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What was the administration route of drug 'AMLODIPINE BESYLATE'? | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
What was the administration route of drug 'BROTIZOLAM'? | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
What was the administration route of drug 'DENOSUMAB'? | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | Subcutaneous | DrugAdministrationRoute | CC BY-NC-ND | 33604051 | 19,790,942 | 2021-03 |
What was the administration route of drug 'DOXAZOSIN MESYLATE'? | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
What was the administration route of drug 'GLIMEPIRIDE'? | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
What was the administration route of drug 'INDOMETHACIN'? | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | Topical | DrugAdministrationRoute | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
What was the administration route of drug 'LETROZOLE'? | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33604051 | 19,790,942 | 2021-03 |
What was the administration route of drug 'LOPERAMIDE HYDROCHLORIDE'? | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
What was the administration route of drug 'LOXOPROFEN SODIUM DIHYDRATE'? | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
What was the administration route of drug 'PRAVASTATIN SODIUM'? | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
What was the administration route of drug 'REBAMIPIDE'? | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
What was the administration route of drug 'VALSARTAN'? | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
What was the outcome of reaction 'Hypoglycaemia'? | Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.
The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.
Introduction
Cancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.
Case report
In March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.
Emergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.
The patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).
Discussion
We present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.
Abemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.
Table I Observations at admission.
Clinical characteristics Value
Body height 154.5 cm
Body-weight (BMI) 57.2 kg (23.96 kg/m2)
Body temperature 34.5˚C
Blood pressure 118/52 mmHg
Pulse 67/min
Oxygen saturation 94%
Consciousness level (GCS) 13 = E4+V4+M5
Table II Physiological data at the time of hospitalization.
Blood and biochemical tests Value
AST 29 IU/l
ALT 21 IU/l
BUN 20.4 mg/dl
Cr 1.4 mg/dl
CK 108 IU/l
Na 141 mEq/l
Cl 108 mEq/l
Ca 8.6 mEq/l
BS 24 mg/dl
WBC 66.1x103/µl
RBC 342x104/µl
Hb 108 g/dl
Ht 31.40%
PLT 12.7x103/µl
Neut 55.2x102/µl
Lymph 7.9x102/µl
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.
Table III Prescription drugs: Daily dose.
Oral medication Dose
Abemaciclib (100 mg) Twice (after breakfast and dinner)
Glimepiride (1 mg) Twice (after breakfast and dinner)
Loxoprofen sodium hydrate (60 mg) Twice (after breakfast and dinner)
Rebamipide (100 mg) Twice (after breakfast and dinner)
Doxazosin mesylate (2 mg) Twice (after breakfast and dinner)
Valsartan (80 mg) Once after breakfast
Amlodipine besilate (5 mg) Once after breakfast
Pravastatin sodium (10 mg) Once after dinner
Loperamide hydrochloride (1 mg) Up to 3 times a day in case of diarrhoea
Brotizolam (0.25 mg) Before sleeping in case of insomnia
Indomethacin patch Topical
Table IV Summary of the treatment.
A, Day 1
Point Time Blood glucose level Treatment
A 23:40 h 24 20 ml of 40% glucose solution i.v. injection
B 23:47 h 91 Patient ate a midnight snack
B, Day 2
Point Time Blood glucose level Treatment
C 7:00 h 38 40 ml of 40% glucose solution i.v. injection
D 7:15 h 161 Patient ate breakfast
E 12:00 h 49 20 ml of 40% glucose solution i.v. injection
F 12:30 h 102 Patient ate lunch
G 13:45 h 41 Oral administration of 10 g
H 14:20 h 74 Oral administration of 10 g
I 17:15 h 35 20 ml of 40% glucose solution i.v. injection
J 17:50 h 40 20 ml of 40% glucose solution i.v. injection
K 18:30 h 53 Oral administration of 10 g glucose
L 21:00 h 102 Medical follow-up
C, Day 3
Point Time Blood glucose level Treatment
M 0:00 h 48 Oral administration of 10 g glucose
N 1:00 h 102 Medical follow-up
O 3:00 h 55 Oral administration of 10 g glucose
P 4:00 h 107 Medical follow-up
Q 7:00 h 87 Medical follow-up | Recovered | ReactionOutcome | CC BY-NC-ND | 33604051 | 19,837,038 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neuropathy peripheral'. | Recurrent Leiomyosarcoma With Malignant Transformation.
The soft tissues are comprised of various structures and supportive tissues in the body, including muscle, connective tissues, endothelium, synovium, fat, lymphatics, and fascia. Soft tissue sarcomas may arise in any part of the body. The most common sites are the trunk and the extremities. Fibrosarcoma is the most common non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) in children, in whom two peaks in incidence are observed. The first is in children younger than five years, and the second is in children and adolescents aged 10-15 years. Infantile fibrosarcoma (IFS) is almost exclusively observed in children younger than two years. Many of these sarcomas are congenital. This tumor is locally aggressive, but rarely metastatic, and occurs in the extremity in 70% of patients. A 29-year-old lady presented to the Oncology unit with the fifth recurrence of fibrosarcoma which was transformed into very vascular and high-grade leiomyosarcoma from the fourth recurrence onwards. Initially, it was diagnosed when she was two days old and radiologically diagnosed as lymphangioma. It was documented as a large lump at the right lumbar region with uniform echogenicity and was excised and the postoperative period was uneventful. At the age of 12 years, she presented with a large mass at the right lumbar region over the surgical scar and complete excision done with R0 resection. Histology revealed well-differentiated fibrosarcoma with varying sizes of fibroblasts and no alignment features. The third relapse was at the age of 27. Complete excision was done and histology reported as spinel cell tumor with the possibility of fibrosarcoma or leiomyosarcoma. It was R0 resection and adjuvant treatment was not offered. Tumour recurred over the same scar within a year. Since the tumor is very big with 10 cm craniocaudal and 9 cm wide neoadjuvant chemotherapy is given: IV doxorubicin and IV cisplatin. Surgery was performed after four cycles and found necrotic tissue only. There were no tumor tissues or any form of spindle cells. Due to the aggressive nature, there was no exact solid tumor to assess margins for recommended adjuvant radiotherapy; IMRT. Due to the delay in finding a spacer to keep the bowel away from the radiotherapy field, radiotherapy was delayed and the tumor recurred within six months. It was a radiologically very vascular tumor and she had severe neuropathy and autotoxicity and could not offer any more chemotherapy. The tumor was rapidly growing and was bigger than the last time. Tumor growth was controlled with antiangiogenesis inhibitor; IV bevacizumab and high dose steroids and opioids for pain. After four months, we could not continue bevacizumab due to very high blood pressure and the patient died while waiting for palliative surgery. Childhood fibrosarcoma, including IFS, has classically been treated with surgery alone or with neoadjuvant chemotherapy and surgery. In cases that are not amenable, surgical resection is done upfront. Patients with IFS have an excellent prognosis, with survival rates of more than 90% in some series. A multidisciplinary approach is essential in managing infantile fibrosarcoma as it has a high potency of recurrence during teenage or later in life with malignant transformation. This could have been prevented when the clinicians are well aware of this risk of recurrence and primary surgery has to be planned very carefully with multidisciplinary involvement.
Introduction
Infantile fibrosarcoma (IFS) is usually found in infants and young children. Sometimes it is also found ultrasonically before birth. Even though it is a rare tumor recurrence is not uncommon. Histopathologically it resembles fibroblasts and they are malignant. The histologic diagnosis is sometimes difficult due to the nature of surrounding soft tissues.
Interestingly they carry a good prognosis. Eighty percent of IFSs are curable and the treatment of choice is surgery. The drawback of surgery is that they are mutilating since the tumor is very big at presentation. According to Daniel Orbach et al. [1], the 10-year survival rate is around 89% with complete excision and neoadjuvant chemotherapy. Treatment decisions would always individualize and a standard treatment plan is made according to initial tumor size and feasibility of achieving adequate resection margins with R0 resection. After resection no adjuvant chemotherapy but active surveillance for group I to II tumors. [1]. According to the Europian Soft Tissue Sarcoma Study Group [2] neoadjuvant anthracycline free and alkylating agents free chemotherapy should be administered to group II patients because they can cause nephrotoxicity and cardiotoxicity in early childhood. Anthracyclines and alkylating agents are kept reserved for use in resistance cases [3].
Case presentation
A lady presented to the Oncology clinic with a history of severe unbearable pain in the right hypochondriac area. She had a large scar at her right loin area and a history of surgical resection of a mass under the scar when 12 years. Her past medical history revealed that she had a large mass in the same area; tumor resection surgery was done when she was two days old. There was a large solid mass; in the right lumbar region with no direct connection to the right kidney. The right kidney appears to be normal, with uniform echogenicity. No other intra-abdominal masses and tumors were detected, and the tumor excised completely. Histologically it was diagnosed to have IFS. She was disease-free for 12 years following surgery; no adjuvant treatment was given. At the age of 12 years, the tumor has recurred with a large mass. Her records carry fibrosarcoma with spindle cell hyperplasia. Adjuvant therapy was not offered due to complete resection margins.
Pathologically reported that the possibility of either a reaction to chronic inflammation or a well-differentiated fibrosarcoma due to the tissue sample being histologically very cellular, with varying sizes of fibroblasts with no increasing mitosis.
At the age of 27 years, she had another recurrence and presented with a large lump at the right lumbar region over the previous scar. There was a contrast-enhanced mass of 6.5 x 9.5 x 8.0 cm at the right loin in the contrast-enhanced CT scan (Figure 1). The lesion is situated at the subcutaneous tissue, a posterior abdominal wall that extended up to the lateral border of the right psoas muscle at the lower pole of the right kidney (Figure 2). The kidney could be identified separately, and the lesion appeared to abut the Gerota’s fascia. Prominent lumbar vessels were noted. The liver, spleen, and pancreas were normal with no ascites. It was consistent with the recurrence of the known fibrosarcoma.
Figure 1 Contrast-enhanced CT image of tumor displacing right kidney.
Figure 2 Contrast-enhanced CT image of tumor extending to posterior abdominal wall.
A pathology report revealed a malignant spindle cell tumor with possibilities of either a leiomyosarcoma or fibrosarcoma FNCLCC (Federation Nationale des Centers de Lutte Contre Le Cancer) grade 3. It was infiltrating the psoas muscle, involving the deep margins. The tumor proliferation index is 30%. She completed neoadjuvant chemotherapy six cycles with IV doxorubicin 60 mg/m2 and IV cyclophosphamide 1,000 mg/m2 every three weeks. After six chemotherapy cycles, the tumor was radiologically stable, and clinically there was a very significant response. At the initial presentation in the second relapse, the patient’s WHO performance status was 3; at the end of four chemotherapy cycles, her WHO performance scale was 0. Definitive surgery was performed four weeks after the last chemotherapy. There were only necrotic tissues and were not clear well-demarcated margins. No active tumor cells were found. Since there were no solid tissues to be found, adjuvant radiotherapy was planned. Since the tumor size was large, we had a problem finding a spacer to locate at the tumor bed to keep the bowels away from the radiation field.
There was a six-month delay in supplying a spacer. Before radiotherapy, a follow-up assessment MRI scan showed a large heterogeneous irregular mass of 8.4 x 7.7 x 10.1 cm with hemorrhagic and fluid-filled areas within the mass, infiltrating the psoas muscle, extending up to the posterior abdominal wall. The right side erector spinae muscle, anterolaterally it abuts the liver with obliterated fat planes. No extensions to the spinal canal or extension into the pelvic bones, right kidney slightly rotated and shifted with slight obliteration of fat planes, no involvement of the right ureter, no hydronephrosis, and left kidney appeared normal with no evidence of any metastasis to the chest or liver and no significant lymphadenopathy. The tumor has recurred very early. The Multi-Disciplinary Team decision was no additional benefit of irradiating and decided to offer palliative care since there is no place for further chemotherapy due to severe toxicity and persistent side effects from previous chemotherapy.
However, the patient was given symptomatic relief with low dose metronomic chemotherapy with IV bevacizumab since it is a very vascular tumor. A Follow-up MRI scan showed that the mass was stable in size, 10.1 x 7.7 x 8.8 cm in completing chemotherapy.
US abdomen and pelvis revealed a known malignant tumor of the abdomen's right side measuring 16.6 x 16.7 x 10.8 cm in size, mildly echogenic bilateral kidneys, and mild ascites. At this point staging, CT revealed pulmonary metastasis. The patient passed away while on metronomic palliative chemotherapy due to pulmonary embolism.
Discussion
IFS is a tumor with a good prognosis, but primary surgery must be decided very carefully, and adequate tumor resection is essential to prevent a recurrence. These tumors tend to recur, and primary tumor control depends on the surgery and surgical skills. Albert J et al. [4], congenital IFS should be considered borderline tumors because its biological behavior is very close to surrounding normal structures. The tumor behavior is better than that of adult fibrosarcoma. Since the histologic diagnosis is not very conclusive in most cases, only long-term clinical follow-up confirms the benign or malignant nature of any individual tumor. This patient was diagnosed to have infantile fibrosarcoma and recurred after 12 years. There was no active follow-up in between, so we are not very certain whether it grew slowly over 12 years or the growth restarted after 12 years. The second recurrence was again after 15 years, and there was no proper follow-up over 15 years. Meantime she had a normal life with good performance. She was graduated and married and had a child. After the second recurrence, the nature of the tumor was transferred into a very aggressive malignant tumor. First recurred within a year but obtained good tumor control with anthracycline-based chemotherapy and alkylating agents. These tumors are very aggressive once transformed into the very aggressive type of tumor; They are rapidly growing with extreme pressure effects due to the tumor volume effect.
L Max Akmond et al. [5] explains in their meta-analysis that there is a minimal benefit with adjuvant chemotherapy and in contrast, we obtained good tumor regression following neoadjuvant chemotherapy; maybe the chemotherapy response to leiomyosarcoma at certain anatomical locations was not good such as Uterine Leiomyosarcoma as mention in the above study. We should not delay in further adjuvant radiotherapy; once the tumor starts behaving very aggressively. The treating clinician should understand the fact that active surveillance of primary tumor control is important. And also the tumor management should invariably be done with a multidisciplinary approach.
Conclusions
This lady presented to us with a very aggressive Leiomyosarcoma at the right loin region, the second recurrence. Initially, it was mentioned as infantile fibrosarcoma diagnosed at birth and the first recurrence at the age of twelve years with histology remains unchanged. After 14 years, her tumor recurred very aggressively and progressed until she was treated with neoadjuvant chemotherapy and achieved a complete pathological response. There are important lessons we need to understand through this case report. Infantile Fibro Sarcomas should be treated with complete tumor resection with expert surgical skills to prevent a recurrence. Secondly, once a tumor recurs, the patient is benefited from neoadjuvant chemotherapy to achieve the best tumor control. Thirdly IFS can later transform into a very aggressive leiomyosarcoma where a multidisciplinary approach is essential with complete surgical excision with adequate tumor margins and adjuvant chemotherapy and radiotherapy.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | CISPLATIN, DOXORUBICIN | DrugsGivenReaction | CC BY | 33604210 | 18,962,420 | 2021-01-13 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'. | Recurrent Leiomyosarcoma With Malignant Transformation.
The soft tissues are comprised of various structures and supportive tissues in the body, including muscle, connective tissues, endothelium, synovium, fat, lymphatics, and fascia. Soft tissue sarcomas may arise in any part of the body. The most common sites are the trunk and the extremities. Fibrosarcoma is the most common non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) in children, in whom two peaks in incidence are observed. The first is in children younger than five years, and the second is in children and adolescents aged 10-15 years. Infantile fibrosarcoma (IFS) is almost exclusively observed in children younger than two years. Many of these sarcomas are congenital. This tumor is locally aggressive, but rarely metastatic, and occurs in the extremity in 70% of patients. A 29-year-old lady presented to the Oncology unit with the fifth recurrence of fibrosarcoma which was transformed into very vascular and high-grade leiomyosarcoma from the fourth recurrence onwards. Initially, it was diagnosed when she was two days old and radiologically diagnosed as lymphangioma. It was documented as a large lump at the right lumbar region with uniform echogenicity and was excised and the postoperative period was uneventful. At the age of 12 years, she presented with a large mass at the right lumbar region over the surgical scar and complete excision done with R0 resection. Histology revealed well-differentiated fibrosarcoma with varying sizes of fibroblasts and no alignment features. The third relapse was at the age of 27. Complete excision was done and histology reported as spinel cell tumor with the possibility of fibrosarcoma or leiomyosarcoma. It was R0 resection and adjuvant treatment was not offered. Tumour recurred over the same scar within a year. Since the tumor is very big with 10 cm craniocaudal and 9 cm wide neoadjuvant chemotherapy is given: IV doxorubicin and IV cisplatin. Surgery was performed after four cycles and found necrotic tissue only. There were no tumor tissues or any form of spindle cells. Due to the aggressive nature, there was no exact solid tumor to assess margins for recommended adjuvant radiotherapy; IMRT. Due to the delay in finding a spacer to keep the bowel away from the radiotherapy field, radiotherapy was delayed and the tumor recurred within six months. It was a radiologically very vascular tumor and she had severe neuropathy and autotoxicity and could not offer any more chemotherapy. The tumor was rapidly growing and was bigger than the last time. Tumor growth was controlled with antiangiogenesis inhibitor; IV bevacizumab and high dose steroids and opioids for pain. After four months, we could not continue bevacizumab due to very high blood pressure and the patient died while waiting for palliative surgery. Childhood fibrosarcoma, including IFS, has classically been treated with surgery alone or with neoadjuvant chemotherapy and surgery. In cases that are not amenable, surgical resection is done upfront. Patients with IFS have an excellent prognosis, with survival rates of more than 90% in some series. A multidisciplinary approach is essential in managing infantile fibrosarcoma as it has a high potency of recurrence during teenage or later in life with malignant transformation. This could have been prevented when the clinicians are well aware of this risk of recurrence and primary surgery has to be planned very carefully with multidisciplinary involvement.
Introduction
Infantile fibrosarcoma (IFS) is usually found in infants and young children. Sometimes it is also found ultrasonically before birth. Even though it is a rare tumor recurrence is not uncommon. Histopathologically it resembles fibroblasts and they are malignant. The histologic diagnosis is sometimes difficult due to the nature of surrounding soft tissues.
Interestingly they carry a good prognosis. Eighty percent of IFSs are curable and the treatment of choice is surgery. The drawback of surgery is that they are mutilating since the tumor is very big at presentation. According to Daniel Orbach et al. [1], the 10-year survival rate is around 89% with complete excision and neoadjuvant chemotherapy. Treatment decisions would always individualize and a standard treatment plan is made according to initial tumor size and feasibility of achieving adequate resection margins with R0 resection. After resection no adjuvant chemotherapy but active surveillance for group I to II tumors. [1]. According to the Europian Soft Tissue Sarcoma Study Group [2] neoadjuvant anthracycline free and alkylating agents free chemotherapy should be administered to group II patients because they can cause nephrotoxicity and cardiotoxicity in early childhood. Anthracyclines and alkylating agents are kept reserved for use in resistance cases [3].
Case presentation
A lady presented to the Oncology clinic with a history of severe unbearable pain in the right hypochondriac area. She had a large scar at her right loin area and a history of surgical resection of a mass under the scar when 12 years. Her past medical history revealed that she had a large mass in the same area; tumor resection surgery was done when she was two days old. There was a large solid mass; in the right lumbar region with no direct connection to the right kidney. The right kidney appears to be normal, with uniform echogenicity. No other intra-abdominal masses and tumors were detected, and the tumor excised completely. Histologically it was diagnosed to have IFS. She was disease-free for 12 years following surgery; no adjuvant treatment was given. At the age of 12 years, the tumor has recurred with a large mass. Her records carry fibrosarcoma with spindle cell hyperplasia. Adjuvant therapy was not offered due to complete resection margins.
Pathologically reported that the possibility of either a reaction to chronic inflammation or a well-differentiated fibrosarcoma due to the tissue sample being histologically very cellular, with varying sizes of fibroblasts with no increasing mitosis.
At the age of 27 years, she had another recurrence and presented with a large lump at the right lumbar region over the previous scar. There was a contrast-enhanced mass of 6.5 x 9.5 x 8.0 cm at the right loin in the contrast-enhanced CT scan (Figure 1). The lesion is situated at the subcutaneous tissue, a posterior abdominal wall that extended up to the lateral border of the right psoas muscle at the lower pole of the right kidney (Figure 2). The kidney could be identified separately, and the lesion appeared to abut the Gerota’s fascia. Prominent lumbar vessels were noted. The liver, spleen, and pancreas were normal with no ascites. It was consistent with the recurrence of the known fibrosarcoma.
Figure 1 Contrast-enhanced CT image of tumor displacing right kidney.
Figure 2 Contrast-enhanced CT image of tumor extending to posterior abdominal wall.
A pathology report revealed a malignant spindle cell tumor with possibilities of either a leiomyosarcoma or fibrosarcoma FNCLCC (Federation Nationale des Centers de Lutte Contre Le Cancer) grade 3. It was infiltrating the psoas muscle, involving the deep margins. The tumor proliferation index is 30%. She completed neoadjuvant chemotherapy six cycles with IV doxorubicin 60 mg/m2 and IV cyclophosphamide 1,000 mg/m2 every three weeks. After six chemotherapy cycles, the tumor was radiologically stable, and clinically there was a very significant response. At the initial presentation in the second relapse, the patient’s WHO performance status was 3; at the end of four chemotherapy cycles, her WHO performance scale was 0. Definitive surgery was performed four weeks after the last chemotherapy. There were only necrotic tissues and were not clear well-demarcated margins. No active tumor cells were found. Since there were no solid tissues to be found, adjuvant radiotherapy was planned. Since the tumor size was large, we had a problem finding a spacer to locate at the tumor bed to keep the bowels away from the radiation field.
There was a six-month delay in supplying a spacer. Before radiotherapy, a follow-up assessment MRI scan showed a large heterogeneous irregular mass of 8.4 x 7.7 x 10.1 cm with hemorrhagic and fluid-filled areas within the mass, infiltrating the psoas muscle, extending up to the posterior abdominal wall. The right side erector spinae muscle, anterolaterally it abuts the liver with obliterated fat planes. No extensions to the spinal canal or extension into the pelvic bones, right kidney slightly rotated and shifted with slight obliteration of fat planes, no involvement of the right ureter, no hydronephrosis, and left kidney appeared normal with no evidence of any metastasis to the chest or liver and no significant lymphadenopathy. The tumor has recurred very early. The Multi-Disciplinary Team decision was no additional benefit of irradiating and decided to offer palliative care since there is no place for further chemotherapy due to severe toxicity and persistent side effects from previous chemotherapy.
However, the patient was given symptomatic relief with low dose metronomic chemotherapy with IV bevacizumab since it is a very vascular tumor. A Follow-up MRI scan showed that the mass was stable in size, 10.1 x 7.7 x 8.8 cm in completing chemotherapy.
US abdomen and pelvis revealed a known malignant tumor of the abdomen's right side measuring 16.6 x 16.7 x 10.8 cm in size, mildly echogenic bilateral kidneys, and mild ascites. At this point staging, CT revealed pulmonary metastasis. The patient passed away while on metronomic palliative chemotherapy due to pulmonary embolism.
Discussion
IFS is a tumor with a good prognosis, but primary surgery must be decided very carefully, and adequate tumor resection is essential to prevent a recurrence. These tumors tend to recur, and primary tumor control depends on the surgery and surgical skills. Albert J et al. [4], congenital IFS should be considered borderline tumors because its biological behavior is very close to surrounding normal structures. The tumor behavior is better than that of adult fibrosarcoma. Since the histologic diagnosis is not very conclusive in most cases, only long-term clinical follow-up confirms the benign or malignant nature of any individual tumor. This patient was diagnosed to have infantile fibrosarcoma and recurred after 12 years. There was no active follow-up in between, so we are not very certain whether it grew slowly over 12 years or the growth restarted after 12 years. The second recurrence was again after 15 years, and there was no proper follow-up over 15 years. Meantime she had a normal life with good performance. She was graduated and married and had a child. After the second recurrence, the nature of the tumor was transferred into a very aggressive malignant tumor. First recurred within a year but obtained good tumor control with anthracycline-based chemotherapy and alkylating agents. These tumors are very aggressive once transformed into the very aggressive type of tumor; They are rapidly growing with extreme pressure effects due to the tumor volume effect.
L Max Akmond et al. [5] explains in their meta-analysis that there is a minimal benefit with adjuvant chemotherapy and in contrast, we obtained good tumor regression following neoadjuvant chemotherapy; maybe the chemotherapy response to leiomyosarcoma at certain anatomical locations was not good such as Uterine Leiomyosarcoma as mention in the above study. We should not delay in further adjuvant radiotherapy; once the tumor starts behaving very aggressively. The treating clinician should understand the fact that active surveillance of primary tumor control is important. And also the tumor management should invariably be done with a multidisciplinary approach.
Conclusions
This lady presented to us with a very aggressive Leiomyosarcoma at the right loin region, the second recurrence. Initially, it was mentioned as infantile fibrosarcoma diagnosed at birth and the first recurrence at the age of twelve years with histology remains unchanged. After 14 years, her tumor recurred very aggressively and progressed until she was treated with neoadjuvant chemotherapy and achieved a complete pathological response. There are important lessons we need to understand through this case report. Infantile Fibro Sarcomas should be treated with complete tumor resection with expert surgical skills to prevent a recurrence. Secondly, once a tumor recurs, the patient is benefited from neoadjuvant chemotherapy to achieve the best tumor control. Thirdly IFS can later transform into a very aggressive leiomyosarcoma where a multidisciplinary approach is essential with complete surgical excision with adequate tumor margins and adjuvant chemotherapy and radiotherapy.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | CISPLATIN, DOXORUBICIN | DrugsGivenReaction | CC BY | 33604210 | 18,962,420 | 2021-01-13 |
What was the administration route of drug 'CISPLATIN'? | Recurrent Leiomyosarcoma With Malignant Transformation.
The soft tissues are comprised of various structures and supportive tissues in the body, including muscle, connective tissues, endothelium, synovium, fat, lymphatics, and fascia. Soft tissue sarcomas may arise in any part of the body. The most common sites are the trunk and the extremities. Fibrosarcoma is the most common non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) in children, in whom two peaks in incidence are observed. The first is in children younger than five years, and the second is in children and adolescents aged 10-15 years. Infantile fibrosarcoma (IFS) is almost exclusively observed in children younger than two years. Many of these sarcomas are congenital. This tumor is locally aggressive, but rarely metastatic, and occurs in the extremity in 70% of patients. A 29-year-old lady presented to the Oncology unit with the fifth recurrence of fibrosarcoma which was transformed into very vascular and high-grade leiomyosarcoma from the fourth recurrence onwards. Initially, it was diagnosed when she was two days old and radiologically diagnosed as lymphangioma. It was documented as a large lump at the right lumbar region with uniform echogenicity and was excised and the postoperative period was uneventful. At the age of 12 years, she presented with a large mass at the right lumbar region over the surgical scar and complete excision done with R0 resection. Histology revealed well-differentiated fibrosarcoma with varying sizes of fibroblasts and no alignment features. The third relapse was at the age of 27. Complete excision was done and histology reported as spinel cell tumor with the possibility of fibrosarcoma or leiomyosarcoma. It was R0 resection and adjuvant treatment was not offered. Tumour recurred over the same scar within a year. Since the tumor is very big with 10 cm craniocaudal and 9 cm wide neoadjuvant chemotherapy is given: IV doxorubicin and IV cisplatin. Surgery was performed after four cycles and found necrotic tissue only. There were no tumor tissues or any form of spindle cells. Due to the aggressive nature, there was no exact solid tumor to assess margins for recommended adjuvant radiotherapy; IMRT. Due to the delay in finding a spacer to keep the bowel away from the radiotherapy field, radiotherapy was delayed and the tumor recurred within six months. It was a radiologically very vascular tumor and she had severe neuropathy and autotoxicity and could not offer any more chemotherapy. The tumor was rapidly growing and was bigger than the last time. Tumor growth was controlled with antiangiogenesis inhibitor; IV bevacizumab and high dose steroids and opioids for pain. After four months, we could not continue bevacizumab due to very high blood pressure and the patient died while waiting for palliative surgery. Childhood fibrosarcoma, including IFS, has classically been treated with surgery alone or with neoadjuvant chemotherapy and surgery. In cases that are not amenable, surgical resection is done upfront. Patients with IFS have an excellent prognosis, with survival rates of more than 90% in some series. A multidisciplinary approach is essential in managing infantile fibrosarcoma as it has a high potency of recurrence during teenage or later in life with malignant transformation. This could have been prevented when the clinicians are well aware of this risk of recurrence and primary surgery has to be planned very carefully with multidisciplinary involvement.
Introduction
Infantile fibrosarcoma (IFS) is usually found in infants and young children. Sometimes it is also found ultrasonically before birth. Even though it is a rare tumor recurrence is not uncommon. Histopathologically it resembles fibroblasts and they are malignant. The histologic diagnosis is sometimes difficult due to the nature of surrounding soft tissues.
Interestingly they carry a good prognosis. Eighty percent of IFSs are curable and the treatment of choice is surgery. The drawback of surgery is that they are mutilating since the tumor is very big at presentation. According to Daniel Orbach et al. [1], the 10-year survival rate is around 89% with complete excision and neoadjuvant chemotherapy. Treatment decisions would always individualize and a standard treatment plan is made according to initial tumor size and feasibility of achieving adequate resection margins with R0 resection. After resection no adjuvant chemotherapy but active surveillance for group I to II tumors. [1]. According to the Europian Soft Tissue Sarcoma Study Group [2] neoadjuvant anthracycline free and alkylating agents free chemotherapy should be administered to group II patients because they can cause nephrotoxicity and cardiotoxicity in early childhood. Anthracyclines and alkylating agents are kept reserved for use in resistance cases [3].
Case presentation
A lady presented to the Oncology clinic with a history of severe unbearable pain in the right hypochondriac area. She had a large scar at her right loin area and a history of surgical resection of a mass under the scar when 12 years. Her past medical history revealed that she had a large mass in the same area; tumor resection surgery was done when she was two days old. There was a large solid mass; in the right lumbar region with no direct connection to the right kidney. The right kidney appears to be normal, with uniform echogenicity. No other intra-abdominal masses and tumors were detected, and the tumor excised completely. Histologically it was diagnosed to have IFS. She was disease-free for 12 years following surgery; no adjuvant treatment was given. At the age of 12 years, the tumor has recurred with a large mass. Her records carry fibrosarcoma with spindle cell hyperplasia. Adjuvant therapy was not offered due to complete resection margins.
Pathologically reported that the possibility of either a reaction to chronic inflammation or a well-differentiated fibrosarcoma due to the tissue sample being histologically very cellular, with varying sizes of fibroblasts with no increasing mitosis.
At the age of 27 years, she had another recurrence and presented with a large lump at the right lumbar region over the previous scar. There was a contrast-enhanced mass of 6.5 x 9.5 x 8.0 cm at the right loin in the contrast-enhanced CT scan (Figure 1). The lesion is situated at the subcutaneous tissue, a posterior abdominal wall that extended up to the lateral border of the right psoas muscle at the lower pole of the right kidney (Figure 2). The kidney could be identified separately, and the lesion appeared to abut the Gerota’s fascia. Prominent lumbar vessels were noted. The liver, spleen, and pancreas were normal with no ascites. It was consistent with the recurrence of the known fibrosarcoma.
Figure 1 Contrast-enhanced CT image of tumor displacing right kidney.
Figure 2 Contrast-enhanced CT image of tumor extending to posterior abdominal wall.
A pathology report revealed a malignant spindle cell tumor with possibilities of either a leiomyosarcoma or fibrosarcoma FNCLCC (Federation Nationale des Centers de Lutte Contre Le Cancer) grade 3. It was infiltrating the psoas muscle, involving the deep margins. The tumor proliferation index is 30%. She completed neoadjuvant chemotherapy six cycles with IV doxorubicin 60 mg/m2 and IV cyclophosphamide 1,000 mg/m2 every three weeks. After six chemotherapy cycles, the tumor was radiologically stable, and clinically there was a very significant response. At the initial presentation in the second relapse, the patient’s WHO performance status was 3; at the end of four chemotherapy cycles, her WHO performance scale was 0. Definitive surgery was performed four weeks after the last chemotherapy. There were only necrotic tissues and were not clear well-demarcated margins. No active tumor cells were found. Since there were no solid tissues to be found, adjuvant radiotherapy was planned. Since the tumor size was large, we had a problem finding a spacer to locate at the tumor bed to keep the bowels away from the radiation field.
There was a six-month delay in supplying a spacer. Before radiotherapy, a follow-up assessment MRI scan showed a large heterogeneous irregular mass of 8.4 x 7.7 x 10.1 cm with hemorrhagic and fluid-filled areas within the mass, infiltrating the psoas muscle, extending up to the posterior abdominal wall. The right side erector spinae muscle, anterolaterally it abuts the liver with obliterated fat planes. No extensions to the spinal canal or extension into the pelvic bones, right kidney slightly rotated and shifted with slight obliteration of fat planes, no involvement of the right ureter, no hydronephrosis, and left kidney appeared normal with no evidence of any metastasis to the chest or liver and no significant lymphadenopathy. The tumor has recurred very early. The Multi-Disciplinary Team decision was no additional benefit of irradiating and decided to offer palliative care since there is no place for further chemotherapy due to severe toxicity and persistent side effects from previous chemotherapy.
However, the patient was given symptomatic relief with low dose metronomic chemotherapy with IV bevacizumab since it is a very vascular tumor. A Follow-up MRI scan showed that the mass was stable in size, 10.1 x 7.7 x 8.8 cm in completing chemotherapy.
US abdomen and pelvis revealed a known malignant tumor of the abdomen's right side measuring 16.6 x 16.7 x 10.8 cm in size, mildly echogenic bilateral kidneys, and mild ascites. At this point staging, CT revealed pulmonary metastasis. The patient passed away while on metronomic palliative chemotherapy due to pulmonary embolism.
Discussion
IFS is a tumor with a good prognosis, but primary surgery must be decided very carefully, and adequate tumor resection is essential to prevent a recurrence. These tumors tend to recur, and primary tumor control depends on the surgery and surgical skills. Albert J et al. [4], congenital IFS should be considered borderline tumors because its biological behavior is very close to surrounding normal structures. The tumor behavior is better than that of adult fibrosarcoma. Since the histologic diagnosis is not very conclusive in most cases, only long-term clinical follow-up confirms the benign or malignant nature of any individual tumor. This patient was diagnosed to have infantile fibrosarcoma and recurred after 12 years. There was no active follow-up in between, so we are not very certain whether it grew slowly over 12 years or the growth restarted after 12 years. The second recurrence was again after 15 years, and there was no proper follow-up over 15 years. Meantime she had a normal life with good performance. She was graduated and married and had a child. After the second recurrence, the nature of the tumor was transferred into a very aggressive malignant tumor. First recurred within a year but obtained good tumor control with anthracycline-based chemotherapy and alkylating agents. These tumors are very aggressive once transformed into the very aggressive type of tumor; They are rapidly growing with extreme pressure effects due to the tumor volume effect.
L Max Akmond et al. [5] explains in their meta-analysis that there is a minimal benefit with adjuvant chemotherapy and in contrast, we obtained good tumor regression following neoadjuvant chemotherapy; maybe the chemotherapy response to leiomyosarcoma at certain anatomical locations was not good such as Uterine Leiomyosarcoma as mention in the above study. We should not delay in further adjuvant radiotherapy; once the tumor starts behaving very aggressively. The treating clinician should understand the fact that active surveillance of primary tumor control is important. And also the tumor management should invariably be done with a multidisciplinary approach.
Conclusions
This lady presented to us with a very aggressive Leiomyosarcoma at the right loin region, the second recurrence. Initially, it was mentioned as infantile fibrosarcoma diagnosed at birth and the first recurrence at the age of twelve years with histology remains unchanged. After 14 years, her tumor recurred very aggressively and progressed until she was treated with neoadjuvant chemotherapy and achieved a complete pathological response. There are important lessons we need to understand through this case report. Infantile Fibro Sarcomas should be treated with complete tumor resection with expert surgical skills to prevent a recurrence. Secondly, once a tumor recurs, the patient is benefited from neoadjuvant chemotherapy to achieve the best tumor control. Thirdly IFS can later transform into a very aggressive leiomyosarcoma where a multidisciplinary approach is essential with complete surgical excision with adequate tumor margins and adjuvant chemotherapy and radiotherapy.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33604210 | 18,962,420 | 2021-01-13 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | Herpes simplex virus-2 associated with a large fungating penile mass.
A 48-year-old male with HIV/AIDS presented with an enlarging nodular lesion on the base of his penis. Histology revealed changes consistent with chronic viral infection and culture grew herpes simplex virus 2 (HSV-2). The lesion was refractory to valacyclovir and intralesional (IL) cidofovir therapy. Urology excised the mass and the defect was repaired primarily with good cosmetic result. Post-operative pathology confirmed HSV-2 despite the unusual appearance of the lesion consisting of nodular mass without gross ulceration.
Introduction
Classic herpes simplex virus 2 (HSV-2) lesions produce painful genital ulcers. When large, papillary genital masses develop, they are typically caused by human papilloma virus (HPV) serotypes. These lesions have been known to grow to impressive size in those with compromised immune systems, such as in human immunodeficiency virus (HIV) infection. The literature has shown effective treatment of large HPV lesions with intralesional (IL) cidofovir, and otolaryngologists use IL cidofovir in the case of laryngeal papillomatosis with good results.1 Optimal treatment of verrucous HSV-2 lesions is less well defined in the literature.
Case presentation
We present the case of a 48-year-old male who presented with four months of an enlarging nodular lesion at the base of his penis (Fig. 1). His medical history included HIV/AIDS, alcohol use disorder, anal dysplasia, pulmonary tuberculosis, Pneumocystis pneumonia, and esophagitis. His viral load was undetectable and CD4 count was 98 cell/mm.3 Dermatology initially performed multiple evaluations of the lesion. Biopsy and histology repeatedly revealed changes consistent with chronic viral infection and culture grew herpes simplex virus 2 (HSV-2) sensitive to acyclovir.Fig. 1 (left) Preoperative depiction of gross lesion and (right) incision at 3 week postoperative check.
Fig. 1
He was treated with valacyclovir 1 gram twice daily and topical trifluridine for four months. After continued growth, IL cidofovir 30 milligrams for three total injections was initiated. Despite this, the mass grew larger and he was referred to Urology for excision. Preoperative exam revealed a 4 × 2cm exophytic nodule at the dorsal base of his penis without ulceration and with significant weeping. He was scheduled for surgical excision; at which time the mass had grown to 5.5 × 2.5cm, forty-seven days later. Pathology examination of the excised lesion showed ulcer positive for HSV-2 and dense chronic lymphoplasmacytic infiltrate (Fig. 2). The defect was closed primarily with good cosmetic result.Fig. 2 (left) H&E 20x; Sections show a dense inflammatory infiltrate composed of lymphocytes, plasma cells, eosinophils, and neutrophils. There are several superficial keratinocytes demonstrating nuclear viropathic changes, and there is no evidence of carcinoma and (right) these cells also demonstrate positive nuclear immunohistochemical staining for HSV.
Fig. 2
Discussion
Verrucous, or hypertrophic, HSV lesions represent fewer than 5% of genital herpes lesions.2 This presentation is typically associated with acyclovir resistance and occurs almost exclusively in immunocompromised patients. Mechanistically, it has been demonstrated to be due to mutations in the pathways regulating viral thymidine kinase enzyme expression. This enzyme normally functions via intracellular phosphorylation of acyclovir, which is a critical first step in the activation of the drug. Mutations that confer decreased or absent expression of this kinase protein underlie 95% of acyclovir resistance.3
In the rare case of hypertrophic HSV lesions, case reports have demonstrated IL cidofovir therapy to be effective in both acyclovir-sensitive and in acyclovir-resistant infections in HIV positive men.4 Moreover, surgical debulking has been shown to be effective for treatment of recalcitrant lesions, but typically is not favored over medical management of genital lesions due to risk of recurrence.5 The optimal management of this uncommon pathology is yet to be fully elucidated.
Conclusion
This case demonstrates the importance to consider causes other than HPV in large genital lesions with concomitant HIV or other immunocompromise. Regarding hypertrophic HSV lesions, several aspects of the above presentation are unusual. First, although verrucous HSV has been described in HIV positive patients, it is highly atypical for these lesions to demonstrate acyclovir-sensitivity. Considering this finding, it is additionally surprising that this lesion continued to grow despite valacyclovir and IL cidofovir treatment. Finally, we have demonstrated that in the event of conservative and medical treatment failure, surgical excision can be a reasonable option with good cosmetic results and substantial improvement in the quality of life of the patient, even in the case of very large lesions.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | CIDOFOVIR, TRIFLURIDINE, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33604244 | 18,987,611 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pathogen resistance'. | Herpes simplex virus-2 associated with a large fungating penile mass.
A 48-year-old male with HIV/AIDS presented with an enlarging nodular lesion on the base of his penis. Histology revealed changes consistent with chronic viral infection and culture grew herpes simplex virus 2 (HSV-2). The lesion was refractory to valacyclovir and intralesional (IL) cidofovir therapy. Urology excised the mass and the defect was repaired primarily with good cosmetic result. Post-operative pathology confirmed HSV-2 despite the unusual appearance of the lesion consisting of nodular mass without gross ulceration.
Introduction
Classic herpes simplex virus 2 (HSV-2) lesions produce painful genital ulcers. When large, papillary genital masses develop, they are typically caused by human papilloma virus (HPV) serotypes. These lesions have been known to grow to impressive size in those with compromised immune systems, such as in human immunodeficiency virus (HIV) infection. The literature has shown effective treatment of large HPV lesions with intralesional (IL) cidofovir, and otolaryngologists use IL cidofovir in the case of laryngeal papillomatosis with good results.1 Optimal treatment of verrucous HSV-2 lesions is less well defined in the literature.
Case presentation
We present the case of a 48-year-old male who presented with four months of an enlarging nodular lesion at the base of his penis (Fig. 1). His medical history included HIV/AIDS, alcohol use disorder, anal dysplasia, pulmonary tuberculosis, Pneumocystis pneumonia, and esophagitis. His viral load was undetectable and CD4 count was 98 cell/mm.3 Dermatology initially performed multiple evaluations of the lesion. Biopsy and histology repeatedly revealed changes consistent with chronic viral infection and culture grew herpes simplex virus 2 (HSV-2) sensitive to acyclovir.Fig. 1 (left) Preoperative depiction of gross lesion and (right) incision at 3 week postoperative check.
Fig. 1
He was treated with valacyclovir 1 gram twice daily and topical trifluridine for four months. After continued growth, IL cidofovir 30 milligrams for three total injections was initiated. Despite this, the mass grew larger and he was referred to Urology for excision. Preoperative exam revealed a 4 × 2cm exophytic nodule at the dorsal base of his penis without ulceration and with significant weeping. He was scheduled for surgical excision; at which time the mass had grown to 5.5 × 2.5cm, forty-seven days later. Pathology examination of the excised lesion showed ulcer positive for HSV-2 and dense chronic lymphoplasmacytic infiltrate (Fig. 2). The defect was closed primarily with good cosmetic result.Fig. 2 (left) H&E 20x; Sections show a dense inflammatory infiltrate composed of lymphocytes, plasma cells, eosinophils, and neutrophils. There are several superficial keratinocytes demonstrating nuclear viropathic changes, and there is no evidence of carcinoma and (right) these cells also demonstrate positive nuclear immunohistochemical staining for HSV.
Fig. 2
Discussion
Verrucous, or hypertrophic, HSV lesions represent fewer than 5% of genital herpes lesions.2 This presentation is typically associated with acyclovir resistance and occurs almost exclusively in immunocompromised patients. Mechanistically, it has been demonstrated to be due to mutations in the pathways regulating viral thymidine kinase enzyme expression. This enzyme normally functions via intracellular phosphorylation of acyclovir, which is a critical first step in the activation of the drug. Mutations that confer decreased or absent expression of this kinase protein underlie 95% of acyclovir resistance.3
In the rare case of hypertrophic HSV lesions, case reports have demonstrated IL cidofovir therapy to be effective in both acyclovir-sensitive and in acyclovir-resistant infections in HIV positive men.4 Moreover, surgical debulking has been shown to be effective for treatment of recalcitrant lesions, but typically is not favored over medical management of genital lesions due to risk of recurrence.5 The optimal management of this uncommon pathology is yet to be fully elucidated.
Conclusion
This case demonstrates the importance to consider causes other than HPV in large genital lesions with concomitant HIV or other immunocompromise. Regarding hypertrophic HSV lesions, several aspects of the above presentation are unusual. First, although verrucous HSV has been described in HIV positive patients, it is highly atypical for these lesions to demonstrate acyclovir-sensitivity. Considering this finding, it is additionally surprising that this lesion continued to grow despite valacyclovir and IL cidofovir treatment. Finally, we have demonstrated that in the event of conservative and medical treatment failure, surgical excision can be a reasonable option with good cosmetic results and substantial improvement in the quality of life of the patient, even in the case of very large lesions.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | CIDOFOVIR, TRIFLURIDINE, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33604244 | 18,987,611 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Herpes simplex virus-2 associated with a large fungating penile mass.
A 48-year-old male with HIV/AIDS presented with an enlarging nodular lesion on the base of his penis. Histology revealed changes consistent with chronic viral infection and culture grew herpes simplex virus 2 (HSV-2). The lesion was refractory to valacyclovir and intralesional (IL) cidofovir therapy. Urology excised the mass and the defect was repaired primarily with good cosmetic result. Post-operative pathology confirmed HSV-2 despite the unusual appearance of the lesion consisting of nodular mass without gross ulceration.
Introduction
Classic herpes simplex virus 2 (HSV-2) lesions produce painful genital ulcers. When large, papillary genital masses develop, they are typically caused by human papilloma virus (HPV) serotypes. These lesions have been known to grow to impressive size in those with compromised immune systems, such as in human immunodeficiency virus (HIV) infection. The literature has shown effective treatment of large HPV lesions with intralesional (IL) cidofovir, and otolaryngologists use IL cidofovir in the case of laryngeal papillomatosis with good results.1 Optimal treatment of verrucous HSV-2 lesions is less well defined in the literature.
Case presentation
We present the case of a 48-year-old male who presented with four months of an enlarging nodular lesion at the base of his penis (Fig. 1). His medical history included HIV/AIDS, alcohol use disorder, anal dysplasia, pulmonary tuberculosis, Pneumocystis pneumonia, and esophagitis. His viral load was undetectable and CD4 count was 98 cell/mm.3 Dermatology initially performed multiple evaluations of the lesion. Biopsy and histology repeatedly revealed changes consistent with chronic viral infection and culture grew herpes simplex virus 2 (HSV-2) sensitive to acyclovir.Fig. 1 (left) Preoperative depiction of gross lesion and (right) incision at 3 week postoperative check.
Fig. 1
He was treated with valacyclovir 1 gram twice daily and topical trifluridine for four months. After continued growth, IL cidofovir 30 milligrams for three total injections was initiated. Despite this, the mass grew larger and he was referred to Urology for excision. Preoperative exam revealed a 4 × 2cm exophytic nodule at the dorsal base of his penis without ulceration and with significant weeping. He was scheduled for surgical excision; at which time the mass had grown to 5.5 × 2.5cm, forty-seven days later. Pathology examination of the excised lesion showed ulcer positive for HSV-2 and dense chronic lymphoplasmacytic infiltrate (Fig. 2). The defect was closed primarily with good cosmetic result.Fig. 2 (left) H&E 20x; Sections show a dense inflammatory infiltrate composed of lymphocytes, plasma cells, eosinophils, and neutrophils. There are several superficial keratinocytes demonstrating nuclear viropathic changes, and there is no evidence of carcinoma and (right) these cells also demonstrate positive nuclear immunohistochemical staining for HSV.
Fig. 2
Discussion
Verrucous, or hypertrophic, HSV lesions represent fewer than 5% of genital herpes lesions.2 This presentation is typically associated with acyclovir resistance and occurs almost exclusively in immunocompromised patients. Mechanistically, it has been demonstrated to be due to mutations in the pathways regulating viral thymidine kinase enzyme expression. This enzyme normally functions via intracellular phosphorylation of acyclovir, which is a critical first step in the activation of the drug. Mutations that confer decreased or absent expression of this kinase protein underlie 95% of acyclovir resistance.3
In the rare case of hypertrophic HSV lesions, case reports have demonstrated IL cidofovir therapy to be effective in both acyclovir-sensitive and in acyclovir-resistant infections in HIV positive men.4 Moreover, surgical debulking has been shown to be effective for treatment of recalcitrant lesions, but typically is not favored over medical management of genital lesions due to risk of recurrence.5 The optimal management of this uncommon pathology is yet to be fully elucidated.
Conclusion
This case demonstrates the importance to consider causes other than HPV in large genital lesions with concomitant HIV or other immunocompromise. Regarding hypertrophic HSV lesions, several aspects of the above presentation are unusual. First, although verrucous HSV has been described in HIV positive patients, it is highly atypical for these lesions to demonstrate acyclovir-sensitivity. Considering this finding, it is additionally surprising that this lesion continued to grow despite valacyclovir and IL cidofovir treatment. Finally, we have demonstrated that in the event of conservative and medical treatment failure, surgical excision can be a reasonable option with good cosmetic results and substantial improvement in the quality of life of the patient, even in the case of very large lesions.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | CIDOFOVIR, TRIFLURIDINE, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33604244 | 18,987,611 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Viral mutation identified'. | Herpes simplex virus-2 associated with a large fungating penile mass.
A 48-year-old male with HIV/AIDS presented with an enlarging nodular lesion on the base of his penis. Histology revealed changes consistent with chronic viral infection and culture grew herpes simplex virus 2 (HSV-2). The lesion was refractory to valacyclovir and intralesional (IL) cidofovir therapy. Urology excised the mass and the defect was repaired primarily with good cosmetic result. Post-operative pathology confirmed HSV-2 despite the unusual appearance of the lesion consisting of nodular mass without gross ulceration.
Introduction
Classic herpes simplex virus 2 (HSV-2) lesions produce painful genital ulcers. When large, papillary genital masses develop, they are typically caused by human papilloma virus (HPV) serotypes. These lesions have been known to grow to impressive size in those with compromised immune systems, such as in human immunodeficiency virus (HIV) infection. The literature has shown effective treatment of large HPV lesions with intralesional (IL) cidofovir, and otolaryngologists use IL cidofovir in the case of laryngeal papillomatosis with good results.1 Optimal treatment of verrucous HSV-2 lesions is less well defined in the literature.
Case presentation
We present the case of a 48-year-old male who presented with four months of an enlarging nodular lesion at the base of his penis (Fig. 1). His medical history included HIV/AIDS, alcohol use disorder, anal dysplasia, pulmonary tuberculosis, Pneumocystis pneumonia, and esophagitis. His viral load was undetectable and CD4 count was 98 cell/mm.3 Dermatology initially performed multiple evaluations of the lesion. Biopsy and histology repeatedly revealed changes consistent with chronic viral infection and culture grew herpes simplex virus 2 (HSV-2) sensitive to acyclovir.Fig. 1 (left) Preoperative depiction of gross lesion and (right) incision at 3 week postoperative check.
Fig. 1
He was treated with valacyclovir 1 gram twice daily and topical trifluridine for four months. After continued growth, IL cidofovir 30 milligrams for three total injections was initiated. Despite this, the mass grew larger and he was referred to Urology for excision. Preoperative exam revealed a 4 × 2cm exophytic nodule at the dorsal base of his penis without ulceration and with significant weeping. He was scheduled for surgical excision; at which time the mass had grown to 5.5 × 2.5cm, forty-seven days later. Pathology examination of the excised lesion showed ulcer positive for HSV-2 and dense chronic lymphoplasmacytic infiltrate (Fig. 2). The defect was closed primarily with good cosmetic result.Fig. 2 (left) H&E 20x; Sections show a dense inflammatory infiltrate composed of lymphocytes, plasma cells, eosinophils, and neutrophils. There are several superficial keratinocytes demonstrating nuclear viropathic changes, and there is no evidence of carcinoma and (right) these cells also demonstrate positive nuclear immunohistochemical staining for HSV.
Fig. 2
Discussion
Verrucous, or hypertrophic, HSV lesions represent fewer than 5% of genital herpes lesions.2 This presentation is typically associated with acyclovir resistance and occurs almost exclusively in immunocompromised patients. Mechanistically, it has been demonstrated to be due to mutations in the pathways regulating viral thymidine kinase enzyme expression. This enzyme normally functions via intracellular phosphorylation of acyclovir, which is a critical first step in the activation of the drug. Mutations that confer decreased or absent expression of this kinase protein underlie 95% of acyclovir resistance.3
In the rare case of hypertrophic HSV lesions, case reports have demonstrated IL cidofovir therapy to be effective in both acyclovir-sensitive and in acyclovir-resistant infections in HIV positive men.4 Moreover, surgical debulking has been shown to be effective for treatment of recalcitrant lesions, but typically is not favored over medical management of genital lesions due to risk of recurrence.5 The optimal management of this uncommon pathology is yet to be fully elucidated.
Conclusion
This case demonstrates the importance to consider causes other than HPV in large genital lesions with concomitant HIV or other immunocompromise. Regarding hypertrophic HSV lesions, several aspects of the above presentation are unusual. First, although verrucous HSV has been described in HIV positive patients, it is highly atypical for these lesions to demonstrate acyclovir-sensitivity. Considering this finding, it is additionally surprising that this lesion continued to grow despite valacyclovir and IL cidofovir treatment. Finally, we have demonstrated that in the event of conservative and medical treatment failure, surgical excision can be a reasonable option with good cosmetic results and substantial improvement in the quality of life of the patient, even in the case of very large lesions.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | CIDOFOVIR, TRIFLURIDINE, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33604244 | 18,987,611 | 2021-05 |
What was the administration route of drug 'CIDOFOVIR'? | Herpes simplex virus-2 associated with a large fungating penile mass.
A 48-year-old male with HIV/AIDS presented with an enlarging nodular lesion on the base of his penis. Histology revealed changes consistent with chronic viral infection and culture grew herpes simplex virus 2 (HSV-2). The lesion was refractory to valacyclovir and intralesional (IL) cidofovir therapy. Urology excised the mass and the defect was repaired primarily with good cosmetic result. Post-operative pathology confirmed HSV-2 despite the unusual appearance of the lesion consisting of nodular mass without gross ulceration.
Introduction
Classic herpes simplex virus 2 (HSV-2) lesions produce painful genital ulcers. When large, papillary genital masses develop, they are typically caused by human papilloma virus (HPV) serotypes. These lesions have been known to grow to impressive size in those with compromised immune systems, such as in human immunodeficiency virus (HIV) infection. The literature has shown effective treatment of large HPV lesions with intralesional (IL) cidofovir, and otolaryngologists use IL cidofovir in the case of laryngeal papillomatosis with good results.1 Optimal treatment of verrucous HSV-2 lesions is less well defined in the literature.
Case presentation
We present the case of a 48-year-old male who presented with four months of an enlarging nodular lesion at the base of his penis (Fig. 1). His medical history included HIV/AIDS, alcohol use disorder, anal dysplasia, pulmonary tuberculosis, Pneumocystis pneumonia, and esophagitis. His viral load was undetectable and CD4 count was 98 cell/mm.3 Dermatology initially performed multiple evaluations of the lesion. Biopsy and histology repeatedly revealed changes consistent with chronic viral infection and culture grew herpes simplex virus 2 (HSV-2) sensitive to acyclovir.Fig. 1 (left) Preoperative depiction of gross lesion and (right) incision at 3 week postoperative check.
Fig. 1
He was treated with valacyclovir 1 gram twice daily and topical trifluridine for four months. After continued growth, IL cidofovir 30 milligrams for three total injections was initiated. Despite this, the mass grew larger and he was referred to Urology for excision. Preoperative exam revealed a 4 × 2cm exophytic nodule at the dorsal base of his penis without ulceration and with significant weeping. He was scheduled for surgical excision; at which time the mass had grown to 5.5 × 2.5cm, forty-seven days later. Pathology examination of the excised lesion showed ulcer positive for HSV-2 and dense chronic lymphoplasmacytic infiltrate (Fig. 2). The defect was closed primarily with good cosmetic result.Fig. 2 (left) H&E 20x; Sections show a dense inflammatory infiltrate composed of lymphocytes, plasma cells, eosinophils, and neutrophils. There are several superficial keratinocytes demonstrating nuclear viropathic changes, and there is no evidence of carcinoma and (right) these cells also demonstrate positive nuclear immunohistochemical staining for HSV.
Fig. 2
Discussion
Verrucous, or hypertrophic, HSV lesions represent fewer than 5% of genital herpes lesions.2 This presentation is typically associated with acyclovir resistance and occurs almost exclusively in immunocompromised patients. Mechanistically, it has been demonstrated to be due to mutations in the pathways regulating viral thymidine kinase enzyme expression. This enzyme normally functions via intracellular phosphorylation of acyclovir, which is a critical first step in the activation of the drug. Mutations that confer decreased or absent expression of this kinase protein underlie 95% of acyclovir resistance.3
In the rare case of hypertrophic HSV lesions, case reports have demonstrated IL cidofovir therapy to be effective in both acyclovir-sensitive and in acyclovir-resistant infections in HIV positive men.4 Moreover, surgical debulking has been shown to be effective for treatment of recalcitrant lesions, but typically is not favored over medical management of genital lesions due to risk of recurrence.5 The optimal management of this uncommon pathology is yet to be fully elucidated.
Conclusion
This case demonstrates the importance to consider causes other than HPV in large genital lesions with concomitant HIV or other immunocompromise. Regarding hypertrophic HSV lesions, several aspects of the above presentation are unusual. First, although verrucous HSV has been described in HIV positive patients, it is highly atypical for these lesions to demonstrate acyclovir-sensitivity. Considering this finding, it is additionally surprising that this lesion continued to grow despite valacyclovir and IL cidofovir treatment. Finally, we have demonstrated that in the event of conservative and medical treatment failure, surgical excision can be a reasonable option with good cosmetic results and substantial improvement in the quality of life of the patient, even in the case of very large lesions.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | Intralesional | DrugAdministrationRoute | CC BY-NC-ND | 33604244 | 18,987,611 | 2021-05 |
What was the administration route of drug 'TRIFLURIDINE'? | Herpes simplex virus-2 associated with a large fungating penile mass.
A 48-year-old male with HIV/AIDS presented with an enlarging nodular lesion on the base of his penis. Histology revealed changes consistent with chronic viral infection and culture grew herpes simplex virus 2 (HSV-2). The lesion was refractory to valacyclovir and intralesional (IL) cidofovir therapy. Urology excised the mass and the defect was repaired primarily with good cosmetic result. Post-operative pathology confirmed HSV-2 despite the unusual appearance of the lesion consisting of nodular mass without gross ulceration.
Introduction
Classic herpes simplex virus 2 (HSV-2) lesions produce painful genital ulcers. When large, papillary genital masses develop, they are typically caused by human papilloma virus (HPV) serotypes. These lesions have been known to grow to impressive size in those with compromised immune systems, such as in human immunodeficiency virus (HIV) infection. The literature has shown effective treatment of large HPV lesions with intralesional (IL) cidofovir, and otolaryngologists use IL cidofovir in the case of laryngeal papillomatosis with good results.1 Optimal treatment of verrucous HSV-2 lesions is less well defined in the literature.
Case presentation
We present the case of a 48-year-old male who presented with four months of an enlarging nodular lesion at the base of his penis (Fig. 1). His medical history included HIV/AIDS, alcohol use disorder, anal dysplasia, pulmonary tuberculosis, Pneumocystis pneumonia, and esophagitis. His viral load was undetectable and CD4 count was 98 cell/mm.3 Dermatology initially performed multiple evaluations of the lesion. Biopsy and histology repeatedly revealed changes consistent with chronic viral infection and culture grew herpes simplex virus 2 (HSV-2) sensitive to acyclovir.Fig. 1 (left) Preoperative depiction of gross lesion and (right) incision at 3 week postoperative check.
Fig. 1
He was treated with valacyclovir 1 gram twice daily and topical trifluridine for four months. After continued growth, IL cidofovir 30 milligrams for three total injections was initiated. Despite this, the mass grew larger and he was referred to Urology for excision. Preoperative exam revealed a 4 × 2cm exophytic nodule at the dorsal base of his penis without ulceration and with significant weeping. He was scheduled for surgical excision; at which time the mass had grown to 5.5 × 2.5cm, forty-seven days later. Pathology examination of the excised lesion showed ulcer positive for HSV-2 and dense chronic lymphoplasmacytic infiltrate (Fig. 2). The defect was closed primarily with good cosmetic result.Fig. 2 (left) H&E 20x; Sections show a dense inflammatory infiltrate composed of lymphocytes, plasma cells, eosinophils, and neutrophils. There are several superficial keratinocytes demonstrating nuclear viropathic changes, and there is no evidence of carcinoma and (right) these cells also demonstrate positive nuclear immunohistochemical staining for HSV.
Fig. 2
Discussion
Verrucous, or hypertrophic, HSV lesions represent fewer than 5% of genital herpes lesions.2 This presentation is typically associated with acyclovir resistance and occurs almost exclusively in immunocompromised patients. Mechanistically, it has been demonstrated to be due to mutations in the pathways regulating viral thymidine kinase enzyme expression. This enzyme normally functions via intracellular phosphorylation of acyclovir, which is a critical first step in the activation of the drug. Mutations that confer decreased or absent expression of this kinase protein underlie 95% of acyclovir resistance.3
In the rare case of hypertrophic HSV lesions, case reports have demonstrated IL cidofovir therapy to be effective in both acyclovir-sensitive and in acyclovir-resistant infections in HIV positive men.4 Moreover, surgical debulking has been shown to be effective for treatment of recalcitrant lesions, but typically is not favored over medical management of genital lesions due to risk of recurrence.5 The optimal management of this uncommon pathology is yet to be fully elucidated.
Conclusion
This case demonstrates the importance to consider causes other than HPV in large genital lesions with concomitant HIV or other immunocompromise. Regarding hypertrophic HSV lesions, several aspects of the above presentation are unusual. First, although verrucous HSV has been described in HIV positive patients, it is highly atypical for these lesions to demonstrate acyclovir-sensitivity. Considering this finding, it is additionally surprising that this lesion continued to grow despite valacyclovir and IL cidofovir treatment. Finally, we have demonstrated that in the event of conservative and medical treatment failure, surgical excision can be a reasonable option with good cosmetic results and substantial improvement in the quality of life of the patient, even in the case of very large lesions.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | Topical | DrugAdministrationRoute | CC BY-NC-ND | 33604244 | 18,987,611 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaphylactic reaction'. | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | ACETAMINOPHEN, AMOXICILLIN\CLAVULANATE POTASSIUM, CHLORPHENIRAMINE MALEATE, IBUPROFEN | DrugsGivenReaction | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug hypersensitivity'. | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | ACETAMINOPHEN, AMOXICILLIN\CLAVULANATE POTASSIUM, CHLORPHENIRAMINE MALEATE, IBUPROFEN | DrugsGivenReaction | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dyspnoea'. | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | ACETAMINOPHEN, AMOXICILLIN\CLAVULANATE POTASSIUM, CHLORPHENIRAMINE MALEATE, IBUPROFEN | DrugsGivenReaction | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rhinorrhoea'. | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | ACETAMINOPHEN, AMOXICILLIN\CLAVULANATE POTASSIUM, CHLORPHENIRAMINE MALEATE, IBUPROFEN | DrugsGivenReaction | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Type I hypersensitivity'. | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | AMOXICILLIN | DrugsGivenReaction | CC BY-NC | 33604273 | 19,111,110 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Wheezing'. | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | ACETAMINOPHEN, AMOXICILLIN\CLAVULANATE POTASSIUM, CHLORPHENIRAMINE MALEATE, IBUPROFEN | DrugsGivenReaction | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
What was the administration route of drug 'ACETAMINOPHEN'? | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | Oral | DrugAdministrationRoute | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
What was the administration route of drug 'AMOXICILLIN\CLAVULANATE POTASSIUM'? | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | Oral | DrugAdministrationRoute | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
What was the administration route of drug 'CHLORPHENIRAMINE MALEATE'? | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | Oral | DrugAdministrationRoute | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
What was the administration route of drug 'IBUPROFEN'? | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | Oral | DrugAdministrationRoute | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
What was the dosage of drug 'ACETAMINOPHEN\HYDROCODONE'? | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | UNKNOWN | DrugDosageText | CC BY-NC | 33604273 | 19,026,862 | 2021-01 |
What was the outcome of reaction 'Anaphylactic reaction'? | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | Recovered | ReactionOutcome | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
What was the outcome of reaction 'Angioedema'? | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | Recovered | ReactionOutcome | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
What was the outcome of reaction 'Dyspnoea'? | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | Recovered | ReactionOutcome | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
What was the outcome of reaction 'Rhinorrhoea'? | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | Recovered | ReactionOutcome | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
What was the outcome of reaction 'Urticaria'? | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | Recovered | ReactionOutcome | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
What was the outcome of reaction 'Wheezing'? | Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly.
We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild.
Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
INTRODUCTION
Drug hypersensitivity reaction is a common concern in children and beta-lactam (BL) antibiotics are commonly implicated [12]. In a review of the inpatient electronic medical records of 8,437 children in Singapore, adverse drug reactions were reported in 222 patients (2.6%), of which 45% were attributed to BL antibiotics [3]. In a questionnaire study of German children of median age 3.5 years, the lifetime prevalence of an adverse drug reaction was 7.5% and BL accounted for 79% of possible allergic reactions [4]. Similarly, in a questionnaire study of Singaporean school children age 7 to 16 years, the prevalence of a self-reported adverse drug reaction was 5% and 57% were related to BL antibiotics [5]. Phone interview of selected subjects revealed that although most patients visited a doctor upon suspected reaction, only 7% were referred to tertiary institutes for further investigation [5]. In the paediatric population, viral exanthems are often misinterpreted as drug hypersensitivity reactions [6]. Prior studies suggest that over 90% of children with suspected BL hypersensitivity do not react upon oral provocation, suggesting that true drug hypersensitivity reactions are uncommon or may wane with time [78].
It is important to confirm the diagnosis of BL hypersensitivity because reported antibiotic allergies are associated with increased use of broad-spectrum antibiotics, longer hospital stay, increased healthcare cost, and persistent parental fear of BL antibiotics [910]. Antibiotic allergy labelling is a public health issue and allergy testing is a recognised component of antimicrobial stewardship [11]. The diagnostic evaluation of suspected drug hypersensitivity helps to minimize unnecessary antibiotic avoidance and is ideally performed 1 to 6 months after complete recovery of the initial reaction [12]. Drug provocation test (DPT) is the gold standard in the evaluation of drug hypersensitivity. While BL skin tests prior to DPT are recommended by most guidelines [1314], there is heterogeneity in clinical practice [151617], particularly with regard to children [18].
In Singapore, there is limited literature on the evaluation of childhood BL hypersensitivity. A study of 111 children clinically diagnosed with drug eruption at a tertiary skin centre in Singapore showed that amoxicillin and ampicillin were the most commonly implicated drugs [19]. Drug hypersensitivity was evaluated based on history, patch test, penicillin specific immunoglobulin E antibodies and, in less than half of the cohort, by DPT. More recently, a study on DPT outcomes in Singaporean adults described 41 BL challenges, of which 3 were positive [20]. The aim of our study is to describe the outcomes of evaluation of children with suspected BL hypersensitivity in KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS
We conducted a retrospective review and included all patients aged 18 years and below who underwent BL DPT for suspected BL hypersensitivity reaction at the paediatric allergy unit in KK Women's and Children's Hospital, Singapore from August 2016 to December 2017.
All patients were evaluated by an attending allergist. Suspected hypersensitivity reactions were defined based on clinical history as immediate if the onset of reaction was ≤1 hour and delayed if onset was >1 hour. Patients with immediate reactions underwent skin prick test (SPT). Patients with immediate reactions were offered DPT if skin tests were negative. Patients with delayed reactions were offered DPT directly. A DPT was considered diagnostic if the patient was challenged with the index drug which caused suspected hypersensitivity. In patients for whom diagnostic DPT was not possible, a DPT to an alternative BL was performed. The electronic case notes were reviewed and data were extracted onto standardized data collection forms. Statistical analysis was carried out using IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA).
1. SPT and intradermal test
SPT was performed using the parenteral preparation of the index drug and a standard BL panel consisting of (1) histamine positive control, (2) diluent negative control, (3) benzylpenicilloyl octa-L-lysine, (PPL, Diater Laboratorios, Madrid, Spain) (4) sodium benzylpenilloate, (MD, Diater Laboratorios) (5) benzylpenicillin, (6) ampicillin, (7) cefazolin, and (8) ceftriaxone. Prior to September 2017, our unit used high concentration benzylpenicillin (333,333 U/mL), ampicillin (167 mg/mL), cefazolin (333 mg/mL), and ceftriaxone (333 mg/mL). Thereafter, we standardized the reagent concentrations to the recommendations of the European Network of Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) for benzylpenicillin (10,000 U/mL), ampicillin (20 mg/mL), cefazolin (2 mg/mL), and ceftriaxone (2 mg/mL) [21]. A positive result was defined as a mean wheal size of 3 mm or larger than the negative control.
Intradermal test (IDT) was performed using ENDA/EAACI [21] standardized concentration of drugs. Mean wheal size increase of 3 mm or larger than the initial bleb or persistence of wheal after 20 minutes with flare and itch were considered positive. Given the discomfort associated with IDT, children with mild reactions proceeded to diagnostic DPT after SPT.
2. Drug provocation test
The DPT consisted of a single therapeutic dose of BL antibiotic administered under physician supervision in an outpatient setting. For example, the single therapeutic dose of amoxicillin was 16.7 mg/kg (not exceeding adult dose 500 mg). If there was no initial reaction, the same dose was self-administered once daily for the next 4 days. A DPT was considered negative if the patient reported no reaction at the end of 5 days.
3. Ethical approval
The study is approved by the Institutional Review Board of KK Women's and Children's Hospital (reference number: 2015/3141). The parents of the study subjects had given their written informed consent.
RESULTS
1. Demographics and suspected hypersensitivity reaction
Over the 16-month study period, a total of 120 children with 121 suspected BL reactions were identified: 103 patients had reported suspected hypersensitivity reaction to a single penicillin, 16 patients to a single cephalosporin, and 1 patient to both penicillin and cephalosporin. Subject demographics are described in Table 1.
Table 1 Subject demographics (n = 120)
Variable Value
Age at DPT (yr) 7.4 (4.2–11.1)
Male sex 73 (61)
Race
Chinese 86 (72)
Malay 14 (12)
Indian 8 (7)
Caucasian 4 (3)
Others 8 (7)
Family history
Paternal history
Atopy 33 (28)
Drug hypersensitivity 8 (7)
BL hypersensitivity 4 (3)
Maternal history
Atopy 38 (32)
Drug hypersensitivity 17 (14)
BL hypersensitivity 8 (7)
Sibling history
Atopy 30 (25)
Personal history of atopy
Rhinitis 72 (60)
Eczema 32 (27)
Doctor-diagnosed asthma 12 (10)
Food allergy 7 (6)
Recurrent urticaria 16 (13)
Chronic spontaneous urticaria 6 (5)
Class of drug (other than BL) that patient reported suspected hypersensitivity
Nonsteroidal anti-inflammatory drug (NSAID) 12 (10)
Macrolide antibiotic 7 (6)
Values are presented as median (interquartile range) or number (%).
DPT, drug provocation test; BL, beta-lactam.
The median age at suspected reaction was 2.0 years (interquartile range [IQR], 1.0–5.0 years) and the median age at DPT was 7.4 years (IQR 4.2–11.1 years). The median time interval between suspected reaction and DPT was 2.6 years (IQR, 1.2–5.7 years).
The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). The most commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). The most commonly reported symptoms were maculopapular rash in 44% (53 of 121), urticaria in 34% (41 of 121), and angioedema in 22% (27 of 121). The clinical characteristics of the suspected hypersensitivity reactions are described in Table 2.
Table 2 Description of suspected hypersensitivity reaction (n = 121)
Variable All reactions (n = 121) Immediate (n = 25) Delayed (n = 80) Uncertain onset (n = 16)
Age at reaction (yr) 2.0 (1.0–5.0) 2.0 (1.0–5.0) 3.0 (1.0–5.3) 1.0 (1.0–2.5)
Beta-lactam antibiotic
Penicillin group 104 (86) 21 (84) 69 (86) 14 (88)
Amoxicillin 54 (45) 10 (40) 38 (48) 6 (38)
Ampicillin 2 (2) 2 (8) - -
Amoxicillin-clavulanate 45 (37) 9 (36) 30 (38) 6 (38)
Cloxacillin 1 (1) - 1 (1) -
Penicillin V 2 (2) - - 2 (13)
Cephalosporin group 17 (14) 4 (16) 11 (14) 2 (13)
Cephalexin 10 (8) 2 (8) 7 (9) 1 (11)
Cefuroxime 2 (2) 1 (4) 1 (1) -
Cefazolin 1 (1) - 1 (1) -
Cefaclor 1 (1) - 1 (1) -
Ceftibuten 1 (1) - - 1 (11)
Cefixime 1 (1) - 1 (1) -
Cefepime 1 (1) 1 (4) - -
Route
Oral 113 (93) 22 (88) 75 (94) 16 (100)
Intravenous 8 (7) 3 (12) 5 (6) -
Reaction with first course of BL 83 (69) 17 (68) 58 (73) 8 (50)
No. of doses to reaction
1 Dose 42 (35) 16 (64) 23 (29) 3 (19)
2–5 Doses 19 (16) 2 (8) 15 (19) 2 (13)
6–10 Doses 5 (4) - 5 (6) -
>10 Doses 3 (2) - 3 (4) -
Clinical reaction
Angioedema 27 (22) 11 (44) 13 (16) 3 (19)
Urticaria 41 (34) 14 (56) 24 (30) 3 (19)
Maculopapular rash 53 (44) 7 (28) 40 (50) 6 (38)
Pustular rash 2 (2) - 2 (3) -
Nonspecific rash 21 (17) 5 (20) 10 (13) 6 (38)
Anaphylaxis* 1 (1) 1 (4) - -
Stevens-Johnson syndrome* 1 (1) - 1 (1) -
Values are presented as median (interquartile range) or number (%).
BL, beta-lactam.
*Alternative etiologies to BL hypersensitivity were found more likely – further described in section Case Description.
2. SPTs and DPTs
A total of 26 SPTs were performed: 18 used high concentration reagents and 8 used ENDA/EAACI [21] concentrations. All patients had negative SPT results. One patient proceeded to IDT and is further described in the section Case Description.
In 118 suspected hypersensitivity reactions, we performed diagnostic DPT to the index drug. This consisted of 104 challenges to the penicillin group of amoxicillin (n = 56, index drug amoxicillin [n = 54] and ampicillin [n = 2]), amoxicillin-clavulanate (n = 45), cloxacillin (n = 1), and penicillin V (n = 2), together with 14 diagnostic challenges to cephalosporin group of cephalexin (n = 11, index drug cephalexin [n = 10] and cefaclor [n = 1]), cefuroxime (n = 2), and ceftibuten (n = 1). In 3 cases, DPT to the index drug was not possible and DPT to an alternative drug was performed. Fig. 1 illustrates the outcomes of DPT to index and alternative drugs.
Fig. 1 Outcome of drug provocation test (DPT). *One patient had a suspected cefazolin DHR. As the patient's parent declined any evaluation of cephalosporin hypersensitivity, the patient underwent amoxicillin DPT. +One patient had a suspected cefixime DHR. As cefixime was unavailable in hospital formulary, the patient underwent ceftibuten DPT. One patient had cefepime hypersensitivity confirmed on IDT and underwent cefuroxime DPT. (Described in section Case Description).
A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs. One DPT was considered to have an equivocal result. The index drug was well tolerated in 92% (96 of 104) of penicillin group drug challenges (95% [56 of 59] of penicillin only challenge; 89% [40 of 45] for amoxicillin-clavulanate challenges) and 100% (14 of 14) of cephalosporin challenges. An analysis of subject demographics and reported hypersensitivity reactions did not reveal significant differences in patients with positive and negative challenge result. Table 3 describes positive DPT reactions.
