis, management, and potential molecular mechanisms.
CASE PRESENTATION
Chief complaints
A 26-year-old Chinese male presented with dyspnea, fatigue, arrhythmias, fever, and cough.
History of present illness
The patient was admitted to the hospital on June 6, 2019 and diagnosed with infective endocarditis, heart failure, and ventricular septal defect, with a series of manifestations of inflammatory response syndrome.
History of past illness
He had a medical history of uncontrolled hypotension and rheumatic heart disease.
Personal and family history
He denied any family history.
Physical examination
He had a body temperature of 39.1 °C and a heart rate of 100 beats per min.
Laboratory examinations
Initial laboratory testing showed no abnormality.
Imaging examinations
The electrocardiosignal data revealed a high echo of the tricuspid valve, suggesting a neoplasm.
FINAL DIAGNOSIS
Infective endocarditis, heart failure, and ventricular septal defect.
TREATMENT
During hospitalization, the patient was treated with multiple courses of drug therapy, which included vancomycin, omeprazole (40 mg q.d. for 10 d), ceftazidime (2 g t.i.d. for 9 d) and metoprolol (50 mg q.d. for 11 d). Based on the bacterial culture and drug susceptibility test, methicillin-resistant Staphylococcus aureus was identified with the minimum inhibitory concentration of less than 2 mg/L. Therefore, according to The Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children[12], vancomycin was prescribed for the patient with infective endocarditis. Initially, the patient was intravenously treated with 1000 mg of vancomycin every 12 h and 960 mg of benzylpenicillin every 8 h on day 2 for suspected gram-positive infections. The blood cultures were negative for two consecutive tests. Then, the intravenous administration of vancomycin was changed to 500 mg for every 8 h on day 3, for a trough concentration of 25.87 µg/mL beyond the upper limit of 20 µg/mL, and the platelet count was maintained within 100-110 × 109/L for 7 d. On day 11, the administration of vancomycin was switched to 500 mg every 12 h, because the platelet count decreased to 51 × 109/L and the peak concentration of vancomycin reached 57.2 µg/mL. Platelet transfusion (1 U) was given on day 11, and the platelet count slightly increased to 64 × 109/L on day 14, but dramatically dropped afterwards to 27 × 109/L on day 17. Then, platelet transfusion (1 U) was given again on day 17, and the platelet count steadily increased up to 67 × 109/L on day 31. The dose of vancomycin was adjusted to 500 mg every 8 h on day 23 when the trough concentration of vancomycin dropped to 8.86 µg/mL in order to ensure the minimal effective treatment concentration (10 µg/mL). However, on day 33, the hemoglobin level sharply dropped from 101 g/L to 54 g/L, the platelet count continuously declined to approximately 40 × 109/L, and platelet transfusion (1 U) was given. The platelet count rebounded to 90 × 109/L on day 35 but dropped to 42 × 109/L again on day 43. Based on these above observations, and along with the time-to-platelet count curve that illustrated the decline in platelet level after the administration of vancomycin (Figure 1), VIT was suspected, vancomycin was discontinued and replaced with daptomycin, and platelet transfusion (1 U) was given on the same day. The platelet count level increased and reached up to 120 × 109/L on day 50 and remained stable thereafter.
Figure 1 Time-to-platelet count curve during hospitalization. Vancomycin was initiated on day 2 and continued on day 43, as indicated by the downward arrows. Platelet transfusion was given on day 11, 17, 33, and 43, as indicated by the upward arrows.
The concurrent antibiotic, benzylpenicillin, was continuously used during the period with little effect on the platelet count. The respiratory rate, white blood cell count, and hemodynamic variables remained stable, and the microbiological cultures from the sputum and urine revealed negative results, implying that no infection was correlated with thrombocytopenia for the present patient. The other causes of thrombocytopenia, including thrombotic thrombocytopenic purpura, hemolytic anemia, disseminated intravascular coagulation, and platelet-clumping pseudothrombocytopenia, were also excluded, because the results of the blood smear, bilirubin, and hemoglobin were normal. There have been no reports on the occurrence of drug-induced thrombocytopenia caused by other medications during treatment, including omeprazole, ceftazidime, and metoprolol. Therefore, a diagnosis of VIT was initially established using the time-to-platelet count curve. In addition, the Naranjo’s Adverse Drug Reaction Probability Scale score (Naranjo score) for vancomycin was 8, indicating the probable correlation between thrombocytopenia and vancomycin.