Table 3 Description of positive DPT reactions
Case Sex Index drug SPT Description of index reaction Description of positive DPT reaction Subsequent DPT result
Age Type Timing Symptom Age Type Timing Symptom
1 F AX - 1 yr Imm 1st dose R 5 yr Imm 1 hr after first dose in clinic UR -
2 F AX-CLV Negative Unk Imm Unk AE, R 15 yr Imm 20 min after home dose on day 2 to 5 AE of eyes -
3 F AX - 10 yr Del 3rd dose UR 11 yr Del 8 hr after first dose MPE -
4 F AX-CLV - 11 yr Unk Unk UR 12 yr Del A few hours after home dose on day 2 & 3 MPE -
5 M AX-CLV - 11 yr Del 6th dose MPE 13 yr Del At least 4 hr after first dose UR, AE of eyes and lip Negative cephalexin DPT
6 M AX-CLV - 2 yr Unk Unk R 3 yr Del 9 hr after first dose UR, AE of eyes -
7 M AX-CLV - 5 yr Del Unk MPE 10 yr Del On day 6 Lip ulcer -
DPT, drug provocation test; SPT, skin prick test; AX, amoxicillin; Imm, Immediate reaction; R, rash, nonspecific; UR, urticaria; AX-CLV, amoxicillin-clavulanate; Unk, unknown; AE, angioedema; Del, delayed reaction; MPE, maculopapular exanthem; Neg, Negative.
3. Case descriptions
One case of Stevens-Johnson syndrome (SJS) was identified in this study population. This was a 5-year-old Chinese boy who presented with symptoms of fever and cough for 7 days and received oral cefuroxime on day 4 to 6 of illness. He experienced conjunctivitis on day 6 of illness. On day 7, the patient's chest radiograph showed left lung consolidation and he was admitted to the hospital. He received a dose of intravenous ceftriaxone and after 8 hours of observation, he experienced generalized rash with targetoid lesions and mucositis. Laboratory investigations confirmed mycoplasma pneumonia infection via particle agglutination antibody titre of 1:640. A diagnosis of SJS secondary to mycoplasma pneumonia was made. A DPT to exclude a cefuroxime hypersensitivity was performed and this was negative. Ceftriaxone drug challenge was not performed.
The only case of anaphylaxis was in a 10-year-old who presented with symptoms of acute angioedema, rhinorrhoea, breathlessness, and wheeze after simultaneous ingestion of amoxicillin-clavulanate (AX-CLV), ibuprofen, and chlorpheniramine. The patient had a background of Angelman syndrome, asthma, and allergic rhinitis. At age 11 years, he experienced facial angioedema and urticaria after paracetamol ingestion. Diagnostic evaluation revealed negative SPT to standard BL panel, negative AX-CLV DPT, negative paracetamol DPT, and positive ibuprofen DPT.
A 9-year-old boy, with a background of Fanconi's anaemia requiring bone marrow transplantation, was referred to the allergy service for the immediate reaction of angioedema and urticaria related to intravenous cefepime, administered for treatment of a central line infection. His SPT was negative to cefepime. Cefepime (2 mg/mL) IDT returned positive thus confirming immediate drug hypersensitivity. DPT to alternative cephalosporin of cefuroxime was negative.
DISCUSSION
This is the first report describing the diagnostic outcomes of suspected BL hypersensitivity in Singaporean children. In our study, 93% of diagnostic BL DPTs are negative. Results are concordant with adult data from Singapore [20] and large childhood studies from Europe [67], Canada [22], and Turkey [2]. Delayed-onset rashes are frequently observed in children treated with BL with subsequent labelling as drug hypersensitivity [23]. Vyles et al. [24] conducted a paediatric Emergency Department survey of 500 children with reported penicillin drug hypersensitivity and concluded that 76% had low-risk symptoms that were unlikely to be consistent with true allergy. We describe a similar trend in Singapore. In our study, suspicion of BL hypersensitivity occurred at a young median age of 2 years, with mild mucocutaneous involvement, and often upon the first encounter with BL. The baseline atopy background of our cohort seemed higher than the general population, with 60% of them having rhinitis, 18% having recurrent or chronic urticaria, likely due to the fact that this is a cohort derived from a tertiary allergy outpatient unit. Whilst a proportion of the cohort presented to the unit with a main concern of drug allergy, many of them were being followed up for other atopic conditions, noted with a label of drug allergy and opportunistically worked up after.
In 92% of our diagnostic penicillin challenges and 100% of cephalosporin challenges, the negative DPT allowed us to “de-label” the suspected antibiotic allergy. A recent systematic review published on the cost of self-reported penicillin allergy estimated a total inpatient cost savings of 1,145–4,254 United States dollar compared to a patient with no reported allergy [25]. Patients with self-reported penicillin allergies are more likely to receive fluoroquinolones, clindamycin, and vancomycin and are more likely to carry Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus [26]. Given that the majority of studied DPTs yielded a negative result, it is clear that all patients with suspected BL hypersensitivity should be referred for diagnostic evaluation.
In 2016, the ENDA/EAACI paediatric task force recommended a general algorithm for the evaluation of drug allergy in children [12]. In children with immediate reactions, the group recommended SPT and immediate reading of IDT prior to diagnostic provocation. The same group also published standards for non-irritant concentrations in skin tests [21]. Interestingly, none of our 18 children who underwent SPT with high concentration reagents experienced irritant effects or positive results.
Mill et al. [27] performed direct DPT to a group of 818 children with suspected amoxicillin allergy, of whom almost 100 reported suspected immediate reactions. In the 17 children with proven immediate allergy upon oral provocation, only 1 patient had a positive SPT and IDT giving a low sensitivity of 6%, albeit with testing to a limited panel of benzylpenicillin and benzylpenicilloyl polylysine reagent. Hence selective amoxicillin allergy could have been missed if SPT and IDT were not performed with amoxicillin. In children with delayed reactions, investigative modalities include patch tests and delayed reading of IDT [14]. Atanaskovic-Markovic et al. [6] reported that when performing IDT in over 1,000 children with suspected delayed BL hypersensitivity, 5.5% had positive delayed IDT readings and thus avoided oral challenge. The IDT is painful and often not well tolerated in young children. In Asia, there may be limited resources to perform delayed IDT reading and patch testing given the requirement for trained personnel, additional clinic visits, and healthcare costs. The EAACI and British Society for Allergy and Clinical Immunology suggest performing oral provocation in children with mild delayed skin reactions without prior skin testing [1213]. In 2015, Vezir et al. [28] proved that this approach was safe by conducting direct oral provocation in 119 children with mild delayed BL allergy. In the 4 patients (3%) who experienced drug reactions, they developed an urticarial rash that was not severe. In 2017, Moral and Caubet [29] wrote about the possibility of direct DPT in children with nonsevere immediate and delayed BL reactions and used the rostrum to call for large multicentric studies to provide strong evidence to change current skin tests guidelines. In our cohort, patients with delayed suspected reactions underwent direct DPT. We performed 26 SPTs for patients with immediate suspected reactions, and all SPTs returned negative. We performed IDT for the single patient with a suspected reaction to the parenteral drug of cefepime without an oral equivalent. In this patient, the positive IDT together with a clinical presentation consistent with an immediate hypersensitivity reaction confirmed the diagnosis and allowed the patient to avoid a high-risk DPT. The rest of our patients with negative SPT results proceeded to DPT, during which 1 patient experienced a mild reaction and 24 had negative DPT.
Similar to Vyles et al. [30], we performed single-dose oral challenge with a good safety profile. Patients with proven BL hypersensitivity had mild reactions of urticaria, angioedema, and macular exanthem within 2 days of oral challenge. Our study supports the opinion that prior skin tests may not be necessary for the evaluation of children who report nonsevere reactions and the direct oral challenge is a safe procedure. However, for patients with history of BL anaphylaxis, we would still recommend SPT and IDT to confirm the diagnosis, identify possible alternatives, followed by DPT to BL with negative skin test results, to confirm safe alternatives. The strength of our study is that this is the first report of challenge proven outcomes in the evaluation of suspected BL hypersensitivity in Singaporean children. This fills an important gap in the currently available local literature. A limitation of our study is the retrospective design. It would have been ideal to evaluate selective clavulanic hypersensitivity in our patients with proven amoxicillin-clavulanate reactions as well as determine cephalosporin tolerance in our patients with proven amoxicillin allergy. However, most parents declined a subsequent DPT.
In conclusion, given rising concerns of antibiotic resistance, it is important that unnecessary use of broad-spectrum antibiotics be avoided. The majority of children with suspected BL hypersensitivity do not react upon oral challenge. Skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.
ACKNOWLEDGEMENTS
The authors would like to thank Nurse Lim Hwee Hoon, Nurse Ding Xiao Mei, and the SPT laboratory technicians for their contributions to patient care and clinical research.
Conflict of Interest: The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization: Si Hui Goh, Wenyin Loh.
Formal analysis: Si Hui Goh, Kok Wee Chong.
Investigation: Si Hui Goh, Kok Wee Chong, Wen Chin Chiang, Anne Goh, Wenyin Loh.
Methodology: Si Hui Goh, Wenyin Loh.
Project administration: Wenyin Loh.
Writing - original draft: Si Hui Goh, Kok Wee Chong.
Writing - review & editing: Wen Chin Chiang, Anne Goh, Wenyin Loh. | Recovered | ReactionOutcome | CC BY-NC | 33604273 | 18,987,981 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adrenocortical insufficiency acute'. | Yttrium-90 radioembolization of isolated hepatic adrenocortical carcinoma metastases with negative surgical pathology.
BACKGROUND
Adrenocortical carcinoma (ACC) is an uncommon malignancy with an estimated 15,400 new cases annually across the globe. The prognosis is generally poor as the disease is often already advanced at initial diagnosis due to non-specific symptoms. Even for local disease, recurrence after surgical resection is high. Treatment choices for advanced disease include mitotane, chemotherapy, ablation, chemoembolization, radioembolization, and external beam radiotherapy, with varying degrees of efficacy. To the best of our knowledge, there have only been two prior case studies of complete clinical and radiological response of stage 4 disease at 1 year and 2 years after yttrium-90 (90Y) microsphere selective internal radiation therapy (SIRT) of isolated hepatic metastases post-surgery and chemotherapy.
METHODS
We present a case of a 58-year-old man with metastatic ACC who was treated with 90Y resin microsphere (SIR-spheres) for local control of liver metastases leading to a surgically proven negative pathology after partial hepatectomy 7 months after SIRT. The patient was initially diagnosed with stage 1 ACC that progressed 6 years later to stage 4 disease with new liver metastases that were deemed unresectable at an outside institution. After review of the case at multidisciplinary tumor board, he was referred for liver directed therapy for local tumor control. Angiographic workup demonstrated partial extrahepatic supply to the tumors from the right inferior phrenic artery, which was successfully embolized on the day of SIRT for flow redistribution. As the patient was being treated with mitotane that suppresses steroid production, he developed post-SIRT adrenal crisis, which was successfully controlled with steroids, highlighting the need for pre SIRT stress dose steroids.
CONCLUSIONS
This case continues to add to the literature supporting 90Y radioembolization as an effective treatment for isolated hepatic ACC metastases. Our case is the first to demonstrate surgically proven negative pathology after radioembolization. Further prospective study is warranted to better establish efficacy as well as safety of SIRT for ACC liver metastases.
Background
Adrenocortical carcinoma (ACC) affects an estimated 0.5 – 2 new cases per million people annually, with a median survival of less than one year for stage 4 disease [1–3]. Overall, the median 5-year survival is 16–44% [4]. The prognosis is considerably better for stage 1 with a 5-year survival of 60%, compared to 0% for stage 4 [1, 2]. However, 70% of patients are initially diagnosed with stage 3 or 4 due to non-specific presentations, most commonly of excess hormone secretion (especially hypercortisolism or Cushing syndrome) or symptoms secondary to mass effect (e.g., abdominal or back pain, nausea, or vomiting) [1, 3]. Treatment of local disease involves surgical resection, but this is infrequently curative, with an 80% recurrence rate even after complete resection [1, 2]. Radiofrequency ablation has demonstrated some success for primary unresectable ACC < 5 cm [1, 5, 6]. Transcatheter arterial chemoembolization (TACE) has been reported with favorable outcomes for isolated hepatic metastatic lesions < 3 cm [1, 7]. To date, there has only been two case reports demonstrating efficacy of 90Y radioembolization for hepatic ACC metastases by follow-up imaging [2, 4]. Three additional cases of 90Y SIRT from a single institution demonstrated prolonged overall survival in patients with hepatic ACC metastases when analyzed in combination with 2 cases of liver-directed therapy treated with TACE [8]. We present a case of successful treatment of isolated hepatic adrenocortical carcinoma metastases, with the benefit of definitive negative surgical pathology after 90Y radioembolization.
Case presentation
A 58-year-old male with no significant past medical history presented to an outside institution with vague fatigue and left upper quadrant pain. A CT scan revealed a 15 ×9 × 9 cm left retroperitoneal mass as well as a 3 cm gastric tumor (Fig. 1). Biopsy of the retroperitoneal mass was consistent with adrenocortical carcinoma. He underwent a left adrenalectomy and partial gastrectomy with pathology confirming ACC and a gastrointestinal stromal tumor (GIST) of the stomach. He then began mitotane, an adrenolytic, for 2.5 years and adjuvant radiation to the adrenal bed.Fig. 1 Incidental left adrenal mass. a Non-contrast CT chest demonstrated a large, heterogeneous left suprarenal mass (asterisk), and a 3 cm gastric nodule (arrow). b Contrast-enhanced CT demonstrated a predominantly necrotic 13.8 × 9.8 × 9.4 cm left suprarenal mass with scattered areas of enhancement and central low-attenuation, with subsequent pathology demonstrating adrenocortical carcinoma
His surveillance was performed at outside institutions, and his scans remained negative for the following 4 years. A follow-up surveillance CT scan done 6 years after diagnosis revealed a 9.5 × 8.7 cm right hepatic mass. This was followed with an MRI at that time that confirmed the presence of suspicious liver metastases (Fig. 2). Right hepatectomy was attempted at an outside institution but aborted due to the suspected presence of “miliary disease” based on the surgeon’s visualization of small plaque-like lesions on the liver surface. Therefore, only a segment 5 hepatic nodule was resected for permanent section and genetic sequencing and a cholecystectomy was performed. Review of the patient’s available images from that time showed no left hepatic lobe lesions visible on imaging. Per the outside surgery report, the patient did receive an [18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) in addition to the MRI prior to surgery, which showed no extrahepatic disease (images not available).Fig. 2 Metastatic adrenocortical carcinoma. a Six years after initial diagnosis, a surveillance non-contrast CT showed a lobulated, hypodense 9.5 × 8.7 cm hepatic segment 5/6 mass. b Contrast-enhanced CT showed peripheral enhancement with central necrosis, suspicious for metastases. c 3-min post-Eovist (Bayer, New Jersey, USA) T1-weighted fat-suppressed MRI showed multiple ring-enhancing right inferior hepatic lesions. d One month after attempted surgical resection, delayed post-Eovist T1-weighted fat-suppressed MRI showed enlarging right inferior hepatic masses
After discussion of the case at our multidisciplinary tumor board, the decision was made for systemic therapy as well as liver directed therapy. The patient started an EDP chemotherapy schedule (etoposide, doxorubicin, and cisplatin). He then underwent visceral angiogram workup which demonstrated collateral supply to a portion of the right hepatic lobe tumors by right inferior phrenic artery branch (Fig. 3). A hepatopulmonary shunt of 3% was observed on planar scintigraphy and single-photon emission computed tomography (SPECT) (Fig. 4) after administration of 214.6 MBq [99mTc]technetium-macroaggregated albumin ([99mTc]Tc-MAA, Drax Image MAA kit; 99.7% purity) into the right hepatic artery. The hepatic volumes were manually calculated using the native basic segmentation tool from General Electric’s Picture Archiving and Communication Systems: total 2084 cm3, volume of liver to be treated 1537 cm3, and volume of tumor in the region 654 cm3. As there is paucity of data on what is the most appropriate dose to deliver to these tumors, a modified BSA model calculated the required activity at 1.8 GBq using an estimated lung mass of 1 kg. However, since these tumors can be radioresistant, we decided to increase the activity to 2 GBq. This would have given an estimated dose of 105 Gy to the tumor by partition model using a T/N ratio of 4, 26 Gy to the normal liver, and 3 Gy to the lungs.Fig. 3 Angiographic workup for radioembolization. Hepatic arteriography demonstrated multiple hypervascular tumors supplied predominantly from right hepatic artery branches (a) and to a lesser extent by a branch of the right inferior phrenic artery (b). Post-surgical clips from prior attempted resection are seen in the inferior right hepatic lobe, which correlated to segment 5 on cross-sectional imaging
Fig. 4 Axial images from pre 90Y 3D CT angiogram. a Intraprocedural selective arterial-phase contrast-enhanced CT of the right hepatic artery obtained during workup arteriography demonstrates hyperenhancing tumors with b hypoenhancing lesions along the posterior inferior liver, thought to be metastases supplied by branches of the right inferior phrenic artery. c SPECT/CT images after administration of [99mTc]Tc-MAA into the right hepatic artery demonstrates intense activity within the majority of tumors in the inferior right hepatic lobe with photopenic peripheral areas that correlate to the hypoenhancing areas seen on 3D CT angiogram. d SPECT/CT images also demonstrate an area of intense focal activity along the posterior surface of hepatic segment VII (arrow), representing subserosal liver metastasis which may correspond to the plaque-like lesions seen during aborted initial surgery
On the procedure day, the patient first underwent bland embolization of the inferior branch of the right inferior phrenic artery using 900 µm Embosphere microspheres (Merit, Utah, USA) to cause redistribution of flow into the tumors along the surface of the right hepatic lobe from the right hepatic artery (Fig. 5). Subsequent 90Y SIR-sphere (Sirtex Medical Inc., Massachusetts, USA) resin embolization of the right hepatic artery was performed (Fig. 6) with a total administered activity to the perfused volume of 2.11 GBq. The patient developed post-procedure adrenal crisis in the recovery room manifested by abdominal pain and diaphoresis, and was treated with 20 mg of dexamethasone followed by 60 mg intravenous hydrocortisone every 6 h. After admission and steroid therapy, he was then discharged in stable condition on post-procedure day 3.Fig. 5 Right inferior phrenic artery. a The inferior branch of the right inferior phrenic artery was superselected, demonstrating tumor blush in the inferior right hepatic lobe. b Post-bland embolization of the inferior branch of the right inferior phrenic artery demonstrated stasis with persistent flow to the remaining branches of the right inferior phrenic artery. c, d Intraprocedural selective 3D contrast-enhanced CT angiogram of the inferior branch of the right inferior phrenic artery demonstrated enhancement of hepatic lesions along the posterior periphery of the right hepatic lobe
Fig. 6 Pre-SIRT redistribution of flow. a Right hepatic artery arteriogram demonstrates the embolized inferior branch of the right phrenic artery, compatible with embolic material (arrows). b, c Intraprocedural selective 3D arterial-phase contrast-enhanced CT of the right hepatic artery demonstrates enhancement of the right hepatic lesions with perfusion of the tumors from the right hepatic artery instead of the right inferior phrenic artery branch that was bland embolized
The patient’s 1-month follow-up MRI showed decrease in the size of the multiple right hepatic metastatic lesions including the small lesions on the liver surface with no new sites of disease. Specifically, no lesions were seen in the left hepatic lobe. 3-month post-radioembolization [18F]FDG PET/CT showed no residual or recurrent disease (Fig. 7). Four- and 5-month post-radioembolization MRI showed continued decrease in size and enhancement of the right hepatic lesions (Fig. 8). Despite the reassuring imaging findings, the patient requested surgical resection of the right hepatic lesions as the data is sparse on the effect of SIRT on ACC hepatic metastases. In conjunction with the multidisciplinary tumor board, surgery was deemed reasonable as the disease was limited to the right hepatic lobe and no miliary disease was seen on imaging. Hence, 7 months after radioembolization, he had partial right hepatectomy at an outside institution with pathology demonstrating no viable tumor including in the resection margin. One-month post-resection MRI showed no residual hepatic lesions (Fig. 9). The patient was in observation and surveillance with regular lab work for adrenal insufficiency, including renin, dehydroepiandrosterone sulfate, and adrenocorticotropic hormone. He declined adjuvant mitotane due to quality-of-life concerns and previous side effects. An incidental periportal lymph node measuring 1-cm short axis was found on CT chest 8 months post-resection (15 months post-radioembolization), which was subsequently found to be metastatic ACC on surgical pathology. Although he developed metastatic periportal lymphadenopathy, the patient is currently 16 months post-surgical resection and 23 months post-radioembolization with no hepatic recurrence.Fig. 7 Post-radioembolization response. a, b 1-month post-radioembolization arterial phase post-Eovist T1-weighted fat-suppressed MRI shows decreased size of right hepatic lesions with no abnormal enhancement. c, d 3-month post-radioembolization PET/CT with [18F]FDG showed no residual activity in the right inferior hepatic tumor bed
Fig. 8 Continued post-radioembolization response. a, b Portal venous phase post-Eovist T1-weighted fat-suppressed MRI taken at 4 months and c, d 5 months post-radioembolization shows continued decrease in size of inferior right hepatic lesions
Fig. 9 No recurrent disease on MRI 1-month post-partial right hepatectomy. a Axial and b coronal portal venous phase post-Eovist T1-weighted MRI images demonstrate blooming artifact from surgical clips in the right hepatic resection margin. Pathology did not demonstrate any viable tumor
Conclusions
The goal of local treatment for ACC is curative, but this is only achieved 20% of the time. Local control with radiofrequency ablation for unresectable tumors or poor surgical candidates has been demonstrated, although progression of metastatic disease is high with 11 out of 13 patients demonstrating recurrence in one study [5]. Options for systemic treatment of advanced ACC have been with an EDP-M schedule (etoposide, doxorubicin, and cisplatin plus mitotane) or a M-S schedule (mitotane plus streptozosin) [9]. These regimens have comparable overall survival (14.8 vs 12 months), but EDP-M has been favored due to improved response rates and progression-free survival (5 vs 2.1 months) [2, 10]. Non-invasive radiation therapy has demonstrated no survival benefit and no reduction in the risk of metastasis [11]. Locoregional radiation therapy and surgical debulking or resection of recurrence has traditionally been palliative in nature. TACE has been reported with favorable outcomes for isolated hepatic metastatic lesions < 3 cm or > 50% lipiodol uptake, with progression in only 5 out of 29 patients (17%) [1, 7].
To the best of our knowledge, ours is the 6th known case for hepatic ACC metastases successfully treated with 90Y radioembolization in combination with chemotherapy, and the 3rd case report of complete clinical and radiological response of isolated hepatic metastases after chemotherapy and surgical resection/debulking of the primary lesion. Ours is, however, the 1st case that demonstrates post-radioembolization pathologic correlation showing no residual viable carcinoma upon resection at 7 months post-radioembolization. Our case also demonstrated that bland embolization of the right inferior phrenic artery that was feeding a portion of the metastatic tumor was an effective strategy for flow redistribution just prior to radioembolization of the right hepatic artery. The metastatic disease burden in our case was limited to the right hepatic lobe, and only one radioembolization procedure was necessary. Two prior cases demonstrated 12-month and 24-month radiologic and clinical response, respectively, and had bilobar disease thus requiring two separate 90Y radioembolizations [2, 4].
Compared to TACE, which requires patients to be admitted, 90Y radioembolization can be performed on an outpatient basis and is more cost-effective. Our case also provides a reminder that close attention should be paid to the clinical status of the patient in the intraprocedural or immediate post-procedure period for signs of adrenal crisis (hypotension, nausea, vomiting, abdominal pain, weakness, fatigue, lethargy, fever, confusion, or coma). Management of adrenal crisis includes volume repletion with normal saline (with or without 5% dextrose) and pre-emptive perioperative IV hydrocortisone. Due to the acuity and severity of the condition, treatment should not be delayed by diagnostic tests.
This case continues to add to the literature supporting 90Y radioembolization as an effective treatment for isolated hepatic ACC metastases. Our case demonstrates complete surgical pathology-proven response 7 months post-radioembolization. In addition, we utilized bland embolization to successfully redistribute flow from a feeding right inferior phrenic artery to the right hepatic artery for effective radioembolization. Our patient unfortunately developed metastatic lymphadenopathy in periportal lymph nodes first detected at 15 months post-radioembolization, but remains disease free in the liver. Further prospective study is warranted to better establish efficacy, as well as safety of SIRT for ACC liver metastases.
Abbreviations
[18F]FDG[18F]Fluoro-2-deoxy-D-glucose
[99mTc]Tc-MAA[99MTc]technetium-macroaggregated albumin
90YYttrium-90
ACCAdrenocortical carcinoma
cmCentimeter
EDPEtoposide, doxorubicin, and cisplatin
GBqGigabecquerel
GISTGastrointestinal stromal tumor
MBqMegabecquerel
mgMilligram
PET/CTPositron emission tomography/computed tomography
PLTPlatelet
SIRTSelective internal radiation therapy
SPECTSingle-photon emission computed tomography
TACETranscatheter arterial chemoembolization
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Acknowledgements
We thank the Columbia University Department of Pathology for providing pathology slides.
Authors' information
SL is a PGY-4 diagnostic and interventional radiology resident at the University of South Florida. JD is an attending pathologist at Moffitt Cancer Center. JHJ is an attending endocrinologist at Moffitt Cancer Center. GE is an attending interventional radiologist at Moffitt Cancer Center.
Authors’ contributions
SL was a major contributor in writing the manuscript. JD performed the histological examination of the pathology specimens, and was an editor of the manuscript. JHJ was the primary provider for the patient when his care transferred to Moffitt Cancer Center, and was an editor for the manuscript. GE performed the procedures in the case and followed the patient in clinic, and was the main editor of the manuscript. All authors read and approved the final manuscript.
Funding
No special funding was provided for this paper.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Need for ethics approval was waived given the nature of the retrospective study involving a single anonymized case. Consent was obtained to obtain patient’s outside records by the patient.
Consent for publication
Consent to publish was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | MITOTANE | DrugsGivenReaction | CC BY | 33604708 | 20,461,114 | 2021-02-18 |
What was the outcome of reaction 'Adrenocortical insufficiency acute'? | Yttrium-90 radioembolization of isolated hepatic adrenocortical carcinoma metastases with negative surgical pathology.
BACKGROUND
Adrenocortical carcinoma (ACC) is an uncommon malignancy with an estimated 15,400 new cases annually across the globe. The prognosis is generally poor as the disease is often already advanced at initial diagnosis due to non-specific symptoms. Even for local disease, recurrence after surgical resection is high. Treatment choices for advanced disease include mitotane, chemotherapy, ablation, chemoembolization, radioembolization, and external beam radiotherapy, with varying degrees of efficacy. To the best of our knowledge, there have only been two prior case studies of complete clinical and radiological response of stage 4 disease at 1 year and 2 years after yttrium-90 (90Y) microsphere selective internal radiation therapy (SIRT) of isolated hepatic metastases post-surgery and chemotherapy.
METHODS
We present a case of a 58-year-old man with metastatic ACC who was treated with 90Y resin microsphere (SIR-spheres) for local control of liver metastases leading to a surgically proven negative pathology after partial hepatectomy 7 months after SIRT. The patient was initially diagnosed with stage 1 ACC that progressed 6 years later to stage 4 disease with new liver metastases that were deemed unresectable at an outside institution. After review of the case at multidisciplinary tumor board, he was referred for liver directed therapy for local tumor control. Angiographic workup demonstrated partial extrahepatic supply to the tumors from the right inferior phrenic artery, which was successfully embolized on the day of SIRT for flow redistribution. As the patient was being treated with mitotane that suppresses steroid production, he developed post-SIRT adrenal crisis, which was successfully controlled with steroids, highlighting the need for pre SIRT stress dose steroids.
CONCLUSIONS
This case continues to add to the literature supporting 90Y radioembolization as an effective treatment for isolated hepatic ACC metastases. Our case is the first to demonstrate surgically proven negative pathology after radioembolization. Further prospective study is warranted to better establish efficacy as well as safety of SIRT for ACC liver metastases.
Background
Adrenocortical carcinoma (ACC) affects an estimated 0.5 – 2 new cases per million people annually, with a median survival of less than one year for stage 4 disease [1–3]. Overall, the median 5-year survival is 16–44% [4]. The prognosis is considerably better for stage 1 with a 5-year survival of 60%, compared to 0% for stage 4 [1, 2]. However, 70% of patients are initially diagnosed with stage 3 or 4 due to non-specific presentations, most commonly of excess hormone secretion (especially hypercortisolism or Cushing syndrome) or symptoms secondary to mass effect (e.g., abdominal or back pain, nausea, or vomiting) [1, 3]. Treatment of local disease involves surgical resection, but this is infrequently curative, with an 80% recurrence rate even after complete resection [1, 2]. Radiofrequency ablation has demonstrated some success for primary unresectable ACC < 5 cm [1, 5, 6]. Transcatheter arterial chemoembolization (TACE) has been reported with favorable outcomes for isolated hepatic metastatic lesions < 3 cm [1, 7]. To date, there has only been two case reports demonstrating efficacy of 90Y radioembolization for hepatic ACC metastases by follow-up imaging [2, 4]. Three additional cases of 90Y SIRT from a single institution demonstrated prolonged overall survival in patients with hepatic ACC metastases when analyzed in combination with 2 cases of liver-directed therapy treated with TACE [8]. We present a case of successful treatment of isolated hepatic adrenocortical carcinoma metastases, with the benefit of definitive negative surgical pathology after 90Y radioembolization.
Case presentation
A 58-year-old male with no significant past medical history presented to an outside institution with vague fatigue and left upper quadrant pain. A CT scan revealed a 15 ×9 × 9 cm left retroperitoneal mass as well as a 3 cm gastric tumor (Fig. 1). Biopsy of the retroperitoneal mass was consistent with adrenocortical carcinoma. He underwent a left adrenalectomy and partial gastrectomy with pathology confirming ACC and a gastrointestinal stromal tumor (GIST) of the stomach. He then began mitotane, an adrenolytic, for 2.5 years and adjuvant radiation to the adrenal bed.Fig. 1 Incidental left adrenal mass. a Non-contrast CT chest demonstrated a large, heterogeneous left suprarenal mass (asterisk), and a 3 cm gastric nodule (arrow). b Contrast-enhanced CT demonstrated a predominantly necrotic 13.8 × 9.8 × 9.4 cm left suprarenal mass with scattered areas of enhancement and central low-attenuation, with subsequent pathology demonstrating adrenocortical carcinoma
His surveillance was performed at outside institutions, and his scans remained negative for the following 4 years. A follow-up surveillance CT scan done 6 years after diagnosis revealed a 9.5 × 8.7 cm right hepatic mass. This was followed with an MRI at that time that confirmed the presence of suspicious liver metastases (Fig. 2). Right hepatectomy was attempted at an outside institution but aborted due to the suspected presence of “miliary disease” based on the surgeon’s visualization of small plaque-like lesions on the liver surface. Therefore, only a segment 5 hepatic nodule was resected for permanent section and genetic sequencing and a cholecystectomy was performed. Review of the patient’s available images from that time showed no left hepatic lobe lesions visible on imaging. Per the outside surgery report, the patient did receive an [18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) in addition to the MRI prior to surgery, which showed no extrahepatic disease (images not available).Fig. 2 Metastatic adrenocortical carcinoma. a Six years after initial diagnosis, a surveillance non-contrast CT showed a lobulated, hypodense 9.5 × 8.7 cm hepatic segment 5/6 mass. b Contrast-enhanced CT showed peripheral enhancement with central necrosis, suspicious for metastases. c 3-min post-Eovist (Bayer, New Jersey, USA) T1-weighted fat-suppressed MRI showed multiple ring-enhancing right inferior hepatic lesions. d One month after attempted surgical resection, delayed post-Eovist T1-weighted fat-suppressed MRI showed enlarging right inferior hepatic masses
After discussion of the case at our multidisciplinary tumor board, the decision was made for systemic therapy as well as liver directed therapy. The patient started an EDP chemotherapy schedule (etoposide, doxorubicin, and cisplatin). He then underwent visceral angiogram workup which demonstrated collateral supply to a portion of the right hepatic lobe tumors by right inferior phrenic artery branch (Fig. 3). A hepatopulmonary shunt of 3% was observed on planar scintigraphy and single-photon emission computed tomography (SPECT) (Fig. 4) after administration of 214.6 MBq [99mTc]technetium-macroaggregated albumin ([99mTc]Tc-MAA, Drax Image MAA kit; 99.7% purity) into the right hepatic artery. The hepatic volumes were manually calculated using the native basic segmentation tool from General Electric’s Picture Archiving and Communication Systems: total 2084 cm3, volume of liver to be treated 1537 cm3, and volume of tumor in the region 654 cm3. As there is paucity of data on what is the most appropriate dose to deliver to these tumors, a modified BSA model calculated the required activity at 1.8 GBq using an estimated lung mass of 1 kg. However, since these tumors can be radioresistant, we decided to increase the activity to 2 GBq. This would have given an estimated dose of 105 Gy to the tumor by partition model using a T/N ratio of 4, 26 Gy to the normal liver, and 3 Gy to the lungs.Fig. 3 Angiographic workup for radioembolization. Hepatic arteriography demonstrated multiple hypervascular tumors supplied predominantly from right hepatic artery branches (a) and to a lesser extent by a branch of the right inferior phrenic artery (b). Post-surgical clips from prior attempted resection are seen in the inferior right hepatic lobe, which correlated to segment 5 on cross-sectional imaging
Fig. 4 Axial images from pre 90Y 3D CT angiogram. a Intraprocedural selective arterial-phase contrast-enhanced CT of the right hepatic artery obtained during workup arteriography demonstrates hyperenhancing tumors with b hypoenhancing lesions along the posterior inferior liver, thought to be metastases supplied by branches of the right inferior phrenic artery. c SPECT/CT images after administration of [99mTc]Tc-MAA into the right hepatic artery demonstrates intense activity within the majority of tumors in the inferior right hepatic lobe with photopenic peripheral areas that correlate to the hypoenhancing areas seen on 3D CT angiogram. d SPECT/CT images also demonstrate an area of intense focal activity along the posterior surface of hepatic segment VII (arrow), representing subserosal liver metastasis which may correspond to the plaque-like lesions seen during aborted initial surgery
On the procedure day, the patient first underwent bland embolization of the inferior branch of the right inferior phrenic artery using 900 µm Embosphere microspheres (Merit, Utah, USA) to cause redistribution of flow into the tumors along the surface of the right hepatic lobe from the right hepatic artery (Fig. 5). Subsequent 90Y SIR-sphere (Sirtex Medical Inc., Massachusetts, USA) resin embolization of the right hepatic artery was performed (Fig. 6) with a total administered activity to the perfused volume of 2.11 GBq. The patient developed post-procedure adrenal crisis in the recovery room manifested by abdominal pain and diaphoresis, and was treated with 20 mg of dexamethasone followed by 60 mg intravenous hydrocortisone every 6 h. After admission and steroid therapy, he was then discharged in stable condition on post-procedure day 3.Fig. 5 Right inferior phrenic artery. a The inferior branch of the right inferior phrenic artery was superselected, demonstrating tumor blush in the inferior right hepatic lobe. b Post-bland embolization of the inferior branch of the right inferior phrenic artery demonstrated stasis with persistent flow to the remaining branches of the right inferior phrenic artery. c, d Intraprocedural selective 3D contrast-enhanced CT angiogram of the inferior branch of the right inferior phrenic artery demonstrated enhancement of hepatic lesions along the posterior periphery of the right hepatic lobe
Fig. 6 Pre-SIRT redistribution of flow. a Right hepatic artery arteriogram demonstrates the embolized inferior branch of the right phrenic artery, compatible with embolic material (arrows). b, c Intraprocedural selective 3D arterial-phase contrast-enhanced CT of the right hepatic artery demonstrates enhancement of the right hepatic lesions with perfusion of the tumors from the right hepatic artery instead of the right inferior phrenic artery branch that was bland embolized
The patient’s 1-month follow-up MRI showed decrease in the size of the multiple right hepatic metastatic lesions including the small lesions on the liver surface with no new sites of disease. Specifically, no lesions were seen in the left hepatic lobe. 3-month post-radioembolization [18F]FDG PET/CT showed no residual or recurrent disease (Fig. 7). Four- and 5-month post-radioembolization MRI showed continued decrease in size and enhancement of the right hepatic lesions (Fig. 8). Despite the reassuring imaging findings, the patient requested surgical resection of the right hepatic lesions as the data is sparse on the effect of SIRT on ACC hepatic metastases. In conjunction with the multidisciplinary tumor board, surgery was deemed reasonable as the disease was limited to the right hepatic lobe and no miliary disease was seen on imaging. Hence, 7 months after radioembolization, he had partial right hepatectomy at an outside institution with pathology demonstrating no viable tumor including in the resection margin. One-month post-resection MRI showed no residual hepatic lesions (Fig. 9). The patient was in observation and surveillance with regular lab work for adrenal insufficiency, including renin, dehydroepiandrosterone sulfate, and adrenocorticotropic hormone. He declined adjuvant mitotane due to quality-of-life concerns and previous side effects. An incidental periportal lymph node measuring 1-cm short axis was found on CT chest 8 months post-resection (15 months post-radioembolization), which was subsequently found to be metastatic ACC on surgical pathology. Although he developed metastatic periportal lymphadenopathy, the patient is currently 16 months post-surgical resection and 23 months post-radioembolization with no hepatic recurrence.Fig. 7 Post-radioembolization response. a, b 1-month post-radioembolization arterial phase post-Eovist T1-weighted fat-suppressed MRI shows decreased size of right hepatic lesions with no abnormal enhancement. c, d 3-month post-radioembolization PET/CT with [18F]FDG showed no residual activity in the right inferior hepatic tumor bed
Fig. 8 Continued post-radioembolization response. a, b Portal venous phase post-Eovist T1-weighted fat-suppressed MRI taken at 4 months and c, d 5 months post-radioembolization shows continued decrease in size of inferior right hepatic lesions
Fig. 9 No recurrent disease on MRI 1-month post-partial right hepatectomy. a Axial and b coronal portal venous phase post-Eovist T1-weighted MRI images demonstrate blooming artifact from surgical clips in the right hepatic resection margin. Pathology did not demonstrate any viable tumor
Conclusions
The goal of local treatment for ACC is curative, but this is only achieved 20% of the time. Local control with radiofrequency ablation for unresectable tumors or poor surgical candidates has been demonstrated, although progression of metastatic disease is high with 11 out of 13 patients demonstrating recurrence in one study [5]. Options for systemic treatment of advanced ACC have been with an EDP-M schedule (etoposide, doxorubicin, and cisplatin plus mitotane) or a M-S schedule (mitotane plus streptozosin) [9]. These regimens have comparable overall survival (14.8 vs 12 months), but EDP-M has been favored due to improved response rates and progression-free survival (5 vs 2.1 months) [2, 10]. Non-invasive radiation therapy has demonstrated no survival benefit and no reduction in the risk of metastasis [11]. Locoregional radiation therapy and surgical debulking or resection of recurrence has traditionally been palliative in nature. TACE has been reported with favorable outcomes for isolated hepatic metastatic lesions < 3 cm or > 50% lipiodol uptake, with progression in only 5 out of 29 patients (17%) [1, 7].
To the best of our knowledge, ours is the 6th known case for hepatic ACC metastases successfully treated with 90Y radioembolization in combination with chemotherapy, and the 3rd case report of complete clinical and radiological response of isolated hepatic metastases after chemotherapy and surgical resection/debulking of the primary lesion. Ours is, however, the 1st case that demonstrates post-radioembolization pathologic correlation showing no residual viable carcinoma upon resection at 7 months post-radioembolization. Our case also demonstrated that bland embolization of the right inferior phrenic artery that was feeding a portion of the metastatic tumor was an effective strategy for flow redistribution just prior to radioembolization of the right hepatic artery. The metastatic disease burden in our case was limited to the right hepatic lobe, and only one radioembolization procedure was necessary. Two prior cases demonstrated 12-month and 24-month radiologic and clinical response, respectively, and had bilobar disease thus requiring two separate 90Y radioembolizations [2, 4].
Compared to TACE, which requires patients to be admitted, 90Y radioembolization can be performed on an outpatient basis and is more cost-effective. Our case also provides a reminder that close attention should be paid to the clinical status of the patient in the intraprocedural or immediate post-procedure period for signs of adrenal crisis (hypotension, nausea, vomiting, abdominal pain, weakness, fatigue, lethargy, fever, confusion, or coma). Management of adrenal crisis includes volume repletion with normal saline (with or without 5% dextrose) and pre-emptive perioperative IV hydrocortisone. Due to the acuity and severity of the condition, treatment should not be delayed by diagnostic tests.
This case continues to add to the literature supporting 90Y radioembolization as an effective treatment for isolated hepatic ACC metastases. Our case demonstrates complete surgical pathology-proven response 7 months post-radioembolization. In addition, we utilized bland embolization to successfully redistribute flow from a feeding right inferior phrenic artery to the right hepatic artery for effective radioembolization. Our patient unfortunately developed metastatic lymphadenopathy in periportal lymph nodes first detected at 15 months post-radioembolization, but remains disease free in the liver. Further prospective study is warranted to better establish efficacy, as well as safety of SIRT for ACC liver metastases.
Abbreviations
[18F]FDG[18F]Fluoro-2-deoxy-D-glucose
[99mTc]Tc-MAA[99MTc]technetium-macroaggregated albumin
90YYttrium-90
ACCAdrenocortical carcinoma
cmCentimeter
EDPEtoposide, doxorubicin, and cisplatin
GBqGigabecquerel
GISTGastrointestinal stromal tumor
MBqMegabecquerel
mgMilligram
PET/CTPositron emission tomography/computed tomography
PLTPlatelet
SIRTSelective internal radiation therapy
SPECTSingle-photon emission computed tomography
TACETranscatheter arterial chemoembolization
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Acknowledgements
We thank the Columbia University Department of Pathology for providing pathology slides.
Authors' information
SL is a PGY-4 diagnostic and interventional radiology resident at the University of South Florida. JD is an attending pathologist at Moffitt Cancer Center. JHJ is an attending endocrinologist at Moffitt Cancer Center. GE is an attending interventional radiologist at Moffitt Cancer Center.
Authors’ contributions
SL was a major contributor in writing the manuscript. JD performed the histological examination of the pathology specimens, and was an editor of the manuscript. JHJ was the primary provider for the patient when his care transferred to Moffitt Cancer Center, and was an editor for the manuscript. GE performed the procedures in the case and followed the patient in clinic, and was the main editor of the manuscript. All authors read and approved the final manuscript.
Funding
No special funding was provided for this paper.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Need for ethics approval was waived given the nature of the retrospective study involving a single anonymized case. Consent was obtained to obtain patient’s outside records by the patient.
Consent for publication
Consent to publish was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33604708 | 20,461,114 | 2021-02-18 |
What was the dosage of drug 'GEMCITABINE HYDROCHLORIDE'? | Right atrial cardiac angiosarcoma treated with concurrent proton beam therapy and paclitaxel: A novel approach to a rare disease.
Cardiac angiosarcoma is a rare malignancy with an aggressive course and poor prognosis. We present a 26-year old man who came to our clinic with shortness of breath and was diagnosed with a right-sided atrial mass. He underwent urgent resection of the mass. The pathology confirmed the mass to be cardiac angiosarcoma with positive microscopic margins (R1 resection). Since reresection was not feasible, the patient started treatment with concurrent paclitaxel (80 mg/m2 weekly) and proton beam therapy (61 Cobalt equivalent delivered over five weeks). After completing the concurrent chemotherapy and radiation therapy, he was treated with adjuvant chemotherapy using gemcitabine (900 mg/m2 on Days 1 and 8) and docetaxel (100 mg/m2 on Day 8) every three weeks. After three cycles, the patient developed severe dermatitis, and hence further chemotherapy was withheld. The patient is alive at 26 months since receiving his surgery and 18 months since the completion of treatment. Patients with cardiac angiosarcoma who undergo R1 resection have a median survival of six months. More radical approaches such as orthotopic heart-lung transplant or prolonged durations of chemotherapy lead to minimal improvement in survival at the cost of increased morbidity. Here, we describe a novel approach to a rare disease that resulted in prolonged survival and led to a better quality of life without any long-term morbidity to the patient.
INTRODUCTION
Cardiac angiosarcoma (CAS) is an extremely rare tumor for which optimal management is unclear. Although surgical resection remains the mainstay of treatment, multimodality treatment, including chemotherapy and radiation therapy (RT), is often used to treat this aggressive malignancy. However, the median survival remains low for patients with positive microscopic margins (R1 resection) after surgical resection of the tumor. In this report, we present a novel approach of combining proton beam therapy (PBT) with chemotherapy followed by adjuvant chemotherapy, which was used to treat our patient with right‐sided CAS who underwent R1 resection.
CASE REPORT
A 26‐year old man presented to the emergency room with severe shortness of breath and pedal edema worsening over one month. He had no significant past medical or surgical history. He denied any habits or illicit drug use. A two‐dimensional echocardiogram showed a large heteroechoic mass measuring 7 × 3.6 cm attached to the roof of the right atrium and prolapsing across the tricuspid valve in the right ventricle with every beat. This finding was further characterized by cardiac resonance imaging as a large frond‐like mobile mass (8.6 × 3.8 cm) attached to the posterior‐inferior right atrial wall with pericardial extension (Figure 1). The patient underwent urgent surgical resection, and pathology revealed epithelioid angiosarcoma Immunoperoxidase stain showed that neoplastic cells were positive for CD31, CD34, ERG, and negative for D2‐440, HHV‐8, and cytokeratin AE1/AE3. The tumor was 10.5 × 6 × 4 cm in size, with positive margins on microscopic review (R1 resection). A PET‐CT scan performed two weeks after surgery did not demonstrate any distant metastasis. Since re‐excision to obtain negative margins was deemed unfeasible, the patient was treated with concurrent PBT and paclitaxel (80 mg/m2 every week for seven cycles). The planning for PBT involved obtaining a four‐dimensional (4‐D) CT simulation with and without intravenous contrast. The region at risk for clinical target volume (CTV) was determined upon the review of cardiac MRI. Based on the images from the 4‐D CT simulation, an internal target volume (ITV) of 5 mm was used to expand the CTV for proton planning (Figure 2). The patient was treated with a 2‐field proton plan on the Mevion S250 with passively scattered beams. A dose of 6120 cobalt gray equivalent (CGE) in 1.8 CGE fractions per day was delivered concurrently with weekly paclitaxel. After completing the concurrent chemotherapy and PBT, he was treated with systemic chemotherapy using gemcitabine (900 mg/m2 on Days 1 and 8) and docetaxel (100 mg/m2 on Day 8). After three cycles, he developed grade 3 dermatitis that led to the discontinuation of therapy. Further treatment was withheld as the patient did not have any tumor recurrence on restaging CT scans. Eighteen months following completion of treatment and 26 months since surgery, the patient remains in complete remission.
FIGURE 1 (a) A four‐chamber balanced steady state free precession (bSSFP) cardiac MRI image showing a large frond‐like mass centered in the right atrium seen prolapsing into the right ventricle (blue arrow). The posterior right atrial wall attachment is also shown (red arrow). (b) The corresponding short‐axis bSSFP image through the basal right atrium clearly shows the inferior attachment of the mass (blue arrow) as well as minimal extension into the pericardial space (red arrow). (c and d) Four‐ and two‐chamber phase‐sensitive inversion recovery (PSIR) delayed contrast‐enhanced demonstrate heterogeneous enhancement within the mass (blue arrows) typical of a neoplastic lesion. The yellow star indicates the inferior vena cava, and the blue arrow denotes pericardial effusion
FIGURE 2 (a) Beam orientation of the two‐field proton plan with internal target volume (ITV) target in light blue color wash. (b) Representative isodose lines and ITV target volume in light blue color wash
DISCUSSION
Previously, the concurrent use of chemotherapy and RT to treat cardiac sarcomas has been described in small case reports. 1 Only one report of a patient with undifferentiated pleomorphic sarcoma of the left atrium has been reported to receive PBT alone to the primary tumor during one of the many relapses. 2 To the best of our knowledge, this is the first report of a patient with a right‐sided CAS to receive PBT with concurrent chemotherapy. The novelty of this report lies in the approach to this patient who underwent R1 resection for cardiac angiosarcoma. The combination of PBT with chemotherapy followed by adjuvant chemotherapy seems to be an effective regimen in patients with cardiac angiosarcoma. Recently, a European study retrospectively examining the treatment approaches in patients with angiosarcoma reported prolonged disease‐free survival (DFS) in patients undergoing multimodality approach combining chemotherapy (neoadjuvant, adjuvant, or both), surgery, and RT. 3 The benefits of PBT in sarcoma stem from the physical characteristics of protons, which lead to improved dose conformality to the tumor volume and help in escalating the doses to the tumor while sparing the surrounding tissue. 4 Dosimetric studies confirm the benefit of using protons over photons in terms of improved sparing of normal tissue and potentially reducing the long term risk of secondary malignancies and RT‐induced sequelae. 4 Anthracyclines are a widely accepted first‐line treatment in most patients with STS. However, in patients with angiosarcoma, taxanes have similar efficacy compared to anthracyclines, but without the cardiotoxicity of anthracyclines. 5 In addition to this, taxanes have been proven to be excellent radiosensitizers, and their concurrent use with RT has yielded durable responses in patients with cutaneous angiosarcoma. 6 The safety and efficacy of combining chemotherapy with PBT has been reported in patients with lung cancer. 7 Since reresection was not possible in our patient, we adopted the strategy of adding chemotherapy (paclitaxel) along with PBT to treat the positive margin. Angiosarcoma of the heart is associated with poor outcomes and has a high risk of metastasis 5 , 8 ; hence we gave the patient adjuvant chemotherapy using gemcitabine and docetaxel.
In a retrospective study of 57 patients with right‐sided cardiac sarcoma, the median survival of those with R0 resection was better than those who had R1 resection (27 vs. four months). 9 In a follow up of this series, the authors added neoadjuvant chemotherapy (doxorubicin and ifosfamide) that improved the median survival of patients with R0 resection to 53 months; however, the survival of those with R1 resection continued to be dismal at nine months. 10 In our patient who underwent an R1 resection, using adjuvant PBT with chemotherapy, followed by systemic chemotherapy, resulted in DFS of 26 months since completion of surgery. Our multimodality approach to this patient has a couple of advantages. First, it avoids the use of anthracyclines that can potentially lead to cardiotoxicity in the long run in this otherwise young patient. Second, the prolonged DFS in our patient suggests the benefit of adding chemotherapy to PBT in achieving durable responses and may negate the effects of R1 resection. Third, given the high‐risk of distant metastasis associated with right‐sided CAS, 11 the addition of adjuvant chemotherapy may be beneficial in prolonging the DFS in such patients. In conclusion, the approach to use concurrent chemotherapy with PBT followed by adjuvant chemotherapy may result in better survival outcomes in patients with cardiac sarcomas who undergo R1 resection. This approach warrants further study in a prospective trial.
CONFLICT OF INTEREST
None to declare. | 900 MG/M2, CYCLIC DAYS 1 AND 8, 3 CYCLES | DrugDosageText | CC BY | 33605065 | 19,051,894 | 2021-04 |
What was the dosage of drug 'GEMCITABINE\GEMCITABINE HYDROCHLORIDE'? | Right atrial cardiac angiosarcoma treated with concurrent proton beam therapy and paclitaxel: A novel approach to a rare disease.
Cardiac angiosarcoma is a rare malignancy with an aggressive course and poor prognosis. We present a 26-year old man who came to our clinic with shortness of breath and was diagnosed with a right-sided atrial mass. He underwent urgent resection of the mass. The pathology confirmed the mass to be cardiac angiosarcoma with positive microscopic margins (R1 resection). Since reresection was not feasible, the patient started treatment with concurrent paclitaxel (80 mg/m2 weekly) and proton beam therapy (61 Cobalt equivalent delivered over five weeks). After completing the concurrent chemotherapy and radiation therapy, he was treated with adjuvant chemotherapy using gemcitabine (900 mg/m2 on Days 1 and 8) and docetaxel (100 mg/m2 on Day 8) every three weeks. After three cycles, the patient developed severe dermatitis, and hence further chemotherapy was withheld. The patient is alive at 26 months since receiving his surgery and 18 months since the completion of treatment. Patients with cardiac angiosarcoma who undergo R1 resection have a median survival of six months. More radical approaches such as orthotopic heart-lung transplant or prolonged durations of chemotherapy lead to minimal improvement in survival at the cost of increased morbidity. Here, we describe a novel approach to a rare disease that resulted in prolonged survival and led to a better quality of life without any long-term morbidity to the patient.
INTRODUCTION
Cardiac angiosarcoma (CAS) is an extremely rare tumor for which optimal management is unclear. Although surgical resection remains the mainstay of treatment, multimodality treatment, including chemotherapy and radiation therapy (RT), is often used to treat this aggressive malignancy. However, the median survival remains low for patients with positive microscopic margins (R1 resection) after surgical resection of the tumor. In this report, we present a novel approach of combining proton beam therapy (PBT) with chemotherapy followed by adjuvant chemotherapy, which was used to treat our patient with right‐sided CAS who underwent R1 resection.
CASE REPORT
A 26‐year old man presented to the emergency room with severe shortness of breath and pedal edema worsening over one month. He had no significant past medical or surgical history. He denied any habits or illicit drug use. A two‐dimensional echocardiogram showed a large heteroechoic mass measuring 7 × 3.6 cm attached to the roof of the right atrium and prolapsing across the tricuspid valve in the right ventricle with every beat. This finding was further characterized by cardiac resonance imaging as a large frond‐like mobile mass (8.6 × 3.8 cm) attached to the posterior‐inferior right atrial wall with pericardial extension (Figure 1). The patient underwent urgent surgical resection, and pathology revealed epithelioid angiosarcoma Immunoperoxidase stain showed that neoplastic cells were positive for CD31, CD34, ERG, and negative for D2‐440, HHV‐8, and cytokeratin AE1/AE3. The tumor was 10.5 × 6 × 4 cm in size, with positive margins on microscopic review (R1 resection). A PET‐CT scan performed two weeks after surgery did not demonstrate any distant metastasis. Since re‐excision to obtain negative margins was deemed unfeasible, the patient was treated with concurrent PBT and paclitaxel (80 mg/m2 every week for seven cycles). The planning for PBT involved obtaining a four‐dimensional (4‐D) CT simulation with and without intravenous contrast. The region at risk for clinical target volume (CTV) was determined upon the review of cardiac MRI. Based on the images from the 4‐D CT simulation, an internal target volume (ITV) of 5 mm was used to expand the CTV for proton planning (Figure 2). The patient was treated with a 2‐field proton plan on the Mevion S250 with passively scattered beams. A dose of 6120 cobalt gray equivalent (CGE) in 1.8 CGE fractions per day was delivered concurrently with weekly paclitaxel. After completing the concurrent chemotherapy and PBT, he was treated with systemic chemotherapy using gemcitabine (900 mg/m2 on Days 1 and 8) and docetaxel (100 mg/m2 on Day 8). After three cycles, he developed grade 3 dermatitis that led to the discontinuation of therapy. Further treatment was withheld as the patient did not have any tumor recurrence on restaging CT scans. Eighteen months following completion of treatment and 26 months since surgery, the patient remains in complete remission.
FIGURE 1 (a) A four‐chamber balanced steady state free precession (bSSFP) cardiac MRI image showing a large frond‐like mass centered in the right atrium seen prolapsing into the right ventricle (blue arrow). The posterior right atrial wall attachment is also shown (red arrow). (b) The corresponding short‐axis bSSFP image through the basal right atrium clearly shows the inferior attachment of the mass (blue arrow) as well as minimal extension into the pericardial space (red arrow). (c and d) Four‐ and two‐chamber phase‐sensitive inversion recovery (PSIR) delayed contrast‐enhanced demonstrate heterogeneous enhancement within the mass (blue arrows) typical of a neoplastic lesion. The yellow star indicates the inferior vena cava, and the blue arrow denotes pericardial effusion
FIGURE 2 (a) Beam orientation of the two‐field proton plan with internal target volume (ITV) target in light blue color wash. (b) Representative isodose lines and ITV target volume in light blue color wash
DISCUSSION
Previously, the concurrent use of chemotherapy and RT to treat cardiac sarcomas has been described in small case reports. 1 Only one report of a patient with undifferentiated pleomorphic sarcoma of the left atrium has been reported to receive PBT alone to the primary tumor during one of the many relapses. 2 To the best of our knowledge, this is the first report of a patient with a right‐sided CAS to receive PBT with concurrent chemotherapy. The novelty of this report lies in the approach to this patient who underwent R1 resection for cardiac angiosarcoma. The combination of PBT with chemotherapy followed by adjuvant chemotherapy seems to be an effective regimen in patients with cardiac angiosarcoma. Recently, a European study retrospectively examining the treatment approaches in patients with angiosarcoma reported prolonged disease‐free survival (DFS) in patients undergoing multimodality approach combining chemotherapy (neoadjuvant, adjuvant, or both), surgery, and RT. 3 The benefits of PBT in sarcoma stem from the physical characteristics of protons, which lead to improved dose conformality to the tumor volume and help in escalating the doses to the tumor while sparing the surrounding tissue. 4 Dosimetric studies confirm the benefit of using protons over photons in terms of improved sparing of normal tissue and potentially reducing the long term risk of secondary malignancies and RT‐induced sequelae. 4 Anthracyclines are a widely accepted first‐line treatment in most patients with STS. However, in patients with angiosarcoma, taxanes have similar efficacy compared to anthracyclines, but without the cardiotoxicity of anthracyclines. 5 In addition to this, taxanes have been proven to be excellent radiosensitizers, and their concurrent use with RT has yielded durable responses in patients with cutaneous angiosarcoma. 6 The safety and efficacy of combining chemotherapy with PBT has been reported in patients with lung cancer. 7 Since reresection was not possible in our patient, we adopted the strategy of adding chemotherapy (paclitaxel) along with PBT to treat the positive margin. Angiosarcoma of the heart is associated with poor outcomes and has a high risk of metastasis 5 , 8 ; hence we gave the patient adjuvant chemotherapy using gemcitabine and docetaxel.
In a retrospective study of 57 patients with right‐sided cardiac sarcoma, the median survival of those with R0 resection was better than those who had R1 resection (27 vs. four months). 9 In a follow up of this series, the authors added neoadjuvant chemotherapy (doxorubicin and ifosfamide) that improved the median survival of patients with R0 resection to 53 months; however, the survival of those with R1 resection continued to be dismal at nine months. 10 In our patient who underwent an R1 resection, using adjuvant PBT with chemotherapy, followed by systemic chemotherapy, resulted in DFS of 26 months since completion of surgery. Our multimodality approach to this patient has a couple of advantages. First, it avoids the use of anthracyclines that can potentially lead to cardiotoxicity in the long run in this otherwise young patient. Second, the prolonged DFS in our patient suggests the benefit of adding chemotherapy to PBT in achieving durable responses and may negate the effects of R1 resection. Third, given the high‐risk of distant metastasis associated with right‐sided CAS, 11 the addition of adjuvant chemotherapy may be beneficial in prolonging the DFS in such patients. In conclusion, the approach to use concurrent chemotherapy with PBT followed by adjuvant chemotherapy may result in better survival outcomes in patients with cardiac sarcomas who undergo R1 resection. This approach warrants further study in a prospective trial.
CONFLICT OF INTEREST
None to declare. | DAYS 1 AND 8 | DrugDosageText | CC BY | 33605065 | 18,959,020 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal exposure during pregnancy'. | Venous sinus thrombosis during COVID-19 infection in pregnancy: a case report.
Although it is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract, cases of this disease with a wide clinical spectrum are emerging as information is shared.
We present the case of a pregnant woman who was diagnosed with venous sinus thrombosis after she developed headache and hemiparesis. Polymerase chain reaction (PCR) positivity lasted for two weeks after COVID-19 had been diagnosed.
In patients with suspected COVID-19, especially in the presence of causes of hypercoagu- lability and presence of atypical features, venous sinus thrombosis needs to be kept in mind in making the differential diagnosis.
pmcINTRODUCTION
The effects of COVID-19 are not limited to the lungs alone. After the virus enters the body, it causes various symptoms through viremia.1 COVID-19 has been implicated in occurrences of cardiovascular and thromboembolic complications due to systemic inflammation and coagulopathy, in the light of the increasing amount of data that has become available over time.2,3,4,5,6,7,8 On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 It has been suggested that COVID-19 predisposes patients to thrombotic pathological conditions in both the venous and the arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 Nevertheless, cases of neurological and cardiac involvement in COVID-positive patients with TMA have also been reported.9
While the mechanism for the susceptibility to thrombosis that has been seen among COVID-19 patients continues to be debated, we wanted through this report to share information regarding the common venous thrombus of the central nervous system that emerged during the subclinical course of COVID-19 in a pregnant patient, which caused rapid parenchymal infarction.
CASE REPORT
A 22-year-old patient who was 35 weeks pregnant was evaluated in the emergency department with a complaint of right-sided weakness. The COVID-19 polymerase chain reaction test was performed and was found to be positive. However, she did not have fever or respiratory distress and then was followed up at home without medication.
The patient started to have throbbing headaches that did not respond to analgesic treatment (paracetamol 1000 mg/day) for four days. The intensity of her headaches gradually increased, such that she was being awakened from sleep, and this condition was accompanied by nausea and vomiting.
After this four-day period, she again felt weakness on her right side when she woke up in the morning. Twelve hours later, she went back to the emergency department because her weakness was increasing. At the emergency department, the patient was found to be normotensive, conscious, cooperative and oriented in a neurological examination. No fundus examination was performed, given that she was COVID-positive. Examinations on the patient’s visual field and vision showed normal results. Other cranial nerve examinations were normal. Her muscle strength ratio was 3/5 in the upper right extremity, 2/5 in the lower right extremity and 5/5 in the upper and lower left extremities. The foot sole skin reflex of the right lower extremity consisted of an extensor response. She presented decreased speech fluency and had difficulty in word finding, which were diagnosed as mild motor aphasia. Laboratory tests revealed high levels of fibrinogen (899 g/l; normal is 180-400) and D-dimer (6.38 mg/l; normal is 0-2). It was noted that the patient had also had high levels of fibrinogen (665 g/l) and D-dimer (2.2 mg/l) in examinations performed 10 days previously.
Diffusion magnetic resonance imaging (MRI) showed cortical diffusion restriction in the left parietal region (Figure 1a) and a hypointense response in the apparent diffusion coefficient (ADC) (Figure 1b). The result from the diffusion MRI was suggestive of venous sinus thrombosis. Widespread loss of flow in the superior sagittal sinus and right transverse sinus, suggesting partial venous thrombosis in the left transverse sinus, was observed in brain magnetic resonance imaging (Figure 2a) and magnetic resonance venous angiography (Figure 2b). The brain MRI and magnetic resonance venography confirmed the diagnosis of venous sinus thrombosis. Thrombosis was not investigated in other parts of the body.
Figure 1. a) Diffusion magnetic resonance imaging; b) Apparent diffusion coefficient.
Figure 2. a) Cranial magnetic resonance imaging; b) Magnetic resonance imaging venography.
The polymerase chain reaction was repeated and the result was again positive. The patient was then hospitalized with the diagnoses of COVID-19 infection and venous sinus thrombosis. Other genetic, hematological and rheumatological examinations were planned, in order to investigate the etiology of her condition. Anticoagulant treatment (low molecular weight heparin) was started after the patient had been found to present a low platelet count (107,000/mm3), through evaluation of a peripheral blood smear.
Diffuse contractions were observed in a non-stress test (NST), and tocolysis was started, consisting of nifedipine and betamethasone treatment. However, the patient’s labor could not be stopped after 18 hours of hospitalization. She was then admitted for an emergency cesarean section because the intracranial pressure was increasing. A healthy baby was delivered.
Subsequently, the patient’s postpartum headache complaints decreased and her speech became fluent without any change in muscle strength deficit. Her thrombocyte counts decreased to 67,000/mm3. Anticoagulant therapy was continued, with peripheral smear follow-ups. Thoracic computed tomography was performed on the patient, who did not present respiratory distress, and the findings were compatible with COVID-19 pneumonia after birth (Figure 3). There was an increase in infection parameters, and the patient was started on hydroxychloroquine and ceftriaxone treatment.
Figure 3. Thoracic computed tomography.
In the examinations performed to ascertain risk factors, the patient was found to be positive for antinuclear antibodies (ANA) and showed prothrombin heterozygous mutation. The patient was negative for anti-cardiolipin antibodies and anti-double stranded DNA (dsDNA), and tests on lupus anticoagulant, homocysteine, protein C, protein S and antithrombin 3 showed results within normal limits.
On the third day following the birth, the patient’s headache complaint became completely resolved, her thrombocyte counts stopped decreasing and her thrombocytopenia improved over the subsequent days. The infection parameters regressed. Partial regression of the lesions was observed on control thoracic computed tomography. The patient’s general condition stabilized and she was discharged on the 10th day of hospitalization, with muscle strength 4-5/5 on the right side, which was mobilized without support. Continuation of low molecular weight heparin (LMWH) treatment was planned, along with neurological and hematological control tests at a polyclinic.
DISCUSSION
It is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract. Cases of this disease with a wide clinical spectrum are emerging as information is shared.
Although the mechanism for thrombotic events in the course of COVID-19 remains unclear, it is known that there is a tendency for such events to occur within the course of this disease. Pulmonary embolism was shown to be the cause of death in an autopsy series.6 The etiology of embolic events is generally multifactorial: it is accepted that these events are triggered by environmental factors on the basis of genetic predisposition. Nonetheless, no reports on underlying genetic or other acquired causes in cases of COVID-19-positive pulmonary embolism have yet been published in the literature.
An increasing number of case reports and series on COVID-19-positive patients are describing a wide variety of neurological symptoms. Encephalopathy has been reported in a total of 93 patients, including 16 (7%) out of 214 hospitalized patients with COVID-19 in Wuhan, China, and 40 (69%) out of 58 patients in intensive care with COVID-19 in France. To date, encephalitis has been described in eight patients and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the cerebrospinal fluid (CSF) of some patients. Anosmia and agnosia are common and may occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease has also emerged as an important complication: stroke was reported in 2-6% of patients hospitalized with COVID-19 in a cohort study.10
Li et al. stated that in a retrospective study in which 219 COVID-19 positive patients were screened, 10 of these patients (4.6%) were ischemic and one of them presented hemorrhagic cerebrovascular disease (0.5%), after an average of 10 days after the onset of COVID-19. They pointed out that the mean age of these patients was greater and their cardiovascular and cerebrovascular risk factors were more severe.11
COVID-19 is thought to predispose patients to thrombotic pathological conditions in both venous and arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 The initial signs of coagulopathy due to COVID-19 have been found to be marked increases in fibrin/fibrinogen-degradation products and D-dimer levels. It was observed that our patient had high levels of fibrinogen and D-dimer from the time when she was diagnosed with COVID-19 to the time when she was diagnosed with venous sinus thrombosis.
In the early stages of the disease, abnormalities in prothrombin time, partial thromboplastin time and platelet count are uncommon.5 Detection of deep vein thrombosis (58%) as the autopsy finding among more than half of the 12 patients who died of COVID-19, and pulmonary embolism as the cause of death among one third of the patients, has emphasized the importance of not ignoring the tendency towards occurrences of thrombosis in the course of this disease. Hence, anticoagulants should be included during treatment planning.6 Analysis on the data on 184 patients with COVID-19 infection who were monitored in an intensive care unit showed that 31% of them had thrombotic complications. Thus, prophylaxis for thrombosis was strongly recommended for patients hospitalized with this diagnosis.7
On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 Thrombotic microangiopathy is characterized by organ damage such as microangiopathic hemolytic anemia, thrombocytopenia, and neurological, renal and cardiac dysfunction. Thrombocytopenia and neurological deficits were also observed in our patient. In another study, anemia, increased lactate dehydrogenase (LDH), thrombocytopenia and organ damage (neurological in all patients and cardiac in one) were explained by thrombotic microangiopathy in three patients with a diagnosis of COVID-19.9
Cerebral venous thrombus differs significantly from arterial infarctions in terms of risk factors. Hypercoagulability is an important risk factor and an important cause of stroke in young people. Women are affected three times more often than men. The most common symptoms are headache, seizures and focal neurological deficits. The diagnosis can be confirmed by magnetic resonance imaging, computed tomography-venography or catheter angiography.
The primary treatment for venous sinus thrombosis is anticoagulation, based on the limited evidence from randomized trials. Although a small series of cases has indicated that endovascular therapy may be promising, these data require confirmation through a randomized trial. Decompressive surgery can be lifesaving for patients at risk of herniation. The prognosis is generally better than that for arterial stroke.12 Although venous sinus thrombosis was previously considered to be a life-threatening condition, it is known that the mortality rate in these cases declines over time. Moreover, increased clinical awareness, development of neuroimaging techniques and improvement in therapeutic management have provided better prognoses through enabling earlier diagnosis and identification of less severe cases.13
Pregnancy and the puerperium are common causes of transient prothrombotic conditions. About 2% of pregnancy-related strokes can be attributed to venous sinus thrombosis. In the puerperium, the rate of venous sinus thrombosis is 12 cases per 100,000 births. This venous rate in the puerperal period is only slightly lower than that of arterial stroke. Women are at risk of venous thromboembolic events during pregnancy and for up to six to eight weeks after delivery. Most cases of pregnancy-related venous sinus thrombosis are seen in the third trimester or, more often, in the puerperium, when the body prepares for delivery through hypercoagulation. In a paper published in Canada, it was reported that frequency of venous sinus thrombosis in the postpartum period is much higher than during pregnancy. In the puerperium period, the presence of infection and use of instrumental delivery or cesarean section increase the risk of venous sinus thrombosis. During pregnancy, it is known that the risk of venous sinus thrombosis increases in the presence of hypertension, infections and excessive vomiting, and as the maternal age increases.14 The European Academy of Neurology has recommended that treatment for acute venous sinus thrombosis should start with oral anticoagulant therapy (vitamin K antagonists) for 3-12 months, according to risk factors.15
Another risk factor with a relationship to venous sinus thrombosis that is clearly known is inflammation. Venous sinus thrombosis is associated with systemic inflammatory conditions such as Behçet’s disease and inflammatory bowel disease, in addition to infections such as otitis, mastoiditis, sinusitis, dental infections and skin abscesses in neighboring tissues and meningitis.13 In the anamnesis and examination of our patient, no finding suggesting adjacent tissue infection or Behçet’s or inflammatory bowel disease was found.
Antinuclear antibody positivity can be seen in autoimmune diseases, especially systemic lupus erythematosus, but it is not a laboratory test specific to autoimmune diseases. Since antinuclear antibody positivity can be observed in acute or chronic infectious processes,16 it was planned that our patient would undergo this examination after discharge. The anamnesis of our patient was negative for rheumatological diseases.
The etiology of venous sinus thrombosis can be explained in terms of the classical Virchow triad, i.e. blood flow stasis, vessel wall changes and changes in blood content. We believe that the combination of pregnancy and systemic inflammation due to COVID-19 caused thrombosis in our patient, on the basis of genetic prothrombin heterozygous mutation.
One of the clinical manifestations of COVID-19 is nonspecific headache, as is also frequently observed during other viral infections. However, this symptom can often be mild enough to lag behind other clinical findings. If there is no visual impairment, focal neurological deficit or seizure, venous sinus thrombosis can be neglected in the differential diagnosis. Our patient was diagnosed not after occurrences of headache and nausea-vomiting, but after admission to the hospital because of the accompanying symptoms of right hemiparesis. In our case, like what has been described in the literature,11 the central nervous system event started on the ninth day after COVID-19 infection began, and a stroke occurred on the 13th day. Thus, within four days, the rapid clinical progression resulted in parenchymal ischemia. The neurological clinical findings rapidly improved in parallel with the end of pregnancy, start of administration of low molecular weight heparin and decrease in infection parameters.
Reports correlating COVID-19, headache and pregnancy are very rare (Table 1).
Table 1. Search of the literature in medical databases for case reports on COVID-19, pregnancy and headache on November 6, 2020
Database Search strategies Papers found Papers related (to pregnancy, headache and COVID-19) Etiology Main neurological symptom
MEDLINE
(via PubMed)
COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
2 2 Spinal anesthesia 1
Pituitary apoplexy 1
Headache
Cochrane COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
Embase COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
CONCLUSION
Headache is one of the common symptoms of COVID-19. In the presence of other risk factors accompanying COVID-19, the risk of thromboembolic events increases significantly. Among patients with suspected COVID-19, considering venous sinus thrombosis in the differential diagnosis may be life-saving, through enabling early diagnosis and treatment. This is especially so in the presence of causes of hypercoagulability such as pregnancy, malignancy and presence of atypical features like analgesic unresponsiveness, awakening from sleep, visual impairment, neurological deficits or seizures.
1 University of Health Sciences, Konya Education and Research Hospital, Konya, Turkey
Sources of funding: None | ACETAMINOPHEN, BETAMETHASONE, NIFEDIPINE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33605306 | 19,062,445 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Normal newborn'. | Venous sinus thrombosis during COVID-19 infection in pregnancy: a case report.
Although it is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract, cases of this disease with a wide clinical spectrum are emerging as information is shared.
We present the case of a pregnant woman who was diagnosed with venous sinus thrombosis after she developed headache and hemiparesis. Polymerase chain reaction (PCR) positivity lasted for two weeks after COVID-19 had been diagnosed.
In patients with suspected COVID-19, especially in the presence of causes of hypercoagu- lability and presence of atypical features, venous sinus thrombosis needs to be kept in mind in making the differential diagnosis.
pmcINTRODUCTION
The effects of COVID-19 are not limited to the lungs alone. After the virus enters the body, it causes various symptoms through viremia.1 COVID-19 has been implicated in occurrences of cardiovascular and thromboembolic complications due to systemic inflammation and coagulopathy, in the light of the increasing amount of data that has become available over time.2,3,4,5,6,7,8 On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 It has been suggested that COVID-19 predisposes patients to thrombotic pathological conditions in both the venous and the arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 Nevertheless, cases of neurological and cardiac involvement in COVID-positive patients with TMA have also been reported.9
While the mechanism for the susceptibility to thrombosis that has been seen among COVID-19 patients continues to be debated, we wanted through this report to share information regarding the common venous thrombus of the central nervous system that emerged during the subclinical course of COVID-19 in a pregnant patient, which caused rapid parenchymal infarction.
CASE REPORT
A 22-year-old patient who was 35 weeks pregnant was evaluated in the emergency department with a complaint of right-sided weakness. The COVID-19 polymerase chain reaction test was performed and was found to be positive. However, she did not have fever or respiratory distress and then was followed up at home without medication.
The patient started to have throbbing headaches that did not respond to analgesic treatment (paracetamol 1000 mg/day) for four days. The intensity of her headaches gradually increased, such that she was being awakened from sleep, and this condition was accompanied by nausea and vomiting.
After this four-day period, she again felt weakness on her right side when she woke up in the morning. Twelve hours later, she went back to the emergency department because her weakness was increasing. At the emergency department, the patient was found to be normotensive, conscious, cooperative and oriented in a neurological examination. No fundus examination was performed, given that she was COVID-positive. Examinations on the patient’s visual field and vision showed normal results. Other cranial nerve examinations were normal. Her muscle strength ratio was 3/5 in the upper right extremity, 2/5 in the lower right extremity and 5/5 in the upper and lower left extremities. The foot sole skin reflex of the right lower extremity consisted of an extensor response. She presented decreased speech fluency and had difficulty in word finding, which were diagnosed as mild motor aphasia. Laboratory tests revealed high levels of fibrinogen (899 g/l; normal is 180-400) and D-dimer (6.38 mg/l; normal is 0-2). It was noted that the patient had also had high levels of fibrinogen (665 g/l) and D-dimer (2.2 mg/l) in examinations performed 10 days previously.