OUTCOME AND FOLLOW-UP
The patient was discharged from the hospital.
DISCUSSION
A literature search for all case reports on VIT published in English from April 1985 to June 2020 was performed on PMC/PubMed, Scopus, and Web of Science. Keywords, which included vancomycin and thrombocytopenia, were used to search the titles and abstracts. References of relevant case reports, according to the brief research, were also carefully checked. The demographic data (e.g., age and gender), platelet count, diagnosis, and treatment were recorded and analyzed.
A total of 36 articles that reported 37 cases with VIT were identified in the literature. Thus, the data of 38 cases, which included the case described in the present report, were reviewed and are summarized in Table 1. Among these cases, 14 cases were females and 24 cases were males. The mean age of these cases was 51.19 ± 26.98 years-old (range: 3 mo to 81-years-old). Furthermore, four children were under 2-years-old, and 36 cases were adults 26-81 years-old. The most common indications for the treatment with vancomycin were endocarditis (n = 6), sepsis (n = 6), pneumonia (n = 5), and cellulitis (n = 2). These were followed by other various indications, such as prosthetic infection, hemodialysis, bone graft, acute pancreatitis, etc. The diagnosis of VIT mainly relied on the platelet count, with or without the Naranjo score[13]. The test results for the vancomycin-dependent antibodies were available for 19 patients, and all except three were positive. Among the 27 patients with available bleeding information, 21 patients exhibited bleeding signs. The treatments for these cases comprised of platelet transfusion, prednisone, dexamethasone, immunoglobulin, and daptomycin, and the discontinuation of vancomycin. For the six cases with endocarditis, VIT was diagnosed as probable by the Naranjo score. The information on bleeding signs was available for four cases, and three of these cases presented with bleeding signs. The presence of vancomycin-dependent antibodies was examined only in two patients, and positive results were obtained in one of them. After vancomycin discontinuation, VIT was generally resolved for all patients within 4-15 d. Despite clinical significance revealed by the present literature review, it must be clearly stated that this is only a narrative review, which possesses all the limitations of the selection of papers. Thus, a methodologically acceptable systematic review should be carried out when more data with high quality are available in order to draw a firm conclusion.
Table 1 Summary of case reports of vancomycin-induced thrombocytopenia
Author (publication year) Age (yr) Gender Indication Platelet count (109/L)1 Naranjo Score Treatment Time for resolution (d)2 Vancomycin-dependentantibodies Bleeding sign
Present case 26 M Endocarditis 27 Probable Platelet transfusion and daptomycin 12 NA +
MacDougall et al[14] (2020) 81 M Prosthetic infection 2 NA Prednisone, immunoglobulin, and daptomycin 10 + -
Ajit et al[27] (2019) 61 M Hemodialysis < 10 NA Prednisone, immunoglobulin, eltrombopag and plasma exchange 15 + +
Getz et al[18] (2019) 71 M Transverse myelitis 8.6 Definite Dexamethasone and immunoglobulin 8 + +
Chen et al[16] (2018) 0 F Purulent meningitis 8 Probable Methylprednisolone 4 + +
Danieletto et al[17] (2017) 57 F Bone graft 9 Probable Tigecycline 7 - -
Kalra et al[28] (2016) 0.7 M Sepsis 30 NA Platelet transfusion 3 NA -
Schueler et al[15] (2016) 55 M Purpura 1 NA Prednisone and immunoglobulin 3 NA +
Yamanouchi et al[29] (2016) 72 F Sepsis 2 NA Steroid therapy and carbapenem 7 + +
Lobo et al[13] (2015) 67 M Pneumonia 2 Probable Platelet transfusion, methylprednisolone and immunoglobulin 3 + +
Ahmed et al[30] (2015) 63 M Diabetic foot 2 Probable Daptomycin 10 + -
Candemir et al[10] (2013) 54 F Hematoma 42 Probable Platelet transfusion and daptomycin 4 NA NA
Wetzel et al[31] (2013) 64 F Sepsis 7 Probable Prednisone and immunoglobulin 8 NA +
Ruggero et al[32] (2012) 41 M Pneumonia 15 Definite Daptomycin 5 NA +
Arnold et al[23] (2013) 66 F Endocarditis 4 Probable Platelet transfusion and immunoglobulin 5 + +
Rowland et al[33] (2013) 51 M Acute pancreatitis 9 Probable Only vancomycin discontinuation 5 NA +
Anand et al[34] (2011) 54 M Cellulitis 1 Possible Corticosteroids and daptomycin 2 + +
Ganly et al[22] (2011) 67 M Sepsis 2 NA Platelet transfusion and immunoglobulin 8 NA +
Shah et al[11] (2009) 60 M Shoulder infection 9 Possible Platelet transfusion 3 + +
Lee et al[35] (2009) 76 M Diabetic foot < 15 Possible Platelet transfusion and teicoplanin. 5 + -
Apiwattanakul et al[36] (2008) 16 F Endocarditis 123 Possible Prednisone and cefotaxime 5 NA -
Kenney et al[20] (2008) 61 M Gangrene and bacteremia 3 Probable Platelet transfusion and immunoglobulin 4 + +
Pauldine et al[37] (2008) 60 M Pneumonia 10 Possible Platelet transfusion 12 + +
Dilli et al[38] (2008) 0.6 M Neonatal respiratory distress 41 NA Only vancomycin discontinuation 3 - NA
O’Donnell et al[21] (2007) 56 F Prosthetic infection 2 Possible Immunoglobulin 7 + +
Bay et al[39] (2006) 2 M Pneumonia 11 NA Only vancomycin discontinuation 4 NA NA
Winteroll et al[24] (2004) 72 M Sepsis 3 Probable Platelet transfusion 10 + +
Peel et al[40] (2003) 45 M Peritonitis 5 Probable Platelet transfusion and prednisone 4 NA +
Marraffa et al[41] (2003) 50 M Endocarditis 10 Probable Clindamycin and methylprednisolone 5 NA +
Rocha et al[42] (2002) 38 F Prosthetic infection 68 Possible Only vancomycin discontinuation 4 NA NA
Shahar et al[43] (2000) 43 F Surgery-site infection 118 Probable Only vancomycin discontinuation 3 NA NA
Govindarajan et al[44] (1999) 72 M Epidural abscess 13 Probable Trimethoprim/sulfmethoxazole 10 NA NA
Kuruppu et al[45] (1999) 72 F Endocarditis 14 Possible Only vancomycin discontinuation 5 - NA
Mizon et al[46] (1997) 71 F Sepsis < 10 Probable Antibiotics withdrawn 4 + +
Zenon et al[47] (1991) 54 M Cellulitis 17 Probable Antibiotics withdrawn 7 NA NA
Christie et al[48] (1990) 73 F Pneumonia 14 Probable Platelet transfusion 2 + NA
Christie et al[48] (1990) 31 M Fever < 10 Possible Platelet transfusion 11 (not continued) + NA
Carmichael et al[49] (1986) 42 F Endocarditis 82 Possible NA 9 NA NA
1 The lowest value during the vancomycin treatment.
2 The time from vancomycin discontinuation to the resolution of vancomycin-induced thrombocytopenia. +: A positive result; -: A negative result. F: Female; M: Male; NA: Not available or not tested.
The present patient with infective endocarditis was diagnosed with VIT, which rapidly progressed. The early diagnosis of VIT was performed using the time-to-platelet count curve and Naranjo score. During treatment, the repeated platelet transfusions failed to increase the platelet levels. Subsequently, simply switching vancomycin to daptomycin returned the platelet count close to the baseline level.