Diffusion magnetic resonance imaging (MRI) showed cortical diffusion restriction in the left parietal region (Figure 1a) and a hypointense response in the apparent diffusion coefficient (ADC) (Figure 1b). The result from the diffusion MRI was suggestive of venous sinus thrombosis. Widespread loss of flow in the superior sagittal sinus and right transverse sinus, suggesting partial venous thrombosis in the left transverse sinus, was observed in brain magnetic resonance imaging (Figure 2a) and magnetic resonance venous angiography (Figure 2b). The brain MRI and magnetic resonance venography confirmed the diagnosis of venous sinus thrombosis. Thrombosis was not investigated in other parts of the body.
Figure 1. a) Diffusion magnetic resonance imaging; b) Apparent diffusion coefficient.
Figure 2. a) Cranial magnetic resonance imaging; b) Magnetic resonance imaging venography.
The polymerase chain reaction was repeated and the result was again positive. The patient was then hospitalized with the diagnoses of COVID-19 infection and venous sinus thrombosis. Other genetic, hematological and rheumatological examinations were planned, in order to investigate the etiology of her condition. Anticoagulant treatment (low molecular weight heparin) was started after the patient had been found to present a low platelet count (107,000/mm3), through evaluation of a peripheral blood smear.
Diffuse contractions were observed in a non-stress test (NST), and tocolysis was started, consisting of nifedipine and betamethasone treatment. However, the patient’s labor could not be stopped after 18 hours of hospitalization. She was then admitted for an emergency cesarean section because the intracranial pressure was increasing. A healthy baby was delivered.
Subsequently, the patient’s postpartum headache complaints decreased and her speech became fluent without any change in muscle strength deficit. Her thrombocyte counts decreased to 67,000/mm3. Anticoagulant therapy was continued, with peripheral smear follow-ups. Thoracic computed tomography was performed on the patient, who did not present respiratory distress, and the findings were compatible with COVID-19 pneumonia after birth (Figure 3). There was an increase in infection parameters, and the patient was started on hydroxychloroquine and ceftriaxone treatment.
Figure 3. Thoracic computed tomography.
In the examinations performed to ascertain risk factors, the patient was found to be positive for antinuclear antibodies (ANA) and showed prothrombin heterozygous mutation. The patient was negative for anti-cardiolipin antibodies and anti-double stranded DNA (dsDNA), and tests on lupus anticoagulant, homocysteine, protein C, protein S and antithrombin 3 showed results within normal limits.
On the third day following the birth, the patient’s headache complaint became completely resolved, her thrombocyte counts stopped decreasing and her thrombocytopenia improved over the subsequent days. The infection parameters regressed. Partial regression of the lesions was observed on control thoracic computed tomography. The patient’s general condition stabilized and she was discharged on the 10th day of hospitalization, with muscle strength 4-5/5 on the right side, which was mobilized without support. Continuation of low molecular weight heparin (LMWH) treatment was planned, along with neurological and hematological control tests at a polyclinic.
DISCUSSION
It is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract. Cases of this disease with a wide clinical spectrum are emerging as information is shared.
Although the mechanism for thrombotic events in the course of COVID-19 remains unclear, it is known that there is a tendency for such events to occur within the course of this disease. Pulmonary embolism was shown to be the cause of death in an autopsy series.6 The etiology of embolic events is generally multifactorial: it is accepted that these events are triggered by environmental factors on the basis of genetic predisposition. Nonetheless, no reports on underlying genetic or other acquired causes in cases of COVID-19-positive pulmonary embolism have yet been published in the literature.
An increasing number of case reports and series on COVID-19-positive patients are describing a wide variety of neurological symptoms. Encephalopathy has been reported in a total of 93 patients, including 16 (7%) out of 214 hospitalized patients with COVID-19 in Wuhan, China, and 40 (69%) out of 58 patients in intensive care with COVID-19 in France. To date, encephalitis has been described in eight patients and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the cerebrospinal fluid (CSF) of some patients. Anosmia and agnosia are common and may occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease has also emerged as an important complication: stroke was reported in 2-6% of patients hospitalized with COVID-19 in a cohort study.10
Li et al. stated that in a retrospective study in which 219 COVID-19 positive patients were screened, 10 of these patients (4.6%) were ischemic and one of them presented hemorrhagic cerebrovascular disease (0.5%), after an average of 10 days after the onset of COVID-19. They pointed out that the mean age of these patients was greater and their cardiovascular and cerebrovascular risk factors were more severe.11
COVID-19 is thought to predispose patients to thrombotic pathological conditions in both venous and arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 The initial signs of coagulopathy due to COVID-19 have been found to be marked increases in fibrin/fibrinogen-degradation products and D-dimer levels. It was observed that our patient had high levels of fibrinogen and D-dimer from the time when she was diagnosed with COVID-19 to the time when she was diagnosed with venous sinus thrombosis.
In the early stages of the disease, abnormalities in prothrombin time, partial thromboplastin time and platelet count are uncommon.5 Detection of deep vein thrombosis (58%) as the autopsy finding among more than half of the 12 patients who died of COVID-19, and pulmonary embolism as the cause of death among one third of the patients, has emphasized the importance of not ignoring the tendency towards occurrences of thrombosis in the course of this disease. Hence, anticoagulants should be included during treatment planning.6 Analysis on the data on 184 patients with COVID-19 infection who were monitored in an intensive care unit showed that 31% of them had thrombotic complications. Thus, prophylaxis for thrombosis was strongly recommended for patients hospitalized with this diagnosis.7
On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 Thrombotic microangiopathy is characterized by organ damage such as microangiopathic hemolytic anemia, thrombocytopenia, and neurological, renal and cardiac dysfunction. Thrombocytopenia and neurological deficits were also observed in our patient. In another study, anemia, increased lactate dehydrogenase (LDH), thrombocytopenia and organ damage (neurological in all patients and cardiac in one) were explained by thrombotic microangiopathy in three patients with a diagnosis of COVID-19.9
Cerebral venous thrombus differs significantly from arterial infarctions in terms of risk factors. Hypercoagulability is an important risk factor and an important cause of stroke in young people. Women are affected three times more often than men. The most common symptoms are headache, seizures and focal neurological deficits. The diagnosis can be confirmed by magnetic resonance imaging, computed tomography-venography or catheter angiography.
The primary treatment for venous sinus thrombosis is anticoagulation, based on the limited evidence from randomized trials. Although a small series of cases has indicated that endovascular therapy may be promising, these data require confirmation through a randomized trial. Decompressive surgery can be lifesaving for patients at risk of herniation. The prognosis is generally better than that for arterial stroke.12 Although venous sinus thrombosis was previously considered to be a life-threatening condition, it is known that the mortality rate in these cases declines over time. Moreover, increased clinical awareness, development of neuroimaging techniques and improvement in therapeutic management have provided better prognoses through enabling earlier diagnosis and identification of less severe cases.13
Pregnancy and the puerperium are common causes of transient prothrombotic conditions. About 2% of pregnancy-related strokes can be attributed to venous sinus thrombosis. In the puerperium, the rate of venous sinus thrombosis is 12 cases per 100,000 births. This venous rate in the puerperal period is only slightly lower than that of arterial stroke. Women are at risk of venous thromboembolic events during pregnancy and for up to six to eight weeks after delivery. Most cases of pregnancy-related venous sinus thrombosis are seen in the third trimester or, more often, in the puerperium, when the body prepares for delivery through hypercoagulation. In a paper published in Canada, it was reported that frequency of venous sinus thrombosis in the postpartum period is much higher than during pregnancy. In the puerperium period, the presence of infection and use of instrumental delivery or cesarean section increase the risk of venous sinus thrombosis. During pregnancy, it is known that the risk of venous sinus thrombosis increases in the presence of hypertension, infections and excessive vomiting, and as the maternal age increases.14 The European Academy of Neurology has recommended that treatment for acute venous sinus thrombosis should start with oral anticoagulant therapy (vitamin K antagonists) for 3-12 months, according to risk factors.15
Another risk factor with a relationship to venous sinus thrombosis that is clearly known is inflammation. Venous sinus thrombosis is associated with systemic inflammatory conditions such as Behçet’s disease and inflammatory bowel disease, in addition to infections such as otitis, mastoiditis, sinusitis, dental infections and skin abscesses in neighboring tissues and meningitis.13 In the anamnesis and examination of our patient, no finding suggesting adjacent tissue infection or Behçet’s or inflammatory bowel disease was found.
Antinuclear antibody positivity can be seen in autoimmune diseases, especially systemic lupus erythematosus, but it is not a laboratory test specific to autoimmune diseases. Since antinuclear antibody positivity can be observed in acute or chronic infectious processes,16 it was planned that our patient would undergo this examination after discharge. The anamnesis of our patient was negative for rheumatological diseases.
The etiology of venous sinus thrombosis can be explained in terms of the classical Virchow triad, i.e. blood flow stasis, vessel wall changes and changes in blood content. We believe that the combination of pregnancy and systemic inflammation due to COVID-19 caused thrombosis in our patient, on the basis of genetic prothrombin heterozygous mutation.
One of the clinical manifestations of COVID-19 is nonspecific headache, as is also frequently observed during other viral infections. However, this symptom can often be mild enough to lag behind other clinical findings. If there is no visual impairment, focal neurological deficit or seizure, venous sinus thrombosis can be neglected in the differential diagnosis. Our patient was diagnosed not after occurrences of headache and nausea-vomiting, but after admission to the hospital because of the accompanying symptoms of right hemiparesis. In our case, like what has been described in the literature,11 the central nervous system event started on the ninth day after COVID-19 infection began, and a stroke occurred on the 13th day. Thus, within four days, the rapid clinical progression resulted in parenchymal ischemia. The neurological clinical findings rapidly improved in parallel with the end of pregnancy, start of administration of low molecular weight heparin and decrease in infection parameters.
Reports correlating COVID-19, headache and pregnancy are very rare (Table 1).
Table 1. Search of the literature in medical databases for case reports on COVID-19, pregnancy and headache on November 6, 2020
Database Search strategies Papers found Papers related (to pregnancy, headache and COVID-19) Etiology Main neurological symptom
MEDLINE
(via PubMed)
COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
2 2 Spinal anesthesia 1
Pituitary apoplexy 1
Headache
Cochrane COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
Embase COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
CONCLUSION
Headache is one of the common symptoms of COVID-19. In the presence of other risk factors accompanying COVID-19, the risk of thromboembolic events increases significantly. Among patients with suspected COVID-19, considering venous sinus thrombosis in the differential diagnosis may be life-saving, through enabling early diagnosis and treatment. This is especially so in the presence of causes of hypercoagulability such as pregnancy, malignancy and presence of atypical features like analgesic unresponsiveness, awakening from sleep, visual impairment, neurological deficits or seizures.
1 University of Health Sciences, Konya Education and Research Hospital, Konya, Turkey
Sources of funding: None | ACETAMINOPHEN, BETAMETHASONE, CEFTRIAXONE, HYDROXYCHLOROQUINE, NIFEDIPINE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33605306 | 19,070,603 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Premature delivery'. | Venous sinus thrombosis during COVID-19 infection in pregnancy: a case report.
Although it is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract, cases of this disease with a wide clinical spectrum are emerging as information is shared.
We present the case of a pregnant woman who was diagnosed with venous sinus thrombosis after she developed headache and hemiparesis. Polymerase chain reaction (PCR) positivity lasted for two weeks after COVID-19 had been diagnosed.
In patients with suspected COVID-19, especially in the presence of causes of hypercoagu- lability and presence of atypical features, venous sinus thrombosis needs to be kept in mind in making the differential diagnosis.
pmcINTRODUCTION
The effects of COVID-19 are not limited to the lungs alone. After the virus enters the body, it causes various symptoms through viremia.1 COVID-19 has been implicated in occurrences of cardiovascular and thromboembolic complications due to systemic inflammation and coagulopathy, in the light of the increasing amount of data that has become available over time.2,3,4,5,6,7,8 On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 It has been suggested that COVID-19 predisposes patients to thrombotic pathological conditions in both the venous and the arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 Nevertheless, cases of neurological and cardiac involvement in COVID-positive patients with TMA have also been reported.9
While the mechanism for the susceptibility to thrombosis that has been seen among COVID-19 patients continues to be debated, we wanted through this report to share information regarding the common venous thrombus of the central nervous system that emerged during the subclinical course of COVID-19 in a pregnant patient, which caused rapid parenchymal infarction.
CASE REPORT
A 22-year-old patient who was 35 weeks pregnant was evaluated in the emergency department with a complaint of right-sided weakness. The COVID-19 polymerase chain reaction test was performed and was found to be positive. However, she did not have fever or respiratory distress and then was followed up at home without medication.
The patient started to have throbbing headaches that did not respond to analgesic treatment (paracetamol 1000 mg/day) for four days. The intensity of her headaches gradually increased, such that she was being awakened from sleep, and this condition was accompanied by nausea and vomiting.
After this four-day period, she again felt weakness on her right side when she woke up in the morning. Twelve hours later, she went back to the emergency department because her weakness was increasing. At the emergency department, the patient was found to be normotensive, conscious, cooperative and oriented in a neurological examination. No fundus examination was performed, given that she was COVID-positive. Examinations on the patient’s visual field and vision showed normal results. Other cranial nerve examinations were normal. Her muscle strength ratio was 3/5 in the upper right extremity, 2/5 in the lower right extremity and 5/5 in the upper and lower left extremities. The foot sole skin reflex of the right lower extremity consisted of an extensor response. She presented decreased speech fluency and had difficulty in word finding, which were diagnosed as mild motor aphasia. Laboratory tests revealed high levels of fibrinogen (899 g/l; normal is 180-400) and D-dimer (6.38 mg/l; normal is 0-2). It was noted that the patient had also had high levels of fibrinogen (665 g/l) and D-dimer (2.2 mg/l) in examinations performed 10 days previously.
Diffusion magnetic resonance imaging (MRI) showed cortical diffusion restriction in the left parietal region (Figure 1a) and a hypointense response in the apparent diffusion coefficient (ADC) (Figure 1b). The result from the diffusion MRI was suggestive of venous sinus thrombosis. Widespread loss of flow in the superior sagittal sinus and right transverse sinus, suggesting partial venous thrombosis in the left transverse sinus, was observed in brain magnetic resonance imaging (Figure 2a) and magnetic resonance venous angiography (Figure 2b). The brain MRI and magnetic resonance venography confirmed the diagnosis of venous sinus thrombosis. Thrombosis was not investigated in other parts of the body.
Figure 1. a) Diffusion magnetic resonance imaging; b) Apparent diffusion coefficient.
Figure 2. a) Cranial magnetic resonance imaging; b) Magnetic resonance imaging venography.
The polymerase chain reaction was repeated and the result was again positive. The patient was then hospitalized with the diagnoses of COVID-19 infection and venous sinus thrombosis. Other genetic, hematological and rheumatological examinations were planned, in order to investigate the etiology of her condition. Anticoagulant treatment (low molecular weight heparin) was started after the patient had been found to present a low platelet count (107,000/mm3), through evaluation of a peripheral blood smear.
Diffuse contractions were observed in a non-stress test (NST), and tocolysis was started, consisting of nifedipine and betamethasone treatment. However, the patient’s labor could not be stopped after 18 hours of hospitalization. She was then admitted for an emergency cesarean section because the intracranial pressure was increasing. A healthy baby was delivered.
Subsequently, the patient’s postpartum headache complaints decreased and her speech became fluent without any change in muscle strength deficit. Her thrombocyte counts decreased to 67,000/mm3. Anticoagulant therapy was continued, with peripheral smear follow-ups. Thoracic computed tomography was performed on the patient, who did not present respiratory distress, and the findings were compatible with COVID-19 pneumonia after birth (Figure 3). There was an increase in infection parameters, and the patient was started on hydroxychloroquine and ceftriaxone treatment.
Figure 3. Thoracic computed tomography.
In the examinations performed to ascertain risk factors, the patient was found to be positive for antinuclear antibodies (ANA) and showed prothrombin heterozygous mutation. The patient was negative for anti-cardiolipin antibodies and anti-double stranded DNA (dsDNA), and tests on lupus anticoagulant, homocysteine, protein C, protein S and antithrombin 3 showed results within normal limits.
On the third day following the birth, the patient’s headache complaint became completely resolved, her thrombocyte counts stopped decreasing and her thrombocytopenia improved over the subsequent days. The infection parameters regressed. Partial regression of the lesions was observed on control thoracic computed tomography. The patient’s general condition stabilized and she was discharged on the 10th day of hospitalization, with muscle strength 4-5/5 on the right side, which was mobilized without support. Continuation of low molecular weight heparin (LMWH) treatment was planned, along with neurological and hematological control tests at a polyclinic.
DISCUSSION
It is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract. Cases of this disease with a wide clinical spectrum are emerging as information is shared.
Although the mechanism for thrombotic events in the course of COVID-19 remains unclear, it is known that there is a tendency for such events to occur within the course of this disease. Pulmonary embolism was shown to be the cause of death in an autopsy series.6 The etiology of embolic events is generally multifactorial: it is accepted that these events are triggered by environmental factors on the basis of genetic predisposition. Nonetheless, no reports on underlying genetic or other acquired causes in cases of COVID-19-positive pulmonary embolism have yet been published in the literature.
An increasing number of case reports and series on COVID-19-positive patients are describing a wide variety of neurological symptoms. Encephalopathy has been reported in a total of 93 patients, including 16 (7%) out of 214 hospitalized patients with COVID-19 in Wuhan, China, and 40 (69%) out of 58 patients in intensive care with COVID-19 in France. To date, encephalitis has been described in eight patients and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the cerebrospinal fluid (CSF) of some patients. Anosmia and agnosia are common and may occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease has also emerged as an important complication: stroke was reported in 2-6% of patients hospitalized with COVID-19 in a cohort study.10
Li et al. stated that in a retrospective study in which 219 COVID-19 positive patients were screened, 10 of these patients (4.6%) were ischemic and one of them presented hemorrhagic cerebrovascular disease (0.5%), after an average of 10 days after the onset of COVID-19. They pointed out that the mean age of these patients was greater and their cardiovascular and cerebrovascular risk factors were more severe.11
COVID-19 is thought to predispose patients to thrombotic pathological conditions in both venous and arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 The initial signs of coagulopathy due to COVID-19 have been found to be marked increases in fibrin/fibrinogen-degradation products and D-dimer levels. It was observed that our patient had high levels of fibrinogen and D-dimer from the time when she was diagnosed with COVID-19 to the time when she was diagnosed with venous sinus thrombosis.
In the early stages of the disease, abnormalities in prothrombin time, partial thromboplastin time and platelet count are uncommon.5 Detection of deep vein thrombosis (58%) as the autopsy finding among more than half of the 12 patients who died of COVID-19, and pulmonary embolism as the cause of death among one third of the patients, has emphasized the importance of not ignoring the tendency towards occurrences of thrombosis in the course of this disease. Hence, anticoagulants should be included during treatment planning.6 Analysis on the data on 184 patients with COVID-19 infection who were monitored in an intensive care unit showed that 31% of them had thrombotic complications. Thus, prophylaxis for thrombosis was strongly recommended for patients hospitalized with this diagnosis.7
On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 Thrombotic microangiopathy is characterized by organ damage such as microangiopathic hemolytic anemia, thrombocytopenia, and neurological, renal and cardiac dysfunction. Thrombocytopenia and neurological deficits were also observed in our patient. In another study, anemia, increased lactate dehydrogenase (LDH), thrombocytopenia and organ damage (neurological in all patients and cardiac in one) were explained by thrombotic microangiopathy in three patients with a diagnosis of COVID-19.9
Cerebral venous thrombus differs significantly from arterial infarctions in terms of risk factors. Hypercoagulability is an important risk factor and an important cause of stroke in young people. Women are affected three times more often than men. The most common symptoms are headache, seizures and focal neurological deficits. The diagnosis can be confirmed by magnetic resonance imaging, computed tomography-venography or catheter angiography.
The primary treatment for venous sinus thrombosis is anticoagulation, based on the limited evidence from randomized trials. Although a small series of cases has indicated that endovascular therapy may be promising, these data require confirmation through a randomized trial. Decompressive surgery can be lifesaving for patients at risk of herniation. The prognosis is generally better than that for arterial stroke.12 Although venous sinus thrombosis was previously considered to be a life-threatening condition, it is known that the mortality rate in these cases declines over time. Moreover, increased clinical awareness, development of neuroimaging techniques and improvement in therapeutic management have provided better prognoses through enabling earlier diagnosis and identification of less severe cases.13
Pregnancy and the puerperium are common causes of transient prothrombotic conditions. About 2% of pregnancy-related strokes can be attributed to venous sinus thrombosis. In the puerperium, the rate of venous sinus thrombosis is 12 cases per 100,000 births. This venous rate in the puerperal period is only slightly lower than that of arterial stroke. Women are at risk of venous thromboembolic events during pregnancy and for up to six to eight weeks after delivery. Most cases of pregnancy-related venous sinus thrombosis are seen in the third trimester or, more often, in the puerperium, when the body prepares for delivery through hypercoagulation. In a paper published in Canada, it was reported that frequency of venous sinus thrombosis in the postpartum period is much higher than during pregnancy. In the puerperium period, the presence of infection and use of instrumental delivery or cesarean section increase the risk of venous sinus thrombosis. During pregnancy, it is known that the risk of venous sinus thrombosis increases in the presence of hypertension, infections and excessive vomiting, and as the maternal age increases.14 The European Academy of Neurology has recommended that treatment for acute venous sinus thrombosis should start with oral anticoagulant therapy (vitamin K antagonists) for 3-12 months, according to risk factors.15
Another risk factor with a relationship to venous sinus thrombosis that is clearly known is inflammation. Venous sinus thrombosis is associated with systemic inflammatory conditions such as Behçet’s disease and inflammatory bowel disease, in addition to infections such as otitis, mastoiditis, sinusitis, dental infections and skin abscesses in neighboring tissues and meningitis.13 In the anamnesis and examination of our patient, no finding suggesting adjacent tissue infection or Behçet’s or inflammatory bowel disease was found.
Antinuclear antibody positivity can be seen in autoimmune diseases, especially systemic lupus erythematosus, but it is not a laboratory test specific to autoimmune diseases. Since antinuclear antibody positivity can be observed in acute or chronic infectious processes,16 it was planned that our patient would undergo this examination after discharge. The anamnesis of our patient was negative for rheumatological diseases.
The etiology of venous sinus thrombosis can be explained in terms of the classical Virchow triad, i.e. blood flow stasis, vessel wall changes and changes in blood content. We believe that the combination of pregnancy and systemic inflammation due to COVID-19 caused thrombosis in our patient, on the basis of genetic prothrombin heterozygous mutation.
One of the clinical manifestations of COVID-19 is nonspecific headache, as is also frequently observed during other viral infections. However, this symptom can often be mild enough to lag behind other clinical findings. If there is no visual impairment, focal neurological deficit or seizure, venous sinus thrombosis can be neglected in the differential diagnosis. Our patient was diagnosed not after occurrences of headache and nausea-vomiting, but after admission to the hospital because of the accompanying symptoms of right hemiparesis. In our case, like what has been described in the literature,11 the central nervous system event started on the ninth day after COVID-19 infection began, and a stroke occurred on the 13th day. Thus, within four days, the rapid clinical progression resulted in parenchymal ischemia. The neurological clinical findings rapidly improved in parallel with the end of pregnancy, start of administration of low molecular weight heparin and decrease in infection parameters.
Reports correlating COVID-19, headache and pregnancy are very rare (Table 1).
Table 1. Search of the literature in medical databases for case reports on COVID-19, pregnancy and headache on November 6, 2020
Database Search strategies Papers found Papers related (to pregnancy, headache and COVID-19) Etiology Main neurological symptom
MEDLINE
(via PubMed)
COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
2 2 Spinal anesthesia 1
Pituitary apoplexy 1
Headache
Cochrane COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
Embase COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
CONCLUSION
Headache is one of the common symptoms of COVID-19. In the presence of other risk factors accompanying COVID-19, the risk of thromboembolic events increases significantly. Among patients with suspected COVID-19, considering venous sinus thrombosis in the differential diagnosis may be life-saving, through enabling early diagnosis and treatment. This is especially so in the presence of causes of hypercoagulability such as pregnancy, malignancy and presence of atypical features like analgesic unresponsiveness, awakening from sleep, visual impairment, neurological deficits or seizures.
1 University of Health Sciences, Konya Education and Research Hospital, Konya, Turkey
Sources of funding: None | ACETAMINOPHEN, BETAMETHASONE, CEFTRIAXONE, HYDROXYCHLOROQUINE, NIFEDIPINE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33605306 | 19,070,603 | 2021 |
What was the administration route of drug 'ACETAMINOPHEN'? | Venous sinus thrombosis during COVID-19 infection in pregnancy: a case report.
Although it is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract, cases of this disease with a wide clinical spectrum are emerging as information is shared.
We present the case of a pregnant woman who was diagnosed with venous sinus thrombosis after she developed headache and hemiparesis. Polymerase chain reaction (PCR) positivity lasted for two weeks after COVID-19 had been diagnosed.
In patients with suspected COVID-19, especially in the presence of causes of hypercoagu- lability and presence of atypical features, venous sinus thrombosis needs to be kept in mind in making the differential diagnosis.
pmcINTRODUCTION
The effects of COVID-19 are not limited to the lungs alone. After the virus enters the body, it causes various symptoms through viremia.1 COVID-19 has been implicated in occurrences of cardiovascular and thromboembolic complications due to systemic inflammation and coagulopathy, in the light of the increasing amount of data that has become available over time.2,3,4,5,6,7,8 On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 It has been suggested that COVID-19 predisposes patients to thrombotic pathological conditions in both the venous and the arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 Nevertheless, cases of neurological and cardiac involvement in COVID-positive patients with TMA have also been reported.9
While the mechanism for the susceptibility to thrombosis that has been seen among COVID-19 patients continues to be debated, we wanted through this report to share information regarding the common venous thrombus of the central nervous system that emerged during the subclinical course of COVID-19 in a pregnant patient, which caused rapid parenchymal infarction.
CASE REPORT
A 22-year-old patient who was 35 weeks pregnant was evaluated in the emergency department with a complaint of right-sided weakness. The COVID-19 polymerase chain reaction test was performed and was found to be positive. However, she did not have fever or respiratory distress and then was followed up at home without medication.
The patient started to have throbbing headaches that did not respond to analgesic treatment (paracetamol 1000 mg/day) for four days. The intensity of her headaches gradually increased, such that she was being awakened from sleep, and this condition was accompanied by nausea and vomiting.
After this four-day period, she again felt weakness on her right side when she woke up in the morning. Twelve hours later, she went back to the emergency department because her weakness was increasing. At the emergency department, the patient was found to be normotensive, conscious, cooperative and oriented in a neurological examination. No fundus examination was performed, given that she was COVID-positive. Examinations on the patient’s visual field and vision showed normal results. Other cranial nerve examinations were normal. Her muscle strength ratio was 3/5 in the upper right extremity, 2/5 in the lower right extremity and 5/5 in the upper and lower left extremities. The foot sole skin reflex of the right lower extremity consisted of an extensor response. She presented decreased speech fluency and had difficulty in word finding, which were diagnosed as mild motor aphasia. Laboratory tests revealed high levels of fibrinogen (899 g/l; normal is 180-400) and D-dimer (6.38 mg/l; normal is 0-2). It was noted that the patient had also had high levels of fibrinogen (665 g/l) and D-dimer (2.2 mg/l) in examinations performed 10 days previously.
Diffusion magnetic resonance imaging (MRI) showed cortical diffusion restriction in the left parietal region (Figure 1a) and a hypointense response in the apparent diffusion coefficient (ADC) (Figure 1b). The result from the diffusion MRI was suggestive of venous sinus thrombosis. Widespread loss of flow in the superior sagittal sinus and right transverse sinus, suggesting partial venous thrombosis in the left transverse sinus, was observed in brain magnetic resonance imaging (Figure 2a) and magnetic resonance venous angiography (Figure 2b). The brain MRI and magnetic resonance venography confirmed the diagnosis of venous sinus thrombosis. Thrombosis was not investigated in other parts of the body.
Figure 1. a) Diffusion magnetic resonance imaging; b) Apparent diffusion coefficient.
Figure 2. a) Cranial magnetic resonance imaging; b) Magnetic resonance imaging venography.
The polymerase chain reaction was repeated and the result was again positive. The patient was then hospitalized with the diagnoses of COVID-19 infection and venous sinus thrombosis. Other genetic, hematological and rheumatological examinations were planned, in order to investigate the etiology of her condition. Anticoagulant treatment (low molecular weight heparin) was started after the patient had been found to present a low platelet count (107,000/mm3), through evaluation of a peripheral blood smear.
Diffuse contractions were observed in a non-stress test (NST), and tocolysis was started, consisting of nifedipine and betamethasone treatment. However, the patient’s labor could not be stopped after 18 hours of hospitalization. She was then admitted for an emergency cesarean section because the intracranial pressure was increasing. A healthy baby was delivered.
Subsequently, the patient’s postpartum headache complaints decreased and her speech became fluent without any change in muscle strength deficit. Her thrombocyte counts decreased to 67,000/mm3. Anticoagulant therapy was continued, with peripheral smear follow-ups. Thoracic computed tomography was performed on the patient, who did not present respiratory distress, and the findings were compatible with COVID-19 pneumonia after birth (Figure 3). There was an increase in infection parameters, and the patient was started on hydroxychloroquine and ceftriaxone treatment.
Figure 3. Thoracic computed tomography.
In the examinations performed to ascertain risk factors, the patient was found to be positive for antinuclear antibodies (ANA) and showed prothrombin heterozygous mutation. The patient was negative for anti-cardiolipin antibodies and anti-double stranded DNA (dsDNA), and tests on lupus anticoagulant, homocysteine, protein C, protein S and antithrombin 3 showed results within normal limits.
On the third day following the birth, the patient’s headache complaint became completely resolved, her thrombocyte counts stopped decreasing and her thrombocytopenia improved over the subsequent days. The infection parameters regressed. Partial regression of the lesions was observed on control thoracic computed tomography. The patient’s general condition stabilized and she was discharged on the 10th day of hospitalization, with muscle strength 4-5/5 on the right side, which was mobilized without support. Continuation of low molecular weight heparin (LMWH) treatment was planned, along with neurological and hematological control tests at a polyclinic.
DISCUSSION
It is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract. Cases of this disease with a wide clinical spectrum are emerging as information is shared.
Although the mechanism for thrombotic events in the course of COVID-19 remains unclear, it is known that there is a tendency for such events to occur within the course of this disease. Pulmonary embolism was shown to be the cause of death in an autopsy series.6 The etiology of embolic events is generally multifactorial: it is accepted that these events are triggered by environmental factors on the basis of genetic predisposition. Nonetheless, no reports on underlying genetic or other acquired causes in cases of COVID-19-positive pulmonary embolism have yet been published in the literature.
An increasing number of case reports and series on COVID-19-positive patients are describing a wide variety of neurological symptoms. Encephalopathy has been reported in a total of 93 patients, including 16 (7%) out of 214 hospitalized patients with COVID-19 in Wuhan, China, and 40 (69%) out of 58 patients in intensive care with COVID-19 in France. To date, encephalitis has been described in eight patients and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the cerebrospinal fluid (CSF) of some patients. Anosmia and agnosia are common and may occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease has also emerged as an important complication: stroke was reported in 2-6% of patients hospitalized with COVID-19 in a cohort study.10
Li et al. stated that in a retrospective study in which 219 COVID-19 positive patients were screened, 10 of these patients (4.6%) were ischemic and one of them presented hemorrhagic cerebrovascular disease (0.5%), after an average of 10 days after the onset of COVID-19. They pointed out that the mean age of these patients was greater and their cardiovascular and cerebrovascular risk factors were more severe.11
COVID-19 is thought to predispose patients to thrombotic pathological conditions in both venous and arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 The initial signs of coagulopathy due to COVID-19 have been found to be marked increases in fibrin/fibrinogen-degradation products and D-dimer levels. It was observed that our patient had high levels of fibrinogen and D-dimer from the time when she was diagnosed with COVID-19 to the time when she was diagnosed with venous sinus thrombosis.
In the early stages of the disease, abnormalities in prothrombin time, partial thromboplastin time and platelet count are uncommon.5 Detection of deep vein thrombosis (58%) as the autopsy finding among more than half of the 12 patients who died of COVID-19, and pulmonary embolism as the cause of death among one third of the patients, has emphasized the importance of not ignoring the tendency towards occurrences of thrombosis in the course of this disease. Hence, anticoagulants should be included during treatment planning.6 Analysis on the data on 184 patients with COVID-19 infection who were monitored in an intensive care unit showed that 31% of them had thrombotic complications. Thus, prophylaxis for thrombosis was strongly recommended for patients hospitalized with this diagnosis.7
On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 Thrombotic microangiopathy is characterized by organ damage such as microangiopathic hemolytic anemia, thrombocytopenia, and neurological, renal and cardiac dysfunction. Thrombocytopenia and neurological deficits were also observed in our patient. In another study, anemia, increased lactate dehydrogenase (LDH), thrombocytopenia and organ damage (neurological in all patients and cardiac in one) were explained by thrombotic microangiopathy in three patients with a diagnosis of COVID-19.9
Cerebral venous thrombus differs significantly from arterial infarctions in terms of risk factors. Hypercoagulability is an important risk factor and an important cause of stroke in young people. Women are affected three times more often than men. The most common symptoms are headache, seizures and focal neurological deficits. The diagnosis can be confirmed by magnetic resonance imaging, computed tomography-venography or catheter angiography.
The primary treatment for venous sinus thrombosis is anticoagulation, based on the limited evidence from randomized trials. Although a small series of cases has indicated that endovascular therapy may be promising, these data require confirmation through a randomized trial. Decompressive surgery can be lifesaving for patients at risk of herniation. The prognosis is generally better than that for arterial stroke.12 Although venous sinus thrombosis was previously considered to be a life-threatening condition, it is known that the mortality rate in these cases declines over time. Moreover, increased clinical awareness, development of neuroimaging techniques and improvement in therapeutic management have provided better prognoses through enabling earlier diagnosis and identification of less severe cases.13
Pregnancy and the puerperium are common causes of transient prothrombotic conditions. About 2% of pregnancy-related strokes can be attributed to venous sinus thrombosis. In the puerperium, the rate of venous sinus thrombosis is 12 cases per 100,000 births. This venous rate in the puerperal period is only slightly lower than that of arterial stroke. Women are at risk of venous thromboembolic events during pregnancy and for up to six to eight weeks after delivery. Most cases of pregnancy-related venous sinus thrombosis are seen in the third trimester or, more often, in the puerperium, when the body prepares for delivery through hypercoagulation. In a paper published in Canada, it was reported that frequency of venous sinus thrombosis in the postpartum period is much higher than during pregnancy. In the puerperium period, the presence of infection and use of instrumental delivery or cesarean section increase the risk of venous sinus thrombosis. During pregnancy, it is known that the risk of venous sinus thrombosis increases in the presence of hypertension, infections and excessive vomiting, and as the maternal age increases.14 The European Academy of Neurology has recommended that treatment for acute venous sinus thrombosis should start with oral anticoagulant therapy (vitamin K antagonists) for 3-12 months, according to risk factors.15
Another risk factor with a relationship to venous sinus thrombosis that is clearly known is inflammation. Venous sinus thrombosis is associated with systemic inflammatory conditions such as Behçet’s disease and inflammatory bowel disease, in addition to infections such as otitis, mastoiditis, sinusitis, dental infections and skin abscesses in neighboring tissues and meningitis.13 In the anamnesis and examination of our patient, no finding suggesting adjacent tissue infection or Behçet’s or inflammatory bowel disease was found.
Antinuclear antibody positivity can be seen in autoimmune diseases, especially systemic lupus erythematosus, but it is not a laboratory test specific to autoimmune diseases. Since antinuclear antibody positivity can be observed in acute or chronic infectious processes,16 it was planned that our patient would undergo this examination after discharge. The anamnesis of our patient was negative for rheumatological diseases.
The etiology of venous sinus thrombosis can be explained in terms of the classical Virchow triad, i.e. blood flow stasis, vessel wall changes and changes in blood content. We believe that the combination of pregnancy and systemic inflammation due to COVID-19 caused thrombosis in our patient, on the basis of genetic prothrombin heterozygous mutation.
One of the clinical manifestations of COVID-19 is nonspecific headache, as is also frequently observed during other viral infections. However, this symptom can often be mild enough to lag behind other clinical findings. If there is no visual impairment, focal neurological deficit or seizure, venous sinus thrombosis can be neglected in the differential diagnosis. Our patient was diagnosed not after occurrences of headache and nausea-vomiting, but after admission to the hospital because of the accompanying symptoms of right hemiparesis. In our case, like what has been described in the literature,11 the central nervous system event started on the ninth day after COVID-19 infection began, and a stroke occurred on the 13th day. Thus, within four days, the rapid clinical progression resulted in parenchymal ischemia. The neurological clinical findings rapidly improved in parallel with the end of pregnancy, start of administration of low molecular weight heparin and decrease in infection parameters.
Reports correlating COVID-19, headache and pregnancy are very rare (Table 1).
Table 1. Search of the literature in medical databases for case reports on COVID-19, pregnancy and headache on November 6, 2020
Database Search strategies Papers found Papers related (to pregnancy, headache and COVID-19) Etiology Main neurological symptom
MEDLINE
(via PubMed)
COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
2 2 Spinal anesthesia 1
Pituitary apoplexy 1
Headache
Cochrane COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
Embase COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
CONCLUSION
Headache is one of the common symptoms of COVID-19. In the presence of other risk factors accompanying COVID-19, the risk of thromboembolic events increases significantly. Among patients with suspected COVID-19, considering venous sinus thrombosis in the differential diagnosis may be life-saving, through enabling early diagnosis and treatment. This is especially so in the presence of causes of hypercoagulability such as pregnancy, malignancy and presence of atypical features like analgesic unresponsiveness, awakening from sleep, visual impairment, neurological deficits or seizures.
1 University of Health Sciences, Konya Education and Research Hospital, Konya, Turkey
Sources of funding: None | Transplacental | DrugAdministrationRoute | CC BY | 33605306 | 19,062,445 | 2021 |
What was the administration route of drug 'BETAMETHASONE'? | Venous sinus thrombosis during COVID-19 infection in pregnancy: a case report.
Although it is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract, cases of this disease with a wide clinical spectrum are emerging as information is shared.
We present the case of a pregnant woman who was diagnosed with venous sinus thrombosis after she developed headache and hemiparesis. Polymerase chain reaction (PCR) positivity lasted for two weeks after COVID-19 had been diagnosed.
In patients with suspected COVID-19, especially in the presence of causes of hypercoagu- lability and presence of atypical features, venous sinus thrombosis needs to be kept in mind in making the differential diagnosis.
pmcINTRODUCTION
The effects of COVID-19 are not limited to the lungs alone. After the virus enters the body, it causes various symptoms through viremia.1 COVID-19 has been implicated in occurrences of cardiovascular and thromboembolic complications due to systemic inflammation and coagulopathy, in the light of the increasing amount of data that has become available over time.2,3,4,5,6,7,8 On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 It has been suggested that COVID-19 predisposes patients to thrombotic pathological conditions in both the venous and the arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 Nevertheless, cases of neurological and cardiac involvement in COVID-positive patients with TMA have also been reported.9
While the mechanism for the susceptibility to thrombosis that has been seen among COVID-19 patients continues to be debated, we wanted through this report to share information regarding the common venous thrombus of the central nervous system that emerged during the subclinical course of COVID-19 in a pregnant patient, which caused rapid parenchymal infarction.
CASE REPORT
A 22-year-old patient who was 35 weeks pregnant was evaluated in the emergency department with a complaint of right-sided weakness. The COVID-19 polymerase chain reaction test was performed and was found to be positive. However, she did not have fever or respiratory distress and then was followed up at home without medication.
The patient started to have throbbing headaches that did not respond to analgesic treatment (paracetamol 1000 mg/day) for four days. The intensity of her headaches gradually increased, such that she was being awakened from sleep, and this condition was accompanied by nausea and vomiting.
After this four-day period, she again felt weakness on her right side when she woke up in the morning. Twelve hours later, she went back to the emergency department because her weakness was increasing. At the emergency department, the patient was found to be normotensive, conscious, cooperative and oriented in a neurological examination. No fundus examination was performed, given that she was COVID-positive. Examinations on the patient’s visual field and vision showed normal results. Other cranial nerve examinations were normal. Her muscle strength ratio was 3/5 in the upper right extremity, 2/5 in the lower right extremity and 5/5 in the upper and lower left extremities. The foot sole skin reflex of the right lower extremity consisted of an extensor response. She presented decreased speech fluency and had difficulty in word finding, which were diagnosed as mild motor aphasia. Laboratory tests revealed high levels of fibrinogen (899 g/l; normal is 180-400) and D-dimer (6.38 mg/l; normal is 0-2). It was noted that the patient had also had high levels of fibrinogen (665 g/l) and D-dimer (2.2 mg/l) in examinations performed 10 days previously.
Diffusion magnetic resonance imaging (MRI) showed cortical diffusion restriction in the left parietal region (Figure 1a) and a hypointense response in the apparent diffusion coefficient (ADC) (Figure 1b). The result from the diffusion MRI was suggestive of venous sinus thrombosis. Widespread loss of flow in the superior sagittal sinus and right transverse sinus, suggesting partial venous thrombosis in the left transverse sinus, was observed in brain magnetic resonance imaging (Figure 2a) and magnetic resonance venous angiography (Figure 2b). The brain MRI and magnetic resonance venography confirmed the diagnosis of venous sinus thrombosis. Thrombosis was not investigated in other parts of the body.
Figure 1. a) Diffusion magnetic resonance imaging; b) Apparent diffusion coefficient.
Figure 2. a) Cranial magnetic resonance imaging; b) Magnetic resonance imaging venography.
The polymerase chain reaction was repeated and the result was again positive. The patient was then hospitalized with the diagnoses of COVID-19 infection and venous sinus thrombosis. Other genetic, hematological and rheumatological examinations were planned, in order to investigate the etiology of her condition. Anticoagulant treatment (low molecular weight heparin) was started after the patient had been found to present a low platelet count (107,000/mm3), through evaluation of a peripheral blood smear.
Diffuse contractions were observed in a non-stress test (NST), and tocolysis was started, consisting of nifedipine and betamethasone treatment. However, the patient’s labor could not be stopped after 18 hours of hospitalization. She was then admitted for an emergency cesarean section because the intracranial pressure was increasing. A healthy baby was delivered.
Subsequently, the patient’s postpartum headache complaints decreased and her speech became fluent without any change in muscle strength deficit. Her thrombocyte counts decreased to 67,000/mm3. Anticoagulant therapy was continued, with peripheral smear follow-ups. Thoracic computed tomography was performed on the patient, who did not present respiratory distress, and the findings were compatible with COVID-19 pneumonia after birth (Figure 3). There was an increase in infection parameters, and the patient was started on hydroxychloroquine and ceftriaxone treatment.
Figure 3. Thoracic computed tomography.
In the examinations performed to ascertain risk factors, the patient was found to be positive for antinuclear antibodies (ANA) and showed prothrombin heterozygous mutation. The patient was negative for anti-cardiolipin antibodies and anti-double stranded DNA (dsDNA), and tests on lupus anticoagulant, homocysteine, protein C, protein S and antithrombin 3 showed results within normal limits.
On the third day following the birth, the patient’s headache complaint became completely resolved, her thrombocyte counts stopped decreasing and her thrombocytopenia improved over the subsequent days. The infection parameters regressed. Partial regression of the lesions was observed on control thoracic computed tomography. The patient’s general condition stabilized and she was discharged on the 10th day of hospitalization, with muscle strength 4-5/5 on the right side, which was mobilized without support. Continuation of low molecular weight heparin (LMWH) treatment was planned, along with neurological and hematological control tests at a polyclinic.
DISCUSSION
It is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract. Cases of this disease with a wide clinical spectrum are emerging as information is shared.
Although the mechanism for thrombotic events in the course of COVID-19 remains unclear, it is known that there is a tendency for such events to occur within the course of this disease. Pulmonary embolism was shown to be the cause of death in an autopsy series.6 The etiology of embolic events is generally multifactorial: it is accepted that these events are triggered by environmental factors on the basis of genetic predisposition. Nonetheless, no reports on underlying genetic or other acquired causes in cases of COVID-19-positive pulmonary embolism have yet been published in the literature.
An increasing number of case reports and series on COVID-19-positive patients are describing a wide variety of neurological symptoms. Encephalopathy has been reported in a total of 93 patients, including 16 (7%) out of 214 hospitalized patients with COVID-19 in Wuhan, China, and 40 (69%) out of 58 patients in intensive care with COVID-19 in France. To date, encephalitis has been described in eight patients and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the cerebrospinal fluid (CSF) of some patients. Anosmia and agnosia are common and may occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease has also emerged as an important complication: stroke was reported in 2-6% of patients hospitalized with COVID-19 in a cohort study.10
Li et al. stated that in a retrospective study in which 219 COVID-19 positive patients were screened, 10 of these patients (4.6%) were ischemic and one of them presented hemorrhagic cerebrovascular disease (0.5%), after an average of 10 days after the onset of COVID-19. They pointed out that the mean age of these patients was greater and their cardiovascular and cerebrovascular risk factors were more severe.11
COVID-19 is thought to predispose patients to thrombotic pathological conditions in both venous and arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 The initial signs of coagulopathy due to COVID-19 have been found to be marked increases in fibrin/fibrinogen-degradation products and D-dimer levels. It was observed that our patient had high levels of fibrinogen and D-dimer from the time when she was diagnosed with COVID-19 to the time when she was diagnosed with venous sinus thrombosis.
In the early stages of the disease, abnormalities in prothrombin time, partial thromboplastin time and platelet count are uncommon.5 Detection of deep vein thrombosis (58%) as the autopsy finding among more than half of the 12 patients who died of COVID-19, and pulmonary embolism as the cause of death among one third of the patients, has emphasized the importance of not ignoring the tendency towards occurrences of thrombosis in the course of this disease. Hence, anticoagulants should be included during treatment planning.6 Analysis on the data on 184 patients with COVID-19 infection who were monitored in an intensive care unit showed that 31% of them had thrombotic complications. Thus, prophylaxis for thrombosis was strongly recommended for patients hospitalized with this diagnosis.7
On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 Thrombotic microangiopathy is characterized by organ damage such as microangiopathic hemolytic anemia, thrombocytopenia, and neurological, renal and cardiac dysfunction. Thrombocytopenia and neurological deficits were also observed in our patient. In another study, anemia, increased lactate dehydrogenase (LDH), thrombocytopenia and organ damage (neurological in all patients and cardiac in one) were explained by thrombotic microangiopathy in three patients with a diagnosis of COVID-19.9
Cerebral venous thrombus differs significantly from arterial infarctions in terms of risk factors. Hypercoagulability is an important risk factor and an important cause of stroke in young people. Women are affected three times more often than men. The most common symptoms are headache, seizures and focal neurological deficits. The diagnosis can be confirmed by magnetic resonance imaging, computed tomography-venography or catheter angiography.
The primary treatment for venous sinus thrombosis is anticoagulation, based on the limited evidence from randomized trials. Although a small series of cases has indicated that endovascular therapy may be promising, these data require confirmation through a randomized trial. Decompressive surgery can be lifesaving for patients at risk of herniation. The prognosis is generally better than that for arterial stroke.12 Although venous sinus thrombosis was previously considered to be a life-threatening condition, it is known that the mortality rate in these cases declines over time. Moreover, increased clinical awareness, development of neuroimaging techniques and improvement in therapeutic management have provided better prognoses through enabling earlier diagnosis and identification of less severe cases.13
Pregnancy and the puerperium are common causes of transient prothrombotic conditions. About 2% of pregnancy-related strokes can be attributed to venous sinus thrombosis. In the puerperium, the rate of venous sinus thrombosis is 12 cases per 100,000 births. This venous rate in the puerperal period is only slightly lower than that of arterial stroke. Women are at risk of venous thromboembolic events during pregnancy and for up to six to eight weeks after delivery. Most cases of pregnancy-related venous sinus thrombosis are seen in the third trimester or, more often, in the puerperium, when the body prepares for delivery through hypercoagulation. In a paper published in Canada, it was reported that frequency of venous sinus thrombosis in the postpartum period is much higher than during pregnancy. In the puerperium period, the presence of infection and use of instrumental delivery or cesarean section increase the risk of venous sinus thrombosis. During pregnancy, it is known that the risk of venous sinus thrombosis increases in the presence of hypertension, infections and excessive vomiting, and as the maternal age increases.14 The European Academy of Neurology has recommended that treatment for acute venous sinus thrombosis should start with oral anticoagulant therapy (vitamin K antagonists) for 3-12 months, according to risk factors.15
Another risk factor with a relationship to venous sinus thrombosis that is clearly known is inflammation. Venous sinus thrombosis is associated with systemic inflammatory conditions such as Behçet’s disease and inflammatory bowel disease, in addition to infections such as otitis, mastoiditis, sinusitis, dental infections and skin abscesses in neighboring tissues and meningitis.13 In the anamnesis and examination of our patient, no finding suggesting adjacent tissue infection or Behçet’s or inflammatory bowel disease was found.
Antinuclear antibody positivity can be seen in autoimmune diseases, especially systemic lupus erythematosus, but it is not a laboratory test specific to autoimmune diseases. Since antinuclear antibody positivity can be observed in acute or chronic infectious processes,16 it was planned that our patient would undergo this examination after discharge. The anamnesis of our patient was negative for rheumatological diseases.
The etiology of venous sinus thrombosis can be explained in terms of the classical Virchow triad, i.e. blood flow stasis, vessel wall changes and changes in blood content. We believe that the combination of pregnancy and systemic inflammation due to COVID-19 caused thrombosis in our patient, on the basis of genetic prothrombin heterozygous mutation.
One of the clinical manifestations of COVID-19 is nonspecific headache, as is also frequently observed during other viral infections. However, this symptom can often be mild enough to lag behind other clinical findings. If there is no visual impairment, focal neurological deficit or seizure, venous sinus thrombosis can be neglected in the differential diagnosis. Our patient was diagnosed not after occurrences of headache and nausea-vomiting, but after admission to the hospital because of the accompanying symptoms of right hemiparesis. In our case, like what has been described in the literature,11 the central nervous system event started on the ninth day after COVID-19 infection began, and a stroke occurred on the 13th day. Thus, within four days, the rapid clinical progression resulted in parenchymal ischemia. The neurological clinical findings rapidly improved in parallel with the end of pregnancy, start of administration of low molecular weight heparin and decrease in infection parameters.
Reports correlating COVID-19, headache and pregnancy are very rare (Table 1).
Table 1. Search of the literature in medical databases for case reports on COVID-19, pregnancy and headache on November 6, 2020
Database Search strategies Papers found Papers related (to pregnancy, headache and COVID-19) Etiology Main neurological symptom
MEDLINE
(via PubMed)
COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
2 2 Spinal anesthesia 1
Pituitary apoplexy 1
Headache
Cochrane COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
Embase COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
CONCLUSION
Headache is one of the common symptoms of COVID-19. In the presence of other risk factors accompanying COVID-19, the risk of thromboembolic events increases significantly. Among patients with suspected COVID-19, considering venous sinus thrombosis in the differential diagnosis may be life-saving, through enabling early diagnosis and treatment. This is especially so in the presence of causes of hypercoagulability such as pregnancy, malignancy and presence of atypical features like analgesic unresponsiveness, awakening from sleep, visual impairment, neurological deficits or seizures.
1 University of Health Sciences, Konya Education and Research Hospital, Konya, Turkey
Sources of funding: None | Transplacental | DrugAdministrationRoute | CC BY | 33605306 | 19,062,445 | 2021 |
What was the administration route of drug 'NIFEDIPINE'? | Venous sinus thrombosis during COVID-19 infection in pregnancy: a case report.
Although it is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract, cases of this disease with a wide clinical spectrum are emerging as information is shared.
We present the case of a pregnant woman who was diagnosed with venous sinus thrombosis after she developed headache and hemiparesis. Polymerase chain reaction (PCR) positivity lasted for two weeks after COVID-19 had been diagnosed.
In patients with suspected COVID-19, especially in the presence of causes of hypercoagu- lability and presence of atypical features, venous sinus thrombosis needs to be kept in mind in making the differential diagnosis.
pmcINTRODUCTION
The effects of COVID-19 are not limited to the lungs alone. After the virus enters the body, it causes various symptoms through viremia.1 COVID-19 has been implicated in occurrences of cardiovascular and thromboembolic complications due to systemic inflammation and coagulopathy, in the light of the increasing amount of data that has become available over time.2,3,4,5,6,7,8 On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 It has been suggested that COVID-19 predisposes patients to thrombotic pathological conditions in both the venous and the arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 Nevertheless, cases of neurological and cardiac involvement in COVID-positive patients with TMA have also been reported.9
While the mechanism for the susceptibility to thrombosis that has been seen among COVID-19 patients continues to be debated, we wanted through this report to share information regarding the common venous thrombus of the central nervous system that emerged during the subclinical course of COVID-19 in a pregnant patient, which caused rapid parenchymal infarction.
CASE REPORT
A 22-year-old patient who was 35 weeks pregnant was evaluated in the emergency department with a complaint of right-sided weakness. The COVID-19 polymerase chain reaction test was performed and was found to be positive. However, she did not have fever or respiratory distress and then was followed up at home without medication.
The patient started to have throbbing headaches that did not respond to analgesic treatment (paracetamol 1000 mg/day) for four days. The intensity of her headaches gradually increased, such that she was being awakened from sleep, and this condition was accompanied by nausea and vomiting.
After this four-day period, she again felt weakness on her right side when she woke up in the morning. Twelve hours later, she went back to the emergency department because her weakness was increasing. At the emergency department, the patient was found to be normotensive, conscious, cooperative and oriented in a neurological examination. No fundus examination was performed, given that she was COVID-positive. Examinations on the patient’s visual field and vision showed normal results. Other cranial nerve examinations were normal. Her muscle strength ratio was 3/5 in the upper right extremity, 2/5 in the lower right extremity and 5/5 in the upper and lower left extremities. The foot sole skin reflex of the right lower extremity consisted of an extensor response. She presented decreased speech fluency and had difficulty in word finding, which were diagnosed as mild motor aphasia. Laboratory tests revealed high levels of fibrinogen (899 g/l; normal is 180-400) and D-dimer (6.38 mg/l; normal is 0-2). It was noted that the patient had also had high levels of fibrinogen (665 g/l) and D-dimer (2.2 mg/l) in examinations performed 10 days previously.
Diffusion magnetic resonance imaging (MRI) showed cortical diffusion restriction in the left parietal region (Figure 1a) and a hypointense response in the apparent diffusion coefficient (ADC) (Figure 1b). The result from the diffusion MRI was suggestive of venous sinus thrombosis. Widespread loss of flow in the superior sagittal sinus and right transverse sinus, suggesting partial venous thrombosis in the left transverse sinus, was observed in brain magnetic resonance imaging (Figure 2a) and magnetic resonance venous angiography (Figure 2b). The brain MRI and magnetic resonance venography confirmed the diagnosis of venous sinus thrombosis. Thrombosis was not investigated in other parts of the body.
Figure 1. a) Diffusion magnetic resonance imaging; b) Apparent diffusion coefficient.
Figure 2. a) Cranial magnetic resonance imaging; b) Magnetic resonance imaging venography.
The polymerase chain reaction was repeated and the result was again positive. The patient was then hospitalized with the diagnoses of COVID-19 infection and venous sinus thrombosis. Other genetic, hematological and rheumatological examinations were planned, in order to investigate the etiology of her condition. Anticoagulant treatment (low molecular weight heparin) was started after the patient had been found to present a low platelet count (107,000/mm3), through evaluation of a peripheral blood smear.
Diffuse contractions were observed in a non-stress test (NST), and tocolysis was started, consisting of nifedipine and betamethasone treatment. However, the patient’s labor could not be stopped after 18 hours of hospitalization. She was then admitted for an emergency cesarean section because the intracranial pressure was increasing. A healthy baby was delivered.
Subsequently, the patient’s postpartum headache complaints decreased and her speech became fluent without any change in muscle strength deficit. Her thrombocyte counts decreased to 67,000/mm3. Anticoagulant therapy was continued, with peripheral smear follow-ups. Thoracic computed tomography was performed on the patient, who did not present respiratory distress, and the findings were compatible with COVID-19 pneumonia after birth (Figure 3). There was an increase in infection parameters, and the patient was started on hydroxychloroquine and ceftriaxone treatment.
Figure 3. Thoracic computed tomography.
In the examinations performed to ascertain risk factors, the patient was found to be positive for antinuclear antibodies (ANA) and showed prothrombin heterozygous mutation. The patient was negative for anti-cardiolipin antibodies and anti-double stranded DNA (dsDNA), and tests on lupus anticoagulant, homocysteine, protein C, protein S and antithrombin 3 showed results within normal limits.
On the third day following the birth, the patient’s headache complaint became completely resolved, her thrombocyte counts stopped decreasing and her thrombocytopenia improved over the subsequent days. The infection parameters regressed. Partial regression of the lesions was observed on control thoracic computed tomography. The patient’s general condition stabilized and she was discharged on the 10th day of hospitalization, with muscle strength 4-5/5 on the right side, which was mobilized without support. Continuation of low molecular weight heparin (LMWH) treatment was planned, along with neurological and hematological control tests at a polyclinic.
DISCUSSION
It is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract. Cases of this disease with a wide clinical spectrum are emerging as information is shared.
Although the mechanism for thrombotic events in the course of COVID-19 remains unclear, it is known that there is a tendency for such events to occur within the course of this disease. Pulmonary embolism was shown to be the cause of death in an autopsy series.6 The etiology of embolic events is generally multifactorial: it is accepted that these events are triggered by environmental factors on the basis of genetic predisposition. Nonetheless, no reports on underlying genetic or other acquired causes in cases of COVID-19-positive pulmonary embolism have yet been published in the literature.
An increasing number of case reports and series on COVID-19-positive patients are describing a wide variety of neurological symptoms. Encephalopathy has been reported in a total of 93 patients, including 16 (7%) out of 214 hospitalized patients with COVID-19 in Wuhan, China, and 40 (69%) out of 58 patients in intensive care with COVID-19 in France. To date, encephalitis has been described in eight patients and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the cerebrospinal fluid (CSF) of some patients. Anosmia and agnosia are common and may occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease has also emerged as an important complication: stroke was reported in 2-6% of patients hospitalized with COVID-19 in a cohort study.10
Li et al. stated that in a retrospective study in which 219 COVID-19 positive patients were screened, 10 of these patients (4.6%) were ischemic and one of them presented hemorrhagic cerebrovascular disease (0.5%), after an average of 10 days after the onset of COVID-19. They pointed out that the mean age of these patients was greater and their cardiovascular and cerebrovascular risk factors were more severe.11
COVID-19 is thought to predispose patients to thrombotic pathological conditions in both venous and arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 The initial signs of coagulopathy due to COVID-19 have been found to be marked increases in fibrin/fibrinogen-degradation products and D-dimer levels. It was observed that our patient had high levels of fibrinogen and D-dimer from the time when she was diagnosed with COVID-19 to the time when she was diagnosed with venous sinus thrombosis.
In the early stages of the disease, abnormalities in prothrombin time, partial thromboplastin time and platelet count are uncommon.5 Detection of deep vein thrombosis (58%) as the autopsy finding among more than half of the 12 patients who died of COVID-19, and pulmonary embolism as the cause of death among one third of the patients, has emphasized the importance of not ignoring the tendency towards occurrences of thrombosis in the course of this disease. Hence, anticoagulants should be included during treatment planning.6 Analysis on the data on 184 patients with COVID-19 infection who were monitored in an intensive care unit showed that 31% of them had thrombotic complications. Thus, prophylaxis for thrombosis was strongly recommended for patients hospitalized with this diagnosis.7
On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 Thrombotic microangiopathy is characterized by organ damage such as microangiopathic hemolytic anemia, thrombocytopenia, and neurological, renal and cardiac dysfunction. Thrombocytopenia and neurological deficits were also observed in our patient. In another study, anemia, increased lactate dehydrogenase (LDH), thrombocytopenia and organ damage (neurological in all patients and cardiac in one) were explained by thrombotic microangiopathy in three patients with a diagnosis of COVID-19.9
Cerebral venous thrombus differs significantly from arterial infarctions in terms of risk factors. Hypercoagulability is an important risk factor and an important cause of stroke in young people. Women are affected three times more often than men. The most common symptoms are headache, seizures and focal neurological deficits. The diagnosis can be confirmed by magnetic resonance imaging, computed tomography-venography or catheter angiography.
The primary treatment for venous sinus thrombosis is anticoagulation, based on the limited evidence from randomized trials. Although a small series of cases has indicated that endovascular therapy may be promising, these data require confirmation through a randomized trial. Decompressive surgery can be lifesaving for patients at risk of herniation. The prognosis is generally better than that for arterial stroke.12 Although venous sinus thrombosis was previously considered to be a life-threatening condition, it is known that the mortality rate in these cases declines over time. Moreover, increased clinical awareness, development of neuroimaging techniques and improvement in therapeutic management have provided better prognoses through enabling earlier diagnosis and identification of less severe cases.13
Pregnancy and the puerperium are common causes of transient prothrombotic conditions. About 2% of pregnancy-related strokes can be attributed to venous sinus thrombosis. In the puerperium, the rate of venous sinus thrombosis is 12 cases per 100,000 births. This venous rate in the puerperal period is only slightly lower than that of arterial stroke. Women are at risk of venous thromboembolic events during pregnancy and for up to six to eight weeks after delivery. Most cases of pregnancy-related venous sinus thrombosis are seen in the third trimester or, more often, in the puerperium, when the body prepares for delivery through hypercoagulation. In a paper published in Canada, it was reported that frequency of venous sinus thrombosis in the postpartum period is much higher than during pregnancy. In the puerperium period, the presence of infection and use of instrumental delivery or cesarean section increase the risk of venous sinus thrombosis. During pregnancy, it is known that the risk of venous sinus thrombosis increases in the presence of hypertension, infections and excessive vomiting, and as the maternal age increases.14 The European Academy of Neurology has recommended that treatment for acute venous sinus thrombosis should start with oral anticoagulant therapy (vitamin K antagonists) for 3-12 months, according to risk factors.15
Another risk factor with a relationship to venous sinus thrombosis that is clearly known is inflammation. Venous sinus thrombosis is associated with systemic inflammatory conditions such as Behçet’s disease and inflammatory bowel disease, in addition to infections such as otitis, mastoiditis, sinusitis, dental infections and skin abscesses in neighboring tissues and meningitis.13 In the anamnesis and examination of our patient, no finding suggesting adjacent tissue infection or Behçet’s or inflammatory bowel disease was found.
Antinuclear antibody positivity can be seen in autoimmune diseases, especially systemic lupus erythematosus, but it is not a laboratory test specific to autoimmune diseases. Since antinuclear antibody positivity can be observed in acute or chronic infectious processes,16 it was planned that our patient would undergo this examination after discharge. The anamnesis of our patient was negative for rheumatological diseases.
The etiology of venous sinus thrombosis can be explained in terms of the classical Virchow triad, i.e. blood flow stasis, vessel wall changes and changes in blood content. We believe that the combination of pregnancy and systemic inflammation due to COVID-19 caused thrombosis in our patient, on the basis of genetic prothrombin heterozygous mutation.
One of the clinical manifestations of COVID-19 is nonspecific headache, as is also frequently observed during other viral infections. However, this symptom can often be mild enough to lag behind other clinical findings. If there is no visual impairment, focal neurological deficit or seizure, venous sinus thrombosis can be neglected in the differential diagnosis. Our patient was diagnosed not after occurrences of headache and nausea-vomiting, but after admission to the hospital because of the accompanying symptoms of right hemiparesis. In our case, like what has been described in the literature,11 the central nervous system event started on the ninth day after COVID-19 infection began, and a stroke occurred on the 13th day. Thus, within four days, the rapid clinical progression resulted in parenchymal ischemia. The neurological clinical findings rapidly improved in parallel with the end of pregnancy, start of administration of low molecular weight heparin and decrease in infection parameters.
Reports correlating COVID-19, headache and pregnancy are very rare (Table 1).
Table 1. Search of the literature in medical databases for case reports on COVID-19, pregnancy and headache on November 6, 2020
Database Search strategies Papers found Papers related (to pregnancy, headache and COVID-19) Etiology Main neurological symptom
MEDLINE
(via PubMed)
COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
2 2 Spinal anesthesia 1
Pituitary apoplexy 1
Headache
Cochrane COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
Embase COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
CONCLUSION
Headache is one of the common symptoms of COVID-19. In the presence of other risk factors accompanying COVID-19, the risk of thromboembolic events increases significantly. Among patients with suspected COVID-19, considering venous sinus thrombosis in the differential diagnosis may be life-saving, through enabling early diagnosis and treatment. This is especially so in the presence of causes of hypercoagulability such as pregnancy, malignancy and presence of atypical features like analgesic unresponsiveness, awakening from sleep, visual impairment, neurological deficits or seizures.
1 University of Health Sciences, Konya Education and Research Hospital, Konya, Turkey
Sources of funding: None | Transplacental | DrugAdministrationRoute | CC BY | 33605306 | 19,062,445 | 2021 |
What was the administration route of drug 'UNSPECIFIED INGREDIENT'? | Venous sinus thrombosis during COVID-19 infection in pregnancy: a case report.
Although it is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract, cases of this disease with a wide clinical spectrum are emerging as information is shared.
We present the case of a pregnant woman who was diagnosed with venous sinus thrombosis after she developed headache and hemiparesis. Polymerase chain reaction (PCR) positivity lasted for two weeks after COVID-19 had been diagnosed.
In patients with suspected COVID-19, especially in the presence of causes of hypercoagu- lability and presence of atypical features, venous sinus thrombosis needs to be kept in mind in making the differential diagnosis.
pmcINTRODUCTION
The effects of COVID-19 are not limited to the lungs alone. After the virus enters the body, it causes various symptoms through viremia.1 COVID-19 has been implicated in occurrences of cardiovascular and thromboembolic complications due to systemic inflammation and coagulopathy, in the light of the increasing amount of data that has become available over time.2,3,4,5,6,7,8 On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 It has been suggested that COVID-19 predisposes patients to thrombotic pathological conditions in both the venous and the arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 Nevertheless, cases of neurological and cardiac involvement in COVID-positive patients with TMA have also been reported.9
While the mechanism for the susceptibility to thrombosis that has been seen among COVID-19 patients continues to be debated, we wanted through this report to share information regarding the common venous thrombus of the central nervous system that emerged during the subclinical course of COVID-19 in a pregnant patient, which caused rapid parenchymal infarction.
CASE REPORT
A 22-year-old patient who was 35 weeks pregnant was evaluated in the emergency department with a complaint of right-sided weakness. The COVID-19 polymerase chain reaction test was performed and was found to be positive. However, she did not have fever or respiratory distress and then was followed up at home without medication.
The patient started to have throbbing headaches that did not respond to analgesic treatment (paracetamol 1000 mg/day) for four days. The intensity of her headaches gradually increased, such that she was being awakened from sleep, and this condition was accompanied by nausea and vomiting.
After this four-day period, she again felt weakness on her right side when she woke up in the morning. Twelve hours later, she went back to the emergency department because her weakness was increasing. At the emergency department, the patient was found to be normotensive, conscious, cooperative and oriented in a neurological examination. No fundus examination was performed, given that she was COVID-positive. Examinations on the patient’s visual field and vision showed normal results. Other cranial nerve examinations were normal. Her muscle strength ratio was 3/5 in the upper right extremity, 2/5 in the lower right extremity and 5/5 in the upper and lower left extremities. The foot sole skin reflex of the right lower extremity consisted of an extensor response. She presented decreased speech fluency and had difficulty in word finding, which were diagnosed as mild motor aphasia. Laboratory tests revealed high levels of fibrinogen (899 g/l; normal is 180-400) and D-dimer (6.38 mg/l; normal is 0-2). It was noted that the patient had also had high levels of fibrinogen (665 g/l) and D-dimer (2.2 mg/l) in examinations performed 10 days previously.
Diffusion magnetic resonance imaging (MRI) showed cortical diffusion restriction in the left parietal region (Figure 1a) and a hypointense response in the apparent diffusion coefficient (ADC) (Figure 1b). The result from the diffusion MRI was suggestive of venous sinus thrombosis. Widespread loss of flow in the superior sagittal sinus and right transverse sinus, suggesting partial venous thrombosis in the left transverse sinus, was observed in brain magnetic resonance imaging (Figure 2a) and magnetic resonance venous angiography (Figure 2b). The brain MRI and magnetic resonance venography confirmed the diagnosis of venous sinus thrombosis. Thrombosis was not investigated in other parts of the body.
Figure 1. a) Diffusion magnetic resonance imaging; b) Apparent diffusion coefficient.
Figure 2. a) Cranial magnetic resonance imaging; b) Magnetic resonance imaging venography.
The polymerase chain reaction was repeated and the result was again positive. The patient was then hospitalized with the diagnoses of COVID-19 infection and venous sinus thrombosis. Other genetic, hematological and rheumatological examinations were planned, in order to investigate the etiology of her condition. Anticoagulant treatment (low molecular weight heparin) was started after the patient had been found to present a low platelet count (107,000/mm3), through evaluation of a peripheral blood smear.
Diffuse contractions were observed in a non-stress test (NST), and tocolysis was started, consisting of nifedipine and betamethasone treatment. However, the patient’s labor could not be stopped after 18 hours of hospitalization. She was then admitted for an emergency cesarean section because the intracranial pressure was increasing. A healthy baby was delivered.
Subsequently, the patient’s postpartum headache complaints decreased and her speech became fluent without any change in muscle strength deficit. Her thrombocyte counts decreased to 67,000/mm3. Anticoagulant therapy was continued, with peripheral smear follow-ups. Thoracic computed tomography was performed on the patient, who did not present respiratory distress, and the findings were compatible with COVID-19 pneumonia after birth (Figure 3). There was an increase in infection parameters, and the patient was started on hydroxychloroquine and ceftriaxone treatment.
Figure 3. Thoracic computed tomography.
In the examinations performed to ascertain risk factors, the patient was found to be positive for antinuclear antibodies (ANA) and showed prothrombin heterozygous mutation. The patient was negative for anti-cardiolipin antibodies and anti-double stranded DNA (dsDNA), and tests on lupus anticoagulant, homocysteine, protein C, protein S and antithrombin 3 showed results within normal limits.
On the third day following the birth, the patient’s headache complaint became completely resolved, her thrombocyte counts stopped decreasing and her thrombocytopenia improved over the subsequent days. The infection parameters regressed. Partial regression of the lesions was observed on control thoracic computed tomography. The patient’s general condition stabilized and she was discharged on the 10th day of hospitalization, with muscle strength 4-5/5 on the right side, which was mobilized without support. Continuation of low molecular weight heparin (LMWH) treatment was planned, along with neurological and hematological control tests at a polyclinic.
DISCUSSION
It is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract. Cases of this disease with a wide clinical spectrum are emerging as information is shared.
Although the mechanism for thrombotic events in the course of COVID-19 remains unclear, it is known that there is a tendency for such events to occur within the course of this disease. Pulmonary embolism was shown to be the cause of death in an autopsy series.6 The etiology of embolic events is generally multifactorial: it is accepted that these events are triggered by environmental factors on the basis of genetic predisposition. Nonetheless, no reports on underlying genetic or other acquired causes in cases of COVID-19-positive pulmonary embolism have yet been published in the literature.
An increasing number of case reports and series on COVID-19-positive patients are describing a wide variety of neurological symptoms. Encephalopathy has been reported in a total of 93 patients, including 16 (7%) out of 214 hospitalized patients with COVID-19 in Wuhan, China, and 40 (69%) out of 58 patients in intensive care with COVID-19 in France. To date, encephalitis has been described in eight patients and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the cerebrospinal fluid (CSF) of some patients. Anosmia and agnosia are common and may occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease has also emerged as an important complication: stroke was reported in 2-6% of patients hospitalized with COVID-19 in a cohort study.10
Li et al. stated that in a retrospective study in which 219 COVID-19 positive patients were screened, 10 of these patients (4.6%) were ischemic and one of them presented hemorrhagic cerebrovascular disease (0.5%), after an average of 10 days after the onset of COVID-19. They pointed out that the mean age of these patients was greater and their cardiovascular and cerebrovascular risk factors were more severe.11
COVID-19 is thought to predispose patients to thrombotic pathological conditions in both venous and arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 The initial signs of coagulopathy due to COVID-19 have been found to be marked increases in fibrin/fibrinogen-degradation products and D-dimer levels. It was observed that our patient had high levels of fibrinogen and D-dimer from the time when she was diagnosed with COVID-19 to the time when she was diagnosed with venous sinus thrombosis.
In the early stages of the disease, abnormalities in prothrombin time, partial thromboplastin time and platelet count are uncommon.5 Detection of deep vein thrombosis (58%) as the autopsy finding among more than half of the 12 patients who died of COVID-19, and pulmonary embolism as the cause of death among one third of the patients, has emphasized the importance of not ignoring the tendency towards occurrences of thrombosis in the course of this disease. Hence, anticoagulants should be included during treatment planning.6 Analysis on the data on 184 patients with COVID-19 infection who were monitored in an intensive care unit showed that 31% of them had thrombotic complications. Thus, prophylaxis for thrombosis was strongly recommended for patients hospitalized with this diagnosis.7
On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 Thrombotic microangiopathy is characterized by organ damage such as microangiopathic hemolytic anemia, thrombocytopenia, and neurological, renal and cardiac dysfunction. Thrombocytopenia and neurological deficits were also observed in our patient. In another study, anemia, increased lactate dehydrogenase (LDH), thrombocytopenia and organ damage (neurological in all patients and cardiac in one) were explained by thrombotic microangiopathy in three patients with a diagnosis of COVID-19.9
Cerebral venous thrombus differs significantly from arterial infarctions in terms of risk factors. Hypercoagulability is an important risk factor and an important cause of stroke in young people. Women are affected three times more often than men. The most common symptoms are headache, seizures and focal neurological deficits. The diagnosis can be confirmed by magnetic resonance imaging, computed tomography-venography or catheter angiography.
The primary treatment for venous sinus thrombosis is anticoagulation, based on the limited evidence from randomized trials. Although a small series of cases has indicated that endovascular therapy may be promising, these data require confirmation through a randomized trial. Decompressive surgery can be lifesaving for patients at risk of herniation. The prognosis is generally better than that for arterial stroke.12 Although venous sinus thrombosis was previously considered to be a life-threatening condition, it is known that the mortality rate in these cases declines over time. Moreover, increased clinical awareness, development of neuroimaging techniques and improvement in therapeutic management have provided better prognoses through enabling earlier diagnosis and identification of less severe cases.13
Pregnancy and the puerperium are common causes of transient prothrombotic conditions. About 2% of pregnancy-related strokes can be attributed to venous sinus thrombosis. In the puerperium, the rate of venous sinus thrombosis is 12 cases per 100,000 births. This venous rate in the puerperal period is only slightly lower than that of arterial stroke. Women are at risk of venous thromboembolic events during pregnancy and for up to six to eight weeks after delivery. Most cases of pregnancy-related venous sinus thrombosis are seen in the third trimester or, more often, in the puerperium, when the body prepares for delivery through hypercoagulation. In a paper published in Canada, it was reported that frequency of venous sinus thrombosis in the postpartum period is much higher than during pregnancy. In the puerperium period, the presence of infection and use of instrumental delivery or cesarean section increase the risk of venous sinus thrombosis. During pregnancy, it is known that the risk of venous sinus thrombosis increases in the presence of hypertension, infections and excessive vomiting, and as the maternal age increases.14 The European Academy of Neurology has recommended that treatment for acute venous sinus thrombosis should start with oral anticoagulant therapy (vitamin K antagonists) for 3-12 months, according to risk factors.15
Another risk factor with a relationship to venous sinus thrombosis that is clearly known is inflammation. Venous sinus thrombosis is associated with systemic inflammatory conditions such as Behçet’s disease and inflammatory bowel disease, in addition to infections such as otitis, mastoiditis, sinusitis, dental infections and skin abscesses in neighboring tissues and meningitis.13 In the anamnesis and examination of our patient, no finding suggesting adjacent tissue infection or Behçet’s or inflammatory bowel disease was found.