The early diagnosis of VIT is quite difficult due to many suspected causes, such as severe infection, disseminated intravascular coagulation, heparin, and other medications. The correct diagnosis can be masked by the simultaneous administration of medications, which can cause drug-induced immune thrombocytopenia[14] or a complicating disease, such as primary idiopathic thrombocytopenic purpura or chronic hepatitis C[15]. Therefore, the early recognition of VIT was of key importance for the following treatment. According to previous studies[6], the investigators used the platelet count at different time points as the initial diagnosis of VIT, which can reveal a definite time-independent relationship with drug administration. All other causes of thrombocytopenia were excluded. Furthermore, the Naranjo score, which has been applied to help with the diagnosis of VIT[16-18], also indicated a probable correlation between thrombocytopenia and vancomycin. Noticeably, endocarditis represents the most common indication that is associated with VIT. The probable correlation between thrombocytopenia and vancomycin can be made through the Naranjo score for all cases, indicating that the Naranjo score is a useful tool to initially diagnose VIT in patients with endocarditis. A bleeding sign is also a useful clinical manifestation to which attention should be given in order to make a definite diagnosis, since most cases would present bleeding signs when VIT occurs. This is particularly true in patents with endocarditis, based on the analyzed data. However, the value of the detection of vancomycin-dependent antibodies in the diagnosis of VIT in patients with endocarditis remains to be elucidated due to the very limited data available.
The critical management after suspicions of VIT is to determine whether to continue or discontinue the vancomycin therapy. The seriousness of the bleeding and the dropping trend of the platelet count should be carefully considered and closely monitored when continuing the vancomycin therapy. However, once VIT is diagnosed, the vancomycin must be stopped, and the platelet transfusion should be taken into consideration as a supplemental treatment for some patients with various success rates, although there are still some transfusion-resistant patients[10,13,19,20]. If vancomycin is not stopped, the survival time of the transfused platelets would be obviously reduced, and the platelet transfusion will not always expectedly increase the platelet count of affected patients[3]. In any of these circumstances, platelet transfusion should be considered for severe thrombocytopenia with a platelet count of below 20 × 109/L and bleeding[19]. In addition to platelet transfusion, therapies with intravenous corticosteroids, intravenous immunoglobulins, rituximab, and plasma exchange have been shown to be beneficial in some cases after vancomycin discontinuation[3,21-23]. However, these medical approaches may not always be effective. In the present case, VIT was effectively resolved by platelet transfusion with the switching of vancomycin to daptomycin.
The mechanisms of VIT remains unclear. The formation of different drug-dependent platelet antibodies, including hapten-dependent, quinine-type, fiban-type and drug-specific antibodies, and other platelet destruction antibodies, are the widely documented mechanisms for VIT[11,21,24]. In contrast, naturally occurring antibodies may not contribute to VIT[25]. It has been postulated that vancomycin can bind to platelet glycoproteins and induce the generation of antibodies, which can attach to the drug-platelet complex, resulting in cell lysis[26]. In the present case, the platelet count gradually dropped after the administration of vancomycin (1000 mg per day) for 7 d. Although the vancomycin was changed to a low-dose (500 mg per day), the platelet count continued to drop. It was postulated that the persistent thrombocytopenia might be due to the anamnestic response for vancomycin re-exposure, and vancomycin-dependent antiplatelet antibodies were formed once vancomycin was re-used.
CONCLUSION
The present case highlights the importance of the accurate diagnosis of VIT in patients with endocarditis. The time-to-platelet count curve and Naranjo score are useful tools for the diagnosis of VIT. The platelet count cannot be normalized simply by platelet transfusion alone. Instead, the discontinuation of vancomycin or switching vancomycin to other antibiotics, such as daptomycin, is essential for effectively treating VIT. Due to the anamnestic response to vancomycin re-exposure and the formation of vancomycin-dependent antiplatelet antibodies, the re-administration of vancomycin should be avoided.