Antinuclear antibody positivity can be seen in autoimmune diseases, especially systemic lupus erythematosus, but it is not a laboratory test specific to autoimmune diseases. Since antinuclear antibody positivity can be observed in acute or chronic infectious processes,16 it was planned that our patient would undergo this examination after discharge. The anamnesis of our patient was negative for rheumatological diseases.
The etiology of venous sinus thrombosis can be explained in terms of the classical Virchow triad, i.e. blood flow stasis, vessel wall changes and changes in blood content. We believe that the combination of pregnancy and systemic inflammation due to COVID-19 caused thrombosis in our patient, on the basis of genetic prothrombin heterozygous mutation.
One of the clinical manifestations of COVID-19 is nonspecific headache, as is also frequently observed during other viral infections. However, this symptom can often be mild enough to lag behind other clinical findings. If there is no visual impairment, focal neurological deficit or seizure, venous sinus thrombosis can be neglected in the differential diagnosis. Our patient was diagnosed not after occurrences of headache and nausea-vomiting, but after admission to the hospital because of the accompanying symptoms of right hemiparesis. In our case, like what has been described in the literature,11 the central nervous system event started on the ninth day after COVID-19 infection began, and a stroke occurred on the 13th day. Thus, within four days, the rapid clinical progression resulted in parenchymal ischemia. The neurological clinical findings rapidly improved in parallel with the end of pregnancy, start of administration of low molecular weight heparin and decrease in infection parameters.
Reports correlating COVID-19, headache and pregnancy are very rare (Table 1).
Table 1. Search of the literature in medical databases for case reports on COVID-19, pregnancy and headache on November 6, 2020
Database Search strategies Papers found Papers related (to pregnancy, headache and COVID-19) Etiology Main neurological symptom
MEDLINE
(via PubMed)
COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
2 2 Spinal anesthesia 1
Pituitary apoplexy 1
Headache
Cochrane COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
Embase COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
CONCLUSION
Headache is one of the common symptoms of COVID-19. In the presence of other risk factors accompanying COVID-19, the risk of thromboembolic events increases significantly. Among patients with suspected COVID-19, considering venous sinus thrombosis in the differential diagnosis may be life-saving, through enabling early diagnosis and treatment. This is especially so in the presence of causes of hypercoagulability such as pregnancy, malignancy and presence of atypical features like analgesic unresponsiveness, awakening from sleep, visual impairment, neurological deficits or seizures.
1 University of Health Sciences, Konya Education and Research Hospital, Konya, Turkey
Sources of funding: None | Transplacental | DrugAdministrationRoute | CC BY | 33605306 | 19,062,445 | 2021 |
What was the outcome of reaction 'Foetal exposure during pregnancy'? | Venous sinus thrombosis during COVID-19 infection in pregnancy: a case report.
Although it is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract, cases of this disease with a wide clinical spectrum are emerging as information is shared.
We present the case of a pregnant woman who was diagnosed with venous sinus thrombosis after she developed headache and hemiparesis. Polymerase chain reaction (PCR) positivity lasted for two weeks after COVID-19 had been diagnosed.
In patients with suspected COVID-19, especially in the presence of causes of hypercoagu- lability and presence of atypical features, venous sinus thrombosis needs to be kept in mind in making the differential diagnosis.
pmcINTRODUCTION
The effects of COVID-19 are not limited to the lungs alone. After the virus enters the body, it causes various symptoms through viremia.1 COVID-19 has been implicated in occurrences of cardiovascular and thromboembolic complications due to systemic inflammation and coagulopathy, in the light of the increasing amount of data that has become available over time.2,3,4,5,6,7,8 On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 It has been suggested that COVID-19 predisposes patients to thrombotic pathological conditions in both the venous and the arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 Nevertheless, cases of neurological and cardiac involvement in COVID-positive patients with TMA have also been reported.9
While the mechanism for the susceptibility to thrombosis that has been seen among COVID-19 patients continues to be debated, we wanted through this report to share information regarding the common venous thrombus of the central nervous system that emerged during the subclinical course of COVID-19 in a pregnant patient, which caused rapid parenchymal infarction.
CASE REPORT
A 22-year-old patient who was 35 weeks pregnant was evaluated in the emergency department with a complaint of right-sided weakness. The COVID-19 polymerase chain reaction test was performed and was found to be positive. However, she did not have fever or respiratory distress and then was followed up at home without medication.
The patient started to have throbbing headaches that did not respond to analgesic treatment (paracetamol 1000 mg/day) for four days. The intensity of her headaches gradually increased, such that she was being awakened from sleep, and this condition was accompanied by nausea and vomiting.
After this four-day period, she again felt weakness on her right side when she woke up in the morning. Twelve hours later, she went back to the emergency department because her weakness was increasing. At the emergency department, the patient was found to be normotensive, conscious, cooperative and oriented in a neurological examination. No fundus examination was performed, given that she was COVID-positive. Examinations on the patient’s visual field and vision showed normal results. Other cranial nerve examinations were normal. Her muscle strength ratio was 3/5 in the upper right extremity, 2/5 in the lower right extremity and 5/5 in the upper and lower left extremities. The foot sole skin reflex of the right lower extremity consisted of an extensor response. She presented decreased speech fluency and had difficulty in word finding, which were diagnosed as mild motor aphasia. Laboratory tests revealed high levels of fibrinogen (899 g/l; normal is 180-400) and D-dimer (6.38 mg/l; normal is 0-2). It was noted that the patient had also had high levels of fibrinogen (665 g/l) and D-dimer (2.2 mg/l) in examinations performed 10 days previously.
Diffusion magnetic resonance imaging (MRI) showed cortical diffusion restriction in the left parietal region (Figure 1a) and a hypointense response in the apparent diffusion coefficient (ADC) (Figure 1b). The result from the diffusion MRI was suggestive of venous sinus thrombosis. Widespread loss of flow in the superior sagittal sinus and right transverse sinus, suggesting partial venous thrombosis in the left transverse sinus, was observed in brain magnetic resonance imaging (Figure 2a) and magnetic resonance venous angiography (Figure 2b). The brain MRI and magnetic resonance venography confirmed the diagnosis of venous sinus thrombosis. Thrombosis was not investigated in other parts of the body.
Figure 1. a) Diffusion magnetic resonance imaging; b) Apparent diffusion coefficient.
Figure 2. a) Cranial magnetic resonance imaging; b) Magnetic resonance imaging venography.
The polymerase chain reaction was repeated and the result was again positive. The patient was then hospitalized with the diagnoses of COVID-19 infection and venous sinus thrombosis. Other genetic, hematological and rheumatological examinations were planned, in order to investigate the etiology of her condition. Anticoagulant treatment (low molecular weight heparin) was started after the patient had been found to present a low platelet count (107,000/mm3), through evaluation of a peripheral blood smear.
Diffuse contractions were observed in a non-stress test (NST), and tocolysis was started, consisting of nifedipine and betamethasone treatment. However, the patient’s labor could not be stopped after 18 hours of hospitalization. She was then admitted for an emergency cesarean section because the intracranial pressure was increasing. A healthy baby was delivered.
Subsequently, the patient’s postpartum headache complaints decreased and her speech became fluent without any change in muscle strength deficit. Her thrombocyte counts decreased to 67,000/mm3. Anticoagulant therapy was continued, with peripheral smear follow-ups. Thoracic computed tomography was performed on the patient, who did not present respiratory distress, and the findings were compatible with COVID-19 pneumonia after birth (Figure 3). There was an increase in infection parameters, and the patient was started on hydroxychloroquine and ceftriaxone treatment.
Figure 3. Thoracic computed tomography.
In the examinations performed to ascertain risk factors, the patient was found to be positive for antinuclear antibodies (ANA) and showed prothrombin heterozygous mutation. The patient was negative for anti-cardiolipin antibodies and anti-double stranded DNA (dsDNA), and tests on lupus anticoagulant, homocysteine, protein C, protein S and antithrombin 3 showed results within normal limits.
On the third day following the birth, the patient’s headache complaint became completely resolved, her thrombocyte counts stopped decreasing and her thrombocytopenia improved over the subsequent days. The infection parameters regressed. Partial regression of the lesions was observed on control thoracic computed tomography. The patient’s general condition stabilized and she was discharged on the 10th day of hospitalization, with muscle strength 4-5/5 on the right side, which was mobilized without support. Continuation of low molecular weight heparin (LMWH) treatment was planned, along with neurological and hematological control tests at a polyclinic.
DISCUSSION
It is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract. Cases of this disease with a wide clinical spectrum are emerging as information is shared.
Although the mechanism for thrombotic events in the course of COVID-19 remains unclear, it is known that there is a tendency for such events to occur within the course of this disease. Pulmonary embolism was shown to be the cause of death in an autopsy series.6 The etiology of embolic events is generally multifactorial: it is accepted that these events are triggered by environmental factors on the basis of genetic predisposition. Nonetheless, no reports on underlying genetic or other acquired causes in cases of COVID-19-positive pulmonary embolism have yet been published in the literature.
An increasing number of case reports and series on COVID-19-positive patients are describing a wide variety of neurological symptoms. Encephalopathy has been reported in a total of 93 patients, including 16 (7%) out of 214 hospitalized patients with COVID-19 in Wuhan, China, and 40 (69%) out of 58 patients in intensive care with COVID-19 in France. To date, encephalitis has been described in eight patients and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the cerebrospinal fluid (CSF) of some patients. Anosmia and agnosia are common and may occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease has also emerged as an important complication: stroke was reported in 2-6% of patients hospitalized with COVID-19 in a cohort study.10
Li et al. stated that in a retrospective study in which 219 COVID-19 positive patients were screened, 10 of these patients (4.6%) were ischemic and one of them presented hemorrhagic cerebrovascular disease (0.5%), after an average of 10 days after the onset of COVID-19. They pointed out that the mean age of these patients was greater and their cardiovascular and cerebrovascular risk factors were more severe.11
COVID-19 is thought to predispose patients to thrombotic pathological conditions in both venous and arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 The initial signs of coagulopathy due to COVID-19 have been found to be marked increases in fibrin/fibrinogen-degradation products and D-dimer levels. It was observed that our patient had high levels of fibrinogen and D-dimer from the time when she was diagnosed with COVID-19 to the time when she was diagnosed with venous sinus thrombosis.
In the early stages of the disease, abnormalities in prothrombin time, partial thromboplastin time and platelet count are uncommon.5 Detection of deep vein thrombosis (58%) as the autopsy finding among more than half of the 12 patients who died of COVID-19, and pulmonary embolism as the cause of death among one third of the patients, has emphasized the importance of not ignoring the tendency towards occurrences of thrombosis in the course of this disease. Hence, anticoagulants should be included during treatment planning.6 Analysis on the data on 184 patients with COVID-19 infection who were monitored in an intensive care unit showed that 31% of them had thrombotic complications. Thus, prophylaxis for thrombosis was strongly recommended for patients hospitalized with this diagnosis.7
On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 Thrombotic microangiopathy is characterized by organ damage such as microangiopathic hemolytic anemia, thrombocytopenia, and neurological, renal and cardiac dysfunction. Thrombocytopenia and neurological deficits were also observed in our patient. In another study, anemia, increased lactate dehydrogenase (LDH), thrombocytopenia and organ damage (neurological in all patients and cardiac in one) were explained by thrombotic microangiopathy in three patients with a diagnosis of COVID-19.9
Cerebral venous thrombus differs significantly from arterial infarctions in terms of risk factors. Hypercoagulability is an important risk factor and an important cause of stroke in young people. Women are affected three times more often than men. The most common symptoms are headache, seizures and focal neurological deficits. The diagnosis can be confirmed by magnetic resonance imaging, computed tomography-venography or catheter angiography.
The primary treatment for venous sinus thrombosis is anticoagulation, based on the limited evidence from randomized trials. Although a small series of cases has indicated that endovascular therapy may be promising, these data require confirmation through a randomized trial. Decompressive surgery can be lifesaving for patients at risk of herniation. The prognosis is generally better than that for arterial stroke.12 Although venous sinus thrombosis was previously considered to be a life-threatening condition, it is known that the mortality rate in these cases declines over time. Moreover, increased clinical awareness, development of neuroimaging techniques and improvement in therapeutic management have provided better prognoses through enabling earlier diagnosis and identification of less severe cases.13
Pregnancy and the puerperium are common causes of transient prothrombotic conditions. About 2% of pregnancy-related strokes can be attributed to venous sinus thrombosis. In the puerperium, the rate of venous sinus thrombosis is 12 cases per 100,000 births. This venous rate in the puerperal period is only slightly lower than that of arterial stroke. Women are at risk of venous thromboembolic events during pregnancy and for up to six to eight weeks after delivery. Most cases of pregnancy-related venous sinus thrombosis are seen in the third trimester or, more often, in the puerperium, when the body prepares for delivery through hypercoagulation. In a paper published in Canada, it was reported that frequency of venous sinus thrombosis in the postpartum period is much higher than during pregnancy. In the puerperium period, the presence of infection and use of instrumental delivery or cesarean section increase the risk of venous sinus thrombosis. During pregnancy, it is known that the risk of venous sinus thrombosis increases in the presence of hypertension, infections and excessive vomiting, and as the maternal age increases.14 The European Academy of Neurology has recommended that treatment for acute venous sinus thrombosis should start with oral anticoagulant therapy (vitamin K antagonists) for 3-12 months, according to risk factors.15
Another risk factor with a relationship to venous sinus thrombosis that is clearly known is inflammation. Venous sinus thrombosis is associated with systemic inflammatory conditions such as Behçet’s disease and inflammatory bowel disease, in addition to infections such as otitis, mastoiditis, sinusitis, dental infections and skin abscesses in neighboring tissues and meningitis.13 In the anamnesis and examination of our patient, no finding suggesting adjacent tissue infection or Behçet’s or inflammatory bowel disease was found.
Antinuclear antibody positivity can be seen in autoimmune diseases, especially systemic lupus erythematosus, but it is not a laboratory test specific to autoimmune diseases. Since antinuclear antibody positivity can be observed in acute or chronic infectious processes,16 it was planned that our patient would undergo this examination after discharge. The anamnesis of our patient was negative for rheumatological diseases.
The etiology of venous sinus thrombosis can be explained in terms of the classical Virchow triad, i.e. blood flow stasis, vessel wall changes and changes in blood content. We believe that the combination of pregnancy and systemic inflammation due to COVID-19 caused thrombosis in our patient, on the basis of genetic prothrombin heterozygous mutation.
One of the clinical manifestations of COVID-19 is nonspecific headache, as is also frequently observed during other viral infections. However, this symptom can often be mild enough to lag behind other clinical findings. If there is no visual impairment, focal neurological deficit or seizure, venous sinus thrombosis can be neglected in the differential diagnosis. Our patient was diagnosed not after occurrences of headache and nausea-vomiting, but after admission to the hospital because of the accompanying symptoms of right hemiparesis. In our case, like what has been described in the literature,11 the central nervous system event started on the ninth day after COVID-19 infection began, and a stroke occurred on the 13th day. Thus, within four days, the rapid clinical progression resulted in parenchymal ischemia. The neurological clinical findings rapidly improved in parallel with the end of pregnancy, start of administration of low molecular weight heparin and decrease in infection parameters.
Reports correlating COVID-19, headache and pregnancy are very rare (Table 1).
Table 1. Search of the literature in medical databases for case reports on COVID-19, pregnancy and headache on November 6, 2020
Database Search strategies Papers found Papers related (to pregnancy, headache and COVID-19) Etiology Main neurological symptom
MEDLINE
(via PubMed)
COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
2 2 Spinal anesthesia 1
Pituitary apoplexy 1
Headache
Cochrane COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
Embase COVID-19 [MESH]
Pregnancy [MESH]
Headache [MESH]
Case Report [ptyp]
0 0 0 0
CONCLUSION
Headache is one of the common symptoms of COVID-19. In the presence of other risk factors accompanying COVID-19, the risk of thromboembolic events increases significantly. Among patients with suspected COVID-19, considering venous sinus thrombosis in the differential diagnosis may be life-saving, through enabling early diagnosis and treatment. This is especially so in the presence of causes of hypercoagulability such as pregnancy, malignancy and presence of atypical features like analgesic unresponsiveness, awakening from sleep, visual impairment, neurological deficits or seizures.
1 University of Health Sciences, Konya Education and Research Hospital, Konya, Turkey
Sources of funding: None | Recovered | ReactionOutcome | CC BY | 33605306 | 19,062,445 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cystitis haemorrhagic'. | Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: A case report.
BACKGROUND
No standard guideline has been established for the treatment of plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and show resistance to commonly used cytostatic drugs.
We present the case of a 52-year-old HIV-negative man who presented with a mass at the left sternoclavicular joint. He had no significant comorbidities and no latent immunosuppression.
METHODS
The largest lymph node measured was 36 × 19 mm. An excisional biopsy showed diffuse proliferation of large lymphoid cells which were positive for CD38 and CD138, but negative for CD20. He was diagnosed with stage IV PBL with a low IPI.
METHODS
The patient was treated with four cycles of induction therapy with bortezomib, epirubicin and dexamethasone. He achieved complete remission. But 3 months after receiving consolidated autologous hematopoietic stem cell transplantation, he relapsed. Allogeneic hematopoietic stem cell transplantation was performed on the patient.
RESULTS
The patient achieved remission again and there were no serious complications after allogeneic hematopoietic stem cell transplantation. This patient was followed up once every three months, and to date, he has been disease-free for more than 4 years.
CONCLUSIONS
The survival of recurrent PBL after autologous hematopoietic stem cell transplantation is very poor. Salvage allogeneic hematopoietic stem cell transplantation may bring long-term survival opportunities for those patients. Further clinical studies are needed to explore the role of allogeneic hematopoietic stem cell transplantation in refractory and recurrent PBL.
pmc1 Introduction
Plasmablastic lymphoma (PBL) is a rare and highly aggressive subtype of diffuse large B-cell lymphoma (DLBCL), characterized by plasma cell antigen differentiation. It was initially described in the setting of human immunodeficiency virus (HIV) infection, but it was also been reported in HIV-negative patients.[1] There is no consensus on the standard of care for PBL. The role of intensification of induction chemotherapy is controversial. And novel agents, bortezomib and lenalidomide, have shown some effectiveness in relapsed cases and may have a relatively important role in frontline treatment.[2,3] The use of autologous stem cell transplantation (ASCT) possibly improves outcomes when used as a consolidation or salvage therapy and may lead to better results than chemotherapy, but the available data remain sparse.[2] The literatures on allogeneic hematopoietic stem cell transplantation (allo-HSCT) treatment for PBL are quite rare compared to ASCT. And given its rarity, most of the data available rely on case reports and case series. Patients with PBL have a poor prognosis, with median survival times shorter than 2 years.[2,4] To the best of our knowledge, the survival of recurrent PBL is worse.[2,5,6] Here, we report a case of HIV-negative PBL in a patient who had recurrence after ASCT, but achieved and maintained complete remission for 4-years after salvage allo-HSCT.
2 Case presentation
The patient was a 52-year-old man who presented in September 2015 with a mass at left sternoclavicular joint without any systemic symptoms. He had no significant comorbidities and no latent immunosuppression. Ultrasonography of lymph nodes indicated multiple lymph node enlargement in the neck, and multiple hypoechoic areas were seen above the left clavicle, the largest of which was 36 × 19 mm. A total body computed tomography (CT) scan showed that soft tissue mass shadows were seen around the left sternoclavicular joint and local cortical absorptions were present. Further investigations with fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) scan confirmed hypermetabolic mass appeared in several places of the body which was considered plasma cell infiltration. An excisional biopsy showed diffuse proliferation of large lymphoid cells (Fig. 1). Immuno-staining of the neoplastic cells showed negative for CD20, CD5, CD30, EREB, MPO, CD117 and Bcl-6, whereas it was positive for CD38, CD138, CD10, CD79a and Bcl-2 (Figs. 2–5). The Ki-67 proliferation index was 95% (Fig. 6). Biopsy of the iliac crest showed no marrow involvement. According to the above analysis, International Prognostic Index (IPI) scores were 2, the patient was diagnosed with stage IV PBL with a low IPI.
Figure 1 H&E (hematoxylin and eosin) image shows large sheets of mostly large plasmacytoid appearing mononuclear cells. (HE Magnification × 400).
Figure 2 CD138, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 3 CD38, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 4 CD10, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 5 CD79a, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 6 Strong and homogenous staining with Ki-67 indicating a high proliferation index. (Magnification × 200).
In addition, laboratory data were as following: Blood routine examination indicated that the white blood cells were 8.1 × 109/L, the hemoglobin was 146 g/L and the platelets were 267 × 109/L. Erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, β2 microglobulin, serum proteins and immunoglobulin levels were all within normal ranges. Immunofixation electrophoresis showed no monoclonal component. Human herpes virus 8 (HHV-8) and Epstein-Barr virus DNA (EBV-DNA) were negative. Besides, serology for HIV was also negative.
From September to December 2015, the patient received 4 cycles of PAD chemotherapy regimens: bortezomib was given at the dose of 2.4 mg/day on day 1, 4, 8, 11, epirubicin at the dose of 20 mg/day on days 1–3, and dexamethasone at the dose of 40 mg/day on days 1–4 and 8–11 of each 28-day cycle. Repeat PET/CT following 4 cycles of chemotherapy showed no abnormal flurodeoxyglucose metabolic foci and enlarged lymph nodes, thus being compatible with a complete response (CR).
Later on, peripheral blood stem cell (PBSC) mobilization was achieved by high-dose cyclophosphamide (2 g, day 1–3), etoposide (300 mg, day 1–3) and granulocyte colony-stimulating factor (G-CSF), and leukapheresis products containing a total of mononuclear cell (MNC) 9.78 × 108/kg and CD34+ cells 6.9 × 106/kg were collected. In April 2016, the patient received autologous hematopoietic stem cell transplantation as consolidation therapy. The conditioning regiments were melphalan (200 mg/m2 -2d) and bortezomib (1.75 mg -6, -3, +1, +4), and a total of 9.78 × 108/kg MNC and 6.9 × 106/kg CD34+ cells PBSC were reinfused. Platelets and white blood cells were recovered at 10 and 11 days after transplantation, respectively. The CT scan performed 1 month after ASCT confirmed a CR.
However, 3 months after ASCT, CT showed a new lesion appeared in the second rib on the right side, which was considered as relapse. After full assessment, the patient underwent HLA half-matched allo-HSCT in September 2016. The conditioning regimen was modified BuCy+ATG (cytarabine 3.5 g -10, -9; busulfan 51.6 mg Q6 h -8, -7, -6; cyclophosphamide 3 g -5, -4; MECCNU 450 mg -3; antithymocyte globulin 2.5 mg/Kg -5, -4, -3, -2), and the scheme for prevention of graft-versus-host disease (GVHD) was cyclosporin, mycophenolate mofetil and short-term methotrexate. The patient developed pulmonary fungal infection 20 days after allo-HSCT and took a turn for the better after treatment with voriconazole injection and voriconazole tablets. Unfortunately, the patient developed severe hemorrhagic cystitis 20 days later, but fortunately the condition improved after symptomatic treatment. There has been no evidence of acute or chronic GVHD. The patient achieved sustained complete donor engraftment as short tandem repeat monitoring was performed every three months after transplantation. A CR was metabolically and clinically confirmed by PET-CT scan after allo-HSCT. The patient is now healthy and in CR for 4 years after allo-HSCT.
3 Discussed
PBL is a distinct variant of diffuse large B-cell lymphoma initially described in HIV-positive patients.[7] Nevertheless, PBL has also been described in HIV-negative individuals, particularly in association with potential immunosuppression such as after solid organ or bone marrow transplantation or with autoimmune disorders and malignanciess.[8–11] HIV-negative PBL, in comparison with HIV-positive PBL, occurs in older patients, with less frequent involvement of oral mucosa or bone marrow and less frequently stages III-IV.[3,12,13] A review of 114 HIV-negative patients with PBL, by Liu et al[12] demonstrated that immunosuppression, MYC gene rearrangement, high-risk international prognostic index, and EBV negativity were poor prognostic factors. And the overall survival (OS) is between 9 and 19 months in HIV-negative patients.[12] Similarly, a systematic review on 76 HIV-negative PBL patients showed median OS of 9 months with 2-year OS rate of 10%.[13]
Given its rarity and peculiar features, there is no standard of care for PBL and the treatment remains a challenge.[11] The use of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and CHOP-like regimens are considered inadequate therapy, resulting short remission period,[3,11] so the NCCN guidelines recommend more intensive regimens,[14] including etoposide, vincristine and doxorubicin with bolus of cyclophosphamide and prednisone (EPOCH),[15] cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide, cytarabine,[16] or hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine.[17] The benefit of ASCT in patients with PBL is not quite clear based on the limited data available. In a single institution report of 9 consecutive HIV-negative PBL patients, 7 patients achieved CR and 1 patient achieved partial response (PR) after chemotherapy.[8] Four patients underwent consolidation with ASCT in first complete remission, and 2 of these patients were alive at median follow-up of 23.9 months. The third patient had disease recurrence at 14 months and the fourth patient had disease recurrence at 2 months after ASCT.[8] Moffitt Cancer Center presented the experience of two HIV-negative patients with PBL in PR that underwent an ASCT, and two patients survived 6 and 12 months.[12]
Given the low efficacy of the standard therapy, and the poor outcome of these patients, there is a need to move toward new therapeutic strategies by incorporating new agents. Bortezomib is the most reported new drug for PBL and has been used as a single dose or in combination. Koji et al[18] show the bortezomib and lenalidomide-based treatment was tolerated and the patient was continued with a PR for over 2 years. Bortezomib and lenalidomide have a certain therapeutic effect, and are mostly used in patients with refractory recurrence.[18,19] There are few case reports showing single-agent lenalidomide or combination with other chemotherapeutic drug in refractory PBL.[20–22] A dramatic response to Brentuximab has been reported in a single case, but the patient died shortly due to previous disease disabilities.[23] A plasmablastic microlymphoma arising in HHV8-associated multicentric Castleman disease in an HIV-negative patient that showed a clinical response to siltuximab, an anti-IL6 antibody.[24] The use of rituximab, a chimeric anti-CD20 monoclonal antibody, is not currently a therapeutic standard because the lack of CD20 expression by PBL cells, but combined with chemotherapy it could improve remission rates.[3,25] Clinical trials with novel immunotherapeutic agents and other drugs targeting some genes involved in the activation of Nuclear factor kappa B pathways, some of which are already ongoing, may show promising results.[18]
The literature on allo-HSCT in PBL is limited compared with ASCT. Only few cases of allo-HSCT for PBL were reported, much less for recurrence PBL. Hamadani[26] reported one patient with PBL in CR2 who underwent a reduced-intensity allogeneic stem cell transplantation, and was alive 2 years after transplantation. Liu et al[8] reported one patient who had disease recurrence at 14 months after ASCT was treated with allo-HSCT. Despite consolidation with allo-HSCT, disease recurred 5 months after, and the patient died. In general, the efficacy of allo-HSCT in the treatment of HIV-negative PBL patients is still not ideal and the survival of recurrent PBL after allo-HSCT is very poor.
In our case, the patient had recurrence after consolidated ASCT. Then, he underwent the salvage allo-HSCT from his daughter and achieved good curative effect. The patient was in long-term complete remission and he is alive now. It may be attributed to his younger age, low IPI score and early allo-HSCT treatment after relapse. As far as we know, this is the first case of such a long survival time after allo-HSCT. For young relapsed patients with PBL, allo-HSCT may bring long-term survival opportunities. Due to the rarity of the disease, it is not feasible to carry out large-scale clinical trials. The evaluation of allogeneic hematopoietic stem cell transplantation in PBL patients requires more accumulation and sharing of clinical experience.
Author contributions
Data curation: An Wu, Ye Sun.
Funding acquisition: Guifang Ouyang, Lixia Sheng.
Methodology: Lixia Sheng.
Writing – original draft: Chunmeng Rong.
Writing – review & editing: Chunmeng Rong.
Abbreviations: allo-HSCT = allogeneic hematopoietic stem cell transplantation, ASCT = autologous hematopoietic stem cell transplantation, CHOP = cyclophosphamide, doxorubicin, vincristine and prednisone, CR = complete response, CT = computed tomography, DLBCL = diffuse large B-cell lymphoma, EBV-DNA = Epstein-Barr virus DNA, GVHD = graft-versus-host disease, HHV-8 = Human herpes virus 8, HIV = human immunodeficiency virus, IPI = International Prognostic Index, MNC = mononuclear cell, OS = overall survival, PBL = plasmablastic lymphoma, PBSC = peripheral blood stem cell, PET-CT = positron emission tomography–computed tomography, PR = partial response.
How to cite this article: Rong C, Sheng L, Wu A, Sun Y, Ouyang G. Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: a case report. Medicine. 2021;100:7(e24498).
The study protocol was approved by the Ethics Review Committee of Ningbo First Hospital.
Patient has provided informed consent for publication of the case, and patient share his experience.
This study was supported by the National Natural Science Foundation of China under grant (number 81401321); Basic Public Welfare Research Project of Zhejiang Province under grant (number LGF19H080002); Medical Health Science and Technology Project of Zhejiang Provincial Health Commission under grant (number 2018PY052); National Science Foundation of Zhejiang Province under grant (number LY17H160005); and Traditional Chinese Medicine Administration of Zhejiang Province under grant (number 2015ZZ018).
The authors declare no conflict of interest.
The datasets generated during and/or analyzed during the current study are publicly available. | BUSULFAN, CYCLOPHOSPHAMIDE, CYCLOSPORINE, CYTARABINE, METHOTREXATE, MYCOPHENOLIC ACID, SEMUSTINE, THYMOCYTE IMMUNE GLOBULIN NOS | DrugsGivenReaction | CC BY | 33607779 | 18,990,270 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fungal infection'. | Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: A case report.
BACKGROUND
No standard guideline has been established for the treatment of plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and show resistance to commonly used cytostatic drugs.
We present the case of a 52-year-old HIV-negative man who presented with a mass at the left sternoclavicular joint. He had no significant comorbidities and no latent immunosuppression.
METHODS
The largest lymph node measured was 36 × 19 mm. An excisional biopsy showed diffuse proliferation of large lymphoid cells which were positive for CD38 and CD138, but negative for CD20. He was diagnosed with stage IV PBL with a low IPI.
METHODS
The patient was treated with four cycles of induction therapy with bortezomib, epirubicin and dexamethasone. He achieved complete remission. But 3 months after receiving consolidated autologous hematopoietic stem cell transplantation, he relapsed. Allogeneic hematopoietic stem cell transplantation was performed on the patient.
RESULTS
The patient achieved remission again and there were no serious complications after allogeneic hematopoietic stem cell transplantation. This patient was followed up once every three months, and to date, he has been disease-free for more than 4 years.
CONCLUSIONS
The survival of recurrent PBL after autologous hematopoietic stem cell transplantation is very poor. Salvage allogeneic hematopoietic stem cell transplantation may bring long-term survival opportunities for those patients. Further clinical studies are needed to explore the role of allogeneic hematopoietic stem cell transplantation in refractory and recurrent PBL.
pmc1 Introduction
Plasmablastic lymphoma (PBL) is a rare and highly aggressive subtype of diffuse large B-cell lymphoma (DLBCL), characterized by plasma cell antigen differentiation. It was initially described in the setting of human immunodeficiency virus (HIV) infection, but it was also been reported in HIV-negative patients.[1] There is no consensus on the standard of care for PBL. The role of intensification of induction chemotherapy is controversial. And novel agents, bortezomib and lenalidomide, have shown some effectiveness in relapsed cases and may have a relatively important role in frontline treatment.[2,3] The use of autologous stem cell transplantation (ASCT) possibly improves outcomes when used as a consolidation or salvage therapy and may lead to better results than chemotherapy, but the available data remain sparse.[2] The literatures on allogeneic hematopoietic stem cell transplantation (allo-HSCT) treatment for PBL are quite rare compared to ASCT. And given its rarity, most of the data available rely on case reports and case series. Patients with PBL have a poor prognosis, with median survival times shorter than 2 years.[2,4] To the best of our knowledge, the survival of recurrent PBL is worse.[2,5,6] Here, we report a case of HIV-negative PBL in a patient who had recurrence after ASCT, but achieved and maintained complete remission for 4-years after salvage allo-HSCT.
2 Case presentation
The patient was a 52-year-old man who presented in September 2015 with a mass at left sternoclavicular joint without any systemic symptoms. He had no significant comorbidities and no latent immunosuppression. Ultrasonography of lymph nodes indicated multiple lymph node enlargement in the neck, and multiple hypoechoic areas were seen above the left clavicle, the largest of which was 36 × 19 mm. A total body computed tomography (CT) scan showed that soft tissue mass shadows were seen around the left sternoclavicular joint and local cortical absorptions were present. Further investigations with fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) scan confirmed hypermetabolic mass appeared in several places of the body which was considered plasma cell infiltration. An excisional biopsy showed diffuse proliferation of large lymphoid cells (Fig. 1). Immuno-staining of the neoplastic cells showed negative for CD20, CD5, CD30, EREB, MPO, CD117 and Bcl-6, whereas it was positive for CD38, CD138, CD10, CD79a and Bcl-2 (Figs. 2–5). The Ki-67 proliferation index was 95% (Fig. 6). Biopsy of the iliac crest showed no marrow involvement. According to the above analysis, International Prognostic Index (IPI) scores were 2, the patient was diagnosed with stage IV PBL with a low IPI.
Figure 1 H&E (hematoxylin and eosin) image shows large sheets of mostly large plasmacytoid appearing mononuclear cells. (HE Magnification × 400).
Figure 2 CD138, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 3 CD38, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 4 CD10, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 5 CD79a, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 6 Strong and homogenous staining with Ki-67 indicating a high proliferation index. (Magnification × 200).
In addition, laboratory data were as following: Blood routine examination indicated that the white blood cells were 8.1 × 109/L, the hemoglobin was 146 g/L and the platelets were 267 × 109/L. Erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, β2 microglobulin, serum proteins and immunoglobulin levels were all within normal ranges. Immunofixation electrophoresis showed no monoclonal component. Human herpes virus 8 (HHV-8) and Epstein-Barr virus DNA (EBV-DNA) were negative. Besides, serology for HIV was also negative.
From September to December 2015, the patient received 4 cycles of PAD chemotherapy regimens: bortezomib was given at the dose of 2.4 mg/day on day 1, 4, 8, 11, epirubicin at the dose of 20 mg/day on days 1–3, and dexamethasone at the dose of 40 mg/day on days 1–4 and 8–11 of each 28-day cycle. Repeat PET/CT following 4 cycles of chemotherapy showed no abnormal flurodeoxyglucose metabolic foci and enlarged lymph nodes, thus being compatible with a complete response (CR).
Later on, peripheral blood stem cell (PBSC) mobilization was achieved by high-dose cyclophosphamide (2 g, day 1–3), etoposide (300 mg, day 1–3) and granulocyte colony-stimulating factor (G-CSF), and leukapheresis products containing a total of mononuclear cell (MNC) 9.78 × 108/kg and CD34+ cells 6.9 × 106/kg were collected. In April 2016, the patient received autologous hematopoietic stem cell transplantation as consolidation therapy. The conditioning regiments were melphalan (200 mg/m2 -2d) and bortezomib (1.75 mg -6, -3, +1, +4), and a total of 9.78 × 108/kg MNC and 6.9 × 106/kg CD34+ cells PBSC were reinfused. Platelets and white blood cells were recovered at 10 and 11 days after transplantation, respectively. The CT scan performed 1 month after ASCT confirmed a CR.
However, 3 months after ASCT, CT showed a new lesion appeared in the second rib on the right side, which was considered as relapse. After full assessment, the patient underwent HLA half-matched allo-HSCT in September 2016. The conditioning regimen was modified BuCy+ATG (cytarabine 3.5 g -10, -9; busulfan 51.6 mg Q6 h -8, -7, -6; cyclophosphamide 3 g -5, -4; MECCNU 450 mg -3; antithymocyte globulin 2.5 mg/Kg -5, -4, -3, -2), and the scheme for prevention of graft-versus-host disease (GVHD) was cyclosporin, mycophenolate mofetil and short-term methotrexate. The patient developed pulmonary fungal infection 20 days after allo-HSCT and took a turn for the better after treatment with voriconazole injection and voriconazole tablets. Unfortunately, the patient developed severe hemorrhagic cystitis 20 days later, but fortunately the condition improved after symptomatic treatment. There has been no evidence of acute or chronic GVHD. The patient achieved sustained complete donor engraftment as short tandem repeat monitoring was performed every three months after transplantation. A CR was metabolically and clinically confirmed by PET-CT scan after allo-HSCT. The patient is now healthy and in CR for 4 years after allo-HSCT.
3 Discussed
PBL is a distinct variant of diffuse large B-cell lymphoma initially described in HIV-positive patients.[7] Nevertheless, PBL has also been described in HIV-negative individuals, particularly in association with potential immunosuppression such as after solid organ or bone marrow transplantation or with autoimmune disorders and malignanciess.[8–11] HIV-negative PBL, in comparison with HIV-positive PBL, occurs in older patients, with less frequent involvement of oral mucosa or bone marrow and less frequently stages III-IV.[3,12,13] A review of 114 HIV-negative patients with PBL, by Liu et al[12] demonstrated that immunosuppression, MYC gene rearrangement, high-risk international prognostic index, and EBV negativity were poor prognostic factors. And the overall survival (OS) is between 9 and 19 months in HIV-negative patients.[12] Similarly, a systematic review on 76 HIV-negative PBL patients showed median OS of 9 months with 2-year OS rate of 10%.[13]
Given its rarity and peculiar features, there is no standard of care for PBL and the treatment remains a challenge.[11] The use of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and CHOP-like regimens are considered inadequate therapy, resulting short remission period,[3,11] so the NCCN guidelines recommend more intensive regimens,[14] including etoposide, vincristine and doxorubicin with bolus of cyclophosphamide and prednisone (EPOCH),[15] cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide, cytarabine,[16] or hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine.[17] The benefit of ASCT in patients with PBL is not quite clear based on the limited data available. In a single institution report of 9 consecutive HIV-negative PBL patients, 7 patients achieved CR and 1 patient achieved partial response (PR) after chemotherapy.[8] Four patients underwent consolidation with ASCT in first complete remission, and 2 of these patients were alive at median follow-up of 23.9 months. The third patient had disease recurrence at 14 months and the fourth patient had disease recurrence at 2 months after ASCT.[8] Moffitt Cancer Center presented the experience of two HIV-negative patients with PBL in PR that underwent an ASCT, and two patients survived 6 and 12 months.[12]
Given the low efficacy of the standard therapy, and the poor outcome of these patients, there is a need to move toward new therapeutic strategies by incorporating new agents. Bortezomib is the most reported new drug for PBL and has been used as a single dose or in combination. Koji et al[18] show the bortezomib and lenalidomide-based treatment was tolerated and the patient was continued with a PR for over 2 years. Bortezomib and lenalidomide have a certain therapeutic effect, and are mostly used in patients with refractory recurrence.[18,19] There are few case reports showing single-agent lenalidomide or combination with other chemotherapeutic drug in refractory PBL.[20–22] A dramatic response to Brentuximab has been reported in a single case, but the patient died shortly due to previous disease disabilities.[23] A plasmablastic microlymphoma arising in HHV8-associated multicentric Castleman disease in an HIV-negative patient that showed a clinical response to siltuximab, an anti-IL6 antibody.[24] The use of rituximab, a chimeric anti-CD20 monoclonal antibody, is not currently a therapeutic standard because the lack of CD20 expression by PBL cells, but combined with chemotherapy it could improve remission rates.[3,25] Clinical trials with novel immunotherapeutic agents and other drugs targeting some genes involved in the activation of Nuclear factor kappa B pathways, some of which are already ongoing, may show promising results.[18]
The literature on allo-HSCT in PBL is limited compared with ASCT. Only few cases of allo-HSCT for PBL were reported, much less for recurrence PBL. Hamadani[26] reported one patient with PBL in CR2 who underwent a reduced-intensity allogeneic stem cell transplantation, and was alive 2 years after transplantation. Liu et al[8] reported one patient who had disease recurrence at 14 months after ASCT was treated with allo-HSCT. Despite consolidation with allo-HSCT, disease recurred 5 months after, and the patient died. In general, the efficacy of allo-HSCT in the treatment of HIV-negative PBL patients is still not ideal and the survival of recurrent PBL after allo-HSCT is very poor.
In our case, the patient had recurrence after consolidated ASCT. Then, he underwent the salvage allo-HSCT from his daughter and achieved good curative effect. The patient was in long-term complete remission and he is alive now. It may be attributed to his younger age, low IPI score and early allo-HSCT treatment after relapse. As far as we know, this is the first case of such a long survival time after allo-HSCT. For young relapsed patients with PBL, allo-HSCT may bring long-term survival opportunities. Due to the rarity of the disease, it is not feasible to carry out large-scale clinical trials. The evaluation of allogeneic hematopoietic stem cell transplantation in PBL patients requires more accumulation and sharing of clinical experience.
Author contributions
Data curation: An Wu, Ye Sun.
Funding acquisition: Guifang Ouyang, Lixia Sheng.
Methodology: Lixia Sheng.
Writing – original draft: Chunmeng Rong.
Writing – review & editing: Chunmeng Rong.
Abbreviations: allo-HSCT = allogeneic hematopoietic stem cell transplantation, ASCT = autologous hematopoietic stem cell transplantation, CHOP = cyclophosphamide, doxorubicin, vincristine and prednisone, CR = complete response, CT = computed tomography, DLBCL = diffuse large B-cell lymphoma, EBV-DNA = Epstein-Barr virus DNA, GVHD = graft-versus-host disease, HHV-8 = Human herpes virus 8, HIV = human immunodeficiency virus, IPI = International Prognostic Index, MNC = mononuclear cell, OS = overall survival, PBL = plasmablastic lymphoma, PBSC = peripheral blood stem cell, PET-CT = positron emission tomography–computed tomography, PR = partial response.
How to cite this article: Rong C, Sheng L, Wu A, Sun Y, Ouyang G. Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: a case report. Medicine. 2021;100:7(e24498).
The study protocol was approved by the Ethics Review Committee of Ningbo First Hospital.
Patient has provided informed consent for publication of the case, and patient share his experience.
This study was supported by the National Natural Science Foundation of China under grant (number 81401321); Basic Public Welfare Research Project of Zhejiang Province under grant (number LGF19H080002); Medical Health Science and Technology Project of Zhejiang Provincial Health Commission under grant (number 2018PY052); National Science Foundation of Zhejiang Province under grant (number LY17H160005); and Traditional Chinese Medicine Administration of Zhejiang Province under grant (number 2015ZZ018).
The authors declare no conflict of interest.
The datasets generated during and/or analyzed during the current study are publicly available. | BUSULFAN, CYCLOPHOSPHAMIDE, CYCLOSPORINE, CYTARABINE, METHOTREXATE, MYCOPHENOLIC ACID, SEMUSTINE, THYMOCYTE IMMUNE GLOBULIN NOS | DrugsGivenReaction | CC BY | 33607779 | 18,990,270 | 2021-02-19 |
What was the dosage of drug 'BUSULFAN'? | Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: A case report.
BACKGROUND
No standard guideline has been established for the treatment of plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and show resistance to commonly used cytostatic drugs.
We present the case of a 52-year-old HIV-negative man who presented with a mass at the left sternoclavicular joint. He had no significant comorbidities and no latent immunosuppression.
METHODS
The largest lymph node measured was 36 × 19 mm. An excisional biopsy showed diffuse proliferation of large lymphoid cells which were positive for CD38 and CD138, but negative for CD20. He was diagnosed with stage IV PBL with a low IPI.
METHODS
The patient was treated with four cycles of induction therapy with bortezomib, epirubicin and dexamethasone. He achieved complete remission. But 3 months after receiving consolidated autologous hematopoietic stem cell transplantation, he relapsed. Allogeneic hematopoietic stem cell transplantation was performed on the patient.
RESULTS
The patient achieved remission again and there were no serious complications after allogeneic hematopoietic stem cell transplantation. This patient was followed up once every three months, and to date, he has been disease-free for more than 4 years.
CONCLUSIONS
The survival of recurrent PBL after autologous hematopoietic stem cell transplantation is very poor. Salvage allogeneic hematopoietic stem cell transplantation may bring long-term survival opportunities for those patients. Further clinical studies are needed to explore the role of allogeneic hematopoietic stem cell transplantation in refractory and recurrent PBL.
pmc1 Introduction
Plasmablastic lymphoma (PBL) is a rare and highly aggressive subtype of diffuse large B-cell lymphoma (DLBCL), characterized by plasma cell antigen differentiation. It was initially described in the setting of human immunodeficiency virus (HIV) infection, but it was also been reported in HIV-negative patients.[1] There is no consensus on the standard of care for PBL. The role of intensification of induction chemotherapy is controversial. And novel agents, bortezomib and lenalidomide, have shown some effectiveness in relapsed cases and may have a relatively important role in frontline treatment.[2,3] The use of autologous stem cell transplantation (ASCT) possibly improves outcomes when used as a consolidation or salvage therapy and may lead to better results than chemotherapy, but the available data remain sparse.[2] The literatures on allogeneic hematopoietic stem cell transplantation (allo-HSCT) treatment for PBL are quite rare compared to ASCT. And given its rarity, most of the data available rely on case reports and case series. Patients with PBL have a poor prognosis, with median survival times shorter than 2 years.[2,4] To the best of our knowledge, the survival of recurrent PBL is worse.[2,5,6] Here, we report a case of HIV-negative PBL in a patient who had recurrence after ASCT, but achieved and maintained complete remission for 4-years after salvage allo-HSCT.
2 Case presentation
The patient was a 52-year-old man who presented in September 2015 with a mass at left sternoclavicular joint without any systemic symptoms. He had no significant comorbidities and no latent immunosuppression. Ultrasonography of lymph nodes indicated multiple lymph node enlargement in the neck, and multiple hypoechoic areas were seen above the left clavicle, the largest of which was 36 × 19 mm. A total body computed tomography (CT) scan showed that soft tissue mass shadows were seen around the left sternoclavicular joint and local cortical absorptions were present. Further investigations with fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) scan confirmed hypermetabolic mass appeared in several places of the body which was considered plasma cell infiltration. An excisional biopsy showed diffuse proliferation of large lymphoid cells (Fig. 1). Immuno-staining of the neoplastic cells showed negative for CD20, CD5, CD30, EREB, MPO, CD117 and Bcl-6, whereas it was positive for CD38, CD138, CD10, CD79a and Bcl-2 (Figs. 2–5). The Ki-67 proliferation index was 95% (Fig. 6). Biopsy of the iliac crest showed no marrow involvement. According to the above analysis, International Prognostic Index (IPI) scores were 2, the patient was diagnosed with stage IV PBL with a low IPI.
Figure 1 H&E (hematoxylin and eosin) image shows large sheets of mostly large plasmacytoid appearing mononuclear cells. (HE Magnification × 400).
Figure 2 CD138, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 3 CD38, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 4 CD10, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 5 CD79a, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 6 Strong and homogenous staining with Ki-67 indicating a high proliferation index. (Magnification × 200).
In addition, laboratory data were as following: Blood routine examination indicated that the white blood cells were 8.1 × 109/L, the hemoglobin was 146 g/L and the platelets were 267 × 109/L. Erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, β2 microglobulin, serum proteins and immunoglobulin levels were all within normal ranges. Immunofixation electrophoresis showed no monoclonal component. Human herpes virus 8 (HHV-8) and Epstein-Barr virus DNA (EBV-DNA) were negative. Besides, serology for HIV was also negative.
From September to December 2015, the patient received 4 cycles of PAD chemotherapy regimens: bortezomib was given at the dose of 2.4 mg/day on day 1, 4, 8, 11, epirubicin at the dose of 20 mg/day on days 1–3, and dexamethasone at the dose of 40 mg/day on days 1–4 and 8–11 of each 28-day cycle. Repeat PET/CT following 4 cycles of chemotherapy showed no abnormal flurodeoxyglucose metabolic foci and enlarged lymph nodes, thus being compatible with a complete response (CR).
Later on, peripheral blood stem cell (PBSC) mobilization was achieved by high-dose cyclophosphamide (2 g, day 1–3), etoposide (300 mg, day 1–3) and granulocyte colony-stimulating factor (G-CSF), and leukapheresis products containing a total of mononuclear cell (MNC) 9.78 × 108/kg and CD34+ cells 6.9 × 106/kg were collected. In April 2016, the patient received autologous hematopoietic stem cell transplantation as consolidation therapy. The conditioning regiments were melphalan (200 mg/m2 -2d) and bortezomib (1.75 mg -6, -3, +1, +4), and a total of 9.78 × 108/kg MNC and 6.9 × 106/kg CD34+ cells PBSC were reinfused. Platelets and white blood cells were recovered at 10 and 11 days after transplantation, respectively. The CT scan performed 1 month after ASCT confirmed a CR.
However, 3 months after ASCT, CT showed a new lesion appeared in the second rib on the right side, which was considered as relapse. After full assessment, the patient underwent HLA half-matched allo-HSCT in September 2016. The conditioning regimen was modified BuCy+ATG (cytarabine 3.5 g -10, -9; busulfan 51.6 mg Q6 h -8, -7, -6; cyclophosphamide 3 g -5, -4; MECCNU 450 mg -3; antithymocyte globulin 2.5 mg/Kg -5, -4, -3, -2), and the scheme for prevention of graft-versus-host disease (GVHD) was cyclosporin, mycophenolate mofetil and short-term methotrexate. The patient developed pulmonary fungal infection 20 days after allo-HSCT and took a turn for the better after treatment with voriconazole injection and voriconazole tablets. Unfortunately, the patient developed severe hemorrhagic cystitis 20 days later, but fortunately the condition improved after symptomatic treatment. There has been no evidence of acute or chronic GVHD. The patient achieved sustained complete donor engraftment as short tandem repeat monitoring was performed every three months after transplantation. A CR was metabolically and clinically confirmed by PET-CT scan after allo-HSCT. The patient is now healthy and in CR for 4 years after allo-HSCT.
3 Discussed
PBL is a distinct variant of diffuse large B-cell lymphoma initially described in HIV-positive patients.[7] Nevertheless, PBL has also been described in HIV-negative individuals, particularly in association with potential immunosuppression such as after solid organ or bone marrow transplantation or with autoimmune disorders and malignanciess.[8–11] HIV-negative PBL, in comparison with HIV-positive PBL, occurs in older patients, with less frequent involvement of oral mucosa or bone marrow and less frequently stages III-IV.[3,12,13] A review of 114 HIV-negative patients with PBL, by Liu et al[12] demonstrated that immunosuppression, MYC gene rearrangement, high-risk international prognostic index, and EBV negativity were poor prognostic factors. And the overall survival (OS) is between 9 and 19 months in HIV-negative patients.[12] Similarly, a systematic review on 76 HIV-negative PBL patients showed median OS of 9 months with 2-year OS rate of 10%.[13]
Given its rarity and peculiar features, there is no standard of care for PBL and the treatment remains a challenge.[11] The use of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and CHOP-like regimens are considered inadequate therapy, resulting short remission period,[3,11] so the NCCN guidelines recommend more intensive regimens,[14] including etoposide, vincristine and doxorubicin with bolus of cyclophosphamide and prednisone (EPOCH),[15] cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide, cytarabine,[16] or hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine.[17] The benefit of ASCT in patients with PBL is not quite clear based on the limited data available. In a single institution report of 9 consecutive HIV-negative PBL patients, 7 patients achieved CR and 1 patient achieved partial response (PR) after chemotherapy.[8] Four patients underwent consolidation with ASCT in first complete remission, and 2 of these patients were alive at median follow-up of 23.9 months. The third patient had disease recurrence at 14 months and the fourth patient had disease recurrence at 2 months after ASCT.[8] Moffitt Cancer Center presented the experience of two HIV-negative patients with PBL in PR that underwent an ASCT, and two patients survived 6 and 12 months.[12]
Given the low efficacy of the standard therapy, and the poor outcome of these patients, there is a need to move toward new therapeutic strategies by incorporating new agents. Bortezomib is the most reported new drug for PBL and has been used as a single dose or in combination. Koji et al[18] show the bortezomib and lenalidomide-based treatment was tolerated and the patient was continued with a PR for over 2 years. Bortezomib and lenalidomide have a certain therapeutic effect, and are mostly used in patients with refractory recurrence.[18,19] There are few case reports showing single-agent lenalidomide or combination with other chemotherapeutic drug in refractory PBL.[20–22] A dramatic response to Brentuximab has been reported in a single case, but the patient died shortly due to previous disease disabilities.[23] A plasmablastic microlymphoma arising in HHV8-associated multicentric Castleman disease in an HIV-negative patient that showed a clinical response to siltuximab, an anti-IL6 antibody.[24] The use of rituximab, a chimeric anti-CD20 monoclonal antibody, is not currently a therapeutic standard because the lack of CD20 expression by PBL cells, but combined with chemotherapy it could improve remission rates.[3,25] Clinical trials with novel immunotherapeutic agents and other drugs targeting some genes involved in the activation of Nuclear factor kappa B pathways, some of which are already ongoing, may show promising results.[18]
The literature on allo-HSCT in PBL is limited compared with ASCT. Only few cases of allo-HSCT for PBL were reported, much less for recurrence PBL. Hamadani[26] reported one patient with PBL in CR2 who underwent a reduced-intensity allogeneic stem cell transplantation, and was alive 2 years after transplantation. Liu et al[8] reported one patient who had disease recurrence at 14 months after ASCT was treated with allo-HSCT. Despite consolidation with allo-HSCT, disease recurred 5 months after, and the patient died. In general, the efficacy of allo-HSCT in the treatment of HIV-negative PBL patients is still not ideal and the survival of recurrent PBL after allo-HSCT is very poor.
In our case, the patient had recurrence after consolidated ASCT. Then, he underwent the salvage allo-HSCT from his daughter and achieved good curative effect. The patient was in long-term complete remission and he is alive now. It may be attributed to his younger age, low IPI score and early allo-HSCT treatment after relapse. As far as we know, this is the first case of such a long survival time after allo-HSCT. For young relapsed patients with PBL, allo-HSCT may bring long-term survival opportunities. Due to the rarity of the disease, it is not feasible to carry out large-scale clinical trials. The evaluation of allogeneic hematopoietic stem cell transplantation in PBL patients requires more accumulation and sharing of clinical experience.
Author contributions
Data curation: An Wu, Ye Sun.
Funding acquisition: Guifang Ouyang, Lixia Sheng.
Methodology: Lixia Sheng.
Writing – original draft: Chunmeng Rong.
Writing – review & editing: Chunmeng Rong.
Abbreviations: allo-HSCT = allogeneic hematopoietic stem cell transplantation, ASCT = autologous hematopoietic stem cell transplantation, CHOP = cyclophosphamide, doxorubicin, vincristine and prednisone, CR = complete response, CT = computed tomography, DLBCL = diffuse large B-cell lymphoma, EBV-DNA = Epstein-Barr virus DNA, GVHD = graft-versus-host disease, HHV-8 = Human herpes virus 8, HIV = human immunodeficiency virus, IPI = International Prognostic Index, MNC = mononuclear cell, OS = overall survival, PBL = plasmablastic lymphoma, PBSC = peripheral blood stem cell, PET-CT = positron emission tomography–computed tomography, PR = partial response.
How to cite this article: Rong C, Sheng L, Wu A, Sun Y, Ouyang G. Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: a case report. Medicine. 2021;100:7(e24498).
The study protocol was approved by the Ethics Review Committee of Ningbo First Hospital.
Patient has provided informed consent for publication of the case, and patient share his experience.
This study was supported by the National Natural Science Foundation of China under grant (number 81401321); Basic Public Welfare Research Project of Zhejiang Province under grant (number LGF19H080002); Medical Health Science and Technology Project of Zhejiang Provincial Health Commission under grant (number 2018PY052); National Science Foundation of Zhejiang Province under grant (number LY17H160005); and Traditional Chinese Medicine Administration of Zhejiang Province under grant (number 2015ZZ018).
The authors declare no conflict of interest.
The datasets generated during and/or analyzed during the current study are publicly available. | 51.6MG Q6H ?8, ?7, ?6 | DrugDosageText | CC BY | 33607779 | 18,990,270 | 2021-02-19 |
What was the dosage of drug 'CYCLOPHOSPHAMIDE'? | Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: A case report.
BACKGROUND
No standard guideline has been established for the treatment of plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and show resistance to commonly used cytostatic drugs.
We present the case of a 52-year-old HIV-negative man who presented with a mass at the left sternoclavicular joint. He had no significant comorbidities and no latent immunosuppression.
METHODS
The largest lymph node measured was 36 × 19 mm. An excisional biopsy showed diffuse proliferation of large lymphoid cells which were positive for CD38 and CD138, but negative for CD20. He was diagnosed with stage IV PBL with a low IPI.
METHODS
The patient was treated with four cycles of induction therapy with bortezomib, epirubicin and dexamethasone. He achieved complete remission. But 3 months after receiving consolidated autologous hematopoietic stem cell transplantation, he relapsed. Allogeneic hematopoietic stem cell transplantation was performed on the patient.
RESULTS
The patient achieved remission again and there were no serious complications after allogeneic hematopoietic stem cell transplantation. This patient was followed up once every three months, and to date, he has been disease-free for more than 4 years.
CONCLUSIONS
The survival of recurrent PBL after autologous hematopoietic stem cell transplantation is very poor. Salvage allogeneic hematopoietic stem cell transplantation may bring long-term survival opportunities for those patients. Further clinical studies are needed to explore the role of allogeneic hematopoietic stem cell transplantation in refractory and recurrent PBL.
pmc1 Introduction
Plasmablastic lymphoma (PBL) is a rare and highly aggressive subtype of diffuse large B-cell lymphoma (DLBCL), characterized by plasma cell antigen differentiation. It was initially described in the setting of human immunodeficiency virus (HIV) infection, but it was also been reported in HIV-negative patients.[1] There is no consensus on the standard of care for PBL. The role of intensification of induction chemotherapy is controversial. And novel agents, bortezomib and lenalidomide, have shown some effectiveness in relapsed cases and may have a relatively important role in frontline treatment.[2,3] The use of autologous stem cell transplantation (ASCT) possibly improves outcomes when used as a consolidation or salvage therapy and may lead to better results than chemotherapy, but the available data remain sparse.[2] The literatures on allogeneic hematopoietic stem cell transplantation (allo-HSCT) treatment for PBL are quite rare compared to ASCT. And given its rarity, most of the data available rely on case reports and case series. Patients with PBL have a poor prognosis, with median survival times shorter than 2 years.[2,4] To the best of our knowledge, the survival of recurrent PBL is worse.[2,5,6] Here, we report a case of HIV-negative PBL in a patient who had recurrence after ASCT, but achieved and maintained complete remission for 4-years after salvage allo-HSCT.
2 Case presentation
The patient was a 52-year-old man who presented in September 2015 with a mass at left sternoclavicular joint without any systemic symptoms. He had no significant comorbidities and no latent immunosuppression. Ultrasonography of lymph nodes indicated multiple lymph node enlargement in the neck, and multiple hypoechoic areas were seen above the left clavicle, the largest of which was 36 × 19 mm. A total body computed tomography (CT) scan showed that soft tissue mass shadows were seen around the left sternoclavicular joint and local cortical absorptions were present. Further investigations with fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) scan confirmed hypermetabolic mass appeared in several places of the body which was considered plasma cell infiltration. An excisional biopsy showed diffuse proliferation of large lymphoid cells (Fig. 1). Immuno-staining of the neoplastic cells showed negative for CD20, CD5, CD30, EREB, MPO, CD117 and Bcl-6, whereas it was positive for CD38, CD138, CD10, CD79a and Bcl-2 (Figs. 2–5). The Ki-67 proliferation index was 95% (Fig. 6). Biopsy of the iliac crest showed no marrow involvement. According to the above analysis, International Prognostic Index (IPI) scores were 2, the patient was diagnosed with stage IV PBL with a low IPI.
Figure 1 H&E (hematoxylin and eosin) image shows large sheets of mostly large plasmacytoid appearing mononuclear cells. (HE Magnification × 400).
Figure 2 CD138, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 3 CD38, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 4 CD10, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 5 CD79a, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 6 Strong and homogenous staining with Ki-67 indicating a high proliferation index. (Magnification × 200).
In addition, laboratory data were as following: Blood routine examination indicated that the white blood cells were 8.1 × 109/L, the hemoglobin was 146 g/L and the platelets were 267 × 109/L. Erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, β2 microglobulin, serum proteins and immunoglobulin levels were all within normal ranges. Immunofixation electrophoresis showed no monoclonal component. Human herpes virus 8 (HHV-8) and Epstein-Barr virus DNA (EBV-DNA) were negative. Besides, serology for HIV was also negative.
From September to December 2015, the patient received 4 cycles of PAD chemotherapy regimens: bortezomib was given at the dose of 2.4 mg/day on day 1, 4, 8, 11, epirubicin at the dose of 20 mg/day on days 1–3, and dexamethasone at the dose of 40 mg/day on days 1–4 and 8–11 of each 28-day cycle. Repeat PET/CT following 4 cycles of chemotherapy showed no abnormal flurodeoxyglucose metabolic foci and enlarged lymph nodes, thus being compatible with a complete response (CR).
Later on, peripheral blood stem cell (PBSC) mobilization was achieved by high-dose cyclophosphamide (2 g, day 1–3), etoposide (300 mg, day 1–3) and granulocyte colony-stimulating factor (G-CSF), and leukapheresis products containing a total of mononuclear cell (MNC) 9.78 × 108/kg and CD34+ cells 6.9 × 106/kg were collected. In April 2016, the patient received autologous hematopoietic stem cell transplantation as consolidation therapy. The conditioning regiments were melphalan (200 mg/m2 -2d) and bortezomib (1.75 mg -6, -3, +1, +4), and a total of 9.78 × 108/kg MNC and 6.9 × 106/kg CD34+ cells PBSC were reinfused. Platelets and white blood cells were recovered at 10 and 11 days after transplantation, respectively. The CT scan performed 1 month after ASCT confirmed a CR.
However, 3 months after ASCT, CT showed a new lesion appeared in the second rib on the right side, which was considered as relapse. After full assessment, the patient underwent HLA half-matched allo-HSCT in September 2016. The conditioning regimen was modified BuCy+ATG (cytarabine 3.5 g -10, -9; busulfan 51.6 mg Q6 h -8, -7, -6; cyclophosphamide 3 g -5, -4; MECCNU 450 mg -3; antithymocyte globulin 2.5 mg/Kg -5, -4, -3, -2), and the scheme for prevention of graft-versus-host disease (GVHD) was cyclosporin, mycophenolate mofetil and short-term methotrexate. The patient developed pulmonary fungal infection 20 days after allo-HSCT and took a turn for the better after treatment with voriconazole injection and voriconazole tablets. Unfortunately, the patient developed severe hemorrhagic cystitis 20 days later, but fortunately the condition improved after symptomatic treatment. There has been no evidence of acute or chronic GVHD. The patient achieved sustained complete donor engraftment as short tandem repeat monitoring was performed every three months after transplantation. A CR was metabolically and clinically confirmed by PET-CT scan after allo-HSCT. The patient is now healthy and in CR for 4 years after allo-HSCT.
3 Discussed
PBL is a distinct variant of diffuse large B-cell lymphoma initially described in HIV-positive patients.[7] Nevertheless, PBL has also been described in HIV-negative individuals, particularly in association with potential immunosuppression such as after solid organ or bone marrow transplantation or with autoimmune disorders and malignanciess.[8–11] HIV-negative PBL, in comparison with HIV-positive PBL, occurs in older patients, with less frequent involvement of oral mucosa or bone marrow and less frequently stages III-IV.[3,12,13] A review of 114 HIV-negative patients with PBL, by Liu et al[12] demonstrated that immunosuppression, MYC gene rearrangement, high-risk international prognostic index, and EBV negativity were poor prognostic factors. And the overall survival (OS) is between 9 and 19 months in HIV-negative patients.[12] Similarly, a systematic review on 76 HIV-negative PBL patients showed median OS of 9 months with 2-year OS rate of 10%.[13]
Given its rarity and peculiar features, there is no standard of care for PBL and the treatment remains a challenge.[11] The use of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and CHOP-like regimens are considered inadequate therapy, resulting short remission period,[3,11] so the NCCN guidelines recommend more intensive regimens,[14] including etoposide, vincristine and doxorubicin with bolus of cyclophosphamide and prednisone (EPOCH),[15] cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide, cytarabine,[16] or hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine.[17] The benefit of ASCT in patients with PBL is not quite clear based on the limited data available. In a single institution report of 9 consecutive HIV-negative PBL patients, 7 patients achieved CR and 1 patient achieved partial response (PR) after chemotherapy.[8] Four patients underwent consolidation with ASCT in first complete remission, and 2 of these patients were alive at median follow-up of 23.9 months. The third patient had disease recurrence at 14 months and the fourth patient had disease recurrence at 2 months after ASCT.[8] Moffitt Cancer Center presented the experience of two HIV-negative patients with PBL in PR that underwent an ASCT, and two patients survived 6 and 12 months.[12]
Given the low efficacy of the standard therapy, and the poor outcome of these patients, there is a need to move toward new therapeutic strategies by incorporating new agents. Bortezomib is the most reported new drug for PBL and has been used as a single dose or in combination. Koji et al[18] show the bortezomib and lenalidomide-based treatment was tolerated and the patient was continued with a PR for over 2 years. Bortezomib and lenalidomide have a certain therapeutic effect, and are mostly used in patients with refractory recurrence.[18,19] There are few case reports showing single-agent lenalidomide or combination with other chemotherapeutic drug in refractory PBL.[20–22] A dramatic response to Brentuximab has been reported in a single case, but the patient died shortly due to previous disease disabilities.[23] A plasmablastic microlymphoma arising in HHV8-associated multicentric Castleman disease in an HIV-negative patient that showed a clinical response to siltuximab, an anti-IL6 antibody.[24] The use of rituximab, a chimeric anti-CD20 monoclonal antibody, is not currently a therapeutic standard because the lack of CD20 expression by PBL cells, but combined with chemotherapy it could improve remission rates.[3,25] Clinical trials with novel immunotherapeutic agents and other drugs targeting some genes involved in the activation of Nuclear factor kappa B pathways, some of which are already ongoing, may show promising results.[18]
The literature on allo-HSCT in PBL is limited compared with ASCT. Only few cases of allo-HSCT for PBL were reported, much less for recurrence PBL. Hamadani[26] reported one patient with PBL in CR2 who underwent a reduced-intensity allogeneic stem cell transplantation, and was alive 2 years after transplantation. Liu et al[8] reported one patient who had disease recurrence at 14 months after ASCT was treated with allo-HSCT. Despite consolidation with allo-HSCT, disease recurred 5 months after, and the patient died. In general, the efficacy of allo-HSCT in the treatment of HIV-negative PBL patients is still not ideal and the survival of recurrent PBL after allo-HSCT is very poor.
In our case, the patient had recurrence after consolidated ASCT. Then, he underwent the salvage allo-HSCT from his daughter and achieved good curative effect. The patient was in long-term complete remission and he is alive now. It may be attributed to his younger age, low IPI score and early allo-HSCT treatment after relapse. As far as we know, this is the first case of such a long survival time after allo-HSCT. For young relapsed patients with PBL, allo-HSCT may bring long-term survival opportunities. Due to the rarity of the disease, it is not feasible to carry out large-scale clinical trials. The evaluation of allogeneic hematopoietic stem cell transplantation in PBL patients requires more accumulation and sharing of clinical experience.
Author contributions
Data curation: An Wu, Ye Sun.
Funding acquisition: Guifang Ouyang, Lixia Sheng.
Methodology: Lixia Sheng.
Writing – original draft: Chunmeng Rong.
Writing – review & editing: Chunmeng Rong.
Abbreviations: allo-HSCT = allogeneic hematopoietic stem cell transplantation, ASCT = autologous hematopoietic stem cell transplantation, CHOP = cyclophosphamide, doxorubicin, vincristine and prednisone, CR = complete response, CT = computed tomography, DLBCL = diffuse large B-cell lymphoma, EBV-DNA = Epstein-Barr virus DNA, GVHD = graft-versus-host disease, HHV-8 = Human herpes virus 8, HIV = human immunodeficiency virus, IPI = International Prognostic Index, MNC = mononuclear cell, OS = overall survival, PBL = plasmablastic lymphoma, PBSC = peripheral blood stem cell, PET-CT = positron emission tomography–computed tomography, PR = partial response.
How to cite this article: Rong C, Sheng L, Wu A, Sun Y, Ouyang G. Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: a case report. Medicine. 2021;100:7(e24498).
The study protocol was approved by the Ethics Review Committee of Ningbo First Hospital.
Patient has provided informed consent for publication of the case, and patient share his experience.
This study was supported by the National Natural Science Foundation of China under grant (number 81401321); Basic Public Welfare Research Project of Zhejiang Province under grant (number LGF19H080002); Medical Health Science and Technology Project of Zhejiang Provincial Health Commission under grant (number 2018PY052); National Science Foundation of Zhejiang Province under grant (number LY17H160005); and Traditional Chinese Medicine Administration of Zhejiang Province under grant (number 2015ZZ018).
The authors declare no conflict of interest.
The datasets generated during and/or analyzed during the current study are publicly available. | 3G ?5, ?4 | DrugDosageText | CC BY | 33607779 | 18,990,270 | 2021-02-19 |
What was the dosage of drug 'CYTARABINE'? | Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: A case report.
BACKGROUND
No standard guideline has been established for the treatment of plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and show resistance to commonly used cytostatic drugs.
We present the case of a 52-year-old HIV-negative man who presented with a mass at the left sternoclavicular joint. He had no significant comorbidities and no latent immunosuppression.
METHODS
The largest lymph node measured was 36 × 19 mm. An excisional biopsy showed diffuse proliferation of large lymphoid cells which were positive for CD38 and CD138, but negative for CD20. He was diagnosed with stage IV PBL with a low IPI.
METHODS
The patient was treated with four cycles of induction therapy with bortezomib, epirubicin and dexamethasone. He achieved complete remission. But 3 months after receiving consolidated autologous hematopoietic stem cell transplantation, he relapsed. Allogeneic hematopoietic stem cell transplantation was performed on the patient.
RESULTS
The patient achieved remission again and there were no serious complications after allogeneic hematopoietic stem cell transplantation. This patient was followed up once every three months, and to date, he has been disease-free for more than 4 years.
CONCLUSIONS
The survival of recurrent PBL after autologous hematopoietic stem cell transplantation is very poor. Salvage allogeneic hematopoietic stem cell transplantation may bring long-term survival opportunities for those patients. Further clinical studies are needed to explore the role of allogeneic hematopoietic stem cell transplantation in refractory and recurrent PBL.
pmc1 Introduction
Plasmablastic lymphoma (PBL) is a rare and highly aggressive subtype of diffuse large B-cell lymphoma (DLBCL), characterized by plasma cell antigen differentiation. It was initially described in the setting of human immunodeficiency virus (HIV) infection, but it was also been reported in HIV-negative patients.[1] There is no consensus on the standard of care for PBL. The role of intensification of induction chemotherapy is controversial. And novel agents, bortezomib and lenalidomide, have shown some effectiveness in relapsed cases and may have a relatively important role in frontline treatment.[2,3] The use of autologous stem cell transplantation (ASCT) possibly improves outcomes when used as a consolidation or salvage therapy and may lead to better results than chemotherapy, but the available data remain sparse.[2] The literatures on allogeneic hematopoietic stem cell transplantation (allo-HSCT) treatment for PBL are quite rare compared to ASCT. And given its rarity, most of the data available rely on case reports and case series. Patients with PBL have a poor prognosis, with median survival times shorter than 2 years.[2,4] To the best of our knowledge, the survival of recurrent PBL is worse.[2,5,6] Here, we report a case of HIV-negative PBL in a patient who had recurrence after ASCT, but achieved and maintained complete remission for 4-years after salvage allo-HSCT.
2 Case presentation
The patient was a 52-year-old man who presented in September 2015 with a mass at left sternoclavicular joint without any systemic symptoms. He had no significant comorbidities and no latent immunosuppression. Ultrasonography of lymph nodes indicated multiple lymph node enlargement in the neck, and multiple hypoechoic areas were seen above the left clavicle, the largest of which was 36 × 19 mm. A total body computed tomography (CT) scan showed that soft tissue mass shadows were seen around the left sternoclavicular joint and local cortical absorptions were present. Further investigations with fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) scan confirmed hypermetabolic mass appeared in several places of the body which was considered plasma cell infiltration. An excisional biopsy showed diffuse proliferation of large lymphoid cells (Fig. 1). Immuno-staining of the neoplastic cells showed negative for CD20, CD5, CD30, EREB, MPO, CD117 and Bcl-6, whereas it was positive for CD38, CD138, CD10, CD79a and Bcl-2 (Figs. 2–5). The Ki-67 proliferation index was 95% (Fig. 6). Biopsy of the iliac crest showed no marrow involvement. According to the above analysis, International Prognostic Index (IPI) scores were 2, the patient was diagnosed with stage IV PBL with a low IPI.
Figure 1 H&E (hematoxylin and eosin) image shows large sheets of mostly large plasmacytoid appearing mononuclear cells. (HE Magnification × 400).
Figure 2 CD138, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 3 CD38, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 4 CD10, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 5 CD79a, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 6 Strong and homogenous staining with Ki-67 indicating a high proliferation index. (Magnification × 200).
In addition, laboratory data were as following: Blood routine examination indicated that the white blood cells were 8.1 × 109/L, the hemoglobin was 146 g/L and the platelets were 267 × 109/L. Erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, β2 microglobulin, serum proteins and immunoglobulin levels were all within normal ranges. Immunofixation electrophoresis showed no monoclonal component. Human herpes virus 8 (HHV-8) and Epstein-Barr virus DNA (EBV-DNA) were negative. Besides, serology for HIV was also negative.
From September to December 2015, the patient received 4 cycles of PAD chemotherapy regimens: bortezomib was given at the dose of 2.4 mg/day on day 1, 4, 8, 11, epirubicin at the dose of 20 mg/day on days 1–3, and dexamethasone at the dose of 40 mg/day on days 1–4 and 8–11 of each 28-day cycle. Repeat PET/CT following 4 cycles of chemotherapy showed no abnormal flurodeoxyglucose metabolic foci and enlarged lymph nodes, thus being compatible with a complete response (CR).
Later on, peripheral blood stem cell (PBSC) mobilization was achieved by high-dose cyclophosphamide (2 g, day 1–3), etoposide (300 mg, day 1–3) and granulocyte colony-stimulating factor (G-CSF), and leukapheresis products containing a total of mononuclear cell (MNC) 9.78 × 108/kg and CD34+ cells 6.9 × 106/kg were collected. In April 2016, the patient received autologous hematopoietic stem cell transplantation as consolidation therapy. The conditioning regiments were melphalan (200 mg/m2 -2d) and bortezomib (1.75 mg -6, -3, +1, +4), and a total of 9.78 × 108/kg MNC and 6.9 × 106/kg CD34+ cells PBSC were reinfused. Platelets and white blood cells were recovered at 10 and 11 days after transplantation, respectively. The CT scan performed 1 month after ASCT confirmed a CR.
However, 3 months after ASCT, CT showed a new lesion appeared in the second rib on the right side, which was considered as relapse. After full assessment, the patient underwent HLA half-matched allo-HSCT in September 2016. The conditioning regimen was modified BuCy+ATG (cytarabine 3.5 g -10, -9; busulfan 51.6 mg Q6 h -8, -7, -6; cyclophosphamide 3 g -5, -4; MECCNU 450 mg -3; antithymocyte globulin 2.5 mg/Kg -5, -4, -3, -2), and the scheme for prevention of graft-versus-host disease (GVHD) was cyclosporin, mycophenolate mofetil and short-term methotrexate. The patient developed pulmonary fungal infection 20 days after allo-HSCT and took a turn for the better after treatment with voriconazole injection and voriconazole tablets. Unfortunately, the patient developed severe hemorrhagic cystitis 20 days later, but fortunately the condition improved after symptomatic treatment. There has been no evidence of acute or chronic GVHD. The patient achieved sustained complete donor engraftment as short tandem repeat monitoring was performed every three months after transplantation. A CR was metabolically and clinically confirmed by PET-CT scan after allo-HSCT. The patient is now healthy and in CR for 4 years after allo-HSCT.
3 Discussed
PBL is a distinct variant of diffuse large B-cell lymphoma initially described in HIV-positive patients.[7] Nevertheless, PBL has also been described in HIV-negative individuals, particularly in association with potential immunosuppression such as after solid organ or bone marrow transplantation or with autoimmune disorders and malignanciess.[8–11] HIV-negative PBL, in comparison with HIV-positive PBL, occurs in older patients, with less frequent involvement of oral mucosa or bone marrow and less frequently stages III-IV.[3,12,13] A review of 114 HIV-negative patients with PBL, by Liu et al[12] demonstrated that immunosuppression, MYC gene rearrangement, high-risk international prognostic index, and EBV negativity were poor prognostic factors. And the overall survival (OS) is between 9 and 19 months in HIV-negative patients.[12] Similarly, a systematic review on 76 HIV-negative PBL patients showed median OS of 9 months with 2-year OS rate of 10%.[13]
Given its rarity and peculiar features, there is no standard of care for PBL and the treatment remains a challenge.[11] The use of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and CHOP-like regimens are considered inadequate therapy, resulting short remission period,[3,11] so the NCCN guidelines recommend more intensive regimens,[14] including etoposide, vincristine and doxorubicin with bolus of cyclophosphamide and prednisone (EPOCH),[15] cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide, cytarabine,[16] or hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine.[17] The benefit of ASCT in patients with PBL is not quite clear based on the limited data available. In a single institution report of 9 consecutive HIV-negative PBL patients, 7 patients achieved CR and 1 patient achieved partial response (PR) after chemotherapy.[8] Four patients underwent consolidation with ASCT in first complete remission, and 2 of these patients were alive at median follow-up of 23.9 months. The third patient had disease recurrence at 14 months and the fourth patient had disease recurrence at 2 months after ASCT.[8] Moffitt Cancer Center presented the experience of two HIV-negative patients with PBL in PR that underwent an ASCT, and two patients survived 6 and 12 months.[12]
Given the low efficacy of the standard therapy, and the poor outcome of these patients, there is a need to move toward new therapeutic strategies by incorporating new agents. Bortezomib is the most reported new drug for PBL and has been used as a single dose or in combination. Koji et al[18] show the bortezomib and lenalidomide-based treatment was tolerated and the patient was continued with a PR for over 2 years. Bortezomib and lenalidomide have a certain therapeutic effect, and are mostly used in patients with refractory recurrence.[18,19] There are few case reports showing single-agent lenalidomide or combination with other chemotherapeutic drug in refractory PBL.[20–22] A dramatic response to Brentuximab has been reported in a single case, but the patient died shortly due to previous disease disabilities.[23] A plasmablastic microlymphoma arising in HHV8-associated multicentric Castleman disease in an HIV-negative patient that showed a clinical response to siltuximab, an anti-IL6 antibody.[24] The use of rituximab, a chimeric anti-CD20 monoclonal antibody, is not currently a therapeutic standard because the lack of CD20 expression by PBL cells, but combined with chemotherapy it could improve remission rates.[3,25] Clinical trials with novel immunotherapeutic agents and other drugs targeting some genes involved in the activation of Nuclear factor kappa B pathways, some of which are already ongoing, may show promising results.[18]
The literature on allo-HSCT in PBL is limited compared with ASCT. Only few cases of allo-HSCT for PBL were reported, much less for recurrence PBL. Hamadani[26] reported one patient with PBL in CR2 who underwent a reduced-intensity allogeneic stem cell transplantation, and was alive 2 years after transplantation. Liu et al[8] reported one patient who had disease recurrence at 14 months after ASCT was treated with allo-HSCT. Despite consolidation with allo-HSCT, disease recurred 5 months after, and the patient died. In general, the efficacy of allo-HSCT in the treatment of HIV-negative PBL patients is still not ideal and the survival of recurrent PBL after allo-HSCT is very poor.
In our case, the patient had recurrence after consolidated ASCT. Then, he underwent the salvage allo-HSCT from his daughter and achieved good curative effect. The patient was in long-term complete remission and he is alive now. It may be attributed to his younger age, low IPI score and early allo-HSCT treatment after relapse. As far as we know, this is the first case of such a long survival time after allo-HSCT. For young relapsed patients with PBL, allo-HSCT may bring long-term survival opportunities. Due to the rarity of the disease, it is not feasible to carry out large-scale clinical trials. The evaluation of allogeneic hematopoietic stem cell transplantation in PBL patients requires more accumulation and sharing of clinical experience.
Author contributions
Data curation: An Wu, Ye Sun.
Funding acquisition: Guifang Ouyang, Lixia Sheng.
Methodology: Lixia Sheng.
Writing – original draft: Chunmeng Rong.
Writing – review & editing: Chunmeng Rong.
Abbreviations: allo-HSCT = allogeneic hematopoietic stem cell transplantation, ASCT = autologous hematopoietic stem cell transplantation, CHOP = cyclophosphamide, doxorubicin, vincristine and prednisone, CR = complete response, CT = computed tomography, DLBCL = diffuse large B-cell lymphoma, EBV-DNA = Epstein-Barr virus DNA, GVHD = graft-versus-host disease, HHV-8 = Human herpes virus 8, HIV = human immunodeficiency virus, IPI = International Prognostic Index, MNC = mononuclear cell, OS = overall survival, PBL = plasmablastic lymphoma, PBSC = peripheral blood stem cell, PET-CT = positron emission tomography–computed tomography, PR = partial response.
How to cite this article: Rong C, Sheng L, Wu A, Sun Y, Ouyang G. Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: a case report. Medicine. 2021;100:7(e24498).
The study protocol was approved by the Ethics Review Committee of Ningbo First Hospital.
Patient has provided informed consent for publication of the case, and patient share his experience.
This study was supported by the National Natural Science Foundation of China under grant (number 81401321); Basic Public Welfare Research Project of Zhejiang Province under grant (number LGF19H080002); Medical Health Science and Technology Project of Zhejiang Provincial Health Commission under grant (number 2018PY052); National Science Foundation of Zhejiang Province under grant (number LY17H160005); and Traditional Chinese Medicine Administration of Zhejiang Province under grant (number 2015ZZ018).
The authors declare no conflict of interest.
The datasets generated during and/or analyzed during the current study are publicly available. | 3.5G ?10, ?9 | DrugDosageText | CC BY | 33607779 | 18,990,270 | 2021-02-19 |
What was the dosage of drug 'METHOTREXATE'? | Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: A case report.
BACKGROUND
No standard guideline has been established for the treatment of plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and show resistance to commonly used cytostatic drugs.
We present the case of a 52-year-old HIV-negative man who presented with a mass at the left sternoclavicular joint. He had no significant comorbidities and no latent immunosuppression.
METHODS
The largest lymph node measured was 36 × 19 mm. An excisional biopsy showed diffuse proliferation of large lymphoid cells which were positive for CD38 and CD138, but negative for CD20. He was diagnosed with stage IV PBL with a low IPI.
METHODS
The patient was treated with four cycles of induction therapy with bortezomib, epirubicin and dexamethasone. He achieved complete remission. But 3 months after receiving consolidated autologous hematopoietic stem cell transplantation, he relapsed. Allogeneic hematopoietic stem cell transplantation was performed on the patient.
RESULTS
The patient achieved remission again and there were no serious complications after allogeneic hematopoietic stem cell transplantation. This patient was followed up once every three months, and to date, he has been disease-free for more than 4 years.
CONCLUSIONS
The survival of recurrent PBL after autologous hematopoietic stem cell transplantation is very poor. Salvage allogeneic hematopoietic stem cell transplantation may bring long-term survival opportunities for those patients. Further clinical studies are needed to explore the role of allogeneic hematopoietic stem cell transplantation in refractory and recurrent PBL.
pmc1 Introduction
Plasmablastic lymphoma (PBL) is a rare and highly aggressive subtype of diffuse large B-cell lymphoma (DLBCL), characterized by plasma cell antigen differentiation. It was initially described in the setting of human immunodeficiency virus (HIV) infection, but it was also been reported in HIV-negative patients.[1] There is no consensus on the standard of care for PBL. The role of intensification of induction chemotherapy is controversial. And novel agents, bortezomib and lenalidomide, have shown some effectiveness in relapsed cases and may have a relatively important role in frontline treatment.[2,3] The use of autologous stem cell transplantation (ASCT) possibly improves outcomes when used as a consolidation or salvage therapy and may lead to better results than chemotherapy, but the available data remain sparse.[2] The literatures on allogeneic hematopoietic stem cell transplantation (allo-HSCT) treatment for PBL are quite rare compared to ASCT. And given its rarity, most of the data available rely on case reports and case series. Patients with PBL have a poor prognosis, with median survival times shorter than 2 years.[2,4] To the best of our knowledge, the survival of recurrent PBL is worse.[2,5,6] Here, we report a case of HIV-negative PBL in a patient who had recurrence after ASCT, but achieved and maintained complete remission for 4-years after salvage allo-HSCT.
2 Case presentation
The patient was a 52-year-old man who presented in September 2015 with a mass at left sternoclavicular joint without any systemic symptoms. He had no significant comorbidities and no latent immunosuppression. Ultrasonography of lymph nodes indicated multiple lymph node enlargement in the neck, and multiple hypoechoic areas were seen above the left clavicle, the largest of which was 36 × 19 mm. A total body computed tomography (CT) scan showed that soft tissue mass shadows were seen around the left sternoclavicular joint and local cortical absorptions were present. Further investigations with fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) scan confirmed hypermetabolic mass appeared in several places of the body which was considered plasma cell infiltration. An excisional biopsy showed diffuse proliferation of large lymphoid cells (Fig. 1). Immuno-staining of the neoplastic cells showed negative for CD20, CD5, CD30, EREB, MPO, CD117 and Bcl-6, whereas it was positive for CD38, CD138, CD10, CD79a and Bcl-2 (Figs. 2–5). The Ki-67 proliferation index was 95% (Fig. 6). Biopsy of the iliac crest showed no marrow involvement. According to the above analysis, International Prognostic Index (IPI) scores were 2, the patient was diagnosed with stage IV PBL with a low IPI.
Figure 1 H&E (hematoxylin and eosin) image shows large sheets of mostly large plasmacytoid appearing mononuclear cells. (HE Magnification × 400).
Figure 2 CD138, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 3 CD38, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 4 CD10, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 5 CD79a, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 6 Strong and homogenous staining with Ki-67 indicating a high proliferation index. (Magnification × 200).
In addition, laboratory data were as following: Blood routine examination indicated that the white blood cells were 8.1 × 109/L, the hemoglobin was 146 g/L and the platelets were 267 × 109/L. Erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, β2 microglobulin, serum proteins and immunoglobulin levels were all within normal ranges. Immunofixation electrophoresis showed no monoclonal component. Human herpes virus 8 (HHV-8) and Epstein-Barr virus DNA (EBV-DNA) were negative. Besides, serology for HIV was also negative.
From September to December 2015, the patient received 4 cycles of PAD chemotherapy regimens: bortezomib was given at the dose of 2.4 mg/day on day 1, 4, 8, 11, epirubicin at the dose of 20 mg/day on days 1–3, and dexamethasone at the dose of 40 mg/day on days 1–4 and 8–11 of each 28-day cycle. Repeat PET/CT following 4 cycles of chemotherapy showed no abnormal flurodeoxyglucose metabolic foci and enlarged lymph nodes, thus being compatible with a complete response (CR).
Later on, peripheral blood stem cell (PBSC) mobilization was achieved by high-dose cyclophosphamide (2 g, day 1–3), etoposide (300 mg, day 1–3) and granulocyte colony-stimulating factor (G-CSF), and leukapheresis products containing a total of mononuclear cell (MNC) 9.78 × 108/kg and CD34+ cells 6.9 × 106/kg were collected. In April 2016, the patient received autologous hematopoietic stem cell transplantation as consolidation therapy. The conditioning regiments were melphalan (200 mg/m2 -2d) and bortezomib (1.75 mg -6, -3, +1, +4), and a total of 9.78 × 108/kg MNC and 6.9 × 106/kg CD34+ cells PBSC were reinfused. Platelets and white blood cells were recovered at 10 and 11 days after transplantation, respectively. The CT scan performed 1 month after ASCT confirmed a CR.
However, 3 months after ASCT, CT showed a new lesion appeared in the second rib on the right side, which was considered as relapse. After full assessment, the patient underwent HLA half-matched allo-HSCT in September 2016. The conditioning regimen was modified BuCy+ATG (cytarabine 3.5 g -10, -9; busulfan 51.6 mg Q6 h -8, -7, -6; cyclophosphamide 3 g -5, -4; MECCNU 450 mg -3; antithymocyte globulin 2.5 mg/Kg -5, -4, -3, -2), and the scheme for prevention of graft-versus-host disease (GVHD) was cyclosporin, mycophenolate mofetil and short-term methotrexate. The patient developed pulmonary fungal infection 20 days after allo-HSCT and took a turn for the better after treatment with voriconazole injection and voriconazole tablets. Unfortunately, the patient developed severe hemorrhagic cystitis 20 days later, but fortunately the condition improved after symptomatic treatment. There has been no evidence of acute or chronic GVHD. The patient achieved sustained complete donor engraftment as short tandem repeat monitoring was performed every three months after transplantation. A CR was metabolically and clinically confirmed by PET-CT scan after allo-HSCT. The patient is now healthy and in CR for 4 years after allo-HSCT.
3 Discussed
PBL is a distinct variant of diffuse large B-cell lymphoma initially described in HIV-positive patients.[7] Nevertheless, PBL has also been described in HIV-negative individuals, particularly in association with potential immunosuppression such as after solid organ or bone marrow transplantation or with autoimmune disorders and malignanciess.[8–11] HIV-negative PBL, in comparison with HIV-positive PBL, occurs in older patients, with less frequent involvement of oral mucosa or bone marrow and less frequently stages III-IV.[3,12,13] A review of 114 HIV-negative patients with PBL, by Liu et al[12] demonstrated that immunosuppression, MYC gene rearrangement, high-risk international prognostic index, and EBV negativity were poor prognostic factors. And the overall survival (OS) is between 9 and 19 months in HIV-negative patients.[12] Similarly, a systematic review on 76 HIV-negative PBL patients showed median OS of 9 months with 2-year OS rate of 10%.[13]
Given its rarity and peculiar features, there is no standard of care for PBL and the treatment remains a challenge.[11] The use of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and CHOP-like regimens are considered inadequate therapy, resulting short remission period,[3,11] so the NCCN guidelines recommend more intensive regimens,[14] including etoposide, vincristine and doxorubicin with bolus of cyclophosphamide and prednisone (EPOCH),[15] cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide, cytarabine,[16] or hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine.[17] The benefit of ASCT in patients with PBL is not quite clear based on the limited data available. In a single institution report of 9 consecutive HIV-negative PBL patients, 7 patients achieved CR and 1 patient achieved partial response (PR) after chemotherapy.[8] Four patients underwent consolidation with ASCT in first complete remission, and 2 of these patients were alive at median follow-up of 23.9 months. The third patient had disease recurrence at 14 months and the fourth patient had disease recurrence at 2 months after ASCT.[8] Moffitt Cancer Center presented the experience of two HIV-negative patients with PBL in PR that underwent an ASCT, and two patients survived 6 and 12 months.[12]
Given the low efficacy of the standard therapy, and the poor outcome of these patients, there is a need to move toward new therapeutic strategies by incorporating new agents. Bortezomib is the most reported new drug for PBL and has been used as a single dose or in combination. Koji et al[18] show the bortezomib and lenalidomide-based treatment was tolerated and the patient was continued with a PR for over 2 years. Bortezomib and lenalidomide have a certain therapeutic effect, and are mostly used in patients with refractory recurrence.[18,19] There are few case reports showing single-agent lenalidomide or combination with other chemotherapeutic drug in refractory PBL.[20–22] A dramatic response to Brentuximab has been reported in a single case, but the patient died shortly due to previous disease disabilities.[23] A plasmablastic microlymphoma arising in HHV8-associated multicentric Castleman disease in an HIV-negative patient that showed a clinical response to siltuximab, an anti-IL6 antibody.[24] The use of rituximab, a chimeric anti-CD20 monoclonal antibody, is not currently a therapeutic standard because the lack of CD20 expression by PBL cells, but combined with chemotherapy it could improve remission rates.[3,25] Clinical trials with novel immunotherapeutic agents and other drugs targeting some genes involved in the activation of Nuclear factor kappa B pathways, some of which are already ongoing, may show promising results.[18]
The literature on allo-HSCT in PBL is limited compared with ASCT. Only few cases of allo-HSCT for PBL were reported, much less for recurrence PBL. Hamadani[26] reported one patient with PBL in CR2 who underwent a reduced-intensity allogeneic stem cell transplantation, and was alive 2 years after transplantation. Liu et al[8] reported one patient who had disease recurrence at 14 months after ASCT was treated with allo-HSCT. Despite consolidation with allo-HSCT, disease recurred 5 months after, and the patient died. In general, the efficacy of allo-HSCT in the treatment of HIV-negative PBL patients is still not ideal and the survival of recurrent PBL after allo-HSCT is very poor.
In our case, the patient had recurrence after consolidated ASCT. Then, he underwent the salvage allo-HSCT from his daughter and achieved good curative effect. The patient was in long-term complete remission and he is alive now. It may be attributed to his younger age, low IPI score and early allo-HSCT treatment after relapse. As far as we know, this is the first case of such a long survival time after allo-HSCT. For young relapsed patients with PBL, allo-HSCT may bring long-term survival opportunities. Due to the rarity of the disease, it is not feasible to carry out large-scale clinical trials. The evaluation of allogeneic hematopoietic stem cell transplantation in PBL patients requires more accumulation and sharing of clinical experience.
Author contributions
Data curation: An Wu, Ye Sun.
Funding acquisition: Guifang Ouyang, Lixia Sheng.
Methodology: Lixia Sheng.
Writing – original draft: Chunmeng Rong.
Writing – review & editing: Chunmeng Rong.
Abbreviations: allo-HSCT = allogeneic hematopoietic stem cell transplantation, ASCT = autologous hematopoietic stem cell transplantation, CHOP = cyclophosphamide, doxorubicin, vincristine and prednisone, CR = complete response, CT = computed tomography, DLBCL = diffuse large B-cell lymphoma, EBV-DNA = Epstein-Barr virus DNA, GVHD = graft-versus-host disease, HHV-8 = Human herpes virus 8, HIV = human immunodeficiency virus, IPI = International Prognostic Index, MNC = mononuclear cell, OS = overall survival, PBL = plasmablastic lymphoma, PBSC = peripheral blood stem cell, PET-CT = positron emission tomography–computed tomography, PR = partial response.
How to cite this article: Rong C, Sheng L, Wu A, Sun Y, Ouyang G. Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: a case report. Medicine. 2021;100:7(e24498).
The study protocol was approved by the Ethics Review Committee of Ningbo First Hospital.
Patient has provided informed consent for publication of the case, and patient share his experience.
This study was supported by the National Natural Science Foundation of China under grant (number 81401321); Basic Public Welfare Research Project of Zhejiang Province under grant (number LGF19H080002); Medical Health Science and Technology Project of Zhejiang Provincial Health Commission under grant (number 2018PY052); National Science Foundation of Zhejiang Province under grant (number LY17H160005); and Traditional Chinese Medicine Administration of Zhejiang Province under grant (number 2015ZZ018).
The authors declare no conflict of interest.
The datasets generated during and/or analyzed during the current study are publicly available. | SHORT?TERM METHOTREXATE | DrugDosageText | CC BY | 33607779 | 18,990,270 | 2021-02-19 |
What was the dosage of drug 'SEMUSTINE'? | Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: A case report.
BACKGROUND
No standard guideline has been established for the treatment of plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and show resistance to commonly used cytostatic drugs.
We present the case of a 52-year-old HIV-negative man who presented with a mass at the left sternoclavicular joint. He had no significant comorbidities and no latent immunosuppression.
METHODS
The largest lymph node measured was 36 × 19 mm. An excisional biopsy showed diffuse proliferation of large lymphoid cells which were positive for CD38 and CD138, but negative for CD20. He was diagnosed with stage IV PBL with a low IPI.
METHODS
The patient was treated with four cycles of induction therapy with bortezomib, epirubicin and dexamethasone. He achieved complete remission. But 3 months after receiving consolidated autologous hematopoietic stem cell transplantation, he relapsed. Allogeneic hematopoietic stem cell transplantation was performed on the patient.
RESULTS
The patient achieved remission again and there were no serious complications after allogeneic hematopoietic stem cell transplantation. This patient was followed up once every three months, and to date, he has been disease-free for more than 4 years.
CONCLUSIONS
The survival of recurrent PBL after autologous hematopoietic stem cell transplantation is very poor. Salvage allogeneic hematopoietic stem cell transplantation may bring long-term survival opportunities for those patients. Further clinical studies are needed to explore the role of allogeneic hematopoietic stem cell transplantation in refractory and recurrent PBL.
pmc1 Introduction
Plasmablastic lymphoma (PBL) is a rare and highly aggressive subtype of diffuse large B-cell lymphoma (DLBCL), characterized by plasma cell antigen differentiation. It was initially described in the setting of human immunodeficiency virus (HIV) infection, but it was also been reported in HIV-negative patients.[1] There is no consensus on the standard of care for PBL. The role of intensification of induction chemotherapy is controversial. And novel agents, bortezomib and lenalidomide, have shown some effectiveness in relapsed cases and may have a relatively important role in frontline treatment.[2,3] The use of autologous stem cell transplantation (ASCT) possibly improves outcomes when used as a consolidation or salvage therapy and may lead to better results than chemotherapy, but the available data remain sparse.[2] The literatures on allogeneic hematopoietic stem cell transplantation (allo-HSCT) treatment for PBL are quite rare compared to ASCT. And given its rarity, most of the data available rely on case reports and case series. Patients with PBL have a poor prognosis, with median survival times shorter than 2 years.[2,4] To the best of our knowledge, the survival of recurrent PBL is worse.[2,5,6] Here, we report a case of HIV-negative PBL in a patient who had recurrence after ASCT, but achieved and maintained complete remission for 4-years after salvage allo-HSCT.
2 Case presentation
The patient was a 52-year-old man who presented in September 2015 with a mass at left sternoclavicular joint without any systemic symptoms. He had no significant comorbidities and no latent immunosuppression. Ultrasonography of lymph nodes indicated multiple lymph node enlargement in the neck, and multiple hypoechoic areas were seen above the left clavicle, the largest of which was 36 × 19 mm. A total body computed tomography (CT) scan showed that soft tissue mass shadows were seen around the left sternoclavicular joint and local cortical absorptions were present. Further investigations with fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) scan confirmed hypermetabolic mass appeared in several places of the body which was considered plasma cell infiltration. An excisional biopsy showed diffuse proliferation of large lymphoid cells (Fig. 1). Immuno-staining of the neoplastic cells showed negative for CD20, CD5, CD30, EREB, MPO, CD117 and Bcl-6, whereas it was positive for CD38, CD138, CD10, CD79a and Bcl-2 (Figs. 2–5). The Ki-67 proliferation index was 95% (Fig. 6). Biopsy of the iliac crest showed no marrow involvement. According to the above analysis, International Prognostic Index (IPI) scores were 2, the patient was diagnosed with stage IV PBL with a low IPI.
Figure 1 H&E (hematoxylin and eosin) image shows large sheets of mostly large plasmacytoid appearing mononuclear cells. (HE Magnification × 400).
Figure 2 CD138, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 3 CD38, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 4 CD10, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 5 CD79a, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 6 Strong and homogenous staining with Ki-67 indicating a high proliferation index. (Magnification × 200).
In addition, laboratory data were as following: Blood routine examination indicated that the white blood cells were 8.1 × 109/L, the hemoglobin was 146 g/L and the platelets were 267 × 109/L. Erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, β2 microglobulin, serum proteins and immunoglobulin levels were all within normal ranges. Immunofixation electrophoresis showed no monoclonal component. Human herpes virus 8 (HHV-8) and Epstein-Barr virus DNA (EBV-DNA) were negative. Besides, serology for HIV was also negative.
From September to December 2015, the patient received 4 cycles of PAD chemotherapy regimens: bortezomib was given at the dose of 2.4 mg/day on day 1, 4, 8, 11, epirubicin at the dose of 20 mg/day on days 1–3, and dexamethasone at the dose of 40 mg/day on days 1–4 and 8–11 of each 28-day cycle. Repeat PET/CT following 4 cycles of chemotherapy showed no abnormal flurodeoxyglucose metabolic foci and enlarged lymph nodes, thus being compatible with a complete response (CR).
Later on, peripheral blood stem cell (PBSC) mobilization was achieved by high-dose cyclophosphamide (2 g, day 1–3), etoposide (300 mg, day 1–3) and granulocyte colony-stimulating factor (G-CSF), and leukapheresis products containing a total of mononuclear cell (MNC) 9.78 × 108/kg and CD34+ cells 6.9 × 106/kg were collected. In April 2016, the patient received autologous hematopoietic stem cell transplantation as consolidation therapy. The conditioning regiments were melphalan (200 mg/m2 -2d) and bortezomib (1.75 mg -6, -3, +1, +4), and a total of 9.78 × 108/kg MNC and 6.9 × 106/kg CD34+ cells PBSC were reinfused. Platelets and white blood cells were recovered at 10 and 11 days after transplantation, respectively. The CT scan performed 1 month after ASCT confirmed a CR.
However, 3 months after ASCT, CT showed a new lesion appeared in the second rib on the right side, which was considered as relapse. After full assessment, the patient underwent HLA half-matched allo-HSCT in September 2016. The conditioning regimen was modified BuCy+ATG (cytarabine 3.5 g -10, -9; busulfan 51.6 mg Q6 h -8, -7, -6; cyclophosphamide 3 g -5, -4; MECCNU 450 mg -3; antithymocyte globulin 2.5 mg/Kg -5, -4, -3, -2), and the scheme for prevention of graft-versus-host disease (GVHD) was cyclosporin, mycophenolate mofetil and short-term methotrexate. The patient developed pulmonary fungal infection 20 days after allo-HSCT and took a turn for the better after treatment with voriconazole injection and voriconazole tablets. Unfortunately, the patient developed severe hemorrhagic cystitis 20 days later, but fortunately the condition improved after symptomatic treatment. There has been no evidence of acute or chronic GVHD. The patient achieved sustained complete donor engraftment as short tandem repeat monitoring was performed every three months after transplantation. A CR was metabolically and clinically confirmed by PET-CT scan after allo-HSCT. The patient is now healthy and in CR for 4 years after allo-HSCT.
3 Discussed
PBL is a distinct variant of diffuse large B-cell lymphoma initially described in HIV-positive patients.[7] Nevertheless, PBL has also been described in HIV-negative individuals, particularly in association with potential immunosuppression such as after solid organ or bone marrow transplantation or with autoimmune disorders and malignanciess.[8–11] HIV-negative PBL, in comparison with HIV-positive PBL, occurs in older patients, with less frequent involvement of oral mucosa or bone marrow and less frequently stages III-IV.[3,12,13] A review of 114 HIV-negative patients with PBL, by Liu et al[12] demonstrated that immunosuppression, MYC gene rearrangement, high-risk international prognostic index, and EBV negativity were poor prognostic factors. And the overall survival (OS) is between 9 and 19 months in HIV-negative patients.[12] Similarly, a systematic review on 76 HIV-negative PBL patients showed median OS of 9 months with 2-year OS rate of 10%.[13]
Given its rarity and peculiar features, there is no standard of care for PBL and the treatment remains a challenge.[11] The use of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and CHOP-like regimens are considered inadequate therapy, resulting short remission period,[3,11] so the NCCN guidelines recommend more intensive regimens,[14] including etoposide, vincristine and doxorubicin with bolus of cyclophosphamide and prednisone (EPOCH),[15] cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide, cytarabine,[16] or hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine.[17] The benefit of ASCT in patients with PBL is not quite clear based on the limited data available. In a single institution report of 9 consecutive HIV-negative PBL patients, 7 patients achieved CR and 1 patient achieved partial response (PR) after chemotherapy.[8] Four patients underwent consolidation with ASCT in first complete remission, and 2 of these patients were alive at median follow-up of 23.9 months. The third patient had disease recurrence at 14 months and the fourth patient had disease recurrence at 2 months after ASCT.[8] Moffitt Cancer Center presented the experience of two HIV-negative patients with PBL in PR that underwent an ASCT, and two patients survived 6 and 12 months.[12]
Given the low efficacy of the standard therapy, and the poor outcome of these patients, there is a need to move toward new therapeutic strategies by incorporating new agents. Bortezomib is the most reported new drug for PBL and has been used as a single dose or in combination. Koji et al[18] show the bortezomib and lenalidomide-based treatment was tolerated and the patient was continued with a PR for over 2 years. Bortezomib and lenalidomide have a certain therapeutic effect, and are mostly used in patients with refractory recurrence.[18,19] There are few case reports showing single-agent lenalidomide or combination with other chemotherapeutic drug in refractory PBL.[20–22] A dramatic response to Brentuximab has been reported in a single case, but the patient died shortly due to previous disease disabilities.[23] A plasmablastic microlymphoma arising in HHV8-associated multicentric Castleman disease in an HIV-negative patient that showed a clinical response to siltuximab, an anti-IL6 antibody.[24] The use of rituximab, a chimeric anti-CD20 monoclonal antibody, is not currently a therapeutic standard because the lack of CD20 expression by PBL cells, but combined with chemotherapy it could improve remission rates.[3,25] Clinical trials with novel immunotherapeutic agents and other drugs targeting some genes involved in the activation of Nuclear factor kappa B pathways, some of which are already ongoing, may show promising results.[18]
The literature on allo-HSCT in PBL is limited compared with ASCT. Only few cases of allo-HSCT for PBL were reported, much less for recurrence PBL. Hamadani[26] reported one patient with PBL in CR2 who underwent a reduced-intensity allogeneic stem cell transplantation, and was alive 2 years after transplantation. Liu et al[8] reported one patient who had disease recurrence at 14 months after ASCT was treated with allo-HSCT. Despite consolidation with allo-HSCT, disease recurred 5 months after, and the patient died. In general, the efficacy of allo-HSCT in the treatment of HIV-negative PBL patients is still not ideal and the survival of recurrent PBL after allo-HSCT is very poor.
In our case, the patient had recurrence after consolidated ASCT. Then, he underwent the salvage allo-HSCT from his daughter and achieved good curative effect. The patient was in long-term complete remission and he is alive now. It may be attributed to his younger age, low IPI score and early allo-HSCT treatment after relapse. As far as we know, this is the first case of such a long survival time after allo-HSCT. For young relapsed patients with PBL, allo-HSCT may bring long-term survival opportunities. Due to the rarity of the disease, it is not feasible to carry out large-scale clinical trials. The evaluation of allogeneic hematopoietic stem cell transplantation in PBL patients requires more accumulation and sharing of clinical experience.
Author contributions
Data curation: An Wu, Ye Sun.
Funding acquisition: Guifang Ouyang, Lixia Sheng.
Methodology: Lixia Sheng.
Writing – original draft: Chunmeng Rong.
Writing – review & editing: Chunmeng Rong.
Abbreviations: allo-HSCT = allogeneic hematopoietic stem cell transplantation, ASCT = autologous hematopoietic stem cell transplantation, CHOP = cyclophosphamide, doxorubicin, vincristine and prednisone, CR = complete response, CT = computed tomography, DLBCL = diffuse large B-cell lymphoma, EBV-DNA = Epstein-Barr virus DNA, GVHD = graft-versus-host disease, HHV-8 = Human herpes virus 8, HIV = human immunodeficiency virus, IPI = International Prognostic Index, MNC = mononuclear cell, OS = overall survival, PBL = plasmablastic lymphoma, PBSC = peripheral blood stem cell, PET-CT = positron emission tomography–computed tomography, PR = partial response.
How to cite this article: Rong C, Sheng L, Wu A, Sun Y, Ouyang G. Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: a case report. Medicine. 2021;100:7(e24498).
The study protocol was approved by the Ethics Review Committee of Ningbo First Hospital.
Patient has provided informed consent for publication of the case, and patient share his experience.
This study was supported by the National Natural Science Foundation of China under grant (number 81401321); Basic Public Welfare Research Project of Zhejiang Province under grant (number LGF19H080002); Medical Health Science and Technology Project of Zhejiang Provincial Health Commission under grant (number 2018PY052); National Science Foundation of Zhejiang Province under grant (number LY17H160005); and Traditional Chinese Medicine Administration of Zhejiang Province under grant (number 2015ZZ018).
The authors declare no conflict of interest.
The datasets generated during and/or analyzed during the current study are publicly available. | MECCNU 450MG ?3 | DrugDosageText | CC BY | 33607779 | 18,990,270 | 2021-02-19 |
What was the dosage of drug 'THYMOCYTE IMMUNE GLOBULIN NOS'? | Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: A case report.
BACKGROUND
No standard guideline has been established for the treatment of plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and show resistance to commonly used cytostatic drugs.
We present the case of a 52-year-old HIV-negative man who presented with a mass at the left sternoclavicular joint. He had no significant comorbidities and no latent immunosuppression.
METHODS
The largest lymph node measured was 36 × 19 mm. An excisional biopsy showed diffuse proliferation of large lymphoid cells which were positive for CD38 and CD138, but negative for CD20. He was diagnosed with stage IV PBL with a low IPI.
METHODS
The patient was treated with four cycles of induction therapy with bortezomib, epirubicin and dexamethasone. He achieved complete remission. But 3 months after receiving consolidated autologous hematopoietic stem cell transplantation, he relapsed. Allogeneic hematopoietic stem cell transplantation was performed on the patient.
RESULTS
The patient achieved remission again and there were no serious complications after allogeneic hematopoietic stem cell transplantation. This patient was followed up once every three months, and to date, he has been disease-free for more than 4 years.
CONCLUSIONS
The survival of recurrent PBL after autologous hematopoietic stem cell transplantation is very poor. Salvage allogeneic hematopoietic stem cell transplantation may bring long-term survival opportunities for those patients. Further clinical studies are needed to explore the role of allogeneic hematopoietic stem cell transplantation in refractory and recurrent PBL.
pmc1 Introduction
Plasmablastic lymphoma (PBL) is a rare and highly aggressive subtype of diffuse large B-cell lymphoma (DLBCL), characterized by plasma cell antigen differentiation. It was initially described in the setting of human immunodeficiency virus (HIV) infection, but it was also been reported in HIV-negative patients.[1] There is no consensus on the standard of care for PBL. The role of intensification of induction chemotherapy is controversial. And novel agents, bortezomib and lenalidomide, have shown some effectiveness in relapsed cases and may have a relatively important role in frontline treatment.[2,3] The use of autologous stem cell transplantation (ASCT) possibly improves outcomes when used as a consolidation or salvage therapy and may lead to better results than chemotherapy, but the available data remain sparse.[2] The literatures on allogeneic hematopoietic stem cell transplantation (allo-HSCT) treatment for PBL are quite rare compared to ASCT. And given its rarity, most of the data available rely on case reports and case series. Patients with PBL have a poor prognosis, with median survival times shorter than 2 years.[2,4] To the best of our knowledge, the survival of recurrent PBL is worse.[2,5,6] Here, we report a case of HIV-negative PBL in a patient who had recurrence after ASCT, but achieved and maintained complete remission for 4-years after salvage allo-HSCT.
2 Case presentation
The patient was a 52-year-old man who presented in September 2015 with a mass at left sternoclavicular joint without any systemic symptoms. He had no significant comorbidities and no latent immunosuppression. Ultrasonography of lymph nodes indicated multiple lymph node enlargement in the neck, and multiple hypoechoic areas were seen above the left clavicle, the largest of which was 36 × 19 mm. A total body computed tomography (CT) scan showed that soft tissue mass shadows were seen around the left sternoclavicular joint and local cortical absorptions were present. Further investigations with fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) scan confirmed hypermetabolic mass appeared in several places of the body which was considered plasma cell infiltration. An excisional biopsy showed diffuse proliferation of large lymphoid cells (Fig. 1). Immuno-staining of the neoplastic cells showed negative for CD20, CD5, CD30, EREB, MPO, CD117 and Bcl-6, whereas it was positive for CD38, CD138, CD10, CD79a and Bcl-2 (Figs. 2–5). The Ki-67 proliferation index was 95% (Fig. 6). Biopsy of the iliac crest showed no marrow involvement. According to the above analysis, International Prognostic Index (IPI) scores were 2, the patient was diagnosed with stage IV PBL with a low IPI.
Figure 1 H&E (hematoxylin and eosin) image shows large sheets of mostly large plasmacytoid appearing mononuclear cells. (HE Magnification × 400).
Figure 2 CD138, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 3 CD38, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 4 CD10, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 5 CD79a, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 6 Strong and homogenous staining with Ki-67 indicating a high proliferation index. (Magnification × 200).
In addition, laboratory data were as following: Blood routine examination indicated that the white blood cells were 8.1 × 109/L, the hemoglobin was 146 g/L and the platelets were 267 × 109/L. Erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, β2 microglobulin, serum proteins and immunoglobulin levels were all within normal ranges. Immunofixation electrophoresis showed no monoclonal component. Human herpes virus 8 (HHV-8) and Epstein-Barr virus DNA (EBV-DNA) were negative. Besides, serology for HIV was also negative.
From September to December 2015, the patient received 4 cycles of PAD chemotherapy regimens: bortezomib was given at the dose of 2.4 mg/day on day 1, 4, 8, 11, epirubicin at the dose of 20 mg/day on days 1–3, and dexamethasone at the dose of 40 mg/day on days 1–4 and 8–11 of each 28-day cycle. Repeat PET/CT following 4 cycles of chemotherapy showed no abnormal flurodeoxyglucose metabolic foci and enlarged lymph nodes, thus being compatible with a complete response (CR).
Later on, peripheral blood stem cell (PBSC) mobilization was achieved by high-dose cyclophosphamide (2 g, day 1–3), etoposide (300 mg, day 1–3) and granulocyte colony-stimulating factor (G-CSF), and leukapheresis products containing a total of mononuclear cell (MNC) 9.78 × 108/kg and CD34+ cells 6.9 × 106/kg were collected. In April 2016, the patient received autologous hematopoietic stem cell transplantation as consolidation therapy. The conditioning regiments were melphalan (200 mg/m2 -2d) and bortezomib (1.75 mg -6, -3, +1, +4), and a total of 9.78 × 108/kg MNC and 6.9 × 106/kg CD34+ cells PBSC were reinfused. Platelets and white blood cells were recovered at 10 and 11 days after transplantation, respectively. The CT scan performed 1 month after ASCT confirmed a CR.
However, 3 months after ASCT, CT showed a new lesion appeared in the second rib on the right side, which was considered as relapse. After full assessment, the patient underwent HLA half-matched allo-HSCT in September 2016. The conditioning regimen was modified BuCy+ATG (cytarabine 3.5 g -10, -9; busulfan 51.6 mg Q6 h -8, -7, -6; cyclophosphamide 3 g -5, -4; MECCNU 450 mg -3; antithymocyte globulin 2.5 mg/Kg -5, -4, -3, -2), and the scheme for prevention of graft-versus-host disease (GVHD) was cyclosporin, mycophenolate mofetil and short-term methotrexate. The patient developed pulmonary fungal infection 20 days after allo-HSCT and took a turn for the better after treatment with voriconazole injection and voriconazole tablets. Unfortunately, the patient developed severe hemorrhagic cystitis 20 days later, but fortunately the condition improved after symptomatic treatment. There has been no evidence of acute or chronic GVHD. The patient achieved sustained complete donor engraftment as short tandem repeat monitoring was performed every three months after transplantation. A CR was metabolically and clinically confirmed by PET-CT scan after allo-HSCT. The patient is now healthy and in CR for 4 years after allo-HSCT.
3 Discussed
PBL is a distinct variant of diffuse large B-cell lymphoma initially described in HIV-positive patients.[7] Nevertheless, PBL has also been described in HIV-negative individuals, particularly in association with potential immunosuppression such as after solid organ or bone marrow transplantation or with autoimmune disorders and malignanciess.[8–11] HIV-negative PBL, in comparison with HIV-positive PBL, occurs in older patients, with less frequent involvement of oral mucosa or bone marrow and less frequently stages III-IV.[3,12,13] A review of 114 HIV-negative patients with PBL, by Liu et al[12] demonstrated that immunosuppression, MYC gene rearrangement, high-risk international prognostic index, and EBV negativity were poor prognostic factors. And the overall survival (OS) is between 9 and 19 months in HIV-negative patients.[12] Similarly, a systematic review on 76 HIV-negative PBL patients showed median OS of 9 months with 2-year OS rate of 10%.[13]
Given its rarity and peculiar features, there is no standard of care for PBL and the treatment remains a challenge.[11] The use of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and CHOP-like regimens are considered inadequate therapy, resulting short remission period,[3,11] so the NCCN guidelines recommend more intensive regimens,[14] including etoposide, vincristine and doxorubicin with bolus of cyclophosphamide and prednisone (EPOCH),[15] cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide, cytarabine,[16] or hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine.[17] The benefit of ASCT in patients with PBL is not quite clear based on the limited data available. In a single institution report of 9 consecutive HIV-negative PBL patients, 7 patients achieved CR and 1 patient achieved partial response (PR) after chemotherapy.[8] Four patients underwent consolidation with ASCT in first complete remission, and 2 of these patients were alive at median follow-up of 23.9 months. The third patient had disease recurrence at 14 months and the fourth patient had disease recurrence at 2 months after ASCT.[8] Moffitt Cancer Center presented the experience of two HIV-negative patients with PBL in PR that underwent an ASCT, and two patients survived 6 and 12 months.[12]
Given the low efficacy of the standard therapy, and the poor outcome of these patients, there is a need to move toward new therapeutic strategies by incorporating new agents. Bortezomib is the most reported new drug for PBL and has been used as a single dose or in combination. Koji et al[18] show the bortezomib and lenalidomide-based treatment was tolerated and the patient was continued with a PR for over 2 years. Bortezomib and lenalidomide have a certain therapeutic effect, and are mostly used in patients with refractory recurrence.[18,19] There are few case reports showing single-agent lenalidomide or combination with other chemotherapeutic drug in refractory PBL.[20–22] A dramatic response to Brentuximab has been reported in a single case, but the patient died shortly due to previous disease disabilities.[23] A plasmablastic microlymphoma arising in HHV8-associated multicentric Castleman disease in an HIV-negative patient that showed a clinical response to siltuximab, an anti-IL6 antibody.[24] The use of rituximab, a chimeric anti-CD20 monoclonal antibody, is not currently a therapeutic standard because the lack of CD20 expression by PBL cells, but combined with chemotherapy it could improve remission rates.[3,25] Clinical trials with novel immunotherapeutic agents and other drugs targeting some genes involved in the activation of Nuclear factor kappa B pathways, some of which are already ongoing, may show promising results.[18]
The literature on allo-HSCT in PBL is limited compared with ASCT. Only few cases of allo-HSCT for PBL were reported, much less for recurrence PBL. Hamadani[26] reported one patient with PBL in CR2 who underwent a reduced-intensity allogeneic stem cell transplantation, and was alive 2 years after transplantation. Liu et al[8] reported one patient who had disease recurrence at 14 months after ASCT was treated with allo-HSCT. Despite consolidation with allo-HSCT, disease recurred 5 months after, and the patient died. In general, the efficacy of allo-HSCT in the treatment of HIV-negative PBL patients is still not ideal and the survival of recurrent PBL after allo-HSCT is very poor.
In our case, the patient had recurrence after consolidated ASCT. Then, he underwent the salvage allo-HSCT from his daughter and achieved good curative effect. The patient was in long-term complete remission and he is alive now. It may be attributed to his younger age, low IPI score and early allo-HSCT treatment after relapse. As far as we know, this is the first case of such a long survival time after allo-HSCT. For young relapsed patients with PBL, allo-HSCT may bring long-term survival opportunities. Due to the rarity of the disease, it is not feasible to carry out large-scale clinical trials. The evaluation of allogeneic hematopoietic stem cell transplantation in PBL patients requires more accumulation and sharing of clinical experience.
Author contributions
Data curation: An Wu, Ye Sun.
Funding acquisition: Guifang Ouyang, Lixia Sheng.
Methodology: Lixia Sheng.
Writing – original draft: Chunmeng Rong.
Writing – review & editing: Chunmeng Rong.
Abbreviations: allo-HSCT = allogeneic hematopoietic stem cell transplantation, ASCT = autologous hematopoietic stem cell transplantation, CHOP = cyclophosphamide, doxorubicin, vincristine and prednisone, CR = complete response, CT = computed tomography, DLBCL = diffuse large B-cell lymphoma, EBV-DNA = Epstein-Barr virus DNA, GVHD = graft-versus-host disease, HHV-8 = Human herpes virus 8, HIV = human immunodeficiency virus, IPI = International Prognostic Index, MNC = mononuclear cell, OS = overall survival, PBL = plasmablastic lymphoma, PBSC = peripheral blood stem cell, PET-CT = positron emission tomography–computed tomography, PR = partial response.
How to cite this article: Rong C, Sheng L, Wu A, Sun Y, Ouyang G. Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: a case report. Medicine. 2021;100:7(e24498).
The study protocol was approved by the Ethics Review Committee of Ningbo First Hospital.
Patient has provided informed consent for publication of the case, and patient share his experience.
This study was supported by the National Natural Science Foundation of China under grant (number 81401321); Basic Public Welfare Research Project of Zhejiang Province under grant (number LGF19H080002); Medical Health Science and Technology Project of Zhejiang Provincial Health Commission under grant (number 2018PY052); National Science Foundation of Zhejiang Province under grant (number LY17H160005); and Traditional Chinese Medicine Administration of Zhejiang Province under grant (number 2015ZZ018).
The authors declare no conflict of interest.
The datasets generated during and/or analyzed during the current study are publicly available. | 2.5MG/KG ?5, ?4, ?3, ?2 | DrugDosageText | CC BY | 33607779 | 18,990,270 | 2021-02-19 |
What was the outcome of reaction 'Cystitis haemorrhagic'? | Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: A case report.
BACKGROUND
No standard guideline has been established for the treatment of plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and show resistance to commonly used cytostatic drugs.
We present the case of a 52-year-old HIV-negative man who presented with a mass at the left sternoclavicular joint. He had no significant comorbidities and no latent immunosuppression.
METHODS
The largest lymph node measured was 36 × 19 mm. An excisional biopsy showed diffuse proliferation of large lymphoid cells which were positive for CD38 and CD138, but negative for CD20. He was diagnosed with stage IV PBL with a low IPI.
METHODS
The patient was treated with four cycles of induction therapy with bortezomib, epirubicin and dexamethasone. He achieved complete remission. But 3 months after receiving consolidated autologous hematopoietic stem cell transplantation, he relapsed. Allogeneic hematopoietic stem cell transplantation was performed on the patient.
RESULTS
The patient achieved remission again and there were no serious complications after allogeneic hematopoietic stem cell transplantation. This patient was followed up once every three months, and to date, he has been disease-free for more than 4 years.
CONCLUSIONS
The survival of recurrent PBL after autologous hematopoietic stem cell transplantation is very poor. Salvage allogeneic hematopoietic stem cell transplantation may bring long-term survival opportunities for those patients. Further clinical studies are needed to explore the role of allogeneic hematopoietic stem cell transplantation in refractory and recurrent PBL.
pmc1 Introduction
Plasmablastic lymphoma (PBL) is a rare and highly aggressive subtype of diffuse large B-cell lymphoma (DLBCL), characterized by plasma cell antigen differentiation. It was initially described in the setting of human immunodeficiency virus (HIV) infection, but it was also been reported in HIV-negative patients.[1] There is no consensus on the standard of care for PBL. The role of intensification of induction chemotherapy is controversial. And novel agents, bortezomib and lenalidomide, have shown some effectiveness in relapsed cases and may have a relatively important role in frontline treatment.[2,3] The use of autologous stem cell transplantation (ASCT) possibly improves outcomes when used as a consolidation or salvage therapy and may lead to better results than chemotherapy, but the available data remain sparse.[2] The literatures on allogeneic hematopoietic stem cell transplantation (allo-HSCT) treatment for PBL are quite rare compared to ASCT. And given its rarity, most of the data available rely on case reports and case series. Patients with PBL have a poor prognosis, with median survival times shorter than 2 years.[2,4] To the best of our knowledge, the survival of recurrent PBL is worse.[2,5,6] Here, we report a case of HIV-negative PBL in a patient who had recurrence after ASCT, but achieved and maintained complete remission for 4-years after salvage allo-HSCT.
2 Case presentation
The patient was a 52-year-old man who presented in September 2015 with a mass at left sternoclavicular joint without any systemic symptoms. He had no significant comorbidities and no latent immunosuppression. Ultrasonography of lymph nodes indicated multiple lymph node enlargement in the neck, and multiple hypoechoic areas were seen above the left clavicle, the largest of which was 36 × 19 mm. A total body computed tomography (CT) scan showed that soft tissue mass shadows were seen around the left sternoclavicular joint and local cortical absorptions were present. Further investigations with fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) scan confirmed hypermetabolic mass appeared in several places of the body which was considered plasma cell infiltration. An excisional biopsy showed diffuse proliferation of large lymphoid cells (Fig. 1). Immuno-staining of the neoplastic cells showed negative for CD20, CD5, CD30, EREB, MPO, CD117 and Bcl-6, whereas it was positive for CD38, CD138, CD10, CD79a and Bcl-2 (Figs. 2–5). The Ki-67 proliferation index was 95% (Fig. 6). Biopsy of the iliac crest showed no marrow involvement. According to the above analysis, International Prognostic Index (IPI) scores were 2, the patient was diagnosed with stage IV PBL with a low IPI.
Figure 1 H&E (hematoxylin and eosin) image shows large sheets of mostly large plasmacytoid appearing mononuclear cells. (HE Magnification × 400).
Figure 2 CD138, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 3 CD38, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 4 CD10, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 5 CD79a, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 6 Strong and homogenous staining with Ki-67 indicating a high proliferation index. (Magnification × 200).
In addition, laboratory data were as following: Blood routine examination indicated that the white blood cells were 8.1 × 109/L, the hemoglobin was 146 g/L and the platelets were 267 × 109/L. Erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, β2 microglobulin, serum proteins and immunoglobulin levels were all within normal ranges. Immunofixation electrophoresis showed no monoclonal component. Human herpes virus 8 (HHV-8) and Epstein-Barr virus DNA (EBV-DNA) were negative. Besides, serology for HIV was also negative.
From September to December 2015, the patient received 4 cycles of PAD chemotherapy regimens: bortezomib was given at the dose of 2.4 mg/day on day 1, 4, 8, 11, epirubicin at the dose of 20 mg/day on days 1–3, and dexamethasone at the dose of 40 mg/day on days 1–4 and 8–11 of each 28-day cycle. Repeat PET/CT following 4 cycles of chemotherapy showed no abnormal flurodeoxyglucose metabolic foci and enlarged lymph nodes, thus being compatible with a complete response (CR).
Later on, peripheral blood stem cell (PBSC) mobilization was achieved by high-dose cyclophosphamide (2 g, day 1–3), etoposide (300 mg, day 1–3) and granulocyte colony-stimulating factor (G-CSF), and leukapheresis products containing a total of mononuclear cell (MNC) 9.78 × 108/kg and CD34+ cells 6.9 × 106/kg were collected. In April 2016, the patient received autologous hematopoietic stem cell transplantation as consolidation therapy. The conditioning regiments were melphalan (200 mg/m2 -2d) and bortezomib (1.75 mg -6, -3, +1, +4), and a total of 9.78 × 108/kg MNC and 6.9 × 106/kg CD34+ cells PBSC were reinfused. Platelets and white blood cells were recovered at 10 and 11 days after transplantation, respectively. The CT scan performed 1 month after ASCT confirmed a CR.
However, 3 months after ASCT, CT showed a new lesion appeared in the second rib on the right side, which was considered as relapse. After full assessment, the patient underwent HLA half-matched allo-HSCT in September 2016. The conditioning regimen was modified BuCy+ATG (cytarabine 3.5 g -10, -9; busulfan 51.6 mg Q6 h -8, -7, -6; cyclophosphamide 3 g -5, -4; MECCNU 450 mg -3; antithymocyte globulin 2.5 mg/Kg -5, -4, -3, -2), and the scheme for prevention of graft-versus-host disease (GVHD) was cyclosporin, mycophenolate mofetil and short-term methotrexate. The patient developed pulmonary fungal infection 20 days after allo-HSCT and took a turn for the better after treatment with voriconazole injection and voriconazole tablets. Unfortunately, the patient developed severe hemorrhagic cystitis 20 days later, but fortunately the condition improved after symptomatic treatment. There has been no evidence of acute or chronic GVHD. The patient achieved sustained complete donor engraftment as short tandem repeat monitoring was performed every three months after transplantation. A CR was metabolically and clinically confirmed by PET-CT scan after allo-HSCT. The patient is now healthy and in CR for 4 years after allo-HSCT.
3 Discussed
PBL is a distinct variant of diffuse large B-cell lymphoma initially described in HIV-positive patients.[7] Nevertheless, PBL has also been described in HIV-negative individuals, particularly in association with potential immunosuppression such as after solid organ or bone marrow transplantation or with autoimmune disorders and malignanciess.[8–11] HIV-negative PBL, in comparison with HIV-positive PBL, occurs in older patients, with less frequent involvement of oral mucosa or bone marrow and less frequently stages III-IV.[3,12,13] A review of 114 HIV-negative patients with PBL, by Liu et al[12] demonstrated that immunosuppression, MYC gene rearrangement, high-risk international prognostic index, and EBV negativity were poor prognostic factors. And the overall survival (OS) is between 9 and 19 months in HIV-negative patients.[12] Similarly, a systematic review on 76 HIV-negative PBL patients showed median OS of 9 months with 2-year OS rate of 10%.[13]
Given its rarity and peculiar features, there is no standard of care for PBL and the treatment remains a challenge.[11] The use of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and CHOP-like regimens are considered inadequate therapy, resulting short remission period,[3,11] so the NCCN guidelines recommend more intensive regimens,[14] including etoposide, vincristine and doxorubicin with bolus of cyclophosphamide and prednisone (EPOCH),[15] cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide, cytarabine,[16] or hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine.[17] The benefit of ASCT in patients with PBL is not quite clear based on the limited data available. In a single institution report of 9 consecutive HIV-negative PBL patients, 7 patients achieved CR and 1 patient achieved partial response (PR) after chemotherapy.[8] Four patients underwent consolidation with ASCT in first complete remission, and 2 of these patients were alive at median follow-up of 23.9 months. The third patient had disease recurrence at 14 months and the fourth patient had disease recurrence at 2 months after ASCT.[8] Moffitt Cancer Center presented the experience of two HIV-negative patients with PBL in PR that underwent an ASCT, and two patients survived 6 and 12 months.[12]
Given the low efficacy of the standard therapy, and the poor outcome of these patients, there is a need to move toward new therapeutic strategies by incorporating new agents. Bortezomib is the most reported new drug for PBL and has been used as a single dose or in combination. Koji et al[18] show the bortezomib and lenalidomide-based treatment was tolerated and the patient was continued with a PR for over 2 years. Bortezomib and lenalidomide have a certain therapeutic effect, and are mostly used in patients with refractory recurrence.[18,19] There are few case reports showing single-agent lenalidomide or combination with other chemotherapeutic drug in refractory PBL.[20–22] A dramatic response to Brentuximab has been reported in a single case, but the patient died shortly due to previous disease disabilities.[23] A plasmablastic microlymphoma arising in HHV8-associated multicentric Castleman disease in an HIV-negative patient that showed a clinical response to siltuximab, an anti-IL6 antibody.[24] The use of rituximab, a chimeric anti-CD20 monoclonal antibody, is not currently a therapeutic standard because the lack of CD20 expression by PBL cells, but combined with chemotherapy it could improve remission rates.[3,25] Clinical trials with novel immunotherapeutic agents and other drugs targeting some genes involved in the activation of Nuclear factor kappa B pathways, some of which are already ongoing, may show promising results.[18]
The literature on allo-HSCT in PBL is limited compared with ASCT. Only few cases of allo-HSCT for PBL were reported, much less for recurrence PBL. Hamadani[26] reported one patient with PBL in CR2 who underwent a reduced-intensity allogeneic stem cell transplantation, and was alive 2 years after transplantation. Liu et al[8] reported one patient who had disease recurrence at 14 months after ASCT was treated with allo-HSCT. Despite consolidation with allo-HSCT, disease recurred 5 months after, and the patient died. In general, the efficacy of allo-HSCT in the treatment of HIV-negative PBL patients is still not ideal and the survival of recurrent PBL after allo-HSCT is very poor.
In our case, the patient had recurrence after consolidated ASCT. Then, he underwent the salvage allo-HSCT from his daughter and achieved good curative effect. The patient was in long-term complete remission and he is alive now. It may be attributed to his younger age, low IPI score and early allo-HSCT treatment after relapse. As far as we know, this is the first case of such a long survival time after allo-HSCT. For young relapsed patients with PBL, allo-HSCT may bring long-term survival opportunities. Due to the rarity of the disease, it is not feasible to carry out large-scale clinical trials. The evaluation of allogeneic hematopoietic stem cell transplantation in PBL patients requires more accumulation and sharing of clinical experience.
Author contributions
Data curation: An Wu, Ye Sun.
Funding acquisition: Guifang Ouyang, Lixia Sheng.
Methodology: Lixia Sheng.
Writing – original draft: Chunmeng Rong.
Writing – review & editing: Chunmeng Rong.
Abbreviations: allo-HSCT = allogeneic hematopoietic stem cell transplantation, ASCT = autologous hematopoietic stem cell transplantation, CHOP = cyclophosphamide, doxorubicin, vincristine and prednisone, CR = complete response, CT = computed tomography, DLBCL = diffuse large B-cell lymphoma, EBV-DNA = Epstein-Barr virus DNA, GVHD = graft-versus-host disease, HHV-8 = Human herpes virus 8, HIV = human immunodeficiency virus, IPI = International Prognostic Index, MNC = mononuclear cell, OS = overall survival, PBL = plasmablastic lymphoma, PBSC = peripheral blood stem cell, PET-CT = positron emission tomography–computed tomography, PR = partial response.
How to cite this article: Rong C, Sheng L, Wu A, Sun Y, Ouyang G. Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: a case report. Medicine. 2021;100:7(e24498).
The study protocol was approved by the Ethics Review Committee of Ningbo First Hospital.
Patient has provided informed consent for publication of the case, and patient share his experience.
This study was supported by the National Natural Science Foundation of China under grant (number 81401321); Basic Public Welfare Research Project of Zhejiang Province under grant (number LGF19H080002); Medical Health Science and Technology Project of Zhejiang Provincial Health Commission under grant (number 2018PY052); National Science Foundation of Zhejiang Province under grant (number LY17H160005); and Traditional Chinese Medicine Administration of Zhejiang Province under grant (number 2015ZZ018).
The authors declare no conflict of interest.
The datasets generated during and/or analyzed during the current study are publicly available. | Recovered | ReactionOutcome | CC BY | 33607779 | 18,990,270 | 2021-02-19 |
What was the outcome of reaction 'Fungal infection'? | Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: A case report.
BACKGROUND
No standard guideline has been established for the treatment of plasmablastic lymphoma (PBL) and prognosis remains extremely poor, given that patients relapse early after chemotherapy and show resistance to commonly used cytostatic drugs.
We present the case of a 52-year-old HIV-negative man who presented with a mass at the left sternoclavicular joint. He had no significant comorbidities and no latent immunosuppression.
METHODS
The largest lymph node measured was 36 × 19 mm. An excisional biopsy showed diffuse proliferation of large lymphoid cells which were positive for CD38 and CD138, but negative for CD20. He was diagnosed with stage IV PBL with a low IPI.
METHODS
The patient was treated with four cycles of induction therapy with bortezomib, epirubicin and dexamethasone. He achieved complete remission. But 3 months after receiving consolidated autologous hematopoietic stem cell transplantation, he relapsed. Allogeneic hematopoietic stem cell transplantation was performed on the patient.
RESULTS
The patient achieved remission again and there were no serious complications after allogeneic hematopoietic stem cell transplantation. This patient was followed up once every three months, and to date, he has been disease-free for more than 4 years.
CONCLUSIONS
The survival of recurrent PBL after autologous hematopoietic stem cell transplantation is very poor. Salvage allogeneic hematopoietic stem cell transplantation may bring long-term survival opportunities for those patients. Further clinical studies are needed to explore the role of allogeneic hematopoietic stem cell transplantation in refractory and recurrent PBL.
pmc1 Introduction
Plasmablastic lymphoma (PBL) is a rare and highly aggressive subtype of diffuse large B-cell lymphoma (DLBCL), characterized by plasma cell antigen differentiation. It was initially described in the setting of human immunodeficiency virus (HIV) infection, but it was also been reported in HIV-negative patients.[1] There is no consensus on the standard of care for PBL. The role of intensification of induction chemotherapy is controversial. And novel agents, bortezomib and lenalidomide, have shown some effectiveness in relapsed cases and may have a relatively important role in frontline treatment.[2,3] The use of autologous stem cell transplantation (ASCT) possibly improves outcomes when used as a consolidation or salvage therapy and may lead to better results than chemotherapy, but the available data remain sparse.[2] The literatures on allogeneic hematopoietic stem cell transplantation (allo-HSCT) treatment for PBL are quite rare compared to ASCT. And given its rarity, most of the data available rely on case reports and case series. Patients with PBL have a poor prognosis, with median survival times shorter than 2 years.[2,4] To the best of our knowledge, the survival of recurrent PBL is worse.[2,5,6] Here, we report a case of HIV-negative PBL in a patient who had recurrence after ASCT, but achieved and maintained complete remission for 4-years after salvage allo-HSCT.
2 Case presentation
The patient was a 52-year-old man who presented in September 2015 with a mass at left sternoclavicular joint without any systemic symptoms. He had no significant comorbidities and no latent immunosuppression. Ultrasonography of lymph nodes indicated multiple lymph node enlargement in the neck, and multiple hypoechoic areas were seen above the left clavicle, the largest of which was 36 × 19 mm. A total body computed tomography (CT) scan showed that soft tissue mass shadows were seen around the left sternoclavicular joint and local cortical absorptions were present. Further investigations with fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) scan confirmed hypermetabolic mass appeared in several places of the body which was considered plasma cell infiltration. An excisional biopsy showed diffuse proliferation of large lymphoid cells (Fig. 1). Immuno-staining of the neoplastic cells showed negative for CD20, CD5, CD30, EREB, MPO, CD117 and Bcl-6, whereas it was positive for CD38, CD138, CD10, CD79a and Bcl-2 (Figs. 2–5). The Ki-67 proliferation index was 95% (Fig. 6). Biopsy of the iliac crest showed no marrow involvement. According to the above analysis, International Prognostic Index (IPI) scores were 2, the patient was diagnosed with stage IV PBL with a low IPI.
Figure 1 H&E (hematoxylin and eosin) image shows large sheets of mostly large plasmacytoid appearing mononuclear cells. (HE Magnification × 400).
Figure 2 CD138, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 3 CD38, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 4 CD10, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 5 CD79a, immunohistochemical stain demonstrates plasmacytic differentiation. (Magnification × 200).
Figure 6 Strong and homogenous staining with Ki-67 indicating a high proliferation index. (Magnification × 200).
In addition, laboratory data were as following: Blood routine examination indicated that the white blood cells were 8.1 × 109/L, the hemoglobin was 146 g/L and the platelets were 267 × 109/L. Erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, β2 microglobulin, serum proteins and immunoglobulin levels were all within normal ranges. Immunofixation electrophoresis showed no monoclonal component. Human herpes virus 8 (HHV-8) and Epstein-Barr virus DNA (EBV-DNA) were negative. Besides, serology for HIV was also negative.
From September to December 2015, the patient received 4 cycles of PAD chemotherapy regimens: bortezomib was given at the dose of 2.4 mg/day on day 1, 4, 8, 11, epirubicin at the dose of 20 mg/day on days 1–3, and dexamethasone at the dose of 40 mg/day on days 1–4 and 8–11 of each 28-day cycle. Repeat PET/CT following 4 cycles of chemotherapy showed no abnormal flurodeoxyglucose metabolic foci and enlarged lymph nodes, thus being compatible with a complete response (CR).
Later on, peripheral blood stem cell (PBSC) mobilization was achieved by high-dose cyclophosphamide (2 g, day 1–3), etoposide (300 mg, day 1–3) and granulocyte colony-stimulating factor (G-CSF), and leukapheresis products containing a total of mononuclear cell (MNC) 9.78 × 108/kg and CD34+ cells 6.9 × 106/kg were collected. In April 2016, the patient received autologous hematopoietic stem cell transplantation as consolidation therapy. The conditioning regiments were melphalan (200 mg/m2 -2d) and bortezomib (1.75 mg -6, -3, +1, +4), and a total of 9.78 × 108/kg MNC and 6.9 × 106/kg CD34+ cells PBSC were reinfused. Platelets and white blood cells were recovered at 10 and 11 days after transplantation, respectively. The CT scan performed 1 month after ASCT confirmed a CR.
However, 3 months after ASCT, CT showed a new lesion appeared in the second rib on the right side, which was considered as relapse. After full assessment, the patient underwent HLA half-matched allo-HSCT in September 2016. The conditioning regimen was modified BuCy+ATG (cytarabine 3.5 g -10, -9; busulfan 51.6 mg Q6 h -8, -7, -6; cyclophosphamide 3 g -5, -4; MECCNU 450 mg -3; antithymocyte globulin 2.5 mg/Kg -5, -4, -3, -2), and the scheme for prevention of graft-versus-host disease (GVHD) was cyclosporin, mycophenolate mofetil and short-term methotrexate. The patient developed pulmonary fungal infection 20 days after allo-HSCT and took a turn for the better after treatment with voriconazole injection and voriconazole tablets. Unfortunately, the patient developed severe hemorrhagic cystitis 20 days later, but fortunately the condition improved after symptomatic treatment. There has been no evidence of acute or chronic GVHD. The patient achieved sustained complete donor engraftment as short tandem repeat monitoring was performed every three months after transplantation. A CR was metabolically and clinically confirmed by PET-CT scan after allo-HSCT. The patient is now healthy and in CR for 4 years after allo-HSCT.
3 Discussed
PBL is a distinct variant of diffuse large B-cell lymphoma initially described in HIV-positive patients.[7] Nevertheless, PBL has also been described in HIV-negative individuals, particularly in association with potential immunosuppression such as after solid organ or bone marrow transplantation or with autoimmune disorders and malignanciess.[8–11] HIV-negative PBL, in comparison with HIV-positive PBL, occurs in older patients, with less frequent involvement of oral mucosa or bone marrow and less frequently stages III-IV.[3,12,13] A review of 114 HIV-negative patients with PBL, by Liu et al[12] demonstrated that immunosuppression, MYC gene rearrangement, high-risk international prognostic index, and EBV negativity were poor prognostic factors. And the overall survival (OS) is between 9 and 19 months in HIV-negative patients.[12] Similarly, a systematic review on 76 HIV-negative PBL patients showed median OS of 9 months with 2-year OS rate of 10%.[13]
Given its rarity and peculiar features, there is no standard of care for PBL and the treatment remains a challenge.[11] The use of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and CHOP-like regimens are considered inadequate therapy, resulting short remission period,[3,11] so the NCCN guidelines recommend more intensive regimens,[14] including etoposide, vincristine and doxorubicin with bolus of cyclophosphamide and prednisone (EPOCH),[15] cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide, cytarabine,[16] or hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine.[17] The benefit of ASCT in patients with PBL is not quite clear based on the limited data available. In a single institution report of 9 consecutive HIV-negative PBL patients, 7 patients achieved CR and 1 patient achieved partial response (PR) after chemotherapy.[8] Four patients underwent consolidation with ASCT in first complete remission, and 2 of these patients were alive at median follow-up of 23.9 months. The third patient had disease recurrence at 14 months and the fourth patient had disease recurrence at 2 months after ASCT.[8] Moffitt Cancer Center presented the experience of two HIV-negative patients with PBL in PR that underwent an ASCT, and two patients survived 6 and 12 months.[12]
Given the low efficacy of the standard therapy, and the poor outcome of these patients, there is a need to move toward new therapeutic strategies by incorporating new agents. Bortezomib is the most reported new drug for PBL and has been used as a single dose or in combination. Koji et al[18] show the bortezomib and lenalidomide-based treatment was tolerated and the patient was continued with a PR for over 2 years. Bortezomib and lenalidomide have a certain therapeutic effect, and are mostly used in patients with refractory recurrence.[18,19] There are few case reports showing single-agent lenalidomide or combination with other chemotherapeutic drug in refractory PBL.[20–22] A dramatic response to Brentuximab has been reported in a single case, but the patient died shortly due to previous disease disabilities.[23] A plasmablastic microlymphoma arising in HHV8-associated multicentric Castleman disease in an HIV-negative patient that showed a clinical response to siltuximab, an anti-IL6 antibody.[24] The use of rituximab, a chimeric anti-CD20 monoclonal antibody, is not currently a therapeutic standard because the lack of CD20 expression by PBL cells, but combined with chemotherapy it could improve remission rates.[3,25] Clinical trials with novel immunotherapeutic agents and other drugs targeting some genes involved in the activation of Nuclear factor kappa B pathways, some of which are already ongoing, may show promising results.[18]
The literature on allo-HSCT in PBL is limited compared with ASCT. Only few cases of allo-HSCT for PBL were reported, much less for recurrence PBL. Hamadani[26] reported one patient with PBL in CR2 who underwent a reduced-intensity allogeneic stem cell transplantation, and was alive 2 years after transplantation. Liu et al[8] reported one patient who had disease recurrence at 14 months after ASCT was treated with allo-HSCT. Despite consolidation with allo-HSCT, disease recurred 5 months after, and the patient died. In general, the efficacy of allo-HSCT in the treatment of HIV-negative PBL patients is still not ideal and the survival of recurrent PBL after allo-HSCT is very poor.
In our case, the patient had recurrence after consolidated ASCT. Then, he underwent the salvage allo-HSCT from his daughter and achieved good curative effect. The patient was in long-term complete remission and he is alive now. It may be attributed to his younger age, low IPI score and early allo-HSCT treatment after relapse. As far as we know, this is the first case of such a long survival time after allo-HSCT. For young relapsed patients with PBL, allo-HSCT may bring long-term survival opportunities. Due to the rarity of the disease, it is not feasible to carry out large-scale clinical trials. The evaluation of allogeneic hematopoietic stem cell transplantation in PBL patients requires more accumulation and sharing of clinical experience.
Author contributions
Data curation: An Wu, Ye Sun.
Funding acquisition: Guifang Ouyang, Lixia Sheng.
Methodology: Lixia Sheng.
Writing – original draft: Chunmeng Rong.
Writing – review & editing: Chunmeng Rong.
Abbreviations: allo-HSCT = allogeneic hematopoietic stem cell transplantation, ASCT = autologous hematopoietic stem cell transplantation, CHOP = cyclophosphamide, doxorubicin, vincristine and prednisone, CR = complete response, CT = computed tomography, DLBCL = diffuse large B-cell lymphoma, EBV-DNA = Epstein-Barr virus DNA, GVHD = graft-versus-host disease, HHV-8 = Human herpes virus 8, HIV = human immunodeficiency virus, IPI = International Prognostic Index, MNC = mononuclear cell, OS = overall survival, PBL = plasmablastic lymphoma, PBSC = peripheral blood stem cell, PET-CT = positron emission tomography–computed tomography, PR = partial response.
How to cite this article: Rong C, Sheng L, Wu A, Sun Y, Ouyang G. Allogeneic hematopoietic stem cell transplantation in a patient with HIV-negative recurrent plasmablastic lymphoma: a case report. Medicine. 2021;100:7(e24498).
The study protocol was approved by the Ethics Review Committee of Ningbo First Hospital.
Patient has provided informed consent for publication of the case, and patient share his experience.
This study was supported by the National Natural Science Foundation of China under grant (number 81401321); Basic Public Welfare Research Project of Zhejiang Province under grant (number LGF19H080002); Medical Health Science and Technology Project of Zhejiang Provincial Health Commission under grant (number 2018PY052); National Science Foundation of Zhejiang Province under grant (number LY17H160005); and Traditional Chinese Medicine Administration of Zhejiang Province under grant (number 2015ZZ018).
The authors declare no conflict of interest.
The datasets generated during and/or analyzed during the current study are publicly available. | Recovered | ReactionOutcome | CC BY | 33607779 | 18,990,270 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Orthostatic hypotension'. | D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: A case report.
BACKGROUND
Cisplatin is one of the key drugs that is frequently used for treating various types of malignancies. Although renal and digestive toxicities are well-known cisplatin-related toxicities, attention should also be paid to acute aortic thrombosis, a relatively rare but potentially fatal disorder caused by cisplatin. Additionally, D-dimer is mainly measured to detect venous thromboembolism or disseminated intravascular coagulation, whereas its usefulness for detecting aortic thrombosis remains unclear. Here, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein acute aortic thrombosis was diagnosed based on elevated D-dimer levels.
A 65-year-old man with stage IV squamous cell lung cancer presented with elevated D-dimer levels during treatment with second-line chemotherapy with cisplatin and S-1. Contrast-enhanced computed tomography (CT) revealed an intramural thrombus, which had not been previously identified, extending from the abdominal aorta to the common iliac artery.
We diagnosed the patient as having acute aortic thrombosis caused by cisplatin.
METHODS
The patient received intravenous administration of unfractionated heparin for 9 days followed by oral warfarin.
RESULTS
One month after initiating treatment, the patient's D-dimer levels decreased to the normal range, and contrast-enhanced CT revealed that the thrombi had nearly completely disappeared without any sequelae or organ damage.
CONCLUSIONS
Our findings revealed that cisplatin can cause acute aortic thrombosis and that regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.
pmc1 Introduction
Cisplatin is one of the most commonly used drugs in the treatment of various types of malignancies, including lung cancer. Renal and digestive toxicities are well-known cisplatin-related toxicities, and it has been reported that 18.1% of cisplatin-treated cancer patients develop thromboembolic events (TEEs).[1] However, most of these TEEs are venous thrombosis, and cisplatin-induced acute aortic thrombosis is a rare and adverse event.[1] Nonetheless, it is clinically important to promptly and accurately detect aortic thrombosis because it may cause a fatal ischemic event.
D-dimer, a marker of fibrin degradation, is mainly measured to detect venous thromboembolism or to diagnose and monitor disseminated intravascular coagulation. However, the efficacy of measuring D-dimer levels to detect aortic thrombosis remains unclear.[2] Herein, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein elevated D-dimer levels led us to the diagnosis of acute aortic thrombosis.
2 Case report
A 62-year-old man with a 75 pack-year smoking history was diagnosed with squamous cell lung carcinoma in June 2018. A chest computed tomography (CT) scan revealed a 42 × 50-mm-sized lesion in the upper lobe of the left lung, and whole-body 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed metastasis in the right iliac bone. Following the clinical stage assessment (stage IVA [cT3N1M1b]), the patient underwent first-line chemotherapy with pembrolizumab. The treatment was discontinued after administering 4 cycles of pembrolizumab, even though its efficacy was determined as partial response. This was because the patient developed oral mucosal disorder and hypothyroidism that were considered to be immune-related adverse events caused by pembrolizumab. In May 2019, after the patient remained in remission for over 8 months, disease progression was detected using FDG-PET, which showed an abnormal uptake in the left lung tumor, left hilar lymph node, and left adrenal gland.
The patient was in a good condition with an Eastern Cooperative Oncology Group performance status of 0. He had no medical history of TEE, however, he had dyslipidemia and hyperuricemia. He had no family history of thromboembolic disease, and physical examination revealed no abnormal findings. Blood test results showed no abnormalities, including normal D-dimer levels (0.6 μg/mL). Echocardiography showed normal left ventricular systolic function without any mural thrombus.