Informed consent statement: An informed written consent was obtained from the patient for the publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: October 13, 2020
First decision: December 13, 2020
Article in press: January 22, 2021
Specialty type: Pharmacology and pharmacy
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Momčilović S S-Editor: Zhang H L-Editor: Filipodia P-Editor: Xing YX | Recovered | ReactionOutcome | CC BY-NC | 33728314 | 19,048,518 | 2021-03-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug eruption'. | Peripherally Inserted Central Catheter-Associated Nocardia nova Endocarditis in a Patient Receiving Intravenous Antibiotics for Chronic Lyme Disease.
Long-term antibiotics are not effective for the therapy of patients with persistent symptoms and a history of Lyme disease. However, some clinicians still prescribe these therapies. We present a case of peripherally inserted central catheter-associated Nocardia nova endocarditis in a patient who had been receiving intravenous antibiotics for the management of chronic Lyme disease. This case highlights an important risk associated with the unscientific use of indwelling peripheral catheters and intravenous antibiotics for the management of such patients.
PRESENTATION OF CASE
A 34-year-old female from New England presented with a 1-month history of daily low-grade fevers, dry cough, loss of appetite, and a 5-pound weight loss. She received 2 separate 5-day courses of azithromycin as an outpatient with no improvement in her symptoms. Ten years before presentation, the patient was diagnosed with Lyme disease. A Western blot for Borrelia burgdorferi-specific immunoglobulin IgM antibodies detected 2 of 3 bands and was interpreted as positive, but a Western blot for IgG antibodies was negative. She was treated with doxycycline for 3 weeks. The patient continued to have polyarthralgia and fatigue and reported that she was diagnosed with chronic Lyme disease 5 years before presentation. She had an indwelling peripherally inserted central catheter (PICC) in place for the previous 22 months for the administration of intravenous (IV) antibiotics that were prescribed to treat chronic Lyme disease. She received a 10-month course of IV ceftriaxone and then a 6-month course of IV doxycycline. She was also prescribed intermittent courses of other agents, such as oral disulfuram and oral doxycycline, for the treatment of chronic Lyme disease. The patient has a history of Ehlers-Danlos syndrome, gastrointestinal malabsorption, which necessitates enteral feeding through a nasogastric tube, postural orthostatic tachycardia syndrome, and psychogenic nonepileptic seizures. She reported that the administration of sulfa drugs caused hives when she was a child. On the day of presentation, the patient had a temperature of 38.1°C and a heart rate of 103 beats per minute. A PICC line was in place in the right arm. The rest of her physical exam was normal. Kidney function, serum glucose, a complete blood count with differential, and liver enzyme tests were all within the normal range. Tests for SARS-CoV-2 and human immunodeficiency virus were negative. A chest x-ray was normal. A chest computed tomography (CT) scan showed multiple scattered pulmonary nodules concerning for emboli (Figure 1). Branching, Gram-positive bacilli grew in 4 of 4 blood cultures bottles taken on the day of her admission to the hospital (Figure 2). The organism stained with a modified acid-fast bacilli stain and was identified as Nocardia nova (Figure 3). The multiple, bilateral small nodular opacities seen on CT scan of the chest were consistent with septic pulmonary emboli. A transthoracic echocardiogram was normal, but transesophageal echocardiogram showed a 3-mm × 1-mm mobile vegetation on the mitral valve. A magnetic resonance image of the brain was normal. Thus, this patient was diagnosed with PICC-associated N nova septic pulmonary emboli and endocarditis.
Figure 1. Computed tomography of the patient’s chest. Multiple scattered nodules in the periphery of the lungs (arrow) were identified.
Figure 2. Gram stain of the organism growing in blood culture.
Figure 3. A modified acid-fast bacilli stain of the organism growing in blood culture.
PATIENT CONSENT
Consent to publish to this case report was obtained from the patient. The article type (“ID Teaching Cases”) does not require formal approval by an ethics committee.