The patient was then treated with second-line chemotherapy comprising 60 mg/m2 cisplatin intravenously, which was administered on day 8, and 100 mg S-1 was orally administered daily from days 1 to 21. On day 14, the patient collapsed due to syncope after defecation, however, he recovered quickly without any sequelae. The patient was diagnosed with orthostatic hypotension based on a positive head-up tilt test; however, no abnormal findings, besides elevated D-dimer levels up to 8.1 μg/mL, were noted on electrocardiography or blood test results. On day 21, although no significant clinical symptoms were noted, contrast-enhanced CT performed to identify the causative lesion of elevated D-dimer levels revealed an intramural thrombus extending from the abdominal aorta to the common iliac artery without any occlusive lesion or progression of cancer (Fig. 1). Based on the patient's clinical course, he was diagnosed as having acute aortic thrombosis caused by cisplatin. To prevent further complications, he immediately received 10,000 to 20,000 U/d unfractionated heparin intravenously for 9 days and 3 mg warfarin orally. The D-dimer levels normalized on day 34, and follow-up contrast-enhanced CT performed on day 44 revealed that the thrombi in the abdominal aorta and common iliac artery had nearly completely disappeared (Fig. 2). Following this, he has been treated with chemotherapy comprising various anti-cancer agents, except for cisplatin, and no recurrence of thrombosis has been identified ever since.
Figure 1 Contrast-enhanced CT on day 21: thrombotic deposits (arrows) were identified in the abdominal aorta and common iliac artery without any occlusive lesion or progression of cancer. CT = computed tomography.
Figure 2 Contrast-enhanced CT on day 44: thrombus nearly completely disappeared. CT = computed tomography.
3 Discussion
We report the case of a man with squamous cell lung cancer who developed acute aortic thrombosis during chemotherapy with cisplatin. Although thrombosis-related symptoms were not remarkable, elevated D-dimer levels led us to perform contrast-enhanced CT, which in turn led to the diagnosis of aortic thrombosis. We consider 2 clinical observations to be crucial in this case report: first, cisplatin-based chemotherapy can cause acute aortic thrombosis, and second, regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.
Cisplatin-based chemotherapy can cause acute aortic thrombosis. Moore et al[1] reported that among 932 patients treated with cisplatin, 169 (18.1%) experienced TEEs during treatment or within 4 weeks after the last dose. Among the 169 patients, 150 (88.8%) had deep venous thrombosis and/or pulmonary embolism, whereas only 19 (11.2%) patients had arterial thrombosis including acute aortic thrombosis.[1] In the present case, we observed the aortic thrombus without any other causative factors including occlusive lesion or progression of cancer. Therefore, we diagnosed him as having acute aortic thrombosis caused by cisplatin.
Acute aortic thrombosis, which occurred during cisplatin-based chemotherapy, has previously been reported in 13 cases (9 with lung cancer,[3–8] 2 with gastrointestinal cancer,[3,9] 1 with testicular seminoma,[10] and 1 with cervical cancer[11]) (Table 1).[11] Eight of the 13 previous cases, as well as our case, presented with thrombi in the abdominal aorta, whereas in 4 cases, thrombi were limited to the thoracic aorta. In previous cases, thrombi were detected between 12 days and 5 months after initiating cisplatin-based chemotherapy. In our case, we identified thrombi on a CT scan on day 21, which is relatively early in the treatment course as compared with the average of the previous cases. Furthermore, etoposide or vinorelbine was used in combination with cisplatin in most of the previous cases, whereas S-1 was administered to only 1 patient besides the one in our case report.
Table 1 Reported cases of cisplatin-related aortic thrombosis.
Case Author Age/sex Cancer type Chemotherapy Location of thrombi D-dimer Detection opportunity Detection time Management
1 Hahn et al[5] 74/M Lung cancer (adenocarcinoma) CDDP/VP16 Ascending aorta 1077 μg/L (0–324 μg/L) Symptom (dyspnea on exertion and chest discomfort) N/A Anticoagulant
2 Ito et al[9] 66/F Gastric cancer CDDP/S-1 Descending arch of the thoracic aorta (FDP: 3.4 μg/mL) Accidental (follow-up CT) Follow up after the first cycle of chemotherapy Anticoagulant
3 Hahn et al[5] 50/M Lung cancer (small cell carcinoma) CDDP/VP16 Aortic arch 3.2 μg/mL Accidental (follow-up CT) Approximately 6 weeks after cisplatin was first administered Anticoagulant
4 Dieckmann et al[10] 49/M Testicular seminoma CDDP/VP16/BLM Descending arch of the thoracic aorta and infrarenal abdominal aorta N/A Accidental (follow-up CT) Follow up after the second cycle of chemotherapy Anticoagulant
5 Fernandes et al[3] 60/F Rectosigmoid adenocarcinoma CDDP/5-FU/FLO Proximal abdominal aorta and extending to the right common iliac artery N/A Accidental (follow-up CT) Six days after completion of the 3rd cycle Anticoagulant
6 Fernandes et al[3] 53/M Lung cancer (small-cell lung adenocarcinoma) CDDP/VP16 Abdominal aorta, extending from the level of the celiac artery to the right common iliac artery N/A Symptom (vomiting and abdominal pain) Approximately 3 months after cisplatin was first administered Anticoagulant
7 Fernandes et al[3] 53/M Lung cancer (adenocarcinoma) CDDP/VNR Abdominal aorta, extending from the level of the celiac plexus to the left common iliac artery N/A Accidental (follow-up CT) Approximately 4.5 months after cisplatin was first administered Anticoagulant
8 Fernandes et al[3] 50/F Non-small cell lung cancer CDDP/VNR Abdominal aorta, extending from the level of the superior mesenteric artery to the level above the origin of the common iliac arteries. N/A Accidental (follow-up CT) Approximately 4.5 months after cisplatin was first administered Anticoagulant
9 Sato et al[6] 68/M Lung cancer (adenocarcinoma) CDDP/VNR From the thoracic artery to the abdominal aorta 5.7 μg/mL Symptom (acute pain in his right leg and intermittent claudication) Thirteen days after cisplatin was first administered Anticoagulant
10 Mathews et al[7] 54/M Lung cancer (adenocarcinoma) CDDP/VP16 Abdominal artery below the renal artery N/A Symptom (discomfort in his right leg) Twelve days after cisplatin was first administered Amputation (below the knee)
11 Mathews et al[7] 54/F Lung cancer (large cell type) CDDP/VP16 Abdominal artery at the level of the renal artery N/A Symptom (leg paresthesia and low back pain) Halfway through the second cycle of chemotherapy Thrombectomy aortobifemoral graft
12 Aoki et al[8] 64/M Lung cancer (adenocarcinoma) CDDP/PEM Aortic arch 2.9 μg/mL Accidental (follow-up CT) Follow up after the first cycle of chemotherapy Anticoagulant
13 Abdel-Razeq et al[12] 59/F Cervical cancer CDDP/5-FU Aortic arch, descending aorta, and popliteal artery N/A Symptom (acute pain in his right leg, nausea, and vomiting) N/A Thrombectomy of the popliteal artery
14 Matsumoto et al (present case) 65/M Lung cancer (squamous cell carcinoma) CDDP/S-1 From the abdominal aorta to the common iliac artery 8.1 μg/mL Accidental (D-dimer increase) Thirteen days after cisplatin was first administered Anticoagulant
Although the exact mechanism by which cisplatin causes TEE remains unknown, it has been reported that cisplatin induces damage to vascular endothelial cells via hypomagnesemia, increased activity of von Willebrand factor, and increased formation of procoagulant endothelial microparticles.[1] Furthermore, platelet activation and upregulation of prothrombotic factors are implicated in cisplatin-related thrombosis.[12]
D-dimer is a product generated by plasmin-induced degradation of stabilized fibrin and is a generic term for mixtures having a D-dimer structure. An increase in D-dimer levels may be a marker for thrombus formation and the enhanced state of secondary fibrinolysis, and thus, is widely used in clinical settings as an important marker for thrombosis detection. As shown in Table 1, 6 of the 13 reported cases were diagnosed while investigating the source of a symptom; however, others were asymptomatic and were diagnosed based on follow-up CT, which evaluates the response to chemotherapy. These findings suggest that aortic thrombosis may follow an asymptomatic course for a period of time; however, there is a high need for its early detection because it may be exacerbated by organ embolism. In our case, D-dimer levels before initiating chemotherapy were normal and increased only after cisplatin was administered. This apparent change encouraged us to perform contrast-enhanced CT, which resulted in the diagnosis of aortic thrombosis relatively early in the treatment course compared to previous cases.
Although many studies have reported the usefulness of D-dimer in cases of intravenous thrombus and aortic aneurysm, its utility in the detection of intra-aortic thrombus remains uncertain. Nevertheless, as shown in Table 1, D-dimer levels were elevated in all 4 previous cases as well as in our case. These results suggest that D-dimer can be a potential diagnostic marker of cisplatin-related aortic thrombosis. Importantly, elevated D-dimer is commonly observed in presence of cancer no matter with or without thrombus. Therefore, regular measurements of D-dimer levels started from before the initiation of cisplatin-based chemotherapy can be useful to distinguish the elevation of D-dimer caused by the chemotherapy from that caused by the cancer itself, and it may helpful for the early detection of aortic thrombosis, especially before the appearance of thrombus-induced symptom. However, we should note that the elevation of D-dimer in patients with cancer can be caused by various factors including cancer itself or intravenous thrombus, thus the further examination such as contrast-enhanced CT is required to investigate the cause of the elevation of D-dimer.
In conclusion, we report a case of acute aortic thrombosis caused by cisplatin. Cisplatin-related arterial thrombus is a relatively rare but important complication that can cause life-threatening ischemic events. Regular measurements of D-dimer levels during chemotherapy with cisplatin may help in the early detection of acute aortic thrombosis.
Author contributions
Conceptualization: Yu Matsumoto, Yasushi Horimasu.
Data curation: Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Investigation: Yu Matsumoto, Yasushi Horimasu.
Methodology: Yu Matsumoto, Yasushi Horimasu.
Supervision: Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Writing – original draft: Yu Matsumoto.
Writing – review & editing: Yu Matsumoto, Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Abbreviations: CT = computed tomography, FDG-PET = fluorodeoxyglucose-positron emission tomography, TEE = thromboembolic event.
How to cite this article: Matsumoto Y, Horimasu Y, Yamaguchi K, Sakamoto S, Masuda T, Nakashima T, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Hattori N. D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: a case report. Medicine. 2021;100:7(e24695).
Informed Consent: The patient provided written informed consent for publishing his clinical information.
The authors have no funding and conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
5-FU = 5-fluorouracil; BLM = bleomycin hydrochloride; CDDP = cisplatin; CT = computed tomography; FDP = fibrinogen/fibrin degradation products; FLO = folinic acid; N/A = not applicable, PEM = pemetrexed sodium hydrate, VNR = vinorelbine detartrate, VP16 = etoposide. | CALCIUM CARBONATE, CHOLECALCIFEROL, CISPLATIN, FEBUXOSTAT, GIMERACIL\OTERACIL\TEGAFUR, LEVOTHYROXINE SODIUM, MAGNESIUM CARBONATE | DrugsGivenReaction | CC BY | 33607810 | 18,948,862 | 2021-02-19 |
What is the weight of the patient? | D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: A case report.
BACKGROUND
Cisplatin is one of the key drugs that is frequently used for treating various types of malignancies. Although renal and digestive toxicities are well-known cisplatin-related toxicities, attention should also be paid to acute aortic thrombosis, a relatively rare but potentially fatal disorder caused by cisplatin. Additionally, D-dimer is mainly measured to detect venous thromboembolism or disseminated intravascular coagulation, whereas its usefulness for detecting aortic thrombosis remains unclear. Here, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein acute aortic thrombosis was diagnosed based on elevated D-dimer levels.
A 65-year-old man with stage IV squamous cell lung cancer presented with elevated D-dimer levels during treatment with second-line chemotherapy with cisplatin and S-1. Contrast-enhanced computed tomography (CT) revealed an intramural thrombus, which had not been previously identified, extending from the abdominal aorta to the common iliac artery.
We diagnosed the patient as having acute aortic thrombosis caused by cisplatin.
METHODS
The patient received intravenous administration of unfractionated heparin for 9 days followed by oral warfarin.
RESULTS
One month after initiating treatment, the patient's D-dimer levels decreased to the normal range, and contrast-enhanced CT revealed that the thrombi had nearly completely disappeared without any sequelae or organ damage.
CONCLUSIONS
Our findings revealed that cisplatin can cause acute aortic thrombosis and that regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.
pmc1 Introduction
Cisplatin is one of the most commonly used drugs in the treatment of various types of malignancies, including lung cancer. Renal and digestive toxicities are well-known cisplatin-related toxicities, and it has been reported that 18.1% of cisplatin-treated cancer patients develop thromboembolic events (TEEs).[1] However, most of these TEEs are venous thrombosis, and cisplatin-induced acute aortic thrombosis is a rare and adverse event.[1] Nonetheless, it is clinically important to promptly and accurately detect aortic thrombosis because it may cause a fatal ischemic event.
D-dimer, a marker of fibrin degradation, is mainly measured to detect venous thromboembolism or to diagnose and monitor disseminated intravascular coagulation. However, the efficacy of measuring D-dimer levels to detect aortic thrombosis remains unclear.[2] Herein, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein elevated D-dimer levels led us to the diagnosis of acute aortic thrombosis.
2 Case report
A 62-year-old man with a 75 pack-year smoking history was diagnosed with squamous cell lung carcinoma in June 2018. A chest computed tomography (CT) scan revealed a 42 × 50-mm-sized lesion in the upper lobe of the left lung, and whole-body 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed metastasis in the right iliac bone. Following the clinical stage assessment (stage IVA [cT3N1M1b]), the patient underwent first-line chemotherapy with pembrolizumab. The treatment was discontinued after administering 4 cycles of pembrolizumab, even though its efficacy was determined as partial response. This was because the patient developed oral mucosal disorder and hypothyroidism that were considered to be immune-related adverse events caused by pembrolizumab. In May 2019, after the patient remained in remission for over 8 months, disease progression was detected using FDG-PET, which showed an abnormal uptake in the left lung tumor, left hilar lymph node, and left adrenal gland.
The patient was in a good condition with an Eastern Cooperative Oncology Group performance status of 0. He had no medical history of TEE, however, he had dyslipidemia and hyperuricemia. He had no family history of thromboembolic disease, and physical examination revealed no abnormal findings. Blood test results showed no abnormalities, including normal D-dimer levels (0.6 μg/mL). Echocardiography showed normal left ventricular systolic function without any mural thrombus.
The patient was then treated with second-line chemotherapy comprising 60 mg/m2 cisplatin intravenously, which was administered on day 8, and 100 mg S-1 was orally administered daily from days 1 to 21. On day 14, the patient collapsed due to syncope after defecation, however, he recovered quickly without any sequelae. The patient was diagnosed with orthostatic hypotension based on a positive head-up tilt test; however, no abnormal findings, besides elevated D-dimer levels up to 8.1 μg/mL, were noted on electrocardiography or blood test results. On day 21, although no significant clinical symptoms were noted, contrast-enhanced CT performed to identify the causative lesion of elevated D-dimer levels revealed an intramural thrombus extending from the abdominal aorta to the common iliac artery without any occlusive lesion or progression of cancer (Fig. 1). Based on the patient's clinical course, he was diagnosed as having acute aortic thrombosis caused by cisplatin. To prevent further complications, he immediately received 10,000 to 20,000 U/d unfractionated heparin intravenously for 9 days and 3 mg warfarin orally. The D-dimer levels normalized on day 34, and follow-up contrast-enhanced CT performed on day 44 revealed that the thrombi in the abdominal aorta and common iliac artery had nearly completely disappeared (Fig. 2). Following this, he has been treated with chemotherapy comprising various anti-cancer agents, except for cisplatin, and no recurrence of thrombosis has been identified ever since.
Figure 1 Contrast-enhanced CT on day 21: thrombotic deposits (arrows) were identified in the abdominal aorta and common iliac artery without any occlusive lesion or progression of cancer. CT = computed tomography.
Figure 2 Contrast-enhanced CT on day 44: thrombus nearly completely disappeared. CT = computed tomography.
3 Discussion
We report the case of a man with squamous cell lung cancer who developed acute aortic thrombosis during chemotherapy with cisplatin. Although thrombosis-related symptoms were not remarkable, elevated D-dimer levels led us to perform contrast-enhanced CT, which in turn led to the diagnosis of aortic thrombosis. We consider 2 clinical observations to be crucial in this case report: first, cisplatin-based chemotherapy can cause acute aortic thrombosis, and second, regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.
Cisplatin-based chemotherapy can cause acute aortic thrombosis. Moore et al[1] reported that among 932 patients treated with cisplatin, 169 (18.1%) experienced TEEs during treatment or within 4 weeks after the last dose. Among the 169 patients, 150 (88.8%) had deep venous thrombosis and/or pulmonary embolism, whereas only 19 (11.2%) patients had arterial thrombosis including acute aortic thrombosis.[1] In the present case, we observed the aortic thrombus without any other causative factors including occlusive lesion or progression of cancer. Therefore, we diagnosed him as having acute aortic thrombosis caused by cisplatin.
Acute aortic thrombosis, which occurred during cisplatin-based chemotherapy, has previously been reported in 13 cases (9 with lung cancer,[3–8] 2 with gastrointestinal cancer,[3,9] 1 with testicular seminoma,[10] and 1 with cervical cancer[11]) (Table 1).[11] Eight of the 13 previous cases, as well as our case, presented with thrombi in the abdominal aorta, whereas in 4 cases, thrombi were limited to the thoracic aorta. In previous cases, thrombi were detected between 12 days and 5 months after initiating cisplatin-based chemotherapy. In our case, we identified thrombi on a CT scan on day 21, which is relatively early in the treatment course as compared with the average of the previous cases. Furthermore, etoposide or vinorelbine was used in combination with cisplatin in most of the previous cases, whereas S-1 was administered to only 1 patient besides the one in our case report.
Table 1 Reported cases of cisplatin-related aortic thrombosis.
Case Author Age/sex Cancer type Chemotherapy Location of thrombi D-dimer Detection opportunity Detection time Management
1 Hahn et al[5] 74/M Lung cancer (adenocarcinoma) CDDP/VP16 Ascending aorta 1077 μg/L (0–324 μg/L) Symptom (dyspnea on exertion and chest discomfort) N/A Anticoagulant
2 Ito et al[9] 66/F Gastric cancer CDDP/S-1 Descending arch of the thoracic aorta (FDP: 3.4 μg/mL) Accidental (follow-up CT) Follow up after the first cycle of chemotherapy Anticoagulant
3 Hahn et al[5] 50/M Lung cancer (small cell carcinoma) CDDP/VP16 Aortic arch 3.2 μg/mL Accidental (follow-up CT) Approximately 6 weeks after cisplatin was first administered Anticoagulant
4 Dieckmann et al[10] 49/M Testicular seminoma CDDP/VP16/BLM Descending arch of the thoracic aorta and infrarenal abdominal aorta N/A Accidental (follow-up CT) Follow up after the second cycle of chemotherapy Anticoagulant
5 Fernandes et al[3] 60/F Rectosigmoid adenocarcinoma CDDP/5-FU/FLO Proximal abdominal aorta and extending to the right common iliac artery N/A Accidental (follow-up CT) Six days after completion of the 3rd cycle Anticoagulant
6 Fernandes et al[3] 53/M Lung cancer (small-cell lung adenocarcinoma) CDDP/VP16 Abdominal aorta, extending from the level of the celiac artery to the right common iliac artery N/A Symptom (vomiting and abdominal pain) Approximately 3 months after cisplatin was first administered Anticoagulant
7 Fernandes et al[3] 53/M Lung cancer (adenocarcinoma) CDDP/VNR Abdominal aorta, extending from the level of the celiac plexus to the left common iliac artery N/A Accidental (follow-up CT) Approximately 4.5 months after cisplatin was first administered Anticoagulant
8 Fernandes et al[3] 50/F Non-small cell lung cancer CDDP/VNR Abdominal aorta, extending from the level of the superior mesenteric artery to the level above the origin of the common iliac arteries. N/A Accidental (follow-up CT) Approximately 4.5 months after cisplatin was first administered Anticoagulant
9 Sato et al[6] 68/M Lung cancer (adenocarcinoma) CDDP/VNR From the thoracic artery to the abdominal aorta 5.7 μg/mL Symptom (acute pain in his right leg and intermittent claudication) Thirteen days after cisplatin was first administered Anticoagulant
10 Mathews et al[7] 54/M Lung cancer (adenocarcinoma) CDDP/VP16 Abdominal artery below the renal artery N/A Symptom (discomfort in his right leg) Twelve days after cisplatin was first administered Amputation (below the knee)
11 Mathews et al[7] 54/F Lung cancer (large cell type) CDDP/VP16 Abdominal artery at the level of the renal artery N/A Symptom (leg paresthesia and low back pain) Halfway through the second cycle of chemotherapy Thrombectomy aortobifemoral graft
12 Aoki et al[8] 64/M Lung cancer (adenocarcinoma) CDDP/PEM Aortic arch 2.9 μg/mL Accidental (follow-up CT) Follow up after the first cycle of chemotherapy Anticoagulant
13 Abdel-Razeq et al[12] 59/F Cervical cancer CDDP/5-FU Aortic arch, descending aorta, and popliteal artery N/A Symptom (acute pain in his right leg, nausea, and vomiting) N/A Thrombectomy of the popliteal artery
14 Matsumoto et al (present case) 65/M Lung cancer (squamous cell carcinoma) CDDP/S-1 From the abdominal aorta to the common iliac artery 8.1 μg/mL Accidental (D-dimer increase) Thirteen days after cisplatin was first administered Anticoagulant
Although the exact mechanism by which cisplatin causes TEE remains unknown, it has been reported that cisplatin induces damage to vascular endothelial cells via hypomagnesemia, increased activity of von Willebrand factor, and increased formation of procoagulant endothelial microparticles.[1] Furthermore, platelet activation and upregulation of prothrombotic factors are implicated in cisplatin-related thrombosis.[12]
D-dimer is a product generated by plasmin-induced degradation of stabilized fibrin and is a generic term for mixtures having a D-dimer structure. An increase in D-dimer levels may be a marker for thrombus formation and the enhanced state of secondary fibrinolysis, and thus, is widely used in clinical settings as an important marker for thrombosis detection. As shown in Table 1, 6 of the 13 reported cases were diagnosed while investigating the source of a symptom; however, others were asymptomatic and were diagnosed based on follow-up CT, which evaluates the response to chemotherapy. These findings suggest that aortic thrombosis may follow an asymptomatic course for a period of time; however, there is a high need for its early detection because it may be exacerbated by organ embolism. In our case, D-dimer levels before initiating chemotherapy were normal and increased only after cisplatin was administered. This apparent change encouraged us to perform contrast-enhanced CT, which resulted in the diagnosis of aortic thrombosis relatively early in the treatment course compared to previous cases.
Although many studies have reported the usefulness of D-dimer in cases of intravenous thrombus and aortic aneurysm, its utility in the detection of intra-aortic thrombus remains uncertain. Nevertheless, as shown in Table 1, D-dimer levels were elevated in all 4 previous cases as well as in our case. These results suggest that D-dimer can be a potential diagnostic marker of cisplatin-related aortic thrombosis. Importantly, elevated D-dimer is commonly observed in presence of cancer no matter with or without thrombus. Therefore, regular measurements of D-dimer levels started from before the initiation of cisplatin-based chemotherapy can be useful to distinguish the elevation of D-dimer caused by the chemotherapy from that caused by the cancer itself, and it may helpful for the early detection of aortic thrombosis, especially before the appearance of thrombus-induced symptom. However, we should note that the elevation of D-dimer in patients with cancer can be caused by various factors including cancer itself or intravenous thrombus, thus the further examination such as contrast-enhanced CT is required to investigate the cause of the elevation of D-dimer.
In conclusion, we report a case of acute aortic thrombosis caused by cisplatin. Cisplatin-related arterial thrombus is a relatively rare but important complication that can cause life-threatening ischemic events. Regular measurements of D-dimer levels during chemotherapy with cisplatin may help in the early detection of acute aortic thrombosis.
Author contributions
Conceptualization: Yu Matsumoto, Yasushi Horimasu.
Data curation: Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Investigation: Yu Matsumoto, Yasushi Horimasu.
Methodology: Yu Matsumoto, Yasushi Horimasu.
Supervision: Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Writing – original draft: Yu Matsumoto.
Writing – review & editing: Yu Matsumoto, Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Abbreviations: CT = computed tomography, FDG-PET = fluorodeoxyglucose-positron emission tomography, TEE = thromboembolic event.
How to cite this article: Matsumoto Y, Horimasu Y, Yamaguchi K, Sakamoto S, Masuda T, Nakashima T, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Hattori N. D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: a case report. Medicine. 2021;100:7(e24695).
Informed Consent: The patient provided written informed consent for publishing his clinical information.
The authors have no funding and conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
5-FU = 5-fluorouracil; BLM = bleomycin hydrochloride; CDDP = cisplatin; CT = computed tomography; FDP = fibrinogen/fibrin degradation products; FLO = folinic acid; N/A = not applicable, PEM = pemetrexed sodium hydrate, VNR = vinorelbine detartrate, VP16 = etoposide. | 69.4 kg. | Weight | CC BY | 33607810 | 18,948,862 | 2021-02-19 |
What was the administration route of drug 'CISPLATIN'? | D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: A case report.
BACKGROUND
Cisplatin is one of the key drugs that is frequently used for treating various types of malignancies. Although renal and digestive toxicities are well-known cisplatin-related toxicities, attention should also be paid to acute aortic thrombosis, a relatively rare but potentially fatal disorder caused by cisplatin. Additionally, D-dimer is mainly measured to detect venous thromboembolism or disseminated intravascular coagulation, whereas its usefulness for detecting aortic thrombosis remains unclear. Here, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein acute aortic thrombosis was diagnosed based on elevated D-dimer levels.
A 65-year-old man with stage IV squamous cell lung cancer presented with elevated D-dimer levels during treatment with second-line chemotherapy with cisplatin and S-1. Contrast-enhanced computed tomography (CT) revealed an intramural thrombus, which had not been previously identified, extending from the abdominal aorta to the common iliac artery.
We diagnosed the patient as having acute aortic thrombosis caused by cisplatin.
METHODS
The patient received intravenous administration of unfractionated heparin for 9 days followed by oral warfarin.
RESULTS
One month after initiating treatment, the patient's D-dimer levels decreased to the normal range, and contrast-enhanced CT revealed that the thrombi had nearly completely disappeared without any sequelae or organ damage.
CONCLUSIONS
Our findings revealed that cisplatin can cause acute aortic thrombosis and that regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.
pmc1 Introduction
Cisplatin is one of the most commonly used drugs in the treatment of various types of malignancies, including lung cancer. Renal and digestive toxicities are well-known cisplatin-related toxicities, and it has been reported that 18.1% of cisplatin-treated cancer patients develop thromboembolic events (TEEs).[1] However, most of these TEEs are venous thrombosis, and cisplatin-induced acute aortic thrombosis is a rare and adverse event.[1] Nonetheless, it is clinically important to promptly and accurately detect aortic thrombosis because it may cause a fatal ischemic event.
D-dimer, a marker of fibrin degradation, is mainly measured to detect venous thromboembolism or to diagnose and monitor disseminated intravascular coagulation. However, the efficacy of measuring D-dimer levels to detect aortic thrombosis remains unclear.[2] Herein, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein elevated D-dimer levels led us to the diagnosis of acute aortic thrombosis.
2 Case report
A 62-year-old man with a 75 pack-year smoking history was diagnosed with squamous cell lung carcinoma in June 2018. A chest computed tomography (CT) scan revealed a 42 × 50-mm-sized lesion in the upper lobe of the left lung, and whole-body 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed metastasis in the right iliac bone. Following the clinical stage assessment (stage IVA [cT3N1M1b]), the patient underwent first-line chemotherapy with pembrolizumab. The treatment was discontinued after administering 4 cycles of pembrolizumab, even though its efficacy was determined as partial response. This was because the patient developed oral mucosal disorder and hypothyroidism that were considered to be immune-related adverse events caused by pembrolizumab. In May 2019, after the patient remained in remission for over 8 months, disease progression was detected using FDG-PET, which showed an abnormal uptake in the left lung tumor, left hilar lymph node, and left adrenal gland.
The patient was in a good condition with an Eastern Cooperative Oncology Group performance status of 0. He had no medical history of TEE, however, he had dyslipidemia and hyperuricemia. He had no family history of thromboembolic disease, and physical examination revealed no abnormal findings. Blood test results showed no abnormalities, including normal D-dimer levels (0.6 μg/mL). Echocardiography showed normal left ventricular systolic function without any mural thrombus.
The patient was then treated with second-line chemotherapy comprising 60 mg/m2 cisplatin intravenously, which was administered on day 8, and 100 mg S-1 was orally administered daily from days 1 to 21. On day 14, the patient collapsed due to syncope after defecation, however, he recovered quickly without any sequelae. The patient was diagnosed with orthostatic hypotension based on a positive head-up tilt test; however, no abnormal findings, besides elevated D-dimer levels up to 8.1 μg/mL, were noted on electrocardiography or blood test results. On day 21, although no significant clinical symptoms were noted, contrast-enhanced CT performed to identify the causative lesion of elevated D-dimer levels revealed an intramural thrombus extending from the abdominal aorta to the common iliac artery without any occlusive lesion or progression of cancer (Fig. 1). Based on the patient's clinical course, he was diagnosed as having acute aortic thrombosis caused by cisplatin. To prevent further complications, he immediately received 10,000 to 20,000 U/d unfractionated heparin intravenously for 9 days and 3 mg warfarin orally. The D-dimer levels normalized on day 34, and follow-up contrast-enhanced CT performed on day 44 revealed that the thrombi in the abdominal aorta and common iliac artery had nearly completely disappeared (Fig. 2). Following this, he has been treated with chemotherapy comprising various anti-cancer agents, except for cisplatin, and no recurrence of thrombosis has been identified ever since.
Figure 1 Contrast-enhanced CT on day 21: thrombotic deposits (arrows) were identified in the abdominal aorta and common iliac artery without any occlusive lesion or progression of cancer. CT = computed tomography.
Figure 2 Contrast-enhanced CT on day 44: thrombus nearly completely disappeared. CT = computed tomography.
3 Discussion
We report the case of a man with squamous cell lung cancer who developed acute aortic thrombosis during chemotherapy with cisplatin. Although thrombosis-related symptoms were not remarkable, elevated D-dimer levels led us to perform contrast-enhanced CT, which in turn led to the diagnosis of aortic thrombosis. We consider 2 clinical observations to be crucial in this case report: first, cisplatin-based chemotherapy can cause acute aortic thrombosis, and second, regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.
Cisplatin-based chemotherapy can cause acute aortic thrombosis. Moore et al[1] reported that among 932 patients treated with cisplatin, 169 (18.1%) experienced TEEs during treatment or within 4 weeks after the last dose. Among the 169 patients, 150 (88.8%) had deep venous thrombosis and/or pulmonary embolism, whereas only 19 (11.2%) patients had arterial thrombosis including acute aortic thrombosis.[1] In the present case, we observed the aortic thrombus without any other causative factors including occlusive lesion or progression of cancer. Therefore, we diagnosed him as having acute aortic thrombosis caused by cisplatin.
Acute aortic thrombosis, which occurred during cisplatin-based chemotherapy, has previously been reported in 13 cases (9 with lung cancer,[3–8] 2 with gastrointestinal cancer,[3,9] 1 with testicular seminoma,[10] and 1 with cervical cancer[11]) (Table 1).[11] Eight of the 13 previous cases, as well as our case, presented with thrombi in the abdominal aorta, whereas in 4 cases, thrombi were limited to the thoracic aorta. In previous cases, thrombi were detected between 12 days and 5 months after initiating cisplatin-based chemotherapy. In our case, we identified thrombi on a CT scan on day 21, which is relatively early in the treatment course as compared with the average of the previous cases. Furthermore, etoposide or vinorelbine was used in combination with cisplatin in most of the previous cases, whereas S-1 was administered to only 1 patient besides the one in our case report.
Table 1 Reported cases of cisplatin-related aortic thrombosis.
Case Author Age/sex Cancer type Chemotherapy Location of thrombi D-dimer Detection opportunity Detection time Management
1 Hahn et al[5] 74/M Lung cancer (adenocarcinoma) CDDP/VP16 Ascending aorta 1077 μg/L (0–324 μg/L) Symptom (dyspnea on exertion and chest discomfort) N/A Anticoagulant
2 Ito et al[9] 66/F Gastric cancer CDDP/S-1 Descending arch of the thoracic aorta (FDP: 3.4 μg/mL) Accidental (follow-up CT) Follow up after the first cycle of chemotherapy Anticoagulant
3 Hahn et al[5] 50/M Lung cancer (small cell carcinoma) CDDP/VP16 Aortic arch 3.2 μg/mL Accidental (follow-up CT) Approximately 6 weeks after cisplatin was first administered Anticoagulant
4 Dieckmann et al[10] 49/M Testicular seminoma CDDP/VP16/BLM Descending arch of the thoracic aorta and infrarenal abdominal aorta N/A Accidental (follow-up CT) Follow up after the second cycle of chemotherapy Anticoagulant
5 Fernandes et al[3] 60/F Rectosigmoid adenocarcinoma CDDP/5-FU/FLO Proximal abdominal aorta and extending to the right common iliac artery N/A Accidental (follow-up CT) Six days after completion of the 3rd cycle Anticoagulant
6 Fernandes et al[3] 53/M Lung cancer (small-cell lung adenocarcinoma) CDDP/VP16 Abdominal aorta, extending from the level of the celiac artery to the right common iliac artery N/A Symptom (vomiting and abdominal pain) Approximately 3 months after cisplatin was first administered Anticoagulant
7 Fernandes et al[3] 53/M Lung cancer (adenocarcinoma) CDDP/VNR Abdominal aorta, extending from the level of the celiac plexus to the left common iliac artery N/A Accidental (follow-up CT) Approximately 4.5 months after cisplatin was first administered Anticoagulant
8 Fernandes et al[3] 50/F Non-small cell lung cancer CDDP/VNR Abdominal aorta, extending from the level of the superior mesenteric artery to the level above the origin of the common iliac arteries. N/A Accidental (follow-up CT) Approximately 4.5 months after cisplatin was first administered Anticoagulant
9 Sato et al[6] 68/M Lung cancer (adenocarcinoma) CDDP/VNR From the thoracic artery to the abdominal aorta 5.7 μg/mL Symptom (acute pain in his right leg and intermittent claudication) Thirteen days after cisplatin was first administered Anticoagulant
10 Mathews et al[7] 54/M Lung cancer (adenocarcinoma) CDDP/VP16 Abdominal artery below the renal artery N/A Symptom (discomfort in his right leg) Twelve days after cisplatin was first administered Amputation (below the knee)
11 Mathews et al[7] 54/F Lung cancer (large cell type) CDDP/VP16 Abdominal artery at the level of the renal artery N/A Symptom (leg paresthesia and low back pain) Halfway through the second cycle of chemotherapy Thrombectomy aortobifemoral graft
12 Aoki et al[8] 64/M Lung cancer (adenocarcinoma) CDDP/PEM Aortic arch 2.9 μg/mL Accidental (follow-up CT) Follow up after the first cycle of chemotherapy Anticoagulant
13 Abdel-Razeq et al[12] 59/F Cervical cancer CDDP/5-FU Aortic arch, descending aorta, and popliteal artery N/A Symptom (acute pain in his right leg, nausea, and vomiting) N/A Thrombectomy of the popliteal artery
14 Matsumoto et al (present case) 65/M Lung cancer (squamous cell carcinoma) CDDP/S-1 From the abdominal aorta to the common iliac artery 8.1 μg/mL Accidental (D-dimer increase) Thirteen days after cisplatin was first administered Anticoagulant
Although the exact mechanism by which cisplatin causes TEE remains unknown, it has been reported that cisplatin induces damage to vascular endothelial cells via hypomagnesemia, increased activity of von Willebrand factor, and increased formation of procoagulant endothelial microparticles.[1] Furthermore, platelet activation and upregulation of prothrombotic factors are implicated in cisplatin-related thrombosis.[12]
D-dimer is a product generated by plasmin-induced degradation of stabilized fibrin and is a generic term for mixtures having a D-dimer structure. An increase in D-dimer levels may be a marker for thrombus formation and the enhanced state of secondary fibrinolysis, and thus, is widely used in clinical settings as an important marker for thrombosis detection. As shown in Table 1, 6 of the 13 reported cases were diagnosed while investigating the source of a symptom; however, others were asymptomatic and were diagnosed based on follow-up CT, which evaluates the response to chemotherapy. These findings suggest that aortic thrombosis may follow an asymptomatic course for a period of time; however, there is a high need for its early detection because it may be exacerbated by organ embolism. In our case, D-dimer levels before initiating chemotherapy were normal and increased only after cisplatin was administered. This apparent change encouraged us to perform contrast-enhanced CT, which resulted in the diagnosis of aortic thrombosis relatively early in the treatment course compared to previous cases.
Although many studies have reported the usefulness of D-dimer in cases of intravenous thrombus and aortic aneurysm, its utility in the detection of intra-aortic thrombus remains uncertain. Nevertheless, as shown in Table 1, D-dimer levels were elevated in all 4 previous cases as well as in our case. These results suggest that D-dimer can be a potential diagnostic marker of cisplatin-related aortic thrombosis. Importantly, elevated D-dimer is commonly observed in presence of cancer no matter with or without thrombus. Therefore, regular measurements of D-dimer levels started from before the initiation of cisplatin-based chemotherapy can be useful to distinguish the elevation of D-dimer caused by the chemotherapy from that caused by the cancer itself, and it may helpful for the early detection of aortic thrombosis, especially before the appearance of thrombus-induced symptom. However, we should note that the elevation of D-dimer in patients with cancer can be caused by various factors including cancer itself or intravenous thrombus, thus the further examination such as contrast-enhanced CT is required to investigate the cause of the elevation of D-dimer.
In conclusion, we report a case of acute aortic thrombosis caused by cisplatin. Cisplatin-related arterial thrombus is a relatively rare but important complication that can cause life-threatening ischemic events. Regular measurements of D-dimer levels during chemotherapy with cisplatin may help in the early detection of acute aortic thrombosis.
Author contributions
Conceptualization: Yu Matsumoto, Yasushi Horimasu.
Data curation: Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Investigation: Yu Matsumoto, Yasushi Horimasu.
Methodology: Yu Matsumoto, Yasushi Horimasu.
Supervision: Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Writing – original draft: Yu Matsumoto.
Writing – review & editing: Yu Matsumoto, Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Abbreviations: CT = computed tomography, FDG-PET = fluorodeoxyglucose-positron emission tomography, TEE = thromboembolic event.
How to cite this article: Matsumoto Y, Horimasu Y, Yamaguchi K, Sakamoto S, Masuda T, Nakashima T, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Hattori N. D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: a case report. Medicine. 2021;100:7(e24695).
Informed Consent: The patient provided written informed consent for publishing his clinical information.
The authors have no funding and conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
5-FU = 5-fluorouracil; BLM = bleomycin hydrochloride; CDDP = cisplatin; CT = computed tomography; FDP = fibrinogen/fibrin degradation products; FLO = folinic acid; N/A = not applicable, PEM = pemetrexed sodium hydrate, VNR = vinorelbine detartrate, VP16 = etoposide. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33607810 | 19,099,234 | 2021-02-19 |
What was the administration route of drug 'GIMERACIL\OTERACIL\TEGAFUR'? | D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: A case report.
BACKGROUND
Cisplatin is one of the key drugs that is frequently used for treating various types of malignancies. Although renal and digestive toxicities are well-known cisplatin-related toxicities, attention should also be paid to acute aortic thrombosis, a relatively rare but potentially fatal disorder caused by cisplatin. Additionally, D-dimer is mainly measured to detect venous thromboembolism or disseminated intravascular coagulation, whereas its usefulness for detecting aortic thrombosis remains unclear. Here, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein acute aortic thrombosis was diagnosed based on elevated D-dimer levels.
A 65-year-old man with stage IV squamous cell lung cancer presented with elevated D-dimer levels during treatment with second-line chemotherapy with cisplatin and S-1. Contrast-enhanced computed tomography (CT) revealed an intramural thrombus, which had not been previously identified, extending from the abdominal aorta to the common iliac artery.
We diagnosed the patient as having acute aortic thrombosis caused by cisplatin.
METHODS
The patient received intravenous administration of unfractionated heparin for 9 days followed by oral warfarin.
RESULTS
One month after initiating treatment, the patient's D-dimer levels decreased to the normal range, and contrast-enhanced CT revealed that the thrombi had nearly completely disappeared without any sequelae or organ damage.
CONCLUSIONS
Our findings revealed that cisplatin can cause acute aortic thrombosis and that regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.
pmc1 Introduction
Cisplatin is one of the most commonly used drugs in the treatment of various types of malignancies, including lung cancer. Renal and digestive toxicities are well-known cisplatin-related toxicities, and it has been reported that 18.1% of cisplatin-treated cancer patients develop thromboembolic events (TEEs).[1] However, most of these TEEs are venous thrombosis, and cisplatin-induced acute aortic thrombosis is a rare and adverse event.[1] Nonetheless, it is clinically important to promptly and accurately detect aortic thrombosis because it may cause a fatal ischemic event.
D-dimer, a marker of fibrin degradation, is mainly measured to detect venous thromboembolism or to diagnose and monitor disseminated intravascular coagulation. However, the efficacy of measuring D-dimer levels to detect aortic thrombosis remains unclear.[2] Herein, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein elevated D-dimer levels led us to the diagnosis of acute aortic thrombosis.
2 Case report
A 62-year-old man with a 75 pack-year smoking history was diagnosed with squamous cell lung carcinoma in June 2018. A chest computed tomography (CT) scan revealed a 42 × 50-mm-sized lesion in the upper lobe of the left lung, and whole-body 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed metastasis in the right iliac bone. Following the clinical stage assessment (stage IVA [cT3N1M1b]), the patient underwent first-line chemotherapy with pembrolizumab. The treatment was discontinued after administering 4 cycles of pembrolizumab, even though its efficacy was determined as partial response. This was because the patient developed oral mucosal disorder and hypothyroidism that were considered to be immune-related adverse events caused by pembrolizumab. In May 2019, after the patient remained in remission for over 8 months, disease progression was detected using FDG-PET, which showed an abnormal uptake in the left lung tumor, left hilar lymph node, and left adrenal gland.
The patient was in a good condition with an Eastern Cooperative Oncology Group performance status of 0. He had no medical history of TEE, however, he had dyslipidemia and hyperuricemia. He had no family history of thromboembolic disease, and physical examination revealed no abnormal findings. Blood test results showed no abnormalities, including normal D-dimer levels (0.6 μg/mL). Echocardiography showed normal left ventricular systolic function without any mural thrombus.
The patient was then treated with second-line chemotherapy comprising 60 mg/m2 cisplatin intravenously, which was administered on day 8, and 100 mg S-1 was orally administered daily from days 1 to 21. On day 14, the patient collapsed due to syncope after defecation, however, he recovered quickly without any sequelae. The patient was diagnosed with orthostatic hypotension based on a positive head-up tilt test; however, no abnormal findings, besides elevated D-dimer levels up to 8.1 μg/mL, were noted on electrocardiography or blood test results. On day 21, although no significant clinical symptoms were noted, contrast-enhanced CT performed to identify the causative lesion of elevated D-dimer levels revealed an intramural thrombus extending from the abdominal aorta to the common iliac artery without any occlusive lesion or progression of cancer (Fig. 1). Based on the patient's clinical course, he was diagnosed as having acute aortic thrombosis caused by cisplatin. To prevent further complications, he immediately received 10,000 to 20,000 U/d unfractionated heparin intravenously for 9 days and 3 mg warfarin orally. The D-dimer levels normalized on day 34, and follow-up contrast-enhanced CT performed on day 44 revealed that the thrombi in the abdominal aorta and common iliac artery had nearly completely disappeared (Fig. 2). Following this, he has been treated with chemotherapy comprising various anti-cancer agents, except for cisplatin, and no recurrence of thrombosis has been identified ever since.
Figure 1 Contrast-enhanced CT on day 21: thrombotic deposits (arrows) were identified in the abdominal aorta and common iliac artery without any occlusive lesion or progression of cancer. CT = computed tomography.
Figure 2 Contrast-enhanced CT on day 44: thrombus nearly completely disappeared. CT = computed tomography.
3 Discussion
We report the case of a man with squamous cell lung cancer who developed acute aortic thrombosis during chemotherapy with cisplatin. Although thrombosis-related symptoms were not remarkable, elevated D-dimer levels led us to perform contrast-enhanced CT, which in turn led to the diagnosis of aortic thrombosis. We consider 2 clinical observations to be crucial in this case report: first, cisplatin-based chemotherapy can cause acute aortic thrombosis, and second, regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.
Cisplatin-based chemotherapy can cause acute aortic thrombosis. Moore et al[1] reported that among 932 patients treated with cisplatin, 169 (18.1%) experienced TEEs during treatment or within 4 weeks after the last dose. Among the 169 patients, 150 (88.8%) had deep venous thrombosis and/or pulmonary embolism, whereas only 19 (11.2%) patients had arterial thrombosis including acute aortic thrombosis.[1] In the present case, we observed the aortic thrombus without any other causative factors including occlusive lesion or progression of cancer. Therefore, we diagnosed him as having acute aortic thrombosis caused by cisplatin.
Acute aortic thrombosis, which occurred during cisplatin-based chemotherapy, has previously been reported in 13 cases (9 with lung cancer,[3–8] 2 with gastrointestinal cancer,[3,9] 1 with testicular seminoma,[10] and 1 with cervical cancer[11]) (Table 1).[11] Eight of the 13 previous cases, as well as our case, presented with thrombi in the abdominal aorta, whereas in 4 cases, thrombi were limited to the thoracic aorta. In previous cases, thrombi were detected between 12 days and 5 months after initiating cisplatin-based chemotherapy. In our case, we identified thrombi on a CT scan on day 21, which is relatively early in the treatment course as compared with the average of the previous cases. Furthermore, etoposide or vinorelbine was used in combination with cisplatin in most of the previous cases, whereas S-1 was administered to only 1 patient besides the one in our case report.
Table 1 Reported cases of cisplatin-related aortic thrombosis.
Case Author Age/sex Cancer type Chemotherapy Location of thrombi D-dimer Detection opportunity Detection time Management
1 Hahn et al[5] 74/M Lung cancer (adenocarcinoma) CDDP/VP16 Ascending aorta 1077 μg/L (0–324 μg/L) Symptom (dyspnea on exertion and chest discomfort) N/A Anticoagulant
2 Ito et al[9] 66/F Gastric cancer CDDP/S-1 Descending arch of the thoracic aorta (FDP: 3.4 μg/mL) Accidental (follow-up CT) Follow up after the first cycle of chemotherapy Anticoagulant
3 Hahn et al[5] 50/M Lung cancer (small cell carcinoma) CDDP/VP16 Aortic arch 3.2 μg/mL Accidental (follow-up CT) Approximately 6 weeks after cisplatin was first administered Anticoagulant
4 Dieckmann et al[10] 49/M Testicular seminoma CDDP/VP16/BLM Descending arch of the thoracic aorta and infrarenal abdominal aorta N/A Accidental (follow-up CT) Follow up after the second cycle of chemotherapy Anticoagulant
5 Fernandes et al[3] 60/F Rectosigmoid adenocarcinoma CDDP/5-FU/FLO Proximal abdominal aorta and extending to the right common iliac artery N/A Accidental (follow-up CT) Six days after completion of the 3rd cycle Anticoagulant
6 Fernandes et al[3] 53/M Lung cancer (small-cell lung adenocarcinoma) CDDP/VP16 Abdominal aorta, extending from the level of the celiac artery to the right common iliac artery N/A Symptom (vomiting and abdominal pain) Approximately 3 months after cisplatin was first administered Anticoagulant
7 Fernandes et al[3] 53/M Lung cancer (adenocarcinoma) CDDP/VNR Abdominal aorta, extending from the level of the celiac plexus to the left common iliac artery N/A Accidental (follow-up CT) Approximately 4.5 months after cisplatin was first administered Anticoagulant
8 Fernandes et al[3] 50/F Non-small cell lung cancer CDDP/VNR Abdominal aorta, extending from the level of the superior mesenteric artery to the level above the origin of the common iliac arteries. N/A Accidental (follow-up CT) Approximately 4.5 months after cisplatin was first administered Anticoagulant
9 Sato et al[6] 68/M Lung cancer (adenocarcinoma) CDDP/VNR From the thoracic artery to the abdominal aorta 5.7 μg/mL Symptom (acute pain in his right leg and intermittent claudication) Thirteen days after cisplatin was first administered Anticoagulant
10 Mathews et al[7] 54/M Lung cancer (adenocarcinoma) CDDP/VP16 Abdominal artery below the renal artery N/A Symptom (discomfort in his right leg) Twelve days after cisplatin was first administered Amputation (below the knee)
11 Mathews et al[7] 54/F Lung cancer (large cell type) CDDP/VP16 Abdominal artery at the level of the renal artery N/A Symptom (leg paresthesia and low back pain) Halfway through the second cycle of chemotherapy Thrombectomy aortobifemoral graft
12 Aoki et al[8] 64/M Lung cancer (adenocarcinoma) CDDP/PEM Aortic arch 2.9 μg/mL Accidental (follow-up CT) Follow up after the first cycle of chemotherapy Anticoagulant
13 Abdel-Razeq et al[12] 59/F Cervical cancer CDDP/5-FU Aortic arch, descending aorta, and popliteal artery N/A Symptom (acute pain in his right leg, nausea, and vomiting) N/A Thrombectomy of the popliteal artery
14 Matsumoto et al (present case) 65/M Lung cancer (squamous cell carcinoma) CDDP/S-1 From the abdominal aorta to the common iliac artery 8.1 μg/mL Accidental (D-dimer increase) Thirteen days after cisplatin was first administered Anticoagulant
Although the exact mechanism by which cisplatin causes TEE remains unknown, it has been reported that cisplatin induces damage to vascular endothelial cells via hypomagnesemia, increased activity of von Willebrand factor, and increased formation of procoagulant endothelial microparticles.[1] Furthermore, platelet activation and upregulation of prothrombotic factors are implicated in cisplatin-related thrombosis.[12]
D-dimer is a product generated by plasmin-induced degradation of stabilized fibrin and is a generic term for mixtures having a D-dimer structure. An increase in D-dimer levels may be a marker for thrombus formation and the enhanced state of secondary fibrinolysis, and thus, is widely used in clinical settings as an important marker for thrombosis detection. As shown in Table 1, 6 of the 13 reported cases were diagnosed while investigating the source of a symptom; however, others were asymptomatic and were diagnosed based on follow-up CT, which evaluates the response to chemotherapy. These findings suggest that aortic thrombosis may follow an asymptomatic course for a period of time; however, there is a high need for its early detection because it may be exacerbated by organ embolism. In our case, D-dimer levels before initiating chemotherapy were normal and increased only after cisplatin was administered. This apparent change encouraged us to perform contrast-enhanced CT, which resulted in the diagnosis of aortic thrombosis relatively early in the treatment course compared to previous cases.
Although many studies have reported the usefulness of D-dimer in cases of intravenous thrombus and aortic aneurysm, its utility in the detection of intra-aortic thrombus remains uncertain. Nevertheless, as shown in Table 1, D-dimer levels were elevated in all 4 previous cases as well as in our case. These results suggest that D-dimer can be a potential diagnostic marker of cisplatin-related aortic thrombosis. Importantly, elevated D-dimer is commonly observed in presence of cancer no matter with or without thrombus. Therefore, regular measurements of D-dimer levels started from before the initiation of cisplatin-based chemotherapy can be useful to distinguish the elevation of D-dimer caused by the chemotherapy from that caused by the cancer itself, and it may helpful for the early detection of aortic thrombosis, especially before the appearance of thrombus-induced symptom. However, we should note that the elevation of D-dimer in patients with cancer can be caused by various factors including cancer itself or intravenous thrombus, thus the further examination such as contrast-enhanced CT is required to investigate the cause of the elevation of D-dimer.
In conclusion, we report a case of acute aortic thrombosis caused by cisplatin. Cisplatin-related arterial thrombus is a relatively rare but important complication that can cause life-threatening ischemic events. Regular measurements of D-dimer levels during chemotherapy with cisplatin may help in the early detection of acute aortic thrombosis.
Author contributions
Conceptualization: Yu Matsumoto, Yasushi Horimasu.
Data curation: Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Investigation: Yu Matsumoto, Yasushi Horimasu.
Methodology: Yu Matsumoto, Yasushi Horimasu.
Supervision: Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Writing – original draft: Yu Matsumoto.
Writing – review & editing: Yu Matsumoto, Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Abbreviations: CT = computed tomography, FDG-PET = fluorodeoxyglucose-positron emission tomography, TEE = thromboembolic event.
How to cite this article: Matsumoto Y, Horimasu Y, Yamaguchi K, Sakamoto S, Masuda T, Nakashima T, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Hattori N. D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: a case report. Medicine. 2021;100:7(e24695).
Informed Consent: The patient provided written informed consent for publishing his clinical information.
The authors have no funding and conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
5-FU = 5-fluorouracil; BLM = bleomycin hydrochloride; CDDP = cisplatin; CT = computed tomography; FDP = fibrinogen/fibrin degradation products; FLO = folinic acid; N/A = not applicable, PEM = pemetrexed sodium hydrate, VNR = vinorelbine detartrate, VP16 = etoposide. | Oral | DrugAdministrationRoute | CC BY | 33607810 | 19,099,234 | 2021-02-19 |
What was the dosage of drug 'CALCIUM CARBONATE'? | D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: A case report.
BACKGROUND
Cisplatin is one of the key drugs that is frequently used for treating various types of malignancies. Although renal and digestive toxicities are well-known cisplatin-related toxicities, attention should also be paid to acute aortic thrombosis, a relatively rare but potentially fatal disorder caused by cisplatin. Additionally, D-dimer is mainly measured to detect venous thromboembolism or disseminated intravascular coagulation, whereas its usefulness for detecting aortic thrombosis remains unclear. Here, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein acute aortic thrombosis was diagnosed based on elevated D-dimer levels.
A 65-year-old man with stage IV squamous cell lung cancer presented with elevated D-dimer levels during treatment with second-line chemotherapy with cisplatin and S-1. Contrast-enhanced computed tomography (CT) revealed an intramural thrombus, which had not been previously identified, extending from the abdominal aorta to the common iliac artery.
We diagnosed the patient as having acute aortic thrombosis caused by cisplatin.
METHODS
The patient received intravenous administration of unfractionated heparin for 9 days followed by oral warfarin.
RESULTS
One month after initiating treatment, the patient's D-dimer levels decreased to the normal range, and contrast-enhanced CT revealed that the thrombi had nearly completely disappeared without any sequelae or organ damage.
CONCLUSIONS
Our findings revealed that cisplatin can cause acute aortic thrombosis and that regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.
pmc1 Introduction
Cisplatin is one of the most commonly used drugs in the treatment of various types of malignancies, including lung cancer. Renal and digestive toxicities are well-known cisplatin-related toxicities, and it has been reported that 18.1% of cisplatin-treated cancer patients develop thromboembolic events (TEEs).[1] However, most of these TEEs are venous thrombosis, and cisplatin-induced acute aortic thrombosis is a rare and adverse event.[1] Nonetheless, it is clinically important to promptly and accurately detect aortic thrombosis because it may cause a fatal ischemic event.
D-dimer, a marker of fibrin degradation, is mainly measured to detect venous thromboembolism or to diagnose and monitor disseminated intravascular coagulation. However, the efficacy of measuring D-dimer levels to detect aortic thrombosis remains unclear.[2] Herein, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein elevated D-dimer levels led us to the diagnosis of acute aortic thrombosis.
2 Case report
A 62-year-old man with a 75 pack-year smoking history was diagnosed with squamous cell lung carcinoma in June 2018. A chest computed tomography (CT) scan revealed a 42 × 50-mm-sized lesion in the upper lobe of the left lung, and whole-body 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed metastasis in the right iliac bone. Following the clinical stage assessment (stage IVA [cT3N1M1b]), the patient underwent first-line chemotherapy with pembrolizumab. The treatment was discontinued after administering 4 cycles of pembrolizumab, even though its efficacy was determined as partial response. This was because the patient developed oral mucosal disorder and hypothyroidism that were considered to be immune-related adverse events caused by pembrolizumab. In May 2019, after the patient remained in remission for over 8 months, disease progression was detected using FDG-PET, which showed an abnormal uptake in the left lung tumor, left hilar lymph node, and left adrenal gland.
The patient was in a good condition with an Eastern Cooperative Oncology Group performance status of 0. He had no medical history of TEE, however, he had dyslipidemia and hyperuricemia. He had no family history of thromboembolic disease, and physical examination revealed no abnormal findings. Blood test results showed no abnormalities, including normal D-dimer levels (0.6 μg/mL). Echocardiography showed normal left ventricular systolic function without any mural thrombus.
The patient was then treated with second-line chemotherapy comprising 60 mg/m2 cisplatin intravenously, which was administered on day 8, and 100 mg S-1 was orally administered daily from days 1 to 21. On day 14, the patient collapsed due to syncope after defecation, however, he recovered quickly without any sequelae. The patient was diagnosed with orthostatic hypotension based on a positive head-up tilt test; however, no abnormal findings, besides elevated D-dimer levels up to 8.1 μg/mL, were noted on electrocardiography or blood test results. On day 21, although no significant clinical symptoms were noted, contrast-enhanced CT performed to identify the causative lesion of elevated D-dimer levels revealed an intramural thrombus extending from the abdominal aorta to the common iliac artery without any occlusive lesion or progression of cancer (Fig. 1). Based on the patient's clinical course, he was diagnosed as having acute aortic thrombosis caused by cisplatin. To prevent further complications, he immediately received 10,000 to 20,000 U/d unfractionated heparin intravenously for 9 days and 3 mg warfarin orally. The D-dimer levels normalized on day 34, and follow-up contrast-enhanced CT performed on day 44 revealed that the thrombi in the abdominal aorta and common iliac artery had nearly completely disappeared (Fig. 2). Following this, he has been treated with chemotherapy comprising various anti-cancer agents, except for cisplatin, and no recurrence of thrombosis has been identified ever since.
Figure 1 Contrast-enhanced CT on day 21: thrombotic deposits (arrows) were identified in the abdominal aorta and common iliac artery without any occlusive lesion or progression of cancer. CT = computed tomography.
Figure 2 Contrast-enhanced CT on day 44: thrombus nearly completely disappeared. CT = computed tomography.
3 Discussion
We report the case of a man with squamous cell lung cancer who developed acute aortic thrombosis during chemotherapy with cisplatin. Although thrombosis-related symptoms were not remarkable, elevated D-dimer levels led us to perform contrast-enhanced CT, which in turn led to the diagnosis of aortic thrombosis. We consider 2 clinical observations to be crucial in this case report: first, cisplatin-based chemotherapy can cause acute aortic thrombosis, and second, regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.
Cisplatin-based chemotherapy can cause acute aortic thrombosis. Moore et al[1] reported that among 932 patients treated with cisplatin, 169 (18.1%) experienced TEEs during treatment or within 4 weeks after the last dose. Among the 169 patients, 150 (88.8%) had deep venous thrombosis and/or pulmonary embolism, whereas only 19 (11.2%) patients had arterial thrombosis including acute aortic thrombosis.[1] In the present case, we observed the aortic thrombus without any other causative factors including occlusive lesion or progression of cancer. Therefore, we diagnosed him as having acute aortic thrombosis caused by cisplatin.
Acute aortic thrombosis, which occurred during cisplatin-based chemotherapy, has previously been reported in 13 cases (9 with lung cancer,[3–8] 2 with gastrointestinal cancer,[3,9] 1 with testicular seminoma,[10] and 1 with cervical cancer[11]) (Table 1).[11] Eight of the 13 previous cases, as well as our case, presented with thrombi in the abdominal aorta, whereas in 4 cases, thrombi were limited to the thoracic aorta. In previous cases, thrombi were detected between 12 days and 5 months after initiating cisplatin-based chemotherapy. In our case, we identified thrombi on a CT scan on day 21, which is relatively early in the treatment course as compared with the average of the previous cases. Furthermore, etoposide or vinorelbine was used in combination with cisplatin in most of the previous cases, whereas S-1 was administered to only 1 patient besides the one in our case report.
Table 1 Reported cases of cisplatin-related aortic thrombosis.
Case Author Age/sex Cancer type Chemotherapy Location of thrombi D-dimer Detection opportunity Detection time Management
1 Hahn et al[5] 74/M Lung cancer (adenocarcinoma) CDDP/VP16 Ascending aorta 1077 μg/L (0–324 μg/L) Symptom (dyspnea on exertion and chest discomfort) N/A Anticoagulant
2 Ito et al[9] 66/F Gastric cancer CDDP/S-1 Descending arch of the thoracic aorta (FDP: 3.4 μg/mL) Accidental (follow-up CT) Follow up after the first cycle of chemotherapy Anticoagulant
3 Hahn et al[5] 50/M Lung cancer (small cell carcinoma) CDDP/VP16 Aortic arch 3.2 μg/mL Accidental (follow-up CT) Approximately 6 weeks after cisplatin was first administered Anticoagulant
4 Dieckmann et al[10] 49/M Testicular seminoma CDDP/VP16/BLM Descending arch of the thoracic aorta and infrarenal abdominal aorta N/A Accidental (follow-up CT) Follow up after the second cycle of chemotherapy Anticoagulant
5 Fernandes et al[3] 60/F Rectosigmoid adenocarcinoma CDDP/5-FU/FLO Proximal abdominal aorta and extending to the right common iliac artery N/A Accidental (follow-up CT) Six days after completion of the 3rd cycle Anticoagulant
6 Fernandes et al[3] 53/M Lung cancer (small-cell lung adenocarcinoma) CDDP/VP16 Abdominal aorta, extending from the level of the celiac artery to the right common iliac artery N/A Symptom (vomiting and abdominal pain) Approximately 3 months after cisplatin was first administered Anticoagulant
7 Fernandes et al[3] 53/M Lung cancer (adenocarcinoma) CDDP/VNR Abdominal aorta, extending from the level of the celiac plexus to the left common iliac artery N/A Accidental (follow-up CT) Approximately 4.5 months after cisplatin was first administered Anticoagulant
8 Fernandes et al[3] 50/F Non-small cell lung cancer CDDP/VNR Abdominal aorta, extending from the level of the superior mesenteric artery to the level above the origin of the common iliac arteries. N/A Accidental (follow-up CT) Approximately 4.5 months after cisplatin was first administered Anticoagulant
9 Sato et al[6] 68/M Lung cancer (adenocarcinoma) CDDP/VNR From the thoracic artery to the abdominal aorta 5.7 μg/mL Symptom (acute pain in his right leg and intermittent claudication) Thirteen days after cisplatin was first administered Anticoagulant
10 Mathews et al[7] 54/M Lung cancer (adenocarcinoma) CDDP/VP16 Abdominal artery below the renal artery N/A Symptom (discomfort in his right leg) Twelve days after cisplatin was first administered Amputation (below the knee)
11 Mathews et al[7] 54/F Lung cancer (large cell type) CDDP/VP16 Abdominal artery at the level of the renal artery N/A Symptom (leg paresthesia and low back pain) Halfway through the second cycle of chemotherapy Thrombectomy aortobifemoral graft
12 Aoki et al[8] 64/M Lung cancer (adenocarcinoma) CDDP/PEM Aortic arch 2.9 μg/mL Accidental (follow-up CT) Follow up after the first cycle of chemotherapy Anticoagulant
13 Abdel-Razeq et al[12] 59/F Cervical cancer CDDP/5-FU Aortic arch, descending aorta, and popliteal artery N/A Symptom (acute pain in his right leg, nausea, and vomiting) N/A Thrombectomy of the popliteal artery
14 Matsumoto et al (present case) 65/M Lung cancer (squamous cell carcinoma) CDDP/S-1 From the abdominal aorta to the common iliac artery 8.1 μg/mL Accidental (D-dimer increase) Thirteen days after cisplatin was first administered Anticoagulant
Although the exact mechanism by which cisplatin causes TEE remains unknown, it has been reported that cisplatin induces damage to vascular endothelial cells via hypomagnesemia, increased activity of von Willebrand factor, and increased formation of procoagulant endothelial microparticles.[1] Furthermore, platelet activation and upregulation of prothrombotic factors are implicated in cisplatin-related thrombosis.[12]
D-dimer is a product generated by plasmin-induced degradation of stabilized fibrin and is a generic term for mixtures having a D-dimer structure. An increase in D-dimer levels may be a marker for thrombus formation and the enhanced state of secondary fibrinolysis, and thus, is widely used in clinical settings as an important marker for thrombosis detection. As shown in Table 1, 6 of the 13 reported cases were diagnosed while investigating the source of a symptom; however, others were asymptomatic and were diagnosed based on follow-up CT, which evaluates the response to chemotherapy. These findings suggest that aortic thrombosis may follow an asymptomatic course for a period of time; however, there is a high need for its early detection because it may be exacerbated by organ embolism. In our case, D-dimer levels before initiating chemotherapy were normal and increased only after cisplatin was administered. This apparent change encouraged us to perform contrast-enhanced CT, which resulted in the diagnosis of aortic thrombosis relatively early in the treatment course compared to previous cases.
Although many studies have reported the usefulness of D-dimer in cases of intravenous thrombus and aortic aneurysm, its utility in the detection of intra-aortic thrombus remains uncertain. Nevertheless, as shown in Table 1, D-dimer levels were elevated in all 4 previous cases as well as in our case. These results suggest that D-dimer can be a potential diagnostic marker of cisplatin-related aortic thrombosis. Importantly, elevated D-dimer is commonly observed in presence of cancer no matter with or without thrombus. Therefore, regular measurements of D-dimer levels started from before the initiation of cisplatin-based chemotherapy can be useful to distinguish the elevation of D-dimer caused by the chemotherapy from that caused by the cancer itself, and it may helpful for the early detection of aortic thrombosis, especially before the appearance of thrombus-induced symptom. However, we should note that the elevation of D-dimer in patients with cancer can be caused by various factors including cancer itself or intravenous thrombus, thus the further examination such as contrast-enhanced CT is required to investigate the cause of the elevation of D-dimer.
In conclusion, we report a case of acute aortic thrombosis caused by cisplatin. Cisplatin-related arterial thrombus is a relatively rare but important complication that can cause life-threatening ischemic events. Regular measurements of D-dimer levels during chemotherapy with cisplatin may help in the early detection of acute aortic thrombosis.
Author contributions
Conceptualization: Yu Matsumoto, Yasushi Horimasu.
Data curation: Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Investigation: Yu Matsumoto, Yasushi Horimasu.
Methodology: Yu Matsumoto, Yasushi Horimasu.
Supervision: Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Writing – original draft: Yu Matsumoto.
Writing – review & editing: Yu Matsumoto, Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Abbreviations: CT = computed tomography, FDG-PET = fluorodeoxyglucose-positron emission tomography, TEE = thromboembolic event.
How to cite this article: Matsumoto Y, Horimasu Y, Yamaguchi K, Sakamoto S, Masuda T, Nakashima T, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Hattori N. D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: a case report. Medicine. 2021;100:7(e24695).
Informed Consent: The patient provided written informed consent for publishing his clinical information.
The authors have no funding and conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
5-FU = 5-fluorouracil; BLM = bleomycin hydrochloride; CDDP = cisplatin; CT = computed tomography; FDP = fibrinogen/fibrin degradation products; FLO = folinic acid; N/A = not applicable, PEM = pemetrexed sodium hydrate, VNR = vinorelbine detartrate, VP16 = etoposide. | PRECIPITATED | DrugDosageText | CC BY | 33607810 | 18,948,862 | 2021-02-19 |
What was the outcome of reaction 'Orthostatic hypotension'? | D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: A case report.
BACKGROUND
Cisplatin is one of the key drugs that is frequently used for treating various types of malignancies. Although renal and digestive toxicities are well-known cisplatin-related toxicities, attention should also be paid to acute aortic thrombosis, a relatively rare but potentially fatal disorder caused by cisplatin. Additionally, D-dimer is mainly measured to detect venous thromboembolism or disseminated intravascular coagulation, whereas its usefulness for detecting aortic thrombosis remains unclear. Here, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein acute aortic thrombosis was diagnosed based on elevated D-dimer levels.
A 65-year-old man with stage IV squamous cell lung cancer presented with elevated D-dimer levels during treatment with second-line chemotherapy with cisplatin and S-1. Contrast-enhanced computed tomography (CT) revealed an intramural thrombus, which had not been previously identified, extending from the abdominal aorta to the common iliac artery.
We diagnosed the patient as having acute aortic thrombosis caused by cisplatin.
METHODS
The patient received intravenous administration of unfractionated heparin for 9 days followed by oral warfarin.
RESULTS
One month after initiating treatment, the patient's D-dimer levels decreased to the normal range, and contrast-enhanced CT revealed that the thrombi had nearly completely disappeared without any sequelae or organ damage.
CONCLUSIONS
Our findings revealed that cisplatin can cause acute aortic thrombosis and that regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.
pmc1 Introduction
Cisplatin is one of the most commonly used drugs in the treatment of various types of malignancies, including lung cancer. Renal and digestive toxicities are well-known cisplatin-related toxicities, and it has been reported that 18.1% of cisplatin-treated cancer patients develop thromboembolic events (TEEs).[1] However, most of these TEEs are venous thrombosis, and cisplatin-induced acute aortic thrombosis is a rare and adverse event.[1] Nonetheless, it is clinically important to promptly and accurately detect aortic thrombosis because it may cause a fatal ischemic event.
D-dimer, a marker of fibrin degradation, is mainly measured to detect venous thromboembolism or to diagnose and monitor disseminated intravascular coagulation. However, the efficacy of measuring D-dimer levels to detect aortic thrombosis remains unclear.[2] Herein, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein elevated D-dimer levels led us to the diagnosis of acute aortic thrombosis.
2 Case report
A 62-year-old man with a 75 pack-year smoking history was diagnosed with squamous cell lung carcinoma in June 2018. A chest computed tomography (CT) scan revealed a 42 × 50-mm-sized lesion in the upper lobe of the left lung, and whole-body 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed metastasis in the right iliac bone. Following the clinical stage assessment (stage IVA [cT3N1M1b]), the patient underwent first-line chemotherapy with pembrolizumab. The treatment was discontinued after administering 4 cycles of pembrolizumab, even though its efficacy was determined as partial response. This was because the patient developed oral mucosal disorder and hypothyroidism that were considered to be immune-related adverse events caused by pembrolizumab. In May 2019, after the patient remained in remission for over 8 months, disease progression was detected using FDG-PET, which showed an abnormal uptake in the left lung tumor, left hilar lymph node, and left adrenal gland.
The patient was in a good condition with an Eastern Cooperative Oncology Group performance status of 0. He had no medical history of TEE, however, he had dyslipidemia and hyperuricemia. He had no family history of thromboembolic disease, and physical examination revealed no abnormal findings. Blood test results showed no abnormalities, including normal D-dimer levels (0.6 μg/mL). Echocardiography showed normal left ventricular systolic function without any mural thrombus.
The patient was then treated with second-line chemotherapy comprising 60 mg/m2 cisplatin intravenously, which was administered on day 8, and 100 mg S-1 was orally administered daily from days 1 to 21. On day 14, the patient collapsed due to syncope after defecation, however, he recovered quickly without any sequelae. The patient was diagnosed with orthostatic hypotension based on a positive head-up tilt test; however, no abnormal findings, besides elevated D-dimer levels up to 8.1 μg/mL, were noted on electrocardiography or blood test results. On day 21, although no significant clinical symptoms were noted, contrast-enhanced CT performed to identify the causative lesion of elevated D-dimer levels revealed an intramural thrombus extending from the abdominal aorta to the common iliac artery without any occlusive lesion or progression of cancer (Fig. 1). Based on the patient's clinical course, he was diagnosed as having acute aortic thrombosis caused by cisplatin. To prevent further complications, he immediately received 10,000 to 20,000 U/d unfractionated heparin intravenously for 9 days and 3 mg warfarin orally. The D-dimer levels normalized on day 34, and follow-up contrast-enhanced CT performed on day 44 revealed that the thrombi in the abdominal aorta and common iliac artery had nearly completely disappeared (Fig. 2). Following this, he has been treated with chemotherapy comprising various anti-cancer agents, except for cisplatin, and no recurrence of thrombosis has been identified ever since.
Figure 1 Contrast-enhanced CT on day 21: thrombotic deposits (arrows) were identified in the abdominal aorta and common iliac artery without any occlusive lesion or progression of cancer. CT = computed tomography.
Figure 2 Contrast-enhanced CT on day 44: thrombus nearly completely disappeared. CT = computed tomography.
3 Discussion
We report the case of a man with squamous cell lung cancer who developed acute aortic thrombosis during chemotherapy with cisplatin. Although thrombosis-related symptoms were not remarkable, elevated D-dimer levels led us to perform contrast-enhanced CT, which in turn led to the diagnosis of aortic thrombosis. We consider 2 clinical observations to be crucial in this case report: first, cisplatin-based chemotherapy can cause acute aortic thrombosis, and second, regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.
Cisplatin-based chemotherapy can cause acute aortic thrombosis. Moore et al[1] reported that among 932 patients treated with cisplatin, 169 (18.1%) experienced TEEs during treatment or within 4 weeks after the last dose. Among the 169 patients, 150 (88.8%) had deep venous thrombosis and/or pulmonary embolism, whereas only 19 (11.2%) patients had arterial thrombosis including acute aortic thrombosis.[1] In the present case, we observed the aortic thrombus without any other causative factors including occlusive lesion or progression of cancer. Therefore, we diagnosed him as having acute aortic thrombosis caused by cisplatin.
Acute aortic thrombosis, which occurred during cisplatin-based chemotherapy, has previously been reported in 13 cases (9 with lung cancer,[3–8] 2 with gastrointestinal cancer,[3,9] 1 with testicular seminoma,[10] and 1 with cervical cancer[11]) (Table 1).[11] Eight of the 13 previous cases, as well as our case, presented with thrombi in the abdominal aorta, whereas in 4 cases, thrombi were limited to the thoracic aorta. In previous cases, thrombi were detected between 12 days and 5 months after initiating cisplatin-based chemotherapy. In our case, we identified thrombi on a CT scan on day 21, which is relatively early in the treatment course as compared with the average of the previous cases. Furthermore, etoposide or vinorelbine was used in combination with cisplatin in most of the previous cases, whereas S-1 was administered to only 1 patient besides the one in our case report.
Table 1 Reported cases of cisplatin-related aortic thrombosis.
Case Author Age/sex Cancer type Chemotherapy Location of thrombi D-dimer Detection opportunity Detection time Management
1 Hahn et al[5] 74/M Lung cancer (adenocarcinoma) CDDP/VP16 Ascending aorta 1077 μg/L (0–324 μg/L) Symptom (dyspnea on exertion and chest discomfort) N/A Anticoagulant
2 Ito et al[9] 66/F Gastric cancer CDDP/S-1 Descending arch of the thoracic aorta (FDP: 3.4 μg/mL) Accidental (follow-up CT) Follow up after the first cycle of chemotherapy Anticoagulant
3 Hahn et al[5] 50/M Lung cancer (small cell carcinoma) CDDP/VP16 Aortic arch 3.2 μg/mL Accidental (follow-up CT) Approximately 6 weeks after cisplatin was first administered Anticoagulant
4 Dieckmann et al[10] 49/M Testicular seminoma CDDP/VP16/BLM Descending arch of the thoracic aorta and infrarenal abdominal aorta N/A Accidental (follow-up CT) Follow up after the second cycle of chemotherapy Anticoagulant
5 Fernandes et al[3] 60/F Rectosigmoid adenocarcinoma CDDP/5-FU/FLO Proximal abdominal aorta and extending to the right common iliac artery N/A Accidental (follow-up CT) Six days after completion of the 3rd cycle Anticoagulant
6 Fernandes et al[3] 53/M Lung cancer (small-cell lung adenocarcinoma) CDDP/VP16 Abdominal aorta, extending from the level of the celiac artery to the right common iliac artery N/A Symptom (vomiting and abdominal pain) Approximately 3 months after cisplatin was first administered Anticoagulant
7 Fernandes et al[3] 53/M Lung cancer (adenocarcinoma) CDDP/VNR Abdominal aorta, extending from the level of the celiac plexus to the left common iliac artery N/A Accidental (follow-up CT) Approximately 4.5 months after cisplatin was first administered Anticoagulant
8 Fernandes et al[3] 50/F Non-small cell lung cancer CDDP/VNR Abdominal aorta, extending from the level of the superior mesenteric artery to the level above the origin of the common iliac arteries. N/A Accidental (follow-up CT) Approximately 4.5 months after cisplatin was first administered Anticoagulant
9 Sato et al[6] 68/M Lung cancer (adenocarcinoma) CDDP/VNR From the thoracic artery to the abdominal aorta 5.7 μg/mL Symptom (acute pain in his right leg and intermittent claudication) Thirteen days after cisplatin was first administered Anticoagulant
10 Mathews et al[7] 54/M Lung cancer (adenocarcinoma) CDDP/VP16 Abdominal artery below the renal artery N/A Symptom (discomfort in his right leg) Twelve days after cisplatin was first administered Amputation (below the knee)
11 Mathews et al[7] 54/F Lung cancer (large cell type) CDDP/VP16 Abdominal artery at the level of the renal artery N/A Symptom (leg paresthesia and low back pain) Halfway through the second cycle of chemotherapy Thrombectomy aortobifemoral graft
12 Aoki et al[8] 64/M Lung cancer (adenocarcinoma) CDDP/PEM Aortic arch 2.9 μg/mL Accidental (follow-up CT) Follow up after the first cycle of chemotherapy Anticoagulant
13 Abdel-Razeq et al[12] 59/F Cervical cancer CDDP/5-FU Aortic arch, descending aorta, and popliteal artery N/A Symptom (acute pain in his right leg, nausea, and vomiting) N/A Thrombectomy of the popliteal artery
14 Matsumoto et al (present case) 65/M Lung cancer (squamous cell carcinoma) CDDP/S-1 From the abdominal aorta to the common iliac artery 8.1 μg/mL Accidental (D-dimer increase) Thirteen days after cisplatin was first administered Anticoagulant
Although the exact mechanism by which cisplatin causes TEE remains unknown, it has been reported that cisplatin induces damage to vascular endothelial cells via hypomagnesemia, increased activity of von Willebrand factor, and increased formation of procoagulant endothelial microparticles.[1] Furthermore, platelet activation and upregulation of prothrombotic factors are implicated in cisplatin-related thrombosis.[12]
D-dimer is a product generated by plasmin-induced degradation of stabilized fibrin and is a generic term for mixtures having a D-dimer structure. An increase in D-dimer levels may be a marker for thrombus formation and the enhanced state of secondary fibrinolysis, and thus, is widely used in clinical settings as an important marker for thrombosis detection. As shown in Table 1, 6 of the 13 reported cases were diagnosed while investigating the source of a symptom; however, others were asymptomatic and were diagnosed based on follow-up CT, which evaluates the response to chemotherapy. These findings suggest that aortic thrombosis may follow an asymptomatic course for a period of time; however, there is a high need for its early detection because it may be exacerbated by organ embolism. In our case, D-dimer levels before initiating chemotherapy were normal and increased only after cisplatin was administered. This apparent change encouraged us to perform contrast-enhanced CT, which resulted in the diagnosis of aortic thrombosis relatively early in the treatment course compared to previous cases.
Although many studies have reported the usefulness of D-dimer in cases of intravenous thrombus and aortic aneurysm, its utility in the detection of intra-aortic thrombus remains uncertain. Nevertheless, as shown in Table 1, D-dimer levels were elevated in all 4 previous cases as well as in our case. These results suggest that D-dimer can be a potential diagnostic marker of cisplatin-related aortic thrombosis. Importantly, elevated D-dimer is commonly observed in presence of cancer no matter with or without thrombus. Therefore, regular measurements of D-dimer levels started from before the initiation of cisplatin-based chemotherapy can be useful to distinguish the elevation of D-dimer caused by the chemotherapy from that caused by the cancer itself, and it may helpful for the early detection of aortic thrombosis, especially before the appearance of thrombus-induced symptom. However, we should note that the elevation of D-dimer in patients with cancer can be caused by various factors including cancer itself or intravenous thrombus, thus the further examination such as contrast-enhanced CT is required to investigate the cause of the elevation of D-dimer.
In conclusion, we report a case of acute aortic thrombosis caused by cisplatin. Cisplatin-related arterial thrombus is a relatively rare but important complication that can cause life-threatening ischemic events. Regular measurements of D-dimer levels during chemotherapy with cisplatin may help in the early detection of acute aortic thrombosis.
Author contributions
Conceptualization: Yu Matsumoto, Yasushi Horimasu.
Data curation: Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Investigation: Yu Matsumoto, Yasushi Horimasu.
Methodology: Yu Matsumoto, Yasushi Horimasu.
Supervision: Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Writing – original draft: Yu Matsumoto.
Writing – review & editing: Yu Matsumoto, Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori.
Abbreviations: CT = computed tomography, FDG-PET = fluorodeoxyglucose-positron emission tomography, TEE = thromboembolic event.
How to cite this article: Matsumoto Y, Horimasu Y, Yamaguchi K, Sakamoto S, Masuda T, Nakashima T, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Hattori N. D-dimer can be a diagnostic marker for cisplatin-related aortic thrombosis: a case report. Medicine. 2021;100:7(e24695).
Informed Consent: The patient provided written informed consent for publishing his clinical information.
The authors have no funding and conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
5-FU = 5-fluorouracil; BLM = bleomycin hydrochloride; CDDP = cisplatin; CT = computed tomography; FDP = fibrinogen/fibrin degradation products; FLO = folinic acid; N/A = not applicable, PEM = pemetrexed sodium hydrate, VNR = vinorelbine detartrate, VP16 = etoposide. | Recovered | ReactionOutcome | CC BY | 33607810 | 18,948,862 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Detachment of retinal pigment epithelium'. | Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: A case report.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease of unknown etiology. GPA affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera. Retinal and choroidal manifestations are rare in GPA, but they often include choroidal neovascularization (CNV).
A 36-year-old man was diagnosed with GPA. He had been taking oral steroid treatment for 8 years. He experienced disease recurrence and the dose of oral prednisolone was increased after steroid pulse therapy. Fundus examination showed small retinal pigment epithelial detachment and serous retinal detachment (SRD). Optical coherence tomography (OCT) revealed a protruded lesion inside the SRD. Fluorescein angiography (FA) showed a small, dot-shaped fluorescein leakage in the SRD, and indocyanine green fluorescein fundus angiography showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. We had to determine whether the protruded lesion inside the SRD was CNV secondary to the inflammation due to GPA or whether it was central serous chorioretinopathy (CSC)-like condition caused by high-dose steroid treatment.
We confirmed that the SRD was due to CSC but not CNV because the protruded lesion examined by B-scan OCT angiography (OCTA) showed no blood flow.
METHODS
We decided to reduce the dose of steroid.
RESULTS
Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed.
CONCLUSIONS
We therefore propose the effectiveness of this advanced function of OCTA for the examination of blood flow signal images to detect CNV.
pmc1 Introduction
Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is a rare systemic autoimmune disease with an unknown etiology. The prevalence of GPA is estimated to be 3 per 100,000, and the annual incidence is approximately 8 to 10 per 1 million, but it varies depending on a person's ethnicity and geographic location.[1] GPA presents with a wide range of clinical manifestations of varying severity. GPA also affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera.[2] Retinal and choroidal manifestations are rare in GPA, but they are recognized as inflammation-based changes, such as retinitis, chorioretinitis, macular edema, exudative retinal detachment, and retinal necrosis. Choroidal inflammation due to GPA can also induce choroidal neovascularization (CNV).[3] Here, we report a case of retinal and choroidal manifestation in a patient with GPA and propose the effectiveness of examination with the advanced B-scan image function of optical coherence tomography angiography (OCTA) to detect blood flow signals.
2 Case report
A 36-year-old man was diagnosed with GPA in 2011. He has been followed up by private practice physicians and his clinical condition was well-controlled with oral prednisolone (0.075 mg/kg) and mizoribine (100 mg) for 8 years. In early 2019, he was referred to our hospital because he experienced disease recurrence with symptoms of arthritis and rapid deterioration of renal function. In addition, he underwent partial small bowel resection for small bowel bleeding. His renal function did not improve, and he was placed on maintenance dialysis. He was given 0.15 mg/kg oral prednisolone after steroid pulse therapy (1,000 mg/d for 3 days). In July 2019, he was referred to the ophthalmology department for the evaluation of GPA and steroid-induced ocular complications. His visual acuity was 20/20 in both eyes (OU). Intraocular pressures were 18 mm Hg in the right eye (OD) and 15 mm Hg in the left eye (OS). Results of slit lamp examination of the anterior segment were unremarkable. Fundus examination and optical coherence tomography (OCT) revealed a small retinal pigment epithelial detachment (PED) in the major temporal arcade in the OD and a small PED and serous retinal detachment (SRD) superior to the optic nerve head in the OS. The patient had previously discontinued visiting the ophthalmology department after 2011 because he had not had any subjective ocular symptoms. However, in January 2019, he presented to the ophthalmology department again with subjective symptoms of vision deterioration. His visual acuity was 20/20 in the OD and 20/25 in the OS. IOPs were 14 mm Hg in the OU. Results of a fundus examination showed multiple small circular SRDs in the major temporal arcade in OU. OCT detected hyperreflective protrusion that had hyporeflective bubble-like structure inside hyperreflective materials in the SRD. In addition, the choroid under the hyperreflective protrusions contained pachyvessel and low serous PED. Fluorescein angiography (FA) showed small, dot-shaped hyperfluorescent leakage from the SRDs. Indocyanine green angiography (ICGA) showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. To determine the appropriate treatment, it was necessary to determine whether the protruded lesions contained choroidal neovascularization (CNV) secondary to the inflammation due to GPA. Alternatively, the protruded lesions could have been fibrin accumulations and the SRDs could have been caused by central serous chorioretinopathy (CSC), which in turn was probably caused by the high-dose steroid treatment. We employed B-scan OCT angiography (OCTA) to detect blood flow. We identified that the protruded lesions had no blood flow inside of them, confirming that the diagnosed SRDs were CSC but not CNV. We decided to reduce the dose of steroid (Fig. 1). Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed for 1.5 years.
Figure 1 Images from a patient with granulomatosis with polyangiitis. (a,b) Color fundus images. Multiple yellow-white lesions in both eyes are noted. (a: right, b: left) (c, d): FA (c) and ICGA (d) images from the right eye. Hyperfluorescent leakages consistent with the yellow-white lesions are noted. (e, f) FA (e) and ICGA (f) images from the left eye. Hyperfluorescent leakages consistent with the yellow-white lesions are noted. (g) OCT image from a yellow-white lesion in the left eye (white line in [b]). hyperreflective protrusion in the serous retinal detachment is noted. (h) B-scan OCT angiography from the same protruded lesion as that in (g). Note that there is no blood flow signal (colored in red) inside the protruded lesion, indicating that it is not an active choroidal neovascularization. FA = fluorescein angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = OCT-angiography.
3 Discussion
Retinal and choroidal manifestations have been reported in GPA; however, their prevalence is not higher than that of other ocular manifestations. Retinal and choroidal manifestations in GPA include SRD and CNV, and they are mainly caused by severe inflammation from GPA. For CNV associated with posterior uveitis, immunosuppressive treatment with steroid is reportedly effective.[4] Nevertheless, steroid treatment is thought to induce CSC.[5] Sometimes, even after examining FA and IA results, it is very difficult to determine whether SRD and/or PED are caused by the uncontrolled inflammation of posterior uveitis or are the side effects of steroid treatment for posterior uveitis. As we showed here, for a case with hyperreflective protrusions in SRD, it is particularly important to evaluate precisely the existence of CNV, a vision-threatening disease. For the last few decades, CNV has been diagnosed only by FA and ICGA. However, Fujita et al recently showed that the accuracy and the diagnosis rate of PCV by IA is not significantly different from those of blood flow examination by B-scan OCTA.[6] Especially for patients with renal dysfunction, multiple examinations with systemic infusion of dyes is not preferable. In the present case, both FA/ICGA and OCTA were performed, and OCTA confirmed the absence of an internal blood flow signal in the protruded lesion, which led us to exclude the possibility of CNV.
Diagnosis of CNV secondary to posterior uveitis or CSC caused by steroid treatment for posterior uveitis is critical because misjudgment might cause exacerbation of the disease. The existence or absence of a blood flow signal, as measured by B-scan OCTA, is very informative and useful for confirming the diagnosis of ocular inflammatory diseases.
4 Ethical statement
Written informed consent was obtained from the patient. Ethical approval was obtained from the Ethics Committee of the Nagoya University Hospital, Nagoya, Japan, in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.
Acknowledgment
The authors thank Editage (www.editage.com) for English language editing.
Author contributions
Conceptualization: Noriko Takashi, Aya Nakamura.
Resources: Noriko Takashi, Aya Nakamura.
Supervision: Yoshihiko Usui, Keiko Kataoka, Yasuki Ito.
Writing – original draft: Aya Nakamura, Hiroki Kaneko.
Writing – review & editing: Hiroki Kaneko.
Abbreviations: CNV = Choroidal neovascularization, CSC = Central serous chorioretinopathy, FA = Fluorescein angiography, GPA = Granulomatosis with polyangiitis, ICGA = Indocyanine green angiography, OCT = Optical coherence tomography, OCTA = Optical coherence tomography angiography, PED = Pigment epithelial detachment, SRD = Serous retinal detachment.
How to cite this article: Takashi N, Nakamura A, Kataoka K, Usui Y, Ito Y, Kaneko H. Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: a case report. Medicine. 2021;100:7(e24789).
This work was partially supported by Grants-in-Aid for Scientific Research (C) (H.K., 19K09988) from JSPS KAKENHI (http://www.jsps.go.jp/), the Eye Research Foundation for the Aged (ERFA, H.K.), the Charitable Trust Fund for Ophthalmic Research in Commemoration of Santen Pharmaceutical's Founder (H.K.), and the Bayer Retina Award Foundation (H.K.).
The swept-source optical coherence tomography (B-scan Doppler OCTA) device used in this manuscript was loaned by Carl Zeiss Meditec.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | MIZORIBINE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33607834 | 19,040,654 | 2021-02-19 |
What was the administration route of drug 'PREDNISOLONE SODIUM PHOSPHATE'? | Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: A case report.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease of unknown etiology. GPA affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera. Retinal and choroidal manifestations are rare in GPA, but they often include choroidal neovascularization (CNV).
A 36-year-old man was diagnosed with GPA. He had been taking oral steroid treatment for 8 years. He experienced disease recurrence and the dose of oral prednisolone was increased after steroid pulse therapy. Fundus examination showed small retinal pigment epithelial detachment and serous retinal detachment (SRD). Optical coherence tomography (OCT) revealed a protruded lesion inside the SRD. Fluorescein angiography (FA) showed a small, dot-shaped fluorescein leakage in the SRD, and indocyanine green fluorescein fundus angiography showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. We had to determine whether the protruded lesion inside the SRD was CNV secondary to the inflammation due to GPA or whether it was central serous chorioretinopathy (CSC)-like condition caused by high-dose steroid treatment.
We confirmed that the SRD was due to CSC but not CNV because the protruded lesion examined by B-scan OCT angiography (OCTA) showed no blood flow.
METHODS
We decided to reduce the dose of steroid.
RESULTS
Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed.
CONCLUSIONS
We therefore propose the effectiveness of this advanced function of OCTA for the examination of blood flow signal images to detect CNV.
pmc1 Introduction
Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is a rare systemic autoimmune disease with an unknown etiology. The prevalence of GPA is estimated to be 3 per 100,000, and the annual incidence is approximately 8 to 10 per 1 million, but it varies depending on a person's ethnicity and geographic location.[1] GPA presents with a wide range of clinical manifestations of varying severity. GPA also affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera.[2] Retinal and choroidal manifestations are rare in GPA, but they are recognized as inflammation-based changes, such as retinitis, chorioretinitis, macular edema, exudative retinal detachment, and retinal necrosis. Choroidal inflammation due to GPA can also induce choroidal neovascularization (CNV).[3] Here, we report a case of retinal and choroidal manifestation in a patient with GPA and propose the effectiveness of examination with the advanced B-scan image function of optical coherence tomography angiography (OCTA) to detect blood flow signals.
2 Case report
A 36-year-old man was diagnosed with GPA in 2011. He has been followed up by private practice physicians and his clinical condition was well-controlled with oral prednisolone (0.075 mg/kg) and mizoribine (100 mg) for 8 years. In early 2019, he was referred to our hospital because he experienced disease recurrence with symptoms of arthritis and rapid deterioration of renal function. In addition, he underwent partial small bowel resection for small bowel bleeding. His renal function did not improve, and he was placed on maintenance dialysis. He was given 0.15 mg/kg oral prednisolone after steroid pulse therapy (1,000 mg/d for 3 days). In July 2019, he was referred to the ophthalmology department for the evaluation of GPA and steroid-induced ocular complications. His visual acuity was 20/20 in both eyes (OU). Intraocular pressures were 18 mm Hg in the right eye (OD) and 15 mm Hg in the left eye (OS). Results of slit lamp examination of the anterior segment were unremarkable. Fundus examination and optical coherence tomography (OCT) revealed a small retinal pigment epithelial detachment (PED) in the major temporal arcade in the OD and a small PED and serous retinal detachment (SRD) superior to the optic nerve head in the OS. The patient had previously discontinued visiting the ophthalmology department after 2011 because he had not had any subjective ocular symptoms. However, in January 2019, he presented to the ophthalmology department again with subjective symptoms of vision deterioration. His visual acuity was 20/20 in the OD and 20/25 in the OS. IOPs were 14 mm Hg in the OU. Results of a fundus examination showed multiple small circular SRDs in the major temporal arcade in OU. OCT detected hyperreflective protrusion that had hyporeflective bubble-like structure inside hyperreflective materials in the SRD. In addition, the choroid under the hyperreflective protrusions contained pachyvessel and low serous PED. Fluorescein angiography (FA) showed small, dot-shaped hyperfluorescent leakage from the SRDs. Indocyanine green angiography (ICGA) showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. To determine the appropriate treatment, it was necessary to determine whether the protruded lesions contained choroidal neovascularization (CNV) secondary to the inflammation due to GPA. Alternatively, the protruded lesions could have been fibrin accumulations and the SRDs could have been caused by central serous chorioretinopathy (CSC), which in turn was probably caused by the high-dose steroid treatment. We employed B-scan OCT angiography (OCTA) to detect blood flow. We identified that the protruded lesions had no blood flow inside of them, confirming that the diagnosed SRDs were CSC but not CNV. We decided to reduce the dose of steroid (Fig. 1). Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed for 1.5 years.
Figure 1 Images from a patient with granulomatosis with polyangiitis. (a,b) Color fundus images. Multiple yellow-white lesions in both eyes are noted. (a: right, b: left) (c, d): FA (c) and ICGA (d) images from the right eye. Hyperfluorescent leakages consistent with the yellow-white lesions are noted. (e, f) FA (e) and ICGA (f) images from the left eye. Hyperfluorescent leakages consistent with the yellow-white lesions are noted. (g) OCT image from a yellow-white lesion in the left eye (white line in [b]). hyperreflective protrusion in the serous retinal detachment is noted. (h) B-scan OCT angiography from the same protruded lesion as that in (g). Note that there is no blood flow signal (colored in red) inside the protruded lesion, indicating that it is not an active choroidal neovascularization. FA = fluorescein angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = OCT-angiography.
3 Discussion
Retinal and choroidal manifestations have been reported in GPA; however, their prevalence is not higher than that of other ocular manifestations. Retinal and choroidal manifestations in GPA include SRD and CNV, and they are mainly caused by severe inflammation from GPA. For CNV associated with posterior uveitis, immunosuppressive treatment with steroid is reportedly effective.[4] Nevertheless, steroid treatment is thought to induce CSC.[5] Sometimes, even after examining FA and IA results, it is very difficult to determine whether SRD and/or PED are caused by the uncontrolled inflammation of posterior uveitis or are the side effects of steroid treatment for posterior uveitis. As we showed here, for a case with hyperreflective protrusions in SRD, it is particularly important to evaluate precisely the existence of CNV, a vision-threatening disease. For the last few decades, CNV has been diagnosed only by FA and ICGA. However, Fujita et al recently showed that the accuracy and the diagnosis rate of PCV by IA is not significantly different from those of blood flow examination by B-scan OCTA.[6] Especially for patients with renal dysfunction, multiple examinations with systemic infusion of dyes is not preferable. In the present case, both FA/ICGA and OCTA were performed, and OCTA confirmed the absence of an internal blood flow signal in the protruded lesion, which led us to exclude the possibility of CNV.
Diagnosis of CNV secondary to posterior uveitis or CSC caused by steroid treatment for posterior uveitis is critical because misjudgment might cause exacerbation of the disease. The existence or absence of a blood flow signal, as measured by B-scan OCTA, is very informative and useful for confirming the diagnosis of ocular inflammatory diseases.
4 Ethical statement
Written informed consent was obtained from the patient. Ethical approval was obtained from the Ethics Committee of the Nagoya University Hospital, Nagoya, Japan, in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.
Acknowledgment
The authors thank Editage (www.editage.com) for English language editing.
Author contributions
Conceptualization: Noriko Takashi, Aya Nakamura.
Resources: Noriko Takashi, Aya Nakamura.
Supervision: Yoshihiko Usui, Keiko Kataoka, Yasuki Ito.
Writing – original draft: Aya Nakamura, Hiroki Kaneko.
Writing – review & editing: Hiroki Kaneko.
Abbreviations: CNV = Choroidal neovascularization, CSC = Central serous chorioretinopathy, FA = Fluorescein angiography, GPA = Granulomatosis with polyangiitis, ICGA = Indocyanine green angiography, OCT = Optical coherence tomography, OCTA = Optical coherence tomography angiography, PED = Pigment epithelial detachment, SRD = Serous retinal detachment.
How to cite this article: Takashi N, Nakamura A, Kataoka K, Usui Y, Ito Y, Kaneko H. Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: a case report. Medicine. 2021;100:7(e24789).
This work was partially supported by Grants-in-Aid for Scientific Research (C) (H.K., 19K09988) from JSPS KAKENHI (http://www.jsps.go.jp/), the Eye Research Foundation for the Aged (ERFA, H.K.), the Charitable Trust Fund for Ophthalmic Research in Commemoration of Santen Pharmaceutical's Founder (H.K.), and the Bayer Retina Award Foundation (H.K.).
The swept-source optical coherence tomography (B-scan Doppler OCTA) device used in this manuscript was loaned by Carl Zeiss Meditec.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | Oral | DrugAdministrationRoute | CC BY | 33607834 | 19,043,627 | 2021-02-19 |
What was the dosage of drug 'MIZORIBINE'? | Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: A case report.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease of unknown etiology. GPA affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera. Retinal and choroidal manifestations are rare in GPA, but they often include choroidal neovascularization (CNV).
A 36-year-old man was diagnosed with GPA. He had been taking oral steroid treatment for 8 years. He experienced disease recurrence and the dose of oral prednisolone was increased after steroid pulse therapy. Fundus examination showed small retinal pigment epithelial detachment and serous retinal detachment (SRD). Optical coherence tomography (OCT) revealed a protruded lesion inside the SRD. Fluorescein angiography (FA) showed a small, dot-shaped fluorescein leakage in the SRD, and indocyanine green fluorescein fundus angiography showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. We had to determine whether the protruded lesion inside the SRD was CNV secondary to the inflammation due to GPA or whether it was central serous chorioretinopathy (CSC)-like condition caused by high-dose steroid treatment.
We confirmed that the SRD was due to CSC but not CNV because the protruded lesion examined by B-scan OCT angiography (OCTA) showed no blood flow.
METHODS
We decided to reduce the dose of steroid.
RESULTS
Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed.
CONCLUSIONS
We therefore propose the effectiveness of this advanced function of OCTA for the examination of blood flow signal images to detect CNV.
pmc1 Introduction
Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is a rare systemic autoimmune disease with an unknown etiology. The prevalence of GPA is estimated to be 3 per 100,000, and the annual incidence is approximately 8 to 10 per 1 million, but it varies depending on a person's ethnicity and geographic location.[1] GPA presents with a wide range of clinical manifestations of varying severity. GPA also affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera.[2] Retinal and choroidal manifestations are rare in GPA, but they are recognized as inflammation-based changes, such as retinitis, chorioretinitis, macular edema, exudative retinal detachment, and retinal necrosis. Choroidal inflammation due to GPA can also induce choroidal neovascularization (CNV).[3] Here, we report a case of retinal and choroidal manifestation in a patient with GPA and propose the effectiveness of examination with the advanced B-scan image function of optical coherence tomography angiography (OCTA) to detect blood flow signals.
2 Case report
A 36-year-old man was diagnosed with GPA in 2011. He has been followed up by private practice physicians and his clinical condition was well-controlled with oral prednisolone (0.075 mg/kg) and mizoribine (100 mg) for 8 years. In early 2019, he was referred to our hospital because he experienced disease recurrence with symptoms of arthritis and rapid deterioration of renal function. In addition, he underwent partial small bowel resection for small bowel bleeding. His renal function did not improve, and he was placed on maintenance dialysis. He was given 0.15 mg/kg oral prednisolone after steroid pulse therapy (1,000 mg/d for 3 days). In July 2019, he was referred to the ophthalmology department for the evaluation of GPA and steroid-induced ocular complications. His visual acuity was 20/20 in both eyes (OU). Intraocular pressures were 18 mm Hg in the right eye (OD) and 15 mm Hg in the left eye (OS). Results of slit lamp examination of the anterior segment were unremarkable. Fundus examination and optical coherence tomography (OCT) revealed a small retinal pigment epithelial detachment (PED) in the major temporal arcade in the OD and a small PED and serous retinal detachment (SRD) superior to the optic nerve head in the OS. The patient had previously discontinued visiting the ophthalmology department after 2011 because he had not had any subjective ocular symptoms. However, in January 2019, he presented to the ophthalmology department again with subjective symptoms of vision deterioration. His visual acuity was 20/20 in the OD and 20/25 in the OS. IOPs were 14 mm Hg in the OU. Results of a fundus examination showed multiple small circular SRDs in the major temporal arcade in OU. OCT detected hyperreflective protrusion that had hyporeflective bubble-like structure inside hyperreflective materials in the SRD. In addition, the choroid under the hyperreflective protrusions contained pachyvessel and low serous PED. Fluorescein angiography (FA) showed small, dot-shaped hyperfluorescent leakage from the SRDs. Indocyanine green angiography (ICGA) showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. To determine the appropriate treatment, it was necessary to determine whether the protruded lesions contained choroidal neovascularization (CNV) secondary to the inflammation due to GPA. Alternatively, the protruded lesions could have been fibrin accumulations and the SRDs could have been caused by central serous chorioretinopathy (CSC), which in turn was probably caused by the high-dose steroid treatment. We employed B-scan OCT angiography (OCTA) to detect blood flow. We identified that the protruded lesions had no blood flow inside of them, confirming that the diagnosed SRDs were CSC but not CNV. We decided to reduce the dose of steroid (Fig. 1). Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed for 1.5 years.
Figure 1 Images from a patient with granulomatosis with polyangiitis. (a,b) Color fundus images. Multiple yellow-white lesions in both eyes are noted. (a: right, b: left) (c, d): FA (c) and ICGA (d) images from the right eye. Hyperfluorescent leakages consistent with the yellow-white lesions are noted. (e, f) FA (e) and ICGA (f) images from the left eye. Hyperfluorescent leakages consistent with the yellow-white lesions are noted. (g) OCT image from a yellow-white lesion in the left eye (white line in [b]). hyperreflective protrusion in the serous retinal detachment is noted. (h) B-scan OCT angiography from the same protruded lesion as that in (g). Note that there is no blood flow signal (colored in red) inside the protruded lesion, indicating that it is not an active choroidal neovascularization. FA = fluorescein angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = OCT-angiography.
3 Discussion
Retinal and choroidal manifestations have been reported in GPA; however, their prevalence is not higher than that of other ocular manifestations. Retinal and choroidal manifestations in GPA include SRD and CNV, and they are mainly caused by severe inflammation from GPA. For CNV associated with posterior uveitis, immunosuppressive treatment with steroid is reportedly effective.[4] Nevertheless, steroid treatment is thought to induce CSC.[5] Sometimes, even after examining FA and IA results, it is very difficult to determine whether SRD and/or PED are caused by the uncontrolled inflammation of posterior uveitis or are the side effects of steroid treatment for posterior uveitis. As we showed here, for a case with hyperreflective protrusions in SRD, it is particularly important to evaluate precisely the existence of CNV, a vision-threatening disease. For the last few decades, CNV has been diagnosed only by FA and ICGA. However, Fujita et al recently showed that the accuracy and the diagnosis rate of PCV by IA is not significantly different from those of blood flow examination by B-scan OCTA.[6] Especially for patients with renal dysfunction, multiple examinations with systemic infusion of dyes is not preferable. In the present case, both FA/ICGA and OCTA were performed, and OCTA confirmed the absence of an internal blood flow signal in the protruded lesion, which led us to exclude the possibility of CNV.
Diagnosis of CNV secondary to posterior uveitis or CSC caused by steroid treatment for posterior uveitis is critical because misjudgment might cause exacerbation of the disease. The existence or absence of a blood flow signal, as measured by B-scan OCTA, is very informative and useful for confirming the diagnosis of ocular inflammatory diseases.
4 Ethical statement
Written informed consent was obtained from the patient. Ethical approval was obtained from the Ethics Committee of the Nagoya University Hospital, Nagoya, Japan, in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.
Acknowledgment
The authors thank Editage (www.editage.com) for English language editing.
Author contributions
Conceptualization: Noriko Takashi, Aya Nakamura.
Resources: Noriko Takashi, Aya Nakamura.
Supervision: Yoshihiko Usui, Keiko Kataoka, Yasuki Ito.
Writing – original draft: Aya Nakamura, Hiroki Kaneko.
Writing – review & editing: Hiroki Kaneko.
Abbreviations: CNV = Choroidal neovascularization, CSC = Central serous chorioretinopathy, FA = Fluorescein angiography, GPA = Granulomatosis with polyangiitis, ICGA = Indocyanine green angiography, OCT = Optical coherence tomography, OCTA = Optical coherence tomography angiography, PED = Pigment epithelial detachment, SRD = Serous retinal detachment.
How to cite this article: Takashi N, Nakamura A, Kataoka K, Usui Y, Ito Y, Kaneko H. Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: a case report. Medicine. 2021;100:7(e24789).
This work was partially supported by Grants-in-Aid for Scientific Research (C) (H.K., 19K09988) from JSPS KAKENHI (http://www.jsps.go.jp/), the Eye Research Foundation for the Aged (ERFA, H.K.), the Charitable Trust Fund for Ophthalmic Research in Commemoration of Santen Pharmaceutical's Founder (H.K.), and the Bayer Retina Award Foundation (H.K.).
The swept-source optical coherence tomography (B-scan Doppler OCTA) device used in this manuscript was loaned by Carl Zeiss Meditec.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | 100 MILLIGRAM | DrugDosageText | CC BY | 33607834 | 20,466,810 | 2021-02-19 |
What was the dosage of drug 'UNSPECIFIED INGREDIENT'? | Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: A case report.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease of unknown etiology. GPA affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera. Retinal and choroidal manifestations are rare in GPA, but they often include choroidal neovascularization (CNV).
A 36-year-old man was diagnosed with GPA. He had been taking oral steroid treatment for 8 years. He experienced disease recurrence and the dose of oral prednisolone was increased after steroid pulse therapy. Fundus examination showed small retinal pigment epithelial detachment and serous retinal detachment (SRD). Optical coherence tomography (OCT) revealed a protruded lesion inside the SRD. Fluorescein angiography (FA) showed a small, dot-shaped fluorescein leakage in the SRD, and indocyanine green fluorescein fundus angiography showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. We had to determine whether the protruded lesion inside the SRD was CNV secondary to the inflammation due to GPA or whether it was central serous chorioretinopathy (CSC)-like condition caused by high-dose steroid treatment.
We confirmed that the SRD was due to CSC but not CNV because the protruded lesion examined by B-scan OCT angiography (OCTA) showed no blood flow.
METHODS
We decided to reduce the dose of steroid.
RESULTS
Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed.
CONCLUSIONS
We therefore propose the effectiveness of this advanced function of OCTA for the examination of blood flow signal images to detect CNV.
pmc1 Introduction
Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is a rare systemic autoimmune disease with an unknown etiology. The prevalence of GPA is estimated to be 3 per 100,000, and the annual incidence is approximately 8 to 10 per 1 million, but it varies depending on a person's ethnicity and geographic location.[1] GPA presents with a wide range of clinical manifestations of varying severity. GPA also affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera.[2] Retinal and choroidal manifestations are rare in GPA, but they are recognized as inflammation-based changes, such as retinitis, chorioretinitis, macular edema, exudative retinal detachment, and retinal necrosis. Choroidal inflammation due to GPA can also induce choroidal neovascularization (CNV).[3] Here, we report a case of retinal and choroidal manifestation in a patient with GPA and propose the effectiveness of examination with the advanced B-scan image function of optical coherence tomography angiography (OCTA) to detect blood flow signals.
2 Case report
A 36-year-old man was diagnosed with GPA in 2011. He has been followed up by private practice physicians and his clinical condition was well-controlled with oral prednisolone (0.075 mg/kg) and mizoribine (100 mg) for 8 years. In early 2019, he was referred to our hospital because he experienced disease recurrence with symptoms of arthritis and rapid deterioration of renal function. In addition, he underwent partial small bowel resection for small bowel bleeding. His renal function did not improve, and he was placed on maintenance dialysis. He was given 0.15 mg/kg oral prednisolone after steroid pulse therapy (1,000 mg/d for 3 days). In July 2019, he was referred to the ophthalmology department for the evaluation of GPA and steroid-induced ocular complications. His visual acuity was 20/20 in both eyes (OU). Intraocular pressures were 18 mm Hg in the right eye (OD) and 15 mm Hg in the left eye (OS). Results of slit lamp examination of the anterior segment were unremarkable. Fundus examination and optical coherence tomography (OCT) revealed a small retinal pigment epithelial detachment (PED) in the major temporal arcade in the OD and a small PED and serous retinal detachment (SRD) superior to the optic nerve head in the OS. The patient had previously discontinued visiting the ophthalmology department after 2011 because he had not had any subjective ocular symptoms. However, in January 2019, he presented to the ophthalmology department again with subjective symptoms of vision deterioration. His visual acuity was 20/20 in the OD and 20/25 in the OS. IOPs were 14 mm Hg in the OU. Results of a fundus examination showed multiple small circular SRDs in the major temporal arcade in OU. OCT detected hyperreflective protrusion that had hyporeflective bubble-like structure inside hyperreflective materials in the SRD. In addition, the choroid under the hyperreflective protrusions contained pachyvessel and low serous PED. Fluorescein angiography (FA) showed small, dot-shaped hyperfluorescent leakage from the SRDs. Indocyanine green angiography (ICGA) showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. To determine the appropriate treatment, it was necessary to determine whether the protruded lesions contained choroidal neovascularization (CNV) secondary to the inflammation due to GPA. Alternatively, the protruded lesions could have been fibrin accumulations and the SRDs could have been caused by central serous chorioretinopathy (CSC), which in turn was probably caused by the high-dose steroid treatment. We employed B-scan OCT angiography (OCTA) to detect blood flow. We identified that the protruded lesions had no blood flow inside of them, confirming that the diagnosed SRDs were CSC but not CNV. We decided to reduce the dose of steroid (Fig. 1). Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed for 1.5 years.
Figure 1 Images from a patient with granulomatosis with polyangiitis. (a,b) Color fundus images. Multiple yellow-white lesions in both eyes are noted. (a: right, b: left) (c, d): FA (c) and ICGA (d) images from the right eye. Hyperfluorescent leakages consistent with the yellow-white lesions are noted. (e, f) FA (e) and ICGA (f) images from the left eye. Hyperfluorescent leakages consistent with the yellow-white lesions are noted. (g) OCT image from a yellow-white lesion in the left eye (white line in [b]). hyperreflective protrusion in the serous retinal detachment is noted. (h) B-scan OCT angiography from the same protruded lesion as that in (g). Note that there is no blood flow signal (colored in red) inside the protruded lesion, indicating that it is not an active choroidal neovascularization. FA = fluorescein angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = OCT-angiography.
3 Discussion
Retinal and choroidal manifestations have been reported in GPA; however, their prevalence is not higher than that of other ocular manifestations. Retinal and choroidal manifestations in GPA include SRD and CNV, and they are mainly caused by severe inflammation from GPA. For CNV associated with posterior uveitis, immunosuppressive treatment with steroid is reportedly effective.[4] Nevertheless, steroid treatment is thought to induce CSC.[5] Sometimes, even after examining FA and IA results, it is very difficult to determine whether SRD and/or PED are caused by the uncontrolled inflammation of posterior uveitis or are the side effects of steroid treatment for posterior uveitis. As we showed here, for a case with hyperreflective protrusions in SRD, it is particularly important to evaluate precisely the existence of CNV, a vision-threatening disease. For the last few decades, CNV has been diagnosed only by FA and ICGA. However, Fujita et al recently showed that the accuracy and the diagnosis rate of PCV by IA is not significantly different from those of blood flow examination by B-scan OCTA.[6] Especially for patients with renal dysfunction, multiple examinations with systemic infusion of dyes is not preferable. In the present case, both FA/ICGA and OCTA were performed, and OCTA confirmed the absence of an internal blood flow signal in the protruded lesion, which led us to exclude the possibility of CNV.
Diagnosis of CNV secondary to posterior uveitis or CSC caused by steroid treatment for posterior uveitis is critical because misjudgment might cause exacerbation of the disease. The existence or absence of a blood flow signal, as measured by B-scan OCTA, is very informative and useful for confirming the diagnosis of ocular inflammatory diseases.
4 Ethical statement
Written informed consent was obtained from the patient. Ethical approval was obtained from the Ethics Committee of the Nagoya University Hospital, Nagoya, Japan, in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.
Acknowledgment
The authors thank Editage (www.editage.com) for English language editing.
Author contributions
Conceptualization: Noriko Takashi, Aya Nakamura.
Resources: Noriko Takashi, Aya Nakamura.
Supervision: Yoshihiko Usui, Keiko Kataoka, Yasuki Ito.
Writing – original draft: Aya Nakamura, Hiroki Kaneko.
Writing – review & editing: Hiroki Kaneko.
Abbreviations: CNV = Choroidal neovascularization, CSC = Central serous chorioretinopathy, FA = Fluorescein angiography, GPA = Granulomatosis with polyangiitis, ICGA = Indocyanine green angiography, OCT = Optical coherence tomography, OCTA = Optical coherence tomography angiography, PED = Pigment epithelial detachment, SRD = Serous retinal detachment.
How to cite this article: Takashi N, Nakamura A, Kataoka K, Usui Y, Ito Y, Kaneko H. Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: a case report. Medicine. 2021;100:7(e24789).
This work was partially supported by Grants-in-Aid for Scientific Research (C) (H.K., 19K09988) from JSPS KAKENHI (http://www.jsps.go.jp/), the Eye Research Foundation for the Aged (ERFA, H.K.), the Charitable Trust Fund for Ophthalmic Research in Commemoration of Santen Pharmaceutical's Founder (H.K.), and the Bayer Retina Award Foundation (H.K.).
The swept-source optical coherence tomography (B-scan Doppler OCTA) device used in this manuscript was loaned by Carl Zeiss Meditec.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | 1000 MILLIGRAM | DrugDosageText | CC BY | 33607834 | 20,466,810 | 2021-02-19 |
What was the outcome of reaction 'Chorioretinopathy'? | Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: A case report.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease of unknown etiology. GPA affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera. Retinal and choroidal manifestations are rare in GPA, but they often include choroidal neovascularization (CNV).
A 36-year-old man was diagnosed with GPA. He had been taking oral steroid treatment for 8 years. He experienced disease recurrence and the dose of oral prednisolone was increased after steroid pulse therapy. Fundus examination showed small retinal pigment epithelial detachment and serous retinal detachment (SRD). Optical coherence tomography (OCT) revealed a protruded lesion inside the SRD. Fluorescein angiography (FA) showed a small, dot-shaped fluorescein leakage in the SRD, and indocyanine green fluorescein fundus angiography showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. We had to determine whether the protruded lesion inside the SRD was CNV secondary to the inflammation due to GPA or whether it was central serous chorioretinopathy (CSC)-like condition caused by high-dose steroid treatment.
We confirmed that the SRD was due to CSC but not CNV because the protruded lesion examined by B-scan OCT angiography (OCTA) showed no blood flow.
METHODS
We decided to reduce the dose of steroid.
RESULTS
Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed.
CONCLUSIONS
We therefore propose the effectiveness of this advanced function of OCTA for the examination of blood flow signal images to detect CNV.
pmc1 Introduction
Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is a rare systemic autoimmune disease with an unknown etiology. The prevalence of GPA is estimated to be 3 per 100,000, and the annual incidence is approximately 8 to 10 per 1 million, but it varies depending on a person's ethnicity and geographic location.[1] GPA presents with a wide range of clinical manifestations of varying severity. GPA also affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera.[2] Retinal and choroidal manifestations are rare in GPA, but they are recognized as inflammation-based changes, such as retinitis, chorioretinitis, macular edema, exudative retinal detachment, and retinal necrosis. Choroidal inflammation due to GPA can also induce choroidal neovascularization (CNV).[3] Here, we report a case of retinal and choroidal manifestation in a patient with GPA and propose the effectiveness of examination with the advanced B-scan image function of optical coherence tomography angiography (OCTA) to detect blood flow signals.
2 Case report
A 36-year-old man was diagnosed with GPA in 2011. He has been followed up by private practice physicians and his clinical condition was well-controlled with oral prednisolone (0.075 mg/kg) and mizoribine (100 mg) for 8 years. In early 2019, he was referred to our hospital because he experienced disease recurrence with symptoms of arthritis and rapid deterioration of renal function. In addition, he underwent partial small bowel resection for small bowel bleeding. His renal function did not improve, and he was placed on maintenance dialysis. He was given 0.15 mg/kg oral prednisolone after steroid pulse therapy (1,000 mg/d for 3 days). In July 2019, he was referred to the ophthalmology department for the evaluation of GPA and steroid-induced ocular complications. His visual acuity was 20/20 in both eyes (OU). Intraocular pressures were 18 mm Hg in the right eye (OD) and 15 mm Hg in the left eye (OS). Results of slit lamp examination of the anterior segment were unremarkable. Fundus examination and optical coherence tomography (OCT) revealed a small retinal pigment epithelial detachment (PED) in the major temporal arcade in the OD and a small PED and serous retinal detachment (SRD) superior to the optic nerve head in the OS. The patient had previously discontinued visiting the ophthalmology department after 2011 because he had not had any subjective ocular symptoms. However, in January 2019, he presented to the ophthalmology department again with subjective symptoms of vision deterioration. His visual acuity was 20/20 in the OD and 20/25 in the OS. IOPs were 14 mm Hg in the OU. Results of a fundus examination showed multiple small circular SRDs in the major temporal arcade in OU. OCT detected hyperreflective protrusion that had hyporeflective bubble-like structure inside hyperreflective materials in the SRD. In addition, the choroid under the hyperreflective protrusions contained pachyvessel and low serous PED. Fluorescein angiography (FA) showed small, dot-shaped hyperfluorescent leakage from the SRDs. Indocyanine green angiography (ICGA) showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. To determine the appropriate treatment, it was necessary to determine whether the protruded lesions contained choroidal neovascularization (CNV) secondary to the inflammation due to GPA. Alternatively, the protruded lesions could have been fibrin accumulations and the SRDs could have been caused by central serous chorioretinopathy (CSC), which in turn was probably caused by the high-dose steroid treatment. We employed B-scan OCT angiography (OCTA) to detect blood flow. We identified that the protruded lesions had no blood flow inside of them, confirming that the diagnosed SRDs were CSC but not CNV. We decided to reduce the dose of steroid (Fig. 1). Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed for 1.5 years.
Figure 1 Images from a patient with granulomatosis with polyangiitis. (a,b) Color fundus images. Multiple yellow-white lesions in both eyes are noted. (a: right, b: left) (c, d): FA (c) and ICGA (d) images from the right eye. Hyperfluorescent leakages consistent with the yellow-white lesions are noted. (e, f) FA (e) and ICGA (f) images from the left eye. Hyperfluorescent leakages consistent with the yellow-white lesions are noted. (g) OCT image from a yellow-white lesion in the left eye (white line in [b]). hyperreflective protrusion in the serous retinal detachment is noted. (h) B-scan OCT angiography from the same protruded lesion as that in (g). Note that there is no blood flow signal (colored in red) inside the protruded lesion, indicating that it is not an active choroidal neovascularization. FA = fluorescein angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = OCT-angiography.
3 Discussion
Retinal and choroidal manifestations have been reported in GPA; however, their prevalence is not higher than that of other ocular manifestations. Retinal and choroidal manifestations in GPA include SRD and CNV, and they are mainly caused by severe inflammation from GPA. For CNV associated with posterior uveitis, immunosuppressive treatment with steroid is reportedly effective.[4] Nevertheless, steroid treatment is thought to induce CSC.[5] Sometimes, even after examining FA and IA results, it is very difficult to determine whether SRD and/or PED are caused by the uncontrolled inflammation of posterior uveitis or are the side effects of steroid treatment for posterior uveitis. As we showed here, for a case with hyperreflective protrusions in SRD, it is particularly important to evaluate precisely the existence of CNV, a vision-threatening disease. For the last few decades, CNV has been diagnosed only by FA and ICGA. However, Fujita et al recently showed that the accuracy and the diagnosis rate of PCV by IA is not significantly different from those of blood flow examination by B-scan OCTA.[6] Especially for patients with renal dysfunction, multiple examinations with systemic infusion of dyes is not preferable. In the present case, both FA/ICGA and OCTA were performed, and OCTA confirmed the absence of an internal blood flow signal in the protruded lesion, which led us to exclude the possibility of CNV.
Diagnosis of CNV secondary to posterior uveitis or CSC caused by steroid treatment for posterior uveitis is critical because misjudgment might cause exacerbation of the disease. The existence or absence of a blood flow signal, as measured by B-scan OCTA, is very informative and useful for confirming the diagnosis of ocular inflammatory diseases.
4 Ethical statement
Written informed consent was obtained from the patient. Ethical approval was obtained from the Ethics Committee of the Nagoya University Hospital, Nagoya, Japan, in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.
Acknowledgment
The authors thank Editage (www.editage.com) for English language editing.
Author contributions
Conceptualization: Noriko Takashi, Aya Nakamura.
Resources: Noriko Takashi, Aya Nakamura.
Supervision: Yoshihiko Usui, Keiko Kataoka, Yasuki Ito.
Writing – original draft: Aya Nakamura, Hiroki Kaneko.
Writing – review & editing: Hiroki Kaneko.
Abbreviations: CNV = Choroidal neovascularization, CSC = Central serous chorioretinopathy, FA = Fluorescein angiography, GPA = Granulomatosis with polyangiitis, ICGA = Indocyanine green angiography, OCT = Optical coherence tomography, OCTA = Optical coherence tomography angiography, PED = Pigment epithelial detachment, SRD = Serous retinal detachment.
How to cite this article: Takashi N, Nakamura A, Kataoka K, Usui Y, Ito Y, Kaneko H. Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: a case report. Medicine. 2021;100:7(e24789).
This work was partially supported by Grants-in-Aid for Scientific Research (C) (H.K., 19K09988) from JSPS KAKENHI (http://www.jsps.go.jp/), the Eye Research Foundation for the Aged (ERFA, H.K.), the Charitable Trust Fund for Ophthalmic Research in Commemoration of Santen Pharmaceutical's Founder (H.K.), and the Bayer Retina Award Foundation (H.K.).
The swept-source optical coherence tomography (B-scan Doppler OCTA) device used in this manuscript was loaned by Carl Zeiss Meditec.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | Recovering | ReactionOutcome | CC BY | 33607834 | 19,040,654 | 2021-02-19 |
What was the outcome of reaction 'Detachment of retinal pigment epithelium'? | Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: A case report.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease of unknown etiology. GPA affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera. Retinal and choroidal manifestations are rare in GPA, but they often include choroidal neovascularization (CNV).
A 36-year-old man was diagnosed with GPA. He had been taking oral steroid treatment for 8 years. He experienced disease recurrence and the dose of oral prednisolone was increased after steroid pulse therapy. Fundus examination showed small retinal pigment epithelial detachment and serous retinal detachment (SRD). Optical coherence tomography (OCT) revealed a protruded lesion inside the SRD. Fluorescein angiography (FA) showed a small, dot-shaped fluorescein leakage in the SRD, and indocyanine green fluorescein fundus angiography showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. We had to determine whether the protruded lesion inside the SRD was CNV secondary to the inflammation due to GPA or whether it was central serous chorioretinopathy (CSC)-like condition caused by high-dose steroid treatment.
We confirmed that the SRD was due to CSC but not CNV because the protruded lesion examined by B-scan OCT angiography (OCTA) showed no blood flow.
METHODS
We decided to reduce the dose of steroid.
RESULTS
Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed.
CONCLUSIONS
We therefore propose the effectiveness of this advanced function of OCTA for the examination of blood flow signal images to detect CNV.
pmc1 Introduction
Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is a rare systemic autoimmune disease with an unknown etiology. The prevalence of GPA is estimated to be 3 per 100,000, and the annual incidence is approximately 8 to 10 per 1 million, but it varies depending on a person's ethnicity and geographic location.[1] GPA presents with a wide range of clinical manifestations of varying severity. GPA also affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera.[2] Retinal and choroidal manifestations are rare in GPA, but they are recognized as inflammation-based changes, such as retinitis, chorioretinitis, macular edema, exudative retinal detachment, and retinal necrosis. Choroidal inflammation due to GPA can also induce choroidal neovascularization (CNV).[3] Here, we report a case of retinal and choroidal manifestation in a patient with GPA and propose the effectiveness of examination with the advanced B-scan image function of optical coherence tomography angiography (OCTA) to detect blood flow signals.
2 Case report
A 36-year-old man was diagnosed with GPA in 2011. He has been followed up by private practice physicians and his clinical condition was well-controlled with oral prednisolone (0.075 mg/kg) and mizoribine (100 mg) for 8 years. In early 2019, he was referred to our hospital because he experienced disease recurrence with symptoms of arthritis and rapid deterioration of renal function. In addition, he underwent partial small bowel resection for small bowel bleeding. His renal function did not improve, and he was placed on maintenance dialysis. He was given 0.15 mg/kg oral prednisolone after steroid pulse therapy (1,000 mg/d for 3 days). In July 2019, he was referred to the ophthalmology department for the evaluation of GPA and steroid-induced ocular complications. His visual acuity was 20/20 in both eyes (OU). Intraocular pressures were 18 mm Hg in the right eye (OD) and 15 mm Hg in the left eye (OS). Results of slit lamp examination of the anterior segment were unremarkable. Fundus examination and optical coherence tomography (OCT) revealed a small retinal pigment epithelial detachment (PED) in the major temporal arcade in the OD and a small PED and serous retinal detachment (SRD) superior to the optic nerve head in the OS. The patient had previously discontinued visiting the ophthalmology department after 2011 because he had not had any subjective ocular symptoms. However, in January 2019, he presented to the ophthalmology department again with subjective symptoms of vision deterioration. His visual acuity was 20/20 in the OD and 20/25 in the OS. IOPs were 14 mm Hg in the OU. Results of a fundus examination showed multiple small circular SRDs in the major temporal arcade in OU. OCT detected hyperreflective protrusion that had hyporeflective bubble-like structure inside hyperreflective materials in the SRD. In addition, the choroid under the hyperreflective protrusions contained pachyvessel and low serous PED. Fluorescein angiography (FA) showed small, dot-shaped hyperfluorescent leakage from the SRDs. Indocyanine green angiography (ICGA) showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. To determine the appropriate treatment, it was necessary to determine whether the protruded lesions contained choroidal neovascularization (CNV) secondary to the inflammation due to GPA. Alternatively, the protruded lesions could have been fibrin accumulations and the SRDs could have been caused by central serous chorioretinopathy (CSC), which in turn was probably caused by the high-dose steroid treatment. We employed B-scan OCT angiography (OCTA) to detect blood flow. We identified that the protruded lesions had no blood flow inside of them, confirming that the diagnosed SRDs were CSC but not CNV. We decided to reduce the dose of steroid (Fig. 1). Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed for 1.5 years.
Figure 1 Images from a patient with granulomatosis with polyangiitis. (a,b) Color fundus images. Multiple yellow-white lesions in both eyes are noted. (a: right, b: left) (c, d): FA (c) and ICGA (d) images from the right eye. Hyperfluorescent leakages consistent with the yellow-white lesions are noted. (e, f) FA (e) and ICGA (f) images from the left eye. Hyperfluorescent leakages consistent with the yellow-white lesions are noted. (g) OCT image from a yellow-white lesion in the left eye (white line in [b]). hyperreflective protrusion in the serous retinal detachment is noted. (h) B-scan OCT angiography from the same protruded lesion as that in (g). Note that there is no blood flow signal (colored in red) inside the protruded lesion, indicating that it is not an active choroidal neovascularization. FA = fluorescein angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = OCT-angiography.
3 Discussion
Retinal and choroidal manifestations have been reported in GPA; however, their prevalence is not higher than that of other ocular manifestations. Retinal and choroidal manifestations in GPA include SRD and CNV, and they are mainly caused by severe inflammation from GPA. For CNV associated with posterior uveitis, immunosuppressive treatment with steroid is reportedly effective.[4] Nevertheless, steroid treatment is thought to induce CSC.[5] Sometimes, even after examining FA and IA results, it is very difficult to determine whether SRD and/or PED are caused by the uncontrolled inflammation of posterior uveitis or are the side effects of steroid treatment for posterior uveitis. As we showed here, for a case with hyperreflective protrusions in SRD, it is particularly important to evaluate precisely the existence of CNV, a vision-threatening disease. For the last few decades, CNV has been diagnosed only by FA and ICGA. However, Fujita et al recently showed that the accuracy and the diagnosis rate of PCV by IA is not significantly different from those of blood flow examination by B-scan OCTA.[6] Especially for patients with renal dysfunction, multiple examinations with systemic infusion of dyes is not preferable. In the present case, both FA/ICGA and OCTA were performed, and OCTA confirmed the absence of an internal blood flow signal in the protruded lesion, which led us to exclude the possibility of CNV.
Diagnosis of CNV secondary to posterior uveitis or CSC caused by steroid treatment for posterior uveitis is critical because misjudgment might cause exacerbation of the disease. The existence or absence of a blood flow signal, as measured by B-scan OCTA, is very informative and useful for confirming the diagnosis of ocular inflammatory diseases.
4 Ethical statement
Written informed consent was obtained from the patient. Ethical approval was obtained from the Ethics Committee of the Nagoya University Hospital, Nagoya, Japan, in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.
Acknowledgment
The authors thank Editage (www.editage.com) for English language editing.
Author contributions
Conceptualization: Noriko Takashi, Aya Nakamura.
Resources: Noriko Takashi, Aya Nakamura.
Supervision: Yoshihiko Usui, Keiko Kataoka, Yasuki Ito.
Writing – original draft: Aya Nakamura, Hiroki Kaneko.
Writing – review & editing: Hiroki Kaneko.
Abbreviations: CNV = Choroidal neovascularization, CSC = Central serous chorioretinopathy, FA = Fluorescein angiography, GPA = Granulomatosis with polyangiitis, ICGA = Indocyanine green angiography, OCT = Optical coherence tomography, OCTA = Optical coherence tomography angiography, PED = Pigment epithelial detachment, SRD = Serous retinal detachment.
How to cite this article: Takashi N, Nakamura A, Kataoka K, Usui Y, Ito Y, Kaneko H. Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: a case report. Medicine. 2021;100:7(e24789).
This work was partially supported by Grants-in-Aid for Scientific Research (C) (H.K., 19K09988) from JSPS KAKENHI (http://www.jsps.go.jp/), the Eye Research Foundation for the Aged (ERFA, H.K.), the Charitable Trust Fund for Ophthalmic Research in Commemoration of Santen Pharmaceutical's Founder (H.K.), and the Bayer Retina Award Foundation (H.K.).
The swept-source optical coherence tomography (B-scan Doppler OCTA) device used in this manuscript was loaned by Carl Zeiss Meditec.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | Recovering | ReactionOutcome | CC BY | 33607834 | 19,040,654 | 2021-02-19 |
What was the outcome of reaction 'Serous retinal detachment'? | Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: A case report.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease of unknown etiology. GPA affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera. Retinal and choroidal manifestations are rare in GPA, but they often include choroidal neovascularization (CNV).
A 36-year-old man was diagnosed with GPA. He had been taking oral steroid treatment for 8 years. He experienced disease recurrence and the dose of oral prednisolone was increased after steroid pulse therapy. Fundus examination showed small retinal pigment epithelial detachment and serous retinal detachment (SRD). Optical coherence tomography (OCT) revealed a protruded lesion inside the SRD. Fluorescein angiography (FA) showed a small, dot-shaped fluorescein leakage in the SRD, and indocyanine green fluorescein fundus angiography showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. We had to determine whether the protruded lesion inside the SRD was CNV secondary to the inflammation due to GPA or whether it was central serous chorioretinopathy (CSC)-like condition caused by high-dose steroid treatment.
We confirmed that the SRD was due to CSC but not CNV because the protruded lesion examined by B-scan OCT angiography (OCTA) showed no blood flow.
METHODS
We decided to reduce the dose of steroid.
RESULTS
Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed.
CONCLUSIONS
We therefore propose the effectiveness of this advanced function of OCTA for the examination of blood flow signal images to detect CNV.
pmc1 Introduction
Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is a rare systemic autoimmune disease with an unknown etiology. The prevalence of GPA is estimated to be 3 per 100,000, and the annual incidence is approximately 8 to 10 per 1 million, but it varies depending on a person's ethnicity and geographic location.[1] GPA presents with a wide range of clinical manifestations of varying severity. GPA also affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera.[2] Retinal and choroidal manifestations are rare in GPA, but they are recognized as inflammation-based changes, such as retinitis, chorioretinitis, macular edema, exudative retinal detachment, and retinal necrosis. Choroidal inflammation due to GPA can also induce choroidal neovascularization (CNV).[3] Here, we report a case of retinal and choroidal manifestation in a patient with GPA and propose the effectiveness of examination with the advanced B-scan image function of optical coherence tomography angiography (OCTA) to detect blood flow signals.
2 Case report
A 36-year-old man was diagnosed with GPA in 2011. He has been followed up by private practice physicians and his clinical condition was well-controlled with oral prednisolone (0.075 mg/kg) and mizoribine (100 mg) for 8 years. In early 2019, he was referred to our hospital because he experienced disease recurrence with symptoms of arthritis and rapid deterioration of renal function. In addition, he underwent partial small bowel resection for small bowel bleeding. His renal function did not improve, and he was placed on maintenance dialysis. He was given 0.15 mg/kg oral prednisolone after steroid pulse therapy (1,000 mg/d for 3 days). In July 2019, he was referred to the ophthalmology department for the evaluation of GPA and steroid-induced ocular complications. His visual acuity was 20/20 in both eyes (OU). Intraocular pressures were 18 mm Hg in the right eye (OD) and 15 mm Hg in the left eye (OS). Results of slit lamp examination of the anterior segment were unremarkable. Fundus examination and optical coherence tomography (OCT) revealed a small retinal pigment epithelial detachment (PED) in the major temporal arcade in the OD and a small PED and serous retinal detachment (SRD) superior to the optic nerve head in the OS. The patient had previously discontinued visiting the ophthalmology department after 2011 because he had not had any subjective ocular symptoms. However, in January 2019, he presented to the ophthalmology department again with subjective symptoms of vision deterioration. His visual acuity was 20/20 in the OD and 20/25 in the OS. IOPs were 14 mm Hg in the OU. Results of a fundus examination showed multiple small circular SRDs in the major temporal arcade in OU. OCT detected hyperreflective protrusion that had hyporeflective bubble-like structure inside hyperreflective materials in the SRD. In addition, the choroid under the hyperreflective protrusions contained pachyvessel and low serous PED. Fluorescein angiography (FA) showed small, dot-shaped hyperfluorescent leakage from the SRDs. Indocyanine green angiography (ICGA) showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. To determine the appropriate treatment, it was necessary to determine whether the protruded lesions contained choroidal neovascularization (CNV) secondary to the inflammation due to GPA. Alternatively, the protruded lesions could have been fibrin accumulations and the SRDs could have been caused by central serous chorioretinopathy (CSC), which in turn was probably caused by the high-dose steroid treatment. We employed B-scan OCT angiography (OCTA) to detect blood flow. We identified that the protruded lesions had no blood flow inside of them, confirming that the diagnosed SRDs were CSC but not CNV. We decided to reduce the dose of steroid (Fig. 1). Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed for 1.5 years.
Figure 1 Images from a patient with granulomatosis with polyangiitis. (a,b) Color fundus images. Multiple yellow-white lesions in both eyes are noted. (a: right, b: left) (c, d): FA (c) and ICGA (d) images from the right eye. Hyperfluorescent leakages consistent with the yellow-white lesions are noted. (e, f) FA (e) and ICGA (f) images from the left eye. Hyperfluorescent leakages consistent with the yellow-white lesions are noted. (g) OCT image from a yellow-white lesion in the left eye (white line in [b]). hyperreflective protrusion in the serous retinal detachment is noted. (h) B-scan OCT angiography from the same protruded lesion as that in (g). Note that there is no blood flow signal (colored in red) inside the protruded lesion, indicating that it is not an active choroidal neovascularization. FA = fluorescein angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = OCT-angiography.
3 Discussion
Retinal and choroidal manifestations have been reported in GPA; however, their prevalence is not higher than that of other ocular manifestations. Retinal and choroidal manifestations in GPA include SRD and CNV, and they are mainly caused by severe inflammation from GPA. For CNV associated with posterior uveitis, immunosuppressive treatment with steroid is reportedly effective.[4] Nevertheless, steroid treatment is thought to induce CSC.[5] Sometimes, even after examining FA and IA results, it is very difficult to determine whether SRD and/or PED are caused by the uncontrolled inflammation of posterior uveitis or are the side effects of steroid treatment for posterior uveitis. As we showed here, for a case with hyperreflective protrusions in SRD, it is particularly important to evaluate precisely the existence of CNV, a vision-threatening disease. For the last few decades, CNV has been diagnosed only by FA and ICGA. However, Fujita et al recently showed that the accuracy and the diagnosis rate of PCV by IA is not significantly different from those of blood flow examination by B-scan OCTA.[6] Especially for patients with renal dysfunction, multiple examinations with systemic infusion of dyes is not preferable. In the present case, both FA/ICGA and OCTA were performed, and OCTA confirmed the absence of an internal blood flow signal in the protruded lesion, which led us to exclude the possibility of CNV.
Diagnosis of CNV secondary to posterior uveitis or CSC caused by steroid treatment for posterior uveitis is critical because misjudgment might cause exacerbation of the disease. The existence or absence of a blood flow signal, as measured by B-scan OCTA, is very informative and useful for confirming the diagnosis of ocular inflammatory diseases.
4 Ethical statement
Written informed consent was obtained from the patient. Ethical approval was obtained from the Ethics Committee of the Nagoya University Hospital, Nagoya, Japan, in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.
Acknowledgment
The authors thank Editage (www.editage.com) for English language editing.
Author contributions
Conceptualization: Noriko Takashi, Aya Nakamura.
Resources: Noriko Takashi, Aya Nakamura.
Supervision: Yoshihiko Usui, Keiko Kataoka, Yasuki Ito.
Writing – original draft: Aya Nakamura, Hiroki Kaneko.
Writing – review & editing: Hiroki Kaneko.
Abbreviations: CNV = Choroidal neovascularization, CSC = Central serous chorioretinopathy, FA = Fluorescein angiography, GPA = Granulomatosis with polyangiitis, ICGA = Indocyanine green angiography, OCT = Optical coherence tomography, OCTA = Optical coherence tomography angiography, PED = Pigment epithelial detachment, SRD = Serous retinal detachment.
How to cite this article: Takashi N, Nakamura A, Kataoka K, Usui Y, Ito Y, Kaneko H. Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: a case report. Medicine. 2021;100:7(e24789).
This work was partially supported by Grants-in-Aid for Scientific Research (C) (H.K., 19K09988) from JSPS KAKENHI (http://www.jsps.go.jp/), the Eye Research Foundation for the Aged (ERFA, H.K.), the Charitable Trust Fund for Ophthalmic Research in Commemoration of Santen Pharmaceutical's Founder (H.K.), and the Bayer Retina Award Foundation (H.K.).
The swept-source optical coherence tomography (B-scan Doppler OCTA) device used in this manuscript was loaned by Carl Zeiss Meditec.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | Recovering | ReactionOutcome | CC BY | 33607834 | 19,040,654 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Choroidal neovascularisation'. | Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: A case report.
BACKGROUND
Half-dose or reduced-fluence photodynamic therapy (PDT) with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications. However, we report a case of chronic central serous chorioretinopathy (CSC) who developed choroidal neovascularization (CNV) secondary to half-dose PDT within only 3 weeks. Such an occurrence following this short a course of treatment has not been reported previously.
A 46-year-old Chinese man who had been diagnosed as acute more than 1 year ago revisited our department recently and complained of blurred vision again in his left eye.
Fluorescein fundus angiography (FFA) and indocyanine green angiography (ICGA) revealed patchy hyperfluorescent dots and optical coherence tomography (OCT) indicated irregular flat pigment epithelium detachment (PED) in the central macula. The patient was diagnosed with chronic CSC.
METHODS
The patient was treated by half-dose PDT with verteporfin. Three weeks later, the patient complained of sudden blurred vision and fundus examination showed macular hemorrhages with a best-corrected visual acuity (BCVA) of 20/250. OCT angiography (OCTA) showed a distinct area of flower-like CNV located within the deep retinal slab. Secondary CNV had developed after a quite short course of half-dose PDT treatment. Subsequently, the patient was administered by 2 intravitreal injections of aflibercept (2 mg).
RESULTS
Two months after the second intravitreal injection, macular hemorrhages and secondary CNV were completely resolved, and the BCVA improved to 20/25.
CONCLUSIONS
Patients of chronic CSC with irregular PED who undergo PDT should be warned of secondary CNV within a short course after treatment. If happened, it should be treated by intravitreal injections of anti-vascular endothelial growth factor agents as soon as possible.
pmc1 Introduction
Central serous chorioretinopathy (CSC) is a common vision-threatening chorioretinal disease that causes idiopathic serous detachment of the retina, which primarily affects males aged 20 to 60 years.[1] Pathogenesis of CSC is incompletely understood due to its multifactorial etiology and wide systemic associations. However, choroidal hyper-perfusion and hyperpermeability are known to play a major role.[2] Photodynamic therapy (PDT) induces choroidal vascular remodeling and decreases choroidal permeability, and is advocated for the treatment of CSC.[3]
A widely reported complication of standard PDT is secondary choroidal neovascularization (CNV).[4] Its mechanism is attributed to the pro-inflammatory effect, choriocapillaris occlusion, and significant reduction in chorioretinal perfusion caused by PDT. Subsequently, half-dose or reduced-fluence PDT with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications.[5,6] Despite this, some rare but severe complications are inevitable.
Recently, a study reported high rates of CNV, detected using optical coherence tomography angiography (OCTA), associated with chronic CSC after half-dose PDT with a mean period of 39.5 months. [7] However, development of CNV, secondary to half-dose PDT for chronic CSC after a short course of treatment, is rare. Here, we report a patient of chronic CSC with serous pigment epithelium detachment (PED) whose visual acuity decreased abruptly due to CNV and macular hemorrhage, following a half-dose PDT, within 3 weeks of the intervention. Fortunately, this case was treated successfully with 2 intravitreal injections of aflibercept (2 mg).
2 Case presentation
More than 1 year ago, a 46-year-old Chinese man presented to our department with blurred vision in his left eye. At the time, he was diagnosed with acute central serous chorioretinopathy. Oral medications were prescribed; however, he was lost to follow-up. He had excellent uncorrected distance acuity (20/20 in both eyes). Records of optical coherence tomography (OCT) B-scan showed neurosensory detachment at the central macula.
He revisited our department recently and complained of blurred vision again since 1 month. At this visit, he underwent a complete ophthalmic examination, including slitlamp biomicroscopy, best-corrected visual acuity (BCVA), non-contact tonometry, detailed fundus examination, fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA), OCT, and OCTA.
The BCVA was 20/20 OD and 20/25 OS. Intraocular pressure was within normal limits, and anterior segment examination was unremarkable in both eyes. Fundus examination of the right eye was normal, but the left eye showed a shallow sensory detachment in the macula (Fig. 1A). On FFA, the lesion revealed patchy hyperfluorescent dots temporal to the fovea in the early and late phases (Fig. 1B). ICGA also revealed patchy hyperfluorescent dots in the middle and late phases (Fig. 1C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at the first visit (Fig. 1D) and subsequent visit (Fig. 1E). OCTA, reported to be useful for identifying hidden CNVs that could not be found via FA and ICGA, did not show a distinct CNV (Fig. 1F).
Figure 1 Multimodal imaging before treatment Fundus photograph showing a shallow sensory detachment in the macula (yellow arrows) in the left eye (A). The lesion revealed patchy hyperfluorescent dots temporal to the fovea in the late phase of FFA (B) and ICGA (C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at both the initial visit (D) and this visit (E). OCTA did not detect a distinct CNV (F).
The patient was diagnosed with chronic CSC. Treatment employed was half-dose PDT with verteporfin. Fifteen minutes after the start of the intravenous infusion of verteporfin (3 mg/m2), a 689 nm laser was delivered (600 mW/cm2; 83 s). The delivered radiation covered the hyperfluorescent area of the corresponding serous subfoveal PED in the middle or late phase of the ICGA. Three weeks later, the patient complained of sudden blurred vision and revisited our department. Fundus examination showed macular hemorrhages (Fig. 2A) with a BCVA of 20/250. OCTA showed a distinct area of flower-like CNV located within the deep retinal slab (Fig. 2B). OCT B-scan revealed subretinal hyperreflective material corresponding to the CNV complex located above the retinal pigment epithelium (RPE) (Fig. 2C). Unfortunately, secondary CNV had developed after half-dose PDT in this case.
Figure 2 Multimodal imaging after half-dose PDT Fundus photograph showing macular hemorrhages approximately 3 weeks after treatment (A). OCTA showing a distinct area of flower-like CNV located within the deep retinal slab (B). OCT B-scan displaying subretinal hyperreflective material corresponding to the CNV complex located above the RPE (C). Three months after two intravitreal injections of aflibercept (2 mg), macular hemorrhages were completely resolved in the fundus (D) and the CNV did not recur in the OCTA image (E), but a small PED was still present on the OCT B-scan (F).
Next day, intravitreal injection of aflibercept (2 mg) was administered. One month later, the patient's symptoms were relieved and his BCVA improved to 20/100. Fundus examination revealed almost complete resolution of macular hemorrhages. OCTA showed the CNV had completely disappeared. To consolidate treatment, a second intravitreal injection of aflibercept (2 mg) was administered. Two months later, the BCVA improved to 20/25. Macular hemorrhages were completely resolved in the fundus (Fig. 2D) The CNV did not recur in the OCTA image (Fig. 2E), but a small PED was present on the OCT B-scan (Fig. 2F).
3 Discussion
Although PDT with verteporfin was originally developed for treating CNV secondary to age-related macular degeneration, it was soon used as an important treatment modality for chronic CSC.[6,8] Full-dose PDT with verteporfin (6 mg/m2 intravenously) used in CSC may sometimes, cause severe complications that are unacceptable for a disease with relatively favorable prognosis. Verteporfin dye might accumulate selectively around the choroidal hyper-permeable area owing to slow blood flow and vascular congestion, which may lead to irreversible occlusion of the choroidal vessels.[9] Additionally, PDT may cause RPE alterations and induce the release of vascular endothelial growth factor (VEGF), contributing to the development of CNV.[10]
Many studies have recommended half-dose or reduced-fluence PDT for treating CSC. [5] More recently, Wu et al[7] reported high rates of CNV associated with chronic CSC after half-dose PDT with a mean period of 39.5 months (range: 4–138 months) from treatment to OCTA examination. However, the development of CNV secondary to half-dose PDT within 1 month of treatment is rare. Hwang et al[11] reported 1 such case of chronic CSC developed secondary CNV and subretinal hemorrhages 1 month after reduced-fluence PDT (30 mJ/cm2). In their case, the PED was small and dome-shaped under the fovea before treatment. Fortunately, their patient recovered his vision after 2 intravitreal bevacizumab injections.
In our case, we employed half-dose PDT (3 mg/m2), reported to result in favorable outcomes with less risk of complications.[5] Unfortunately, secondary CNV developed 3 weeks post-treatment. To the best of our knowledge, such an occurrence following this short a course of treatment has not been reported previously. Although the pathophysiology of CSC is poorly understood, it is reasonable to apply optimized PDT at the area of choroidal congestion and RPE leakage, thus preventing the disease from developing. Choriocapillary thinning secondary to the underlying choroidal congestion, long-standing serous PED, and pre-existing defects in Bruch's membrane due to chronic RPE changes, may be a risk factor for the development of CNV. Demircan et al[12] reported that choriocapillaris perfusion seemed to decrease in the very early period following half-fluence PDT and returned to normal after 1 month of therapy. Therefore, half-dose PDT may further exacerbate the already compromised choriocapillaries and increase the incidence of CNV. Undoubtedly, the risk does not outweigh the benefits of optimized PDT for the treatment of CSC. However, patients undergoing PDT with relatively good vision should be warned of this rare complication.
Another rare complication secondary to PDT, which needs to be distinguished from secondary CNV, is PDT-induced acute exudative maculopathy (PAEM).[13] PAEM is defined as a massive subretinal serofibrinous exudation with or without acute severe vision impairment.[14] It occurs within days after PDT but has a self-resolving course and favorable prognosis. PAEM is rarely reported after treatment of chronic CSC, with only 3 cases reported in the literature. The pathogenesis includes breakdown of the blood-retinal barrier, RPE pump dysfunction, and inflammatory surge of VEGF occurring after PDT. OCTA is a useful tool to distinguish PAEM from CNV.
To summarize, CNV secondary to half-dose PDT for chronic CSC after a quite short course of treatment is rare. Considering an otherwise favorable prognosis for CSC treatment, patients with chronic CSC who undergo PDT should be warned of this rare complication. Fortunately, it can be successfully treated by intravitreal injection of anti-VEGF agents.
4 Disclosure
The Institutional Review Board of the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University approved the protocol, and our study was performed in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and all accompanying images. There is no conflict of interest exists in the submission of this manuscript, and manuscript is approved by all authors for publication.
Author contributions
ZWZ, XNB and JZ collected the clinical information of the patient, analyzed and interpreted the clinical data. ZWZ wrote the drafting of this manuscript. ZFW and JZ reviewed and edited the manuscript. JZ was responsible for supervision. All authors read and approved the final manuscript.
Conceptualization: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Funding acquisition: Zhengwei Zhang.
Supervision: Jie Zhang.
Validation: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Writing – original draft: Zhengwei Zhang.
Writing – review & editing: Zhifeng Wu, Jie Zhang.
Abbreviations: BCVA = best-corrected visual acuity, CNV = choroidal neovascularization, CSC = central serous chorioretinopathy, FFA = fluorescein fundus angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = optical coherence tomography angiography, PAEM = PDT-induced acute exudative maculopathy, PDT = photodynamic therapy, PED = pigment epithelium detachment, RPE = retinal pigment epithelium, VEGF = vascular endothelial growth factor.
How to cite this article: Zhang Z, Bao X, Wu Z, Zhang J. Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: a case report. Medicine. 2021;100:7(e24790).
This study was supported by the fund of Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (Grant No. HB2020030) and the Development Fund of Wuxi Science and Technology (Grant No. WX18IIAN019).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | VERTEPORFIN | DrugsGivenReaction | CC BY | 33607835 | 18,984,537 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Detachment of retinal pigment epithelium'. | Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: A case report.
BACKGROUND
Half-dose or reduced-fluence photodynamic therapy (PDT) with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications. However, we report a case of chronic central serous chorioretinopathy (CSC) who developed choroidal neovascularization (CNV) secondary to half-dose PDT within only 3 weeks. Such an occurrence following this short a course of treatment has not been reported previously.
A 46-year-old Chinese man who had been diagnosed as acute more than 1 year ago revisited our department recently and complained of blurred vision again in his left eye.
Fluorescein fundus angiography (FFA) and indocyanine green angiography (ICGA) revealed patchy hyperfluorescent dots and optical coherence tomography (OCT) indicated irregular flat pigment epithelium detachment (PED) in the central macula. The patient was diagnosed with chronic CSC.
METHODS
The patient was treated by half-dose PDT with verteporfin. Three weeks later, the patient complained of sudden blurred vision and fundus examination showed macular hemorrhages with a best-corrected visual acuity (BCVA) of 20/250. OCT angiography (OCTA) showed a distinct area of flower-like CNV located within the deep retinal slab. Secondary CNV had developed after a quite short course of half-dose PDT treatment. Subsequently, the patient was administered by 2 intravitreal injections of aflibercept (2 mg).
RESULTS
Two months after the second intravitreal injection, macular hemorrhages and secondary CNV were completely resolved, and the BCVA improved to 20/25.
CONCLUSIONS
Patients of chronic CSC with irregular PED who undergo PDT should be warned of secondary CNV within a short course after treatment. If happened, it should be treated by intravitreal injections of anti-vascular endothelial growth factor agents as soon as possible.
pmc1 Introduction
Central serous chorioretinopathy (CSC) is a common vision-threatening chorioretinal disease that causes idiopathic serous detachment of the retina, which primarily affects males aged 20 to 60 years.[1] Pathogenesis of CSC is incompletely understood due to its multifactorial etiology and wide systemic associations. However, choroidal hyper-perfusion and hyperpermeability are known to play a major role.[2] Photodynamic therapy (PDT) induces choroidal vascular remodeling and decreases choroidal permeability, and is advocated for the treatment of CSC.[3]
A widely reported complication of standard PDT is secondary choroidal neovascularization (CNV).[4] Its mechanism is attributed to the pro-inflammatory effect, choriocapillaris occlusion, and significant reduction in chorioretinal perfusion caused by PDT. Subsequently, half-dose or reduced-fluence PDT with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications.[5,6] Despite this, some rare but severe complications are inevitable.
Recently, a study reported high rates of CNV, detected using optical coherence tomography angiography (OCTA), associated with chronic CSC after half-dose PDT with a mean period of 39.5 months. [7] However, development of CNV, secondary to half-dose PDT for chronic CSC after a short course of treatment, is rare. Here, we report a patient of chronic CSC with serous pigment epithelium detachment (PED) whose visual acuity decreased abruptly due to CNV and macular hemorrhage, following a half-dose PDT, within 3 weeks of the intervention. Fortunately, this case was treated successfully with 2 intravitreal injections of aflibercept (2 mg).
2 Case presentation
More than 1 year ago, a 46-year-old Chinese man presented to our department with blurred vision in his left eye. At the time, he was diagnosed with acute central serous chorioretinopathy. Oral medications were prescribed; however, he was lost to follow-up. He had excellent uncorrected distance acuity (20/20 in both eyes). Records of optical coherence tomography (OCT) B-scan showed neurosensory detachment at the central macula.
He revisited our department recently and complained of blurred vision again since 1 month. At this visit, he underwent a complete ophthalmic examination, including slitlamp biomicroscopy, best-corrected visual acuity (BCVA), non-contact tonometry, detailed fundus examination, fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA), OCT, and OCTA.
The BCVA was 20/20 OD and 20/25 OS. Intraocular pressure was within normal limits, and anterior segment examination was unremarkable in both eyes. Fundus examination of the right eye was normal, but the left eye showed a shallow sensory detachment in the macula (Fig. 1A). On FFA, the lesion revealed patchy hyperfluorescent dots temporal to the fovea in the early and late phases (Fig. 1B). ICGA also revealed patchy hyperfluorescent dots in the middle and late phases (Fig. 1C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at the first visit (Fig. 1D) and subsequent visit (Fig. 1E). OCTA, reported to be useful for identifying hidden CNVs that could not be found via FA and ICGA, did not show a distinct CNV (Fig. 1F).
Figure 1 Multimodal imaging before treatment Fundus photograph showing a shallow sensory detachment in the macula (yellow arrows) in the left eye (A). The lesion revealed patchy hyperfluorescent dots temporal to the fovea in the late phase of FFA (B) and ICGA (C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at both the initial visit (D) and this visit (E). OCTA did not detect a distinct CNV (F).
The patient was diagnosed with chronic CSC. Treatment employed was half-dose PDT with verteporfin. Fifteen minutes after the start of the intravenous infusion of verteporfin (3 mg/m2), a 689 nm laser was delivered (600 mW/cm2; 83 s). The delivered radiation covered the hyperfluorescent area of the corresponding serous subfoveal PED in the middle or late phase of the ICGA. Three weeks later, the patient complained of sudden blurred vision and revisited our department. Fundus examination showed macular hemorrhages (Fig. 2A) with a BCVA of 20/250. OCTA showed a distinct area of flower-like CNV located within the deep retinal slab (Fig. 2B). OCT B-scan revealed subretinal hyperreflective material corresponding to the CNV complex located above the retinal pigment epithelium (RPE) (Fig. 2C). Unfortunately, secondary CNV had developed after half-dose PDT in this case.
Figure 2 Multimodal imaging after half-dose PDT Fundus photograph showing macular hemorrhages approximately 3 weeks after treatment (A). OCTA showing a distinct area of flower-like CNV located within the deep retinal slab (B). OCT B-scan displaying subretinal hyperreflective material corresponding to the CNV complex located above the RPE (C). Three months after two intravitreal injections of aflibercept (2 mg), macular hemorrhages were completely resolved in the fundus (D) and the CNV did not recur in the OCTA image (E), but a small PED was still present on the OCT B-scan (F).
Next day, intravitreal injection of aflibercept (2 mg) was administered. One month later, the patient's symptoms were relieved and his BCVA improved to 20/100. Fundus examination revealed almost complete resolution of macular hemorrhages. OCTA showed the CNV had completely disappeared. To consolidate treatment, a second intravitreal injection of aflibercept (2 mg) was administered. Two months later, the BCVA improved to 20/25. Macular hemorrhages were completely resolved in the fundus (Fig. 2D) The CNV did not recur in the OCTA image (Fig. 2E), but a small PED was present on the OCT B-scan (Fig. 2F).
3 Discussion
Although PDT with verteporfin was originally developed for treating CNV secondary to age-related macular degeneration, it was soon used as an important treatment modality for chronic CSC.[6,8] Full-dose PDT with verteporfin (6 mg/m2 intravenously) used in CSC may sometimes, cause severe complications that are unacceptable for a disease with relatively favorable prognosis. Verteporfin dye might accumulate selectively around the choroidal hyper-permeable area owing to slow blood flow and vascular congestion, which may lead to irreversible occlusion of the choroidal vessels.[9] Additionally, PDT may cause RPE alterations and induce the release of vascular endothelial growth factor (VEGF), contributing to the development of CNV.[10]
Many studies have recommended half-dose or reduced-fluence PDT for treating CSC. [5] More recently, Wu et al[7] reported high rates of CNV associated with chronic CSC after half-dose PDT with a mean period of 39.5 months (range: 4–138 months) from treatment to OCTA examination. However, the development of CNV secondary to half-dose PDT within 1 month of treatment is rare. Hwang et al[11] reported 1 such case of chronic CSC developed secondary CNV and subretinal hemorrhages 1 month after reduced-fluence PDT (30 mJ/cm2). In their case, the PED was small and dome-shaped under the fovea before treatment. Fortunately, their patient recovered his vision after 2 intravitreal bevacizumab injections.
In our case, we employed half-dose PDT (3 mg/m2), reported to result in favorable outcomes with less risk of complications.[5] Unfortunately, secondary CNV developed 3 weeks post-treatment. To the best of our knowledge, such an occurrence following this short a course of treatment has not been reported previously. Although the pathophysiology of CSC is poorly understood, it is reasonable to apply optimized PDT at the area of choroidal congestion and RPE leakage, thus preventing the disease from developing. Choriocapillary thinning secondary to the underlying choroidal congestion, long-standing serous PED, and pre-existing defects in Bruch's membrane due to chronic RPE changes, may be a risk factor for the development of CNV. Demircan et al[12] reported that choriocapillaris perfusion seemed to decrease in the very early period following half-fluence PDT and returned to normal after 1 month of therapy. Therefore, half-dose PDT may further exacerbate the already compromised choriocapillaries and increase the incidence of CNV. Undoubtedly, the risk does not outweigh the benefits of optimized PDT for the treatment of CSC. However, patients undergoing PDT with relatively good vision should be warned of this rare complication.
Another rare complication secondary to PDT, which needs to be distinguished from secondary CNV, is PDT-induced acute exudative maculopathy (PAEM).[13] PAEM is defined as a massive subretinal serofibrinous exudation with or without acute severe vision impairment.[14] It occurs within days after PDT but has a self-resolving course and favorable prognosis. PAEM is rarely reported after treatment of chronic CSC, with only 3 cases reported in the literature. The pathogenesis includes breakdown of the blood-retinal barrier, RPE pump dysfunction, and inflammatory surge of VEGF occurring after PDT. OCTA is a useful tool to distinguish PAEM from CNV.
To summarize, CNV secondary to half-dose PDT for chronic CSC after a quite short course of treatment is rare. Considering an otherwise favorable prognosis for CSC treatment, patients with chronic CSC who undergo PDT should be warned of this rare complication. Fortunately, it can be successfully treated by intravitreal injection of anti-VEGF agents.
4 Disclosure
The Institutional Review Board of the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University approved the protocol, and our study was performed in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and all accompanying images. There is no conflict of interest exists in the submission of this manuscript, and manuscript is approved by all authors for publication.
Author contributions
ZWZ, XNB and JZ collected the clinical information of the patient, analyzed and interpreted the clinical data. ZWZ wrote the drafting of this manuscript. ZFW and JZ reviewed and edited the manuscript. JZ was responsible for supervision. All authors read and approved the final manuscript.
Conceptualization: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Funding acquisition: Zhengwei Zhang.
Supervision: Jie Zhang.
Validation: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Writing – original draft: Zhengwei Zhang.
Writing – review & editing: Zhifeng Wu, Jie Zhang.
Abbreviations: BCVA = best-corrected visual acuity, CNV = choroidal neovascularization, CSC = central serous chorioretinopathy, FFA = fluorescein fundus angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = optical coherence tomography angiography, PAEM = PDT-induced acute exudative maculopathy, PDT = photodynamic therapy, PED = pigment epithelium detachment, RPE = retinal pigment epithelium, VEGF = vascular endothelial growth factor.
How to cite this article: Zhang Z, Bao X, Wu Z, Zhang J. Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: a case report. Medicine. 2021;100:7(e24790).
This study was supported by the fund of Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (Grant No. HB2020030) and the Development Fund of Wuxi Science and Technology (Grant No. WX18IIAN019).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | VERTEPORFIN | DrugsGivenReaction | CC BY | 33607835 | 18,984,537 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: A case report.
BACKGROUND
Half-dose or reduced-fluence photodynamic therapy (PDT) with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications. However, we report a case of chronic central serous chorioretinopathy (CSC) who developed choroidal neovascularization (CNV) secondary to half-dose PDT within only 3 weeks. Such an occurrence following this short a course of treatment has not been reported previously.
A 46-year-old Chinese man who had been diagnosed as acute more than 1 year ago revisited our department recently and complained of blurred vision again in his left eye.
Fluorescein fundus angiography (FFA) and indocyanine green angiography (ICGA) revealed patchy hyperfluorescent dots and optical coherence tomography (OCT) indicated irregular flat pigment epithelium detachment (PED) in the central macula. The patient was diagnosed with chronic CSC.
METHODS
The patient was treated by half-dose PDT with verteporfin. Three weeks later, the patient complained of sudden blurred vision and fundus examination showed macular hemorrhages with a best-corrected visual acuity (BCVA) of 20/250. OCT angiography (OCTA) showed a distinct area of flower-like CNV located within the deep retinal slab. Secondary CNV had developed after a quite short course of half-dose PDT treatment. Subsequently, the patient was administered by 2 intravitreal injections of aflibercept (2 mg).
RESULTS
Two months after the second intravitreal injection, macular hemorrhages and secondary CNV were completely resolved, and the BCVA improved to 20/25.
CONCLUSIONS
Patients of chronic CSC with irregular PED who undergo PDT should be warned of secondary CNV within a short course after treatment. If happened, it should be treated by intravitreal injections of anti-vascular endothelial growth factor agents as soon as possible.
pmc1 Introduction
Central serous chorioretinopathy (CSC) is a common vision-threatening chorioretinal disease that causes idiopathic serous detachment of the retina, which primarily affects males aged 20 to 60 years.[1] Pathogenesis of CSC is incompletely understood due to its multifactorial etiology and wide systemic associations. However, choroidal hyper-perfusion and hyperpermeability are known to play a major role.[2] Photodynamic therapy (PDT) induces choroidal vascular remodeling and decreases choroidal permeability, and is advocated for the treatment of CSC.[3]
A widely reported complication of standard PDT is secondary choroidal neovascularization (CNV).[4] Its mechanism is attributed to the pro-inflammatory effect, choriocapillaris occlusion, and significant reduction in chorioretinal perfusion caused by PDT. Subsequently, half-dose or reduced-fluence PDT with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications.[5,6] Despite this, some rare but severe complications are inevitable.
Recently, a study reported high rates of CNV, detected using optical coherence tomography angiography (OCTA), associated with chronic CSC after half-dose PDT with a mean period of 39.5 months. [7] However, development of CNV, secondary to half-dose PDT for chronic CSC after a short course of treatment, is rare. Here, we report a patient of chronic CSC with serous pigment epithelium detachment (PED) whose visual acuity decreased abruptly due to CNV and macular hemorrhage, following a half-dose PDT, within 3 weeks of the intervention. Fortunately, this case was treated successfully with 2 intravitreal injections of aflibercept (2 mg).
2 Case presentation
More than 1 year ago, a 46-year-old Chinese man presented to our department with blurred vision in his left eye. At the time, he was diagnosed with acute central serous chorioretinopathy. Oral medications were prescribed; however, he was lost to follow-up. He had excellent uncorrected distance acuity (20/20 in both eyes). Records of optical coherence tomography (OCT) B-scan showed neurosensory detachment at the central macula.
He revisited our department recently and complained of blurred vision again since 1 month. At this visit, he underwent a complete ophthalmic examination, including slitlamp biomicroscopy, best-corrected visual acuity (BCVA), non-contact tonometry, detailed fundus examination, fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA), OCT, and OCTA.
The BCVA was 20/20 OD and 20/25 OS. Intraocular pressure was within normal limits, and anterior segment examination was unremarkable in both eyes. Fundus examination of the right eye was normal, but the left eye showed a shallow sensory detachment in the macula (Fig. 1A). On FFA, the lesion revealed patchy hyperfluorescent dots temporal to the fovea in the early and late phases (Fig. 1B). ICGA also revealed patchy hyperfluorescent dots in the middle and late phases (Fig. 1C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at the first visit (Fig. 1D) and subsequent visit (Fig. 1E). OCTA, reported to be useful for identifying hidden CNVs that could not be found via FA and ICGA, did not show a distinct CNV (Fig. 1F).
Figure 1 Multimodal imaging before treatment Fundus photograph showing a shallow sensory detachment in the macula (yellow arrows) in the left eye (A). The lesion revealed patchy hyperfluorescent dots temporal to the fovea in the late phase of FFA (B) and ICGA (C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at both the initial visit (D) and this visit (E). OCTA did not detect a distinct CNV (F).
The patient was diagnosed with chronic CSC. Treatment employed was half-dose PDT with verteporfin. Fifteen minutes after the start of the intravenous infusion of verteporfin (3 mg/m2), a 689 nm laser was delivered (600 mW/cm2; 83 s). The delivered radiation covered the hyperfluorescent area of the corresponding serous subfoveal PED in the middle or late phase of the ICGA. Three weeks later, the patient complained of sudden blurred vision and revisited our department. Fundus examination showed macular hemorrhages (Fig. 2A) with a BCVA of 20/250. OCTA showed a distinct area of flower-like CNV located within the deep retinal slab (Fig. 2B). OCT B-scan revealed subretinal hyperreflective material corresponding to the CNV complex located above the retinal pigment epithelium (RPE) (Fig. 2C). Unfortunately, secondary CNV had developed after half-dose PDT in this case.
Figure 2 Multimodal imaging after half-dose PDT Fundus photograph showing macular hemorrhages approximately 3 weeks after treatment (A). OCTA showing a distinct area of flower-like CNV located within the deep retinal slab (B). OCT B-scan displaying subretinal hyperreflective material corresponding to the CNV complex located above the RPE (C). Three months after two intravitreal injections of aflibercept (2 mg), macular hemorrhages were completely resolved in the fundus (D) and the CNV did not recur in the OCTA image (E), but a small PED was still present on the OCT B-scan (F).
Next day, intravitreal injection of aflibercept (2 mg) was administered. One month later, the patient's symptoms were relieved and his BCVA improved to 20/100. Fundus examination revealed almost complete resolution of macular hemorrhages. OCTA showed the CNV had completely disappeared. To consolidate treatment, a second intravitreal injection of aflibercept (2 mg) was administered. Two months later, the BCVA improved to 20/25. Macular hemorrhages were completely resolved in the fundus (Fig. 2D) The CNV did not recur in the OCTA image (Fig. 2E), but a small PED was present on the OCT B-scan (Fig. 2F).
3 Discussion
Although PDT with verteporfin was originally developed for treating CNV secondary to age-related macular degeneration, it was soon used as an important treatment modality for chronic CSC.[6,8] Full-dose PDT with verteporfin (6 mg/m2 intravenously) used in CSC may sometimes, cause severe complications that are unacceptable for a disease with relatively favorable prognosis. Verteporfin dye might accumulate selectively around the choroidal hyper-permeable area owing to slow blood flow and vascular congestion, which may lead to irreversible occlusion of the choroidal vessels.[9] Additionally, PDT may cause RPE alterations and induce the release of vascular endothelial growth factor (VEGF), contributing to the development of CNV.[10]
Many studies have recommended half-dose or reduced-fluence PDT for treating CSC. [5] More recently, Wu et al[7] reported high rates of CNV associated with chronic CSC after half-dose PDT with a mean period of 39.5 months (range: 4–138 months) from treatment to OCTA examination. However, the development of CNV secondary to half-dose PDT within 1 month of treatment is rare. Hwang et al[11] reported 1 such case of chronic CSC developed secondary CNV and subretinal hemorrhages 1 month after reduced-fluence PDT (30 mJ/cm2). In their case, the PED was small and dome-shaped under the fovea before treatment. Fortunately, their patient recovered his vision after 2 intravitreal bevacizumab injections.
In our case, we employed half-dose PDT (3 mg/m2), reported to result in favorable outcomes with less risk of complications.[5] Unfortunately, secondary CNV developed 3 weeks post-treatment. To the best of our knowledge, such an occurrence following this short a course of treatment has not been reported previously. Although the pathophysiology of CSC is poorly understood, it is reasonable to apply optimized PDT at the area of choroidal congestion and RPE leakage, thus preventing the disease from developing. Choriocapillary thinning secondary to the underlying choroidal congestion, long-standing serous PED, and pre-existing defects in Bruch's membrane due to chronic RPE changes, may be a risk factor for the development of CNV. Demircan et al[12] reported that choriocapillaris perfusion seemed to decrease in the very early period following half-fluence PDT and returned to normal after 1 month of therapy. Therefore, half-dose PDT may further exacerbate the already compromised choriocapillaries and increase the incidence of CNV. Undoubtedly, the risk does not outweigh the benefits of optimized PDT for the treatment of CSC. However, patients undergoing PDT with relatively good vision should be warned of this rare complication.
Another rare complication secondary to PDT, which needs to be distinguished from secondary CNV, is PDT-induced acute exudative maculopathy (PAEM).[13] PAEM is defined as a massive subretinal serofibrinous exudation with or without acute severe vision impairment.[14] It occurs within days after PDT but has a self-resolving course and favorable prognosis. PAEM is rarely reported after treatment of chronic CSC, with only 3 cases reported in the literature. The pathogenesis includes breakdown of the blood-retinal barrier, RPE pump dysfunction, and inflammatory surge of VEGF occurring after PDT. OCTA is a useful tool to distinguish PAEM from CNV.
To summarize, CNV secondary to half-dose PDT for chronic CSC after a quite short course of treatment is rare. Considering an otherwise favorable prognosis for CSC treatment, patients with chronic CSC who undergo PDT should be warned of this rare complication. Fortunately, it can be successfully treated by intravitreal injection of anti-VEGF agents.
4 Disclosure
The Institutional Review Board of the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University approved the protocol, and our study was performed in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and all accompanying images. There is no conflict of interest exists in the submission of this manuscript, and manuscript is approved by all authors for publication.
Author contributions
ZWZ, XNB and JZ collected the clinical information of the patient, analyzed and interpreted the clinical data. ZWZ wrote the drafting of this manuscript. ZFW and JZ reviewed and edited the manuscript. JZ was responsible for supervision. All authors read and approved the final manuscript.
Conceptualization: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Funding acquisition: Zhengwei Zhang.
Supervision: Jie Zhang.
Validation: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Writing – original draft: Zhengwei Zhang.
Writing – review & editing: Zhifeng Wu, Jie Zhang.
Abbreviations: BCVA = best-corrected visual acuity, CNV = choroidal neovascularization, CSC = central serous chorioretinopathy, FFA = fluorescein fundus angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = optical coherence tomography angiography, PAEM = PDT-induced acute exudative maculopathy, PDT = photodynamic therapy, PED = pigment epithelium detachment, RPE = retinal pigment epithelium, VEGF = vascular endothelial growth factor.
How to cite this article: Zhang Z, Bao X, Wu Z, Zhang J. Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: a case report. Medicine. 2021;100:7(e24790).
This study was supported by the fund of Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (Grant No. HB2020030) and the Development Fund of Wuxi Science and Technology (Grant No. WX18IIAN019).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | VERTEPORFIN | DrugsGivenReaction | CC BY | 33607835 | 18,984,537 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Retinal haemorrhage'. | Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: A case report.
BACKGROUND
Half-dose or reduced-fluence photodynamic therapy (PDT) with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications. However, we report a case of chronic central serous chorioretinopathy (CSC) who developed choroidal neovascularization (CNV) secondary to half-dose PDT within only 3 weeks. Such an occurrence following this short a course of treatment has not been reported previously.
A 46-year-old Chinese man who had been diagnosed as acute more than 1 year ago revisited our department recently and complained of blurred vision again in his left eye.
Fluorescein fundus angiography (FFA) and indocyanine green angiography (ICGA) revealed patchy hyperfluorescent dots and optical coherence tomography (OCT) indicated irregular flat pigment epithelium detachment (PED) in the central macula. The patient was diagnosed with chronic CSC.
METHODS
The patient was treated by half-dose PDT with verteporfin. Three weeks later, the patient complained of sudden blurred vision and fundus examination showed macular hemorrhages with a best-corrected visual acuity (BCVA) of 20/250. OCT angiography (OCTA) showed a distinct area of flower-like CNV located within the deep retinal slab. Secondary CNV had developed after a quite short course of half-dose PDT treatment. Subsequently, the patient was administered by 2 intravitreal injections of aflibercept (2 mg).
RESULTS
Two months after the second intravitreal injection, macular hemorrhages and secondary CNV were completely resolved, and the BCVA improved to 20/25.
CONCLUSIONS
Patients of chronic CSC with irregular PED who undergo PDT should be warned of secondary CNV within a short course after treatment. If happened, it should be treated by intravitreal injections of anti-vascular endothelial growth factor agents as soon as possible.
pmc1 Introduction
Central serous chorioretinopathy (CSC) is a common vision-threatening chorioretinal disease that causes idiopathic serous detachment of the retina, which primarily affects males aged 20 to 60 years.[1] Pathogenesis of CSC is incompletely understood due to its multifactorial etiology and wide systemic associations. However, choroidal hyper-perfusion and hyperpermeability are known to play a major role.[2] Photodynamic therapy (PDT) induces choroidal vascular remodeling and decreases choroidal permeability, and is advocated for the treatment of CSC.[3]
A widely reported complication of standard PDT is secondary choroidal neovascularization (CNV).[4] Its mechanism is attributed to the pro-inflammatory effect, choriocapillaris occlusion, and significant reduction in chorioretinal perfusion caused by PDT. Subsequently, half-dose or reduced-fluence PDT with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications.[5,6] Despite this, some rare but severe complications are inevitable.
Recently, a study reported high rates of CNV, detected using optical coherence tomography angiography (OCTA), associated with chronic CSC after half-dose PDT with a mean period of 39.5 months. [7] However, development of CNV, secondary to half-dose PDT for chronic CSC after a short course of treatment, is rare. Here, we report a patient of chronic CSC with serous pigment epithelium detachment (PED) whose visual acuity decreased abruptly due to CNV and macular hemorrhage, following a half-dose PDT, within 3 weeks of the intervention. Fortunately, this case was treated successfully with 2 intravitreal injections of aflibercept (2 mg).
2 Case presentation
More than 1 year ago, a 46-year-old Chinese man presented to our department with blurred vision in his left eye. At the time, he was diagnosed with acute central serous chorioretinopathy. Oral medications were prescribed; however, he was lost to follow-up. He had excellent uncorrected distance acuity (20/20 in both eyes). Records of optical coherence tomography (OCT) B-scan showed neurosensory detachment at the central macula.
He revisited our department recently and complained of blurred vision again since 1 month. At this visit, he underwent a complete ophthalmic examination, including slitlamp biomicroscopy, best-corrected visual acuity (BCVA), non-contact tonometry, detailed fundus examination, fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA), OCT, and OCTA.
The BCVA was 20/20 OD and 20/25 OS. Intraocular pressure was within normal limits, and anterior segment examination was unremarkable in both eyes. Fundus examination of the right eye was normal, but the left eye showed a shallow sensory detachment in the macula (Fig. 1A). On FFA, the lesion revealed patchy hyperfluorescent dots temporal to the fovea in the early and late phases (Fig. 1B). ICGA also revealed patchy hyperfluorescent dots in the middle and late phases (Fig. 1C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at the first visit (Fig. 1D) and subsequent visit (Fig. 1E). OCTA, reported to be useful for identifying hidden CNVs that could not be found via FA and ICGA, did not show a distinct CNV (Fig. 1F).
Figure 1 Multimodal imaging before treatment Fundus photograph showing a shallow sensory detachment in the macula (yellow arrows) in the left eye (A). The lesion revealed patchy hyperfluorescent dots temporal to the fovea in the late phase of FFA (B) and ICGA (C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at both the initial visit (D) and this visit (E). OCTA did not detect a distinct CNV (F).
The patient was diagnosed with chronic CSC. Treatment employed was half-dose PDT with verteporfin. Fifteen minutes after the start of the intravenous infusion of verteporfin (3 mg/m2), a 689 nm laser was delivered (600 mW/cm2; 83 s). The delivered radiation covered the hyperfluorescent area of the corresponding serous subfoveal PED in the middle or late phase of the ICGA. Three weeks later, the patient complained of sudden blurred vision and revisited our department. Fundus examination showed macular hemorrhages (Fig. 2A) with a BCVA of 20/250. OCTA showed a distinct area of flower-like CNV located within the deep retinal slab (Fig. 2B). OCT B-scan revealed subretinal hyperreflective material corresponding to the CNV complex located above the retinal pigment epithelium (RPE) (Fig. 2C). Unfortunately, secondary CNV had developed after half-dose PDT in this case.
Figure 2 Multimodal imaging after half-dose PDT Fundus photograph showing macular hemorrhages approximately 3 weeks after treatment (A). OCTA showing a distinct area of flower-like CNV located within the deep retinal slab (B). OCT B-scan displaying subretinal hyperreflective material corresponding to the CNV complex located above the RPE (C). Three months after two intravitreal injections of aflibercept (2 mg), macular hemorrhages were completely resolved in the fundus (D) and the CNV did not recur in the OCTA image (E), but a small PED was still present on the OCT B-scan (F).
Next day, intravitreal injection of aflibercept (2 mg) was administered. One month later, the patient's symptoms were relieved and his BCVA improved to 20/100. Fundus examination revealed almost complete resolution of macular hemorrhages. OCTA showed the CNV had completely disappeared. To consolidate treatment, a second intravitreal injection of aflibercept (2 mg) was administered. Two months later, the BCVA improved to 20/25. Macular hemorrhages were completely resolved in the fundus (Fig. 2D) The CNV did not recur in the OCTA image (Fig. 2E), but a small PED was present on the OCT B-scan (Fig. 2F).
3 Discussion
Although PDT with verteporfin was originally developed for treating CNV secondary to age-related macular degeneration, it was soon used as an important treatment modality for chronic CSC.[6,8] Full-dose PDT with verteporfin (6 mg/m2 intravenously) used in CSC may sometimes, cause severe complications that are unacceptable for a disease with relatively favorable prognosis. Verteporfin dye might accumulate selectively around the choroidal hyper-permeable area owing to slow blood flow and vascular congestion, which may lead to irreversible occlusion of the choroidal vessels.[9] Additionally, PDT may cause RPE alterations and induce the release of vascular endothelial growth factor (VEGF), contributing to the development of CNV.[10]
Many studies have recommended half-dose or reduced-fluence PDT for treating CSC. [5] More recently, Wu et al[7] reported high rates of CNV associated with chronic CSC after half-dose PDT with a mean period of 39.5 months (range: 4–138 months) from treatment to OCTA examination. However, the development of CNV secondary to half-dose PDT within 1 month of treatment is rare. Hwang et al[11] reported 1 such case of chronic CSC developed secondary CNV and subretinal hemorrhages 1 month after reduced-fluence PDT (30 mJ/cm2). In their case, the PED was small and dome-shaped under the fovea before treatment. Fortunately, their patient recovered his vision after 2 intravitreal bevacizumab injections.
In our case, we employed half-dose PDT (3 mg/m2), reported to result in favorable outcomes with less risk of complications.[5] Unfortunately, secondary CNV developed 3 weeks post-treatment. To the best of our knowledge, such an occurrence following this short a course of treatment has not been reported previously. Although the pathophysiology of CSC is poorly understood, it is reasonable to apply optimized PDT at the area of choroidal congestion and RPE leakage, thus preventing the disease from developing. Choriocapillary thinning secondary to the underlying choroidal congestion, long-standing serous PED, and pre-existing defects in Bruch's membrane due to chronic RPE changes, may be a risk factor for the development of CNV. Demircan et al[12] reported that choriocapillaris perfusion seemed to decrease in the very early period following half-fluence PDT and returned to normal after 1 month of therapy. Therefore, half-dose PDT may further exacerbate the already compromised choriocapillaries and increase the incidence of CNV. Undoubtedly, the risk does not outweigh the benefits of optimized PDT for the treatment of CSC. However, patients undergoing PDT with relatively good vision should be warned of this rare complication.
Another rare complication secondary to PDT, which needs to be distinguished from secondary CNV, is PDT-induced acute exudative maculopathy (PAEM).[13] PAEM is defined as a massive subretinal serofibrinous exudation with or without acute severe vision impairment.[14] It occurs within days after PDT but has a self-resolving course and favorable prognosis. PAEM is rarely reported after treatment of chronic CSC, with only 3 cases reported in the literature. The pathogenesis includes breakdown of the blood-retinal barrier, RPE pump dysfunction, and inflammatory surge of VEGF occurring after PDT. OCTA is a useful tool to distinguish PAEM from CNV.
To summarize, CNV secondary to half-dose PDT for chronic CSC after a quite short course of treatment is rare. Considering an otherwise favorable prognosis for CSC treatment, patients with chronic CSC who undergo PDT should be warned of this rare complication. Fortunately, it can be successfully treated by intravitreal injection of anti-VEGF agents.
4 Disclosure
The Institutional Review Board of the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University approved the protocol, and our study was performed in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and all accompanying images. There is no conflict of interest exists in the submission of this manuscript, and manuscript is approved by all authors for publication.
Author contributions
ZWZ, XNB and JZ collected the clinical information of the patient, analyzed and interpreted the clinical data. ZWZ wrote the drafting of this manuscript. ZFW and JZ reviewed and edited the manuscript. JZ was responsible for supervision. All authors read and approved the final manuscript.
Conceptualization: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Funding acquisition: Zhengwei Zhang.
Supervision: Jie Zhang.
Validation: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Writing – original draft: Zhengwei Zhang.
Writing – review & editing: Zhifeng Wu, Jie Zhang.
Abbreviations: BCVA = best-corrected visual acuity, CNV = choroidal neovascularization, CSC = central serous chorioretinopathy, FFA = fluorescein fundus angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = optical coherence tomography angiography, PAEM = PDT-induced acute exudative maculopathy, PDT = photodynamic therapy, PED = pigment epithelium detachment, RPE = retinal pigment epithelium, VEGF = vascular endothelial growth factor.
How to cite this article: Zhang Z, Bao X, Wu Z, Zhang J. Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: a case report. Medicine. 2021;100:7(e24790).
This study was supported by the fund of Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (Grant No. HB2020030) and the Development Fund of Wuxi Science and Technology (Grant No. WX18IIAN019).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | VERTEPORFIN | DrugsGivenReaction | CC BY | 33607835 | 18,984,537 | 2021-02-19 |
What was the administration route of drug 'VERTEPORFIN'? | Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: A case report.
BACKGROUND
Half-dose or reduced-fluence photodynamic therapy (PDT) with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications. However, we report a case of chronic central serous chorioretinopathy (CSC) who developed choroidal neovascularization (CNV) secondary to half-dose PDT within only 3 weeks. Such an occurrence following this short a course of treatment has not been reported previously.
A 46-year-old Chinese man who had been diagnosed as acute more than 1 year ago revisited our department recently and complained of blurred vision again in his left eye.
Fluorescein fundus angiography (FFA) and indocyanine green angiography (ICGA) revealed patchy hyperfluorescent dots and optical coherence tomography (OCT) indicated irregular flat pigment epithelium detachment (PED) in the central macula. The patient was diagnosed with chronic CSC.
METHODS
The patient was treated by half-dose PDT with verteporfin. Three weeks later, the patient complained of sudden blurred vision and fundus examination showed macular hemorrhages with a best-corrected visual acuity (BCVA) of 20/250. OCT angiography (OCTA) showed a distinct area of flower-like CNV located within the deep retinal slab. Secondary CNV had developed after a quite short course of half-dose PDT treatment. Subsequently, the patient was administered by 2 intravitreal injections of aflibercept (2 mg).
RESULTS
Two months after the second intravitreal injection, macular hemorrhages and secondary CNV were completely resolved, and the BCVA improved to 20/25.
CONCLUSIONS
Patients of chronic CSC with irregular PED who undergo PDT should be warned of secondary CNV within a short course after treatment. If happened, it should be treated by intravitreal injections of anti-vascular endothelial growth factor agents as soon as possible.
pmc1 Introduction
Central serous chorioretinopathy (CSC) is a common vision-threatening chorioretinal disease that causes idiopathic serous detachment of the retina, which primarily affects males aged 20 to 60 years.[1] Pathogenesis of CSC is incompletely understood due to its multifactorial etiology and wide systemic associations. However, choroidal hyper-perfusion and hyperpermeability are known to play a major role.[2] Photodynamic therapy (PDT) induces choroidal vascular remodeling and decreases choroidal permeability, and is advocated for the treatment of CSC.[3]
A widely reported complication of standard PDT is secondary choroidal neovascularization (CNV).[4] Its mechanism is attributed to the pro-inflammatory effect, choriocapillaris occlusion, and significant reduction in chorioretinal perfusion caused by PDT. Subsequently, half-dose or reduced-fluence PDT with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications.[5,6] Despite this, some rare but severe complications are inevitable.
Recently, a study reported high rates of CNV, detected using optical coherence tomography angiography (OCTA), associated with chronic CSC after half-dose PDT with a mean period of 39.5 months. [7] However, development of CNV, secondary to half-dose PDT for chronic CSC after a short course of treatment, is rare. Here, we report a patient of chronic CSC with serous pigment epithelium detachment (PED) whose visual acuity decreased abruptly due to CNV and macular hemorrhage, following a half-dose PDT, within 3 weeks of the intervention. Fortunately, this case was treated successfully with 2 intravitreal injections of aflibercept (2 mg).
2 Case presentation
More than 1 year ago, a 46-year-old Chinese man presented to our department with blurred vision in his left eye. At the time, he was diagnosed with acute central serous chorioretinopathy. Oral medications were prescribed; however, he was lost to follow-up. He had excellent uncorrected distance acuity (20/20 in both eyes). Records of optical coherence tomography (OCT) B-scan showed neurosensory detachment at the central macula.
He revisited our department recently and complained of blurred vision again since 1 month. At this visit, he underwent a complete ophthalmic examination, including slitlamp biomicroscopy, best-corrected visual acuity (BCVA), non-contact tonometry, detailed fundus examination, fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA), OCT, and OCTA.
The BCVA was 20/20 OD and 20/25 OS. Intraocular pressure was within normal limits, and anterior segment examination was unremarkable in both eyes. Fundus examination of the right eye was normal, but the left eye showed a shallow sensory detachment in the macula (Fig. 1A). On FFA, the lesion revealed patchy hyperfluorescent dots temporal to the fovea in the early and late phases (Fig. 1B). ICGA also revealed patchy hyperfluorescent dots in the middle and late phases (Fig. 1C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at the first visit (Fig. 1D) and subsequent visit (Fig. 1E). OCTA, reported to be useful for identifying hidden CNVs that could not be found via FA and ICGA, did not show a distinct CNV (Fig. 1F).
Figure 1 Multimodal imaging before treatment Fundus photograph showing a shallow sensory detachment in the macula (yellow arrows) in the left eye (A). The lesion revealed patchy hyperfluorescent dots temporal to the fovea in the late phase of FFA (B) and ICGA (C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at both the initial visit (D) and this visit (E). OCTA did not detect a distinct CNV (F).
The patient was diagnosed with chronic CSC. Treatment employed was half-dose PDT with verteporfin. Fifteen minutes after the start of the intravenous infusion of verteporfin (3 mg/m2), a 689 nm laser was delivered (600 mW/cm2; 83 s). The delivered radiation covered the hyperfluorescent area of the corresponding serous subfoveal PED in the middle or late phase of the ICGA. Three weeks later, the patient complained of sudden blurred vision and revisited our department. Fundus examination showed macular hemorrhages (Fig. 2A) with a BCVA of 20/250. OCTA showed a distinct area of flower-like CNV located within the deep retinal slab (Fig. 2B). OCT B-scan revealed subretinal hyperreflective material corresponding to the CNV complex located above the retinal pigment epithelium (RPE) (Fig. 2C). Unfortunately, secondary CNV had developed after half-dose PDT in this case.
Figure 2 Multimodal imaging after half-dose PDT Fundus photograph showing macular hemorrhages approximately 3 weeks after treatment (A). OCTA showing a distinct area of flower-like CNV located within the deep retinal slab (B). OCT B-scan displaying subretinal hyperreflective material corresponding to the CNV complex located above the RPE (C). Three months after two intravitreal injections of aflibercept (2 mg), macular hemorrhages were completely resolved in the fundus (D) and the CNV did not recur in the OCTA image (E), but a small PED was still present on the OCT B-scan (F).
Next day, intravitreal injection of aflibercept (2 mg) was administered. One month later, the patient's symptoms were relieved and his BCVA improved to 20/100. Fundus examination revealed almost complete resolution of macular hemorrhages. OCTA showed the CNV had completely disappeared. To consolidate treatment, a second intravitreal injection of aflibercept (2 mg) was administered. Two months later, the BCVA improved to 20/25. Macular hemorrhages were completely resolved in the fundus (Fig. 2D) The CNV did not recur in the OCTA image (Fig. 2E), but a small PED was present on the OCT B-scan (Fig. 2F).
3 Discussion
Although PDT with verteporfin was originally developed for treating CNV secondary to age-related macular degeneration, it was soon used as an important treatment modality for chronic CSC.[6,8] Full-dose PDT with verteporfin (6 mg/m2 intravenously) used in CSC may sometimes, cause severe complications that are unacceptable for a disease with relatively favorable prognosis. Verteporfin dye might accumulate selectively around the choroidal hyper-permeable area owing to slow blood flow and vascular congestion, which may lead to irreversible occlusion of the choroidal vessels.[9] Additionally, PDT may cause RPE alterations and induce the release of vascular endothelial growth factor (VEGF), contributing to the development of CNV.[10]
Many studies have recommended half-dose or reduced-fluence PDT for treating CSC. [5] More recently, Wu et al[7] reported high rates of CNV associated with chronic CSC after half-dose PDT with a mean period of 39.5 months (range: 4–138 months) from treatment to OCTA examination. However, the development of CNV secondary to half-dose PDT within 1 month of treatment is rare. Hwang et al[11] reported 1 such case of chronic CSC developed secondary CNV and subretinal hemorrhages 1 month after reduced-fluence PDT (30 mJ/cm2). In their case, the PED was small and dome-shaped under the fovea before treatment. Fortunately, their patient recovered his vision after 2 intravitreal bevacizumab injections.
In our case, we employed half-dose PDT (3 mg/m2), reported to result in favorable outcomes with less risk of complications.[5] Unfortunately, secondary CNV developed 3 weeks post-treatment. To the best of our knowledge, such an occurrence following this short a course of treatment has not been reported previously. Although the pathophysiology of CSC is poorly understood, it is reasonable to apply optimized PDT at the area of choroidal congestion and RPE leakage, thus preventing the disease from developing. Choriocapillary thinning secondary to the underlying choroidal congestion, long-standing serous PED, and pre-existing defects in Bruch's membrane due to chronic RPE changes, may be a risk factor for the development of CNV. Demircan et al[12] reported that choriocapillaris perfusion seemed to decrease in the very early period following half-fluence PDT and returned to normal after 1 month of therapy. Therefore, half-dose PDT may further exacerbate the already compromised choriocapillaries and increase the incidence of CNV. Undoubtedly, the risk does not outweigh the benefits of optimized PDT for the treatment of CSC. However, patients undergoing PDT with relatively good vision should be warned of this rare complication.
Another rare complication secondary to PDT, which needs to be distinguished from secondary CNV, is PDT-induced acute exudative maculopathy (PAEM).[13] PAEM is defined as a massive subretinal serofibrinous exudation with or without acute severe vision impairment.[14] It occurs within days after PDT but has a self-resolving course and favorable prognosis. PAEM is rarely reported after treatment of chronic CSC, with only 3 cases reported in the literature. The pathogenesis includes breakdown of the blood-retinal barrier, RPE pump dysfunction, and inflammatory surge of VEGF occurring after PDT. OCTA is a useful tool to distinguish PAEM from CNV.
To summarize, CNV secondary to half-dose PDT for chronic CSC after a quite short course of treatment is rare. Considering an otherwise favorable prognosis for CSC treatment, patients with chronic CSC who undergo PDT should be warned of this rare complication. Fortunately, it can be successfully treated by intravitreal injection of anti-VEGF agents.
4 Disclosure
The Institutional Review Board of the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University approved the protocol, and our study was performed in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and all accompanying images. There is no conflict of interest exists in the submission of this manuscript, and manuscript is approved by all authors for publication.
Author contributions
ZWZ, XNB and JZ collected the clinical information of the patient, analyzed and interpreted the clinical data. ZWZ wrote the drafting of this manuscript. ZFW and JZ reviewed and edited the manuscript. JZ was responsible for supervision. All authors read and approved the final manuscript.
Conceptualization: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Funding acquisition: Zhengwei Zhang.
Supervision: Jie Zhang.
Validation: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Writing – original draft: Zhengwei Zhang.
Writing – review & editing: Zhifeng Wu, Jie Zhang.
Abbreviations: BCVA = best-corrected visual acuity, CNV = choroidal neovascularization, CSC = central serous chorioretinopathy, FFA = fluorescein fundus angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = optical coherence tomography angiography, PAEM = PDT-induced acute exudative maculopathy, PDT = photodynamic therapy, PED = pigment epithelium detachment, RPE = retinal pigment epithelium, VEGF = vascular endothelial growth factor.
How to cite this article: Zhang Z, Bao X, Wu Z, Zhang J. Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: a case report. Medicine. 2021;100:7(e24790).
This study was supported by the fund of Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (Grant No. HB2020030) and the Development Fund of Wuxi Science and Technology (Grant No. WX18IIAN019).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33607835 | 18,984,537 | 2021-02-19 |
What was the dosage of drug 'VERTEPORFIN'? | Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: A case report.
BACKGROUND
Half-dose or reduced-fluence photodynamic therapy (PDT) with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications. However, we report a case of chronic central serous chorioretinopathy (CSC) who developed choroidal neovascularization (CNV) secondary to half-dose PDT within only 3 weeks. Such an occurrence following this short a course of treatment has not been reported previously.
A 46-year-old Chinese man who had been diagnosed as acute more than 1 year ago revisited our department recently and complained of blurred vision again in his left eye.
Fluorescein fundus angiography (FFA) and indocyanine green angiography (ICGA) revealed patchy hyperfluorescent dots and optical coherence tomography (OCT) indicated irregular flat pigment epithelium detachment (PED) in the central macula. The patient was diagnosed with chronic CSC.
METHODS
The patient was treated by half-dose PDT with verteporfin. Three weeks later, the patient complained of sudden blurred vision and fundus examination showed macular hemorrhages with a best-corrected visual acuity (BCVA) of 20/250. OCT angiography (OCTA) showed a distinct area of flower-like CNV located within the deep retinal slab. Secondary CNV had developed after a quite short course of half-dose PDT treatment. Subsequently, the patient was administered by 2 intravitreal injections of aflibercept (2 mg).
RESULTS
Two months after the second intravitreal injection, macular hemorrhages and secondary CNV were completely resolved, and the BCVA improved to 20/25.
CONCLUSIONS
Patients of chronic CSC with irregular PED who undergo PDT should be warned of secondary CNV within a short course after treatment. If happened, it should be treated by intravitreal injections of anti-vascular endothelial growth factor agents as soon as possible.
pmc1 Introduction
Central serous chorioretinopathy (CSC) is a common vision-threatening chorioretinal disease that causes idiopathic serous detachment of the retina, which primarily affects males aged 20 to 60 years.[1] Pathogenesis of CSC is incompletely understood due to its multifactorial etiology and wide systemic associations. However, choroidal hyper-perfusion and hyperpermeability are known to play a major role.[2] Photodynamic therapy (PDT) induces choroidal vascular remodeling and decreases choroidal permeability, and is advocated for the treatment of CSC.[3]
A widely reported complication of standard PDT is secondary choroidal neovascularization (CNV).[4] Its mechanism is attributed to the pro-inflammatory effect, choriocapillaris occlusion, and significant reduction in chorioretinal perfusion caused by PDT. Subsequently, half-dose or reduced-fluence PDT with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications.[5,6] Despite this, some rare but severe complications are inevitable.
Recently, a study reported high rates of CNV, detected using optical coherence tomography angiography (OCTA), associated with chronic CSC after half-dose PDT with a mean period of 39.5 months. [7] However, development of CNV, secondary to half-dose PDT for chronic CSC after a short course of treatment, is rare. Here, we report a patient of chronic CSC with serous pigment epithelium detachment (PED) whose visual acuity decreased abruptly due to CNV and macular hemorrhage, following a half-dose PDT, within 3 weeks of the intervention. Fortunately, this case was treated successfully with 2 intravitreal injections of aflibercept (2 mg).
2 Case presentation
More than 1 year ago, a 46-year-old Chinese man presented to our department with blurred vision in his left eye. At the time, he was diagnosed with acute central serous chorioretinopathy. Oral medications were prescribed; however, he was lost to follow-up. He had excellent uncorrected distance acuity (20/20 in both eyes). Records of optical coherence tomography (OCT) B-scan showed neurosensory detachment at the central macula.
He revisited our department recently and complained of blurred vision again since 1 month. At this visit, he underwent a complete ophthalmic examination, including slitlamp biomicroscopy, best-corrected visual acuity (BCVA), non-contact tonometry, detailed fundus examination, fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA), OCT, and OCTA.
The BCVA was 20/20 OD and 20/25 OS. Intraocular pressure was within normal limits, and anterior segment examination was unremarkable in both eyes. Fundus examination of the right eye was normal, but the left eye showed a shallow sensory detachment in the macula (Fig. 1A). On FFA, the lesion revealed patchy hyperfluorescent dots temporal to the fovea in the early and late phases (Fig. 1B). ICGA also revealed patchy hyperfluorescent dots in the middle and late phases (Fig. 1C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at the first visit (Fig. 1D) and subsequent visit (Fig. 1E). OCTA, reported to be useful for identifying hidden CNVs that could not be found via FA and ICGA, did not show a distinct CNV (Fig. 1F).
Figure 1 Multimodal imaging before treatment Fundus photograph showing a shallow sensory detachment in the macula (yellow arrows) in the left eye (A). The lesion revealed patchy hyperfluorescent dots temporal to the fovea in the late phase of FFA (B) and ICGA (C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at both the initial visit (D) and this visit (E). OCTA did not detect a distinct CNV (F).
The patient was diagnosed with chronic CSC. Treatment employed was half-dose PDT with verteporfin. Fifteen minutes after the start of the intravenous infusion of verteporfin (3 mg/m2), a 689 nm laser was delivered (600 mW/cm2; 83 s). The delivered radiation covered the hyperfluorescent area of the corresponding serous subfoveal PED in the middle or late phase of the ICGA. Three weeks later, the patient complained of sudden blurred vision and revisited our department. Fundus examination showed macular hemorrhages (Fig. 2A) with a BCVA of 20/250. OCTA showed a distinct area of flower-like CNV located within the deep retinal slab (Fig. 2B). OCT B-scan revealed subretinal hyperreflective material corresponding to the CNV complex located above the retinal pigment epithelium (RPE) (Fig. 2C). Unfortunately, secondary CNV had developed after half-dose PDT in this case.
Figure 2 Multimodal imaging after half-dose PDT Fundus photograph showing macular hemorrhages approximately 3 weeks after treatment (A). OCTA showing a distinct area of flower-like CNV located within the deep retinal slab (B). OCT B-scan displaying subretinal hyperreflective material corresponding to the CNV complex located above the RPE (C). Three months after two intravitreal injections of aflibercept (2 mg), macular hemorrhages were completely resolved in the fundus (D) and the CNV did not recur in the OCTA image (E), but a small PED was still present on the OCT B-scan (F).
Next day, intravitreal injection of aflibercept (2 mg) was administered. One month later, the patient's symptoms were relieved and his BCVA improved to 20/100. Fundus examination revealed almost complete resolution of macular hemorrhages. OCTA showed the CNV had completely disappeared. To consolidate treatment, a second intravitreal injection of aflibercept (2 mg) was administered. Two months later, the BCVA improved to 20/25. Macular hemorrhages were completely resolved in the fundus (Fig. 2D) The CNV did not recur in the OCTA image (Fig. 2E), but a small PED was present on the OCT B-scan (Fig. 2F).
3 Discussion
Although PDT with verteporfin was originally developed for treating CNV secondary to age-related macular degeneration, it was soon used as an important treatment modality for chronic CSC.[6,8] Full-dose PDT with verteporfin (6 mg/m2 intravenously) used in CSC may sometimes, cause severe complications that are unacceptable for a disease with relatively favorable prognosis. Verteporfin dye might accumulate selectively around the choroidal hyper-permeable area owing to slow blood flow and vascular congestion, which may lead to irreversible occlusion of the choroidal vessels.[9] Additionally, PDT may cause RPE alterations and induce the release of vascular endothelial growth factor (VEGF), contributing to the development of CNV.[10]
Many studies have recommended half-dose or reduced-fluence PDT for treating CSC. [5] More recently, Wu et al[7] reported high rates of CNV associated with chronic CSC after half-dose PDT with a mean period of 39.5 months (range: 4–138 months) from treatment to OCTA examination. However, the development of CNV secondary to half-dose PDT within 1 month of treatment is rare. Hwang et al[11] reported 1 such case of chronic CSC developed secondary CNV and subretinal hemorrhages 1 month after reduced-fluence PDT (30 mJ/cm2). In their case, the PED was small and dome-shaped under the fovea before treatment. Fortunately, their patient recovered his vision after 2 intravitreal bevacizumab injections.
In our case, we employed half-dose PDT (3 mg/m2), reported to result in favorable outcomes with less risk of complications.[5] Unfortunately, secondary CNV developed 3 weeks post-treatment. To the best of our knowledge, such an occurrence following this short a course of treatment has not been reported previously. Although the pathophysiology of CSC is poorly understood, it is reasonable to apply optimized PDT at the area of choroidal congestion and RPE leakage, thus preventing the disease from developing. Choriocapillary thinning secondary to the underlying choroidal congestion, long-standing serous PED, and pre-existing defects in Bruch's membrane due to chronic RPE changes, may be a risk factor for the development of CNV. Demircan et al[12] reported that choriocapillaris perfusion seemed to decrease in the very early period following half-fluence PDT and returned to normal after 1 month of therapy. Therefore, half-dose PDT may further exacerbate the already compromised choriocapillaries and increase the incidence of CNV. Undoubtedly, the risk does not outweigh the benefits of optimized PDT for the treatment of CSC. However, patients undergoing PDT with relatively good vision should be warned of this rare complication.
Another rare complication secondary to PDT, which needs to be distinguished from secondary CNV, is PDT-induced acute exudative maculopathy (PAEM).[13] PAEM is defined as a massive subretinal serofibrinous exudation with or without acute severe vision impairment.[14] It occurs within days after PDT but has a self-resolving course and favorable prognosis. PAEM is rarely reported after treatment of chronic CSC, with only 3 cases reported in the literature. The pathogenesis includes breakdown of the blood-retinal barrier, RPE pump dysfunction, and inflammatory surge of VEGF occurring after PDT. OCTA is a useful tool to distinguish PAEM from CNV.
To summarize, CNV secondary to half-dose PDT for chronic CSC after a quite short course of treatment is rare. Considering an otherwise favorable prognosis for CSC treatment, patients with chronic CSC who undergo PDT should be warned of this rare complication. Fortunately, it can be successfully treated by intravitreal injection of anti-VEGF agents.
4 Disclosure
The Institutional Review Board of the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University approved the protocol, and our study was performed in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and all accompanying images. There is no conflict of interest exists in the submission of this manuscript, and manuscript is approved by all authors for publication.
Author contributions
ZWZ, XNB and JZ collected the clinical information of the patient, analyzed and interpreted the clinical data. ZWZ wrote the drafting of this manuscript. ZFW and JZ reviewed and edited the manuscript. JZ was responsible for supervision. All authors read and approved the final manuscript.
Conceptualization: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Funding acquisition: Zhengwei Zhang.
Supervision: Jie Zhang.
Validation: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Writing – original draft: Zhengwei Zhang.
Writing – review & editing: Zhifeng Wu, Jie Zhang.
Abbreviations: BCVA = best-corrected visual acuity, CNV = choroidal neovascularization, CSC = central serous chorioretinopathy, FFA = fluorescein fundus angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = optical coherence tomography angiography, PAEM = PDT-induced acute exudative maculopathy, PDT = photodynamic therapy, PED = pigment epithelium detachment, RPE = retinal pigment epithelium, VEGF = vascular endothelial growth factor.
How to cite this article: Zhang Z, Bao X, Wu Z, Zhang J. Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: a case report. Medicine. 2021;100:7(e24790).
This study was supported by the fund of Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (Grant No. HB2020030) and the Development Fund of Wuxi Science and Technology (Grant No. WX18IIAN019).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | ALONG WITH HALF?DOSE PDT | DrugDosageText | CC BY | 33607835 | 18,984,537 | 2021-02-19 |
What was the outcome of reaction 'Choroidal neovascularisation'? | Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: A case report.
BACKGROUND
Half-dose or reduced-fluence photodynamic therapy (PDT) with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications. However, we report a case of chronic central serous chorioretinopathy (CSC) who developed choroidal neovascularization (CNV) secondary to half-dose PDT within only 3 weeks. Such an occurrence following this short a course of treatment has not been reported previously.
A 46-year-old Chinese man who had been diagnosed as acute more than 1 year ago revisited our department recently and complained of blurred vision again in his left eye.
Fluorescein fundus angiography (FFA) and indocyanine green angiography (ICGA) revealed patchy hyperfluorescent dots and optical coherence tomography (OCT) indicated irregular flat pigment epithelium detachment (PED) in the central macula. The patient was diagnosed with chronic CSC.
METHODS
The patient was treated by half-dose PDT with verteporfin. Three weeks later, the patient complained of sudden blurred vision and fundus examination showed macular hemorrhages with a best-corrected visual acuity (BCVA) of 20/250. OCT angiography (OCTA) showed a distinct area of flower-like CNV located within the deep retinal slab. Secondary CNV had developed after a quite short course of half-dose PDT treatment. Subsequently, the patient was administered by 2 intravitreal injections of aflibercept (2 mg).
RESULTS
Two months after the second intravitreal injection, macular hemorrhages and secondary CNV were completely resolved, and the BCVA improved to 20/25.
CONCLUSIONS
Patients of chronic CSC with irregular PED who undergo PDT should be warned of secondary CNV within a short course after treatment. If happened, it should be treated by intravitreal injections of anti-vascular endothelial growth factor agents as soon as possible.
pmc1 Introduction
Central serous chorioretinopathy (CSC) is a common vision-threatening chorioretinal disease that causes idiopathic serous detachment of the retina, which primarily affects males aged 20 to 60 years.[1] Pathogenesis of CSC is incompletely understood due to its multifactorial etiology and wide systemic associations. However, choroidal hyper-perfusion and hyperpermeability are known to play a major role.[2] Photodynamic therapy (PDT) induces choroidal vascular remodeling and decreases choroidal permeability, and is advocated for the treatment of CSC.[3]
A widely reported complication of standard PDT is secondary choroidal neovascularization (CNV).[4] Its mechanism is attributed to the pro-inflammatory effect, choriocapillaris occlusion, and significant reduction in chorioretinal perfusion caused by PDT. Subsequently, half-dose or reduced-fluence PDT with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications.[5,6] Despite this, some rare but severe complications are inevitable.
Recently, a study reported high rates of CNV, detected using optical coherence tomography angiography (OCTA), associated with chronic CSC after half-dose PDT with a mean period of 39.5 months. [7] However, development of CNV, secondary to half-dose PDT for chronic CSC after a short course of treatment, is rare. Here, we report a patient of chronic CSC with serous pigment epithelium detachment (PED) whose visual acuity decreased abruptly due to CNV and macular hemorrhage, following a half-dose PDT, within 3 weeks of the intervention. Fortunately, this case was treated successfully with 2 intravitreal injections of aflibercept (2 mg).
2 Case presentation
More than 1 year ago, a 46-year-old Chinese man presented to our department with blurred vision in his left eye. At the time, he was diagnosed with acute central serous chorioretinopathy. Oral medications were prescribed; however, he was lost to follow-up. He had excellent uncorrected distance acuity (20/20 in both eyes). Records of optical coherence tomography (OCT) B-scan showed neurosensory detachment at the central macula.
He revisited our department recently and complained of blurred vision again since 1 month. At this visit, he underwent a complete ophthalmic examination, including slitlamp biomicroscopy, best-corrected visual acuity (BCVA), non-contact tonometry, detailed fundus examination, fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA), OCT, and OCTA.
The BCVA was 20/20 OD and 20/25 OS. Intraocular pressure was within normal limits, and anterior segment examination was unremarkable in both eyes. Fundus examination of the right eye was normal, but the left eye showed a shallow sensory detachment in the macula (Fig. 1A). On FFA, the lesion revealed patchy hyperfluorescent dots temporal to the fovea in the early and late phases (Fig. 1B). ICGA also revealed patchy hyperfluorescent dots in the middle and late phases (Fig. 1C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at the first visit (Fig. 1D) and subsequent visit (Fig. 1E). OCTA, reported to be useful for identifying hidden CNVs that could not be found via FA and ICGA, did not show a distinct CNV (Fig. 1F).
Figure 1 Multimodal imaging before treatment Fundus photograph showing a shallow sensory detachment in the macula (yellow arrows) in the left eye (A). The lesion revealed patchy hyperfluorescent dots temporal to the fovea in the late phase of FFA (B) and ICGA (C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at both the initial visit (D) and this visit (E). OCTA did not detect a distinct CNV (F).
The patient was diagnosed with chronic CSC. Treatment employed was half-dose PDT with verteporfin. Fifteen minutes after the start of the intravenous infusion of verteporfin (3 mg/m2), a 689 nm laser was delivered (600 mW/cm2; 83 s). The delivered radiation covered the hyperfluorescent area of the corresponding serous subfoveal PED in the middle or late phase of the ICGA. Three weeks later, the patient complained of sudden blurred vision and revisited our department. Fundus examination showed macular hemorrhages (Fig. 2A) with a BCVA of 20/250. OCTA showed a distinct area of flower-like CNV located within the deep retinal slab (Fig. 2B). OCT B-scan revealed subretinal hyperreflective material corresponding to the CNV complex located above the retinal pigment epithelium (RPE) (Fig. 2C). Unfortunately, secondary CNV had developed after half-dose PDT in this case.
Figure 2 Multimodal imaging after half-dose PDT Fundus photograph showing macular hemorrhages approximately 3 weeks after treatment (A). OCTA showing a distinct area of flower-like CNV located within the deep retinal slab (B). OCT B-scan displaying subretinal hyperreflective material corresponding to the CNV complex located above the RPE (C). Three months after two intravitreal injections of aflibercept (2 mg), macular hemorrhages were completely resolved in the fundus (D) and the CNV did not recur in the OCTA image (E), but a small PED was still present on the OCT B-scan (F).
Next day, intravitreal injection of aflibercept (2 mg) was administered. One month later, the patient's symptoms were relieved and his BCVA improved to 20/100. Fundus examination revealed almost complete resolution of macular hemorrhages. OCTA showed the CNV had completely disappeared. To consolidate treatment, a second intravitreal injection of aflibercept (2 mg) was administered. Two months later, the BCVA improved to 20/25. Macular hemorrhages were completely resolved in the fundus (Fig. 2D) The CNV did not recur in the OCTA image (Fig. 2E), but a small PED was present on the OCT B-scan (Fig. 2F).
3 Discussion
Although PDT with verteporfin was originally developed for treating CNV secondary to age-related macular degeneration, it was soon used as an important treatment modality for chronic CSC.[6,8] Full-dose PDT with verteporfin (6 mg/m2 intravenously) used in CSC may sometimes, cause severe complications that are unacceptable for a disease with relatively favorable prognosis. Verteporfin dye might accumulate selectively around the choroidal hyper-permeable area owing to slow blood flow and vascular congestion, which may lead to irreversible occlusion of the choroidal vessels.[9] Additionally, PDT may cause RPE alterations and induce the release of vascular endothelial growth factor (VEGF), contributing to the development of CNV.[10]
Many studies have recommended half-dose or reduced-fluence PDT for treating CSC. [5] More recently, Wu et al[7] reported high rates of CNV associated with chronic CSC after half-dose PDT with a mean period of 39.5 months (range: 4–138 months) from treatment to OCTA examination. However, the development of CNV secondary to half-dose PDT within 1 month of treatment is rare. Hwang et al[11] reported 1 such case of chronic CSC developed secondary CNV and subretinal hemorrhages 1 month after reduced-fluence PDT (30 mJ/cm2). In their case, the PED was small and dome-shaped under the fovea before treatment. Fortunately, their patient recovered his vision after 2 intravitreal bevacizumab injections.
In our case, we employed half-dose PDT (3 mg/m2), reported to result in favorable outcomes with less risk of complications.[5] Unfortunately, secondary CNV developed 3 weeks post-treatment. To the best of our knowledge, such an occurrence following this short a course of treatment has not been reported previously. Although the pathophysiology of CSC is poorly understood, it is reasonable to apply optimized PDT at the area of choroidal congestion and RPE leakage, thus preventing the disease from developing. Choriocapillary thinning secondary to the underlying choroidal congestion, long-standing serous PED, and pre-existing defects in Bruch's membrane due to chronic RPE changes, may be a risk factor for the development of CNV. Demircan et al[12] reported that choriocapillaris perfusion seemed to decrease in the very early period following half-fluence PDT and returned to normal after 1 month of therapy. Therefore, half-dose PDT may further exacerbate the already compromised choriocapillaries and increase the incidence of CNV. Undoubtedly, the risk does not outweigh the benefits of optimized PDT for the treatment of CSC. However, patients undergoing PDT with relatively good vision should be warned of this rare complication.
Another rare complication secondary to PDT, which needs to be distinguished from secondary CNV, is PDT-induced acute exudative maculopathy (PAEM).[13] PAEM is defined as a massive subretinal serofibrinous exudation with or without acute severe vision impairment.[14] It occurs within days after PDT but has a self-resolving course and favorable prognosis. PAEM is rarely reported after treatment of chronic CSC, with only 3 cases reported in the literature. The pathogenesis includes breakdown of the blood-retinal barrier, RPE pump dysfunction, and inflammatory surge of VEGF occurring after PDT. OCTA is a useful tool to distinguish PAEM from CNV.
To summarize, CNV secondary to half-dose PDT for chronic CSC after a quite short course of treatment is rare. Considering an otherwise favorable prognosis for CSC treatment, patients with chronic CSC who undergo PDT should be warned of this rare complication. Fortunately, it can be successfully treated by intravitreal injection of anti-VEGF agents.
4 Disclosure
The Institutional Review Board of the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University approved the protocol, and our study was performed in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and all accompanying images. There is no conflict of interest exists in the submission of this manuscript, and manuscript is approved by all authors for publication.
Author contributions
ZWZ, XNB and JZ collected the clinical information of the patient, analyzed and interpreted the clinical data. ZWZ wrote the drafting of this manuscript. ZFW and JZ reviewed and edited the manuscript. JZ was responsible for supervision. All authors read and approved the final manuscript.
Conceptualization: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Funding acquisition: Zhengwei Zhang.
Supervision: Jie Zhang.
Validation: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Writing – original draft: Zhengwei Zhang.
Writing – review & editing: Zhifeng Wu, Jie Zhang.
Abbreviations: BCVA = best-corrected visual acuity, CNV = choroidal neovascularization, CSC = central serous chorioretinopathy, FFA = fluorescein fundus angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = optical coherence tomography angiography, PAEM = PDT-induced acute exudative maculopathy, PDT = photodynamic therapy, PED = pigment epithelium detachment, RPE = retinal pigment epithelium, VEGF = vascular endothelial growth factor.
How to cite this article: Zhang Z, Bao X, Wu Z, Zhang J. Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: a case report. Medicine. 2021;100:7(e24790).
This study was supported by the fund of Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (Grant No. HB2020030) and the Development Fund of Wuxi Science and Technology (Grant No. WX18IIAN019).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | Recovered | ReactionOutcome | CC BY | 33607835 | 18,984,537 | 2021-02-19 |
What was the outcome of reaction 'Product use in unapproved indication'? | Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: A case report.
BACKGROUND
Half-dose or reduced-fluence photodynamic therapy (PDT) with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications. However, we report a case of chronic central serous chorioretinopathy (CSC) who developed choroidal neovascularization (CNV) secondary to half-dose PDT within only 3 weeks. Such an occurrence following this short a course of treatment has not been reported previously.
A 46-year-old Chinese man who had been diagnosed as acute more than 1 year ago revisited our department recently and complained of blurred vision again in his left eye.
Fluorescein fundus angiography (FFA) and indocyanine green angiography (ICGA) revealed patchy hyperfluorescent dots and optical coherence tomography (OCT) indicated irregular flat pigment epithelium detachment (PED) in the central macula. The patient was diagnosed with chronic CSC.
METHODS
The patient was treated by half-dose PDT with verteporfin. Three weeks later, the patient complained of sudden blurred vision and fundus examination showed macular hemorrhages with a best-corrected visual acuity (BCVA) of 20/250. OCT angiography (OCTA) showed a distinct area of flower-like CNV located within the deep retinal slab. Secondary CNV had developed after a quite short course of half-dose PDT treatment. Subsequently, the patient was administered by 2 intravitreal injections of aflibercept (2 mg).
RESULTS
Two months after the second intravitreal injection, macular hemorrhages and secondary CNV were completely resolved, and the BCVA improved to 20/25.
CONCLUSIONS
Patients of chronic CSC with irregular PED who undergo PDT should be warned of secondary CNV within a short course after treatment. If happened, it should be treated by intravitreal injections of anti-vascular endothelial growth factor agents as soon as possible.
pmc1 Introduction
Central serous chorioretinopathy (CSC) is a common vision-threatening chorioretinal disease that causes idiopathic serous detachment of the retina, which primarily affects males aged 20 to 60 years.[1] Pathogenesis of CSC is incompletely understood due to its multifactorial etiology and wide systemic associations. However, choroidal hyper-perfusion and hyperpermeability are known to play a major role.[2] Photodynamic therapy (PDT) induces choroidal vascular remodeling and decreases choroidal permeability, and is advocated for the treatment of CSC.[3]
A widely reported complication of standard PDT is secondary choroidal neovascularization (CNV).[4] Its mechanism is attributed to the pro-inflammatory effect, choriocapillaris occlusion, and significant reduction in chorioretinal perfusion caused by PDT. Subsequently, half-dose or reduced-fluence PDT with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications.[5,6] Despite this, some rare but severe complications are inevitable.
Recently, a study reported high rates of CNV, detected using optical coherence tomography angiography (OCTA), associated with chronic CSC after half-dose PDT with a mean period of 39.5 months. [7] However, development of CNV, secondary to half-dose PDT for chronic CSC after a short course of treatment, is rare. Here, we report a patient of chronic CSC with serous pigment epithelium detachment (PED) whose visual acuity decreased abruptly due to CNV and macular hemorrhage, following a half-dose PDT, within 3 weeks of the intervention. Fortunately, this case was treated successfully with 2 intravitreal injections of aflibercept (2 mg).
2 Case presentation
More than 1 year ago, a 46-year-old Chinese man presented to our department with blurred vision in his left eye. At the time, he was diagnosed with acute central serous chorioretinopathy. Oral medications were prescribed; however, he was lost to follow-up. He had excellent uncorrected distance acuity (20/20 in both eyes). Records of optical coherence tomography (OCT) B-scan showed neurosensory detachment at the central macula.
He revisited our department recently and complained of blurred vision again since 1 month. At this visit, he underwent a complete ophthalmic examination, including slitlamp biomicroscopy, best-corrected visual acuity (BCVA), non-contact tonometry, detailed fundus examination, fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA), OCT, and OCTA.
The BCVA was 20/20 OD and 20/25 OS. Intraocular pressure was within normal limits, and anterior segment examination was unremarkable in both eyes. Fundus examination of the right eye was normal, but the left eye showed a shallow sensory detachment in the macula (Fig. 1A). On FFA, the lesion revealed patchy hyperfluorescent dots temporal to the fovea in the early and late phases (Fig. 1B). ICGA also revealed patchy hyperfluorescent dots in the middle and late phases (Fig. 1C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at the first visit (Fig. 1D) and subsequent visit (Fig. 1E). OCTA, reported to be useful for identifying hidden CNVs that could not be found via FA and ICGA, did not show a distinct CNV (Fig. 1F).
Figure 1 Multimodal imaging before treatment Fundus photograph showing a shallow sensory detachment in the macula (yellow arrows) in the left eye (A). The lesion revealed patchy hyperfluorescent dots temporal to the fovea in the late phase of FFA (B) and ICGA (C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at both the initial visit (D) and this visit (E). OCTA did not detect a distinct CNV (F).
The patient was diagnosed with chronic CSC. Treatment employed was half-dose PDT with verteporfin. Fifteen minutes after the start of the intravenous infusion of verteporfin (3 mg/m2), a 689 nm laser was delivered (600 mW/cm2; 83 s). The delivered radiation covered the hyperfluorescent area of the corresponding serous subfoveal PED in the middle or late phase of the ICGA. Three weeks later, the patient complained of sudden blurred vision and revisited our department. Fundus examination showed macular hemorrhages (Fig. 2A) with a BCVA of 20/250. OCTA showed a distinct area of flower-like CNV located within the deep retinal slab (Fig. 2B). OCT B-scan revealed subretinal hyperreflective material corresponding to the CNV complex located above the retinal pigment epithelium (RPE) (Fig. 2C). Unfortunately, secondary CNV had developed after half-dose PDT in this case.
Figure 2 Multimodal imaging after half-dose PDT Fundus photograph showing macular hemorrhages approximately 3 weeks after treatment (A). OCTA showing a distinct area of flower-like CNV located within the deep retinal slab (B). OCT B-scan displaying subretinal hyperreflective material corresponding to the CNV complex located above the RPE (C). Three months after two intravitreal injections of aflibercept (2 mg), macular hemorrhages were completely resolved in the fundus (D) and the CNV did not recur in the OCTA image (E), but a small PED was still present on the OCT B-scan (F).
Next day, intravitreal injection of aflibercept (2 mg) was administered. One month later, the patient's symptoms were relieved and his BCVA improved to 20/100. Fundus examination revealed almost complete resolution of macular hemorrhages. OCTA showed the CNV had completely disappeared. To consolidate treatment, a second intravitreal injection of aflibercept (2 mg) was administered. Two months later, the BCVA improved to 20/25. Macular hemorrhages were completely resolved in the fundus (Fig. 2D) The CNV did not recur in the OCTA image (Fig. 2E), but a small PED was present on the OCT B-scan (Fig. 2F).
3 Discussion
Although PDT with verteporfin was originally developed for treating CNV secondary to age-related macular degeneration, it was soon used as an important treatment modality for chronic CSC.[6,8] Full-dose PDT with verteporfin (6 mg/m2 intravenously) used in CSC may sometimes, cause severe complications that are unacceptable for a disease with relatively favorable prognosis. Verteporfin dye might accumulate selectively around the choroidal hyper-permeable area owing to slow blood flow and vascular congestion, which may lead to irreversible occlusion of the choroidal vessels.[9] Additionally, PDT may cause RPE alterations and induce the release of vascular endothelial growth factor (VEGF), contributing to the development of CNV.[10]
Many studies have recommended half-dose or reduced-fluence PDT for treating CSC. [5] More recently, Wu et al[7] reported high rates of CNV associated with chronic CSC after half-dose PDT with a mean period of 39.5 months (range: 4–138 months) from treatment to OCTA examination. However, the development of CNV secondary to half-dose PDT within 1 month of treatment is rare. Hwang et al[11] reported 1 such case of chronic CSC developed secondary CNV and subretinal hemorrhages 1 month after reduced-fluence PDT (30 mJ/cm2). In their case, the PED was small and dome-shaped under the fovea before treatment. Fortunately, their patient recovered his vision after 2 intravitreal bevacizumab injections.
In our case, we employed half-dose PDT (3 mg/m2), reported to result in favorable outcomes with less risk of complications.[5] Unfortunately, secondary CNV developed 3 weeks post-treatment. To the best of our knowledge, such an occurrence following this short a course of treatment has not been reported previously. Although the pathophysiology of CSC is poorly understood, it is reasonable to apply optimized PDT at the area of choroidal congestion and RPE leakage, thus preventing the disease from developing. Choriocapillary thinning secondary to the underlying choroidal congestion, long-standing serous PED, and pre-existing defects in Bruch's membrane due to chronic RPE changes, may be a risk factor for the development of CNV. Demircan et al[12] reported that choriocapillaris perfusion seemed to decrease in the very early period following half-fluence PDT and returned to normal after 1 month of therapy. Therefore, half-dose PDT may further exacerbate the already compromised choriocapillaries and increase the incidence of CNV. Undoubtedly, the risk does not outweigh the benefits of optimized PDT for the treatment of CSC. However, patients undergoing PDT with relatively good vision should be warned of this rare complication.
Another rare complication secondary to PDT, which needs to be distinguished from secondary CNV, is