DISCUSSION
In this study, we present the case of a patient with a severe complication associated with the unscientific use of IV antibiotics for management of persistent symptoms and a diagnosis of Lyme disease. Several randomized controlled trials have compared long-term antibiotics with placebo for the treatment of these patients [1–4]. In each of these studies, longer term antibiotic treatment did not improve symptoms in patients compared with placebo. However, complications of long-term antibiotic treatment for Lyme disease include PICC-line associated bacteremia, which can be life threatening [5]. Despite these data and a recommendation from the Infectious Diseases Society of America against the use of extended courses of antibiotics in this setting [6], some clinicians still prescribe such therapies [7, 8].
The patient was initially diagnosed with Lyme disease when an immunoblot for B burgdorferi-specific IgM antibodies was positive; however, the immunoblot for IgG antibodies was negative. Borrelia burgdorferi IgM immunoblots have poor specificity, particularly when the IgG test is negative, and can lead to the misdiagnosis of Lyme disease [9]. Thus, an isolated positive B burgdorferi IgM immunoblot should not be used to diagnose Lyme disease in patients who have had symptoms for more than 6 weeks.
Nocardia sp are Gram-positive, beaded, weakly acid-fast, branching bacilli that are uncommon causes of bacteremia and endocarditis [10]. It is interesting to note that N nova was the most common pathogen in a case series of patients with Nocardia sp bacteremia and an underlying cancer, recovered in 6 of 17 cases [11]. Ten of 17 patients in this study had central catheter-associated bacteremia, and the authors found that Nocardia sp promoted biofilm formation on central venous catheters in vitro [11]. Patients with central venous catheter-associated Nocardia sp bacteremia responded well to catheter removal and antibiotic therapy [11].
Data from randomized controlled trials are not available to guide treatment for nocardiosis. Based on cumulative clinical experience, trimethoprim-sulfamethoxazole is the mainstay of therapy for patients with nocardiosis. Patients who are allergic to trimethoprim-sulfamethoxazole should be desensitized to enable treatment with this agent. Most authorities recommend that severe infection with Nocardia sp, such as endocarditis in this patient, be managed with combination therapy. For severe disease outside the central nervous system, the combination of trimethoprim-sulfamethoxazole and amikacin for initial therapy is recommended until antimicrobial susceptibility data are available. The combination of imipenem and amikacin is also used in this setting. The optimal duration of therapy for patients with nocardiosis is not known. Shorter antibiotic courses for Nocardia sp infection are associated with a high risk of relapse, even in immunocompetent hosts. Thus, most infectious disease clinicians recommend that patients with severe nocardiosis be treated with antibiotics for 6 to 12 months.
FOLLOW-UP
The patient’s PICC line was removed and she was started on imipenem, given her history of a severe allergy to trimethoprim-sulfamethoxazole. On the second hospital day, the patient’s fever resolved, and her symptoms improved markedly. During her hospital stay, she was desensitized to trimethoprim-sulfamethoxazole. She was discharged on trimethoprim-sulfamethoxazole and amikacin while awaiting the identification and susceptibility of the Nocardia sp. Ten days into therapy, the patient developed a diffuse maculopapular drug rash. The trimethoprim-sulfamethoxazole was discontinued, imipenem was restarted, and the amikacin therapy continued. Her rash resolved. After 4 weeks of empiric antibiotic treatment, the organism was identified as N nova that was sensitive to trimethoprim-sulfamethoxazole, amikacin, ceftriaxone, imipenem, and linezolid, but resistant to tetracyclines, fluoroquinolones, and amoxicillin/clavulanate. Imipenem and amikacin were discontinued, and the patient was started on ceftriaxone, given her history of malabsorption and inability to tolerate oral antibiotics. A 6-month course of ceftriaxone is planned for this patient, after which a CT scan of the chest will be obtained to ensure resolution of the septic emboli. The PICC line used to administer ceftriaxone will then be removed.
Acknowledgments
Financial support. R. P.-W.’s research is funded by R01 AI130289 from the National Institute of Allergy and Infectious Diseases and an Innovator Award from the Kenneth Rainin Foundation.
Potential conflicts of interests. All authors have no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | AMIKACIN, AZITHROMYCIN ANHYDROUS, CEFTRIAXONE, DISULFIRAM, DOXYCYCLINE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC-ND | 33728358 | 19,724,199 | 2021-03 |
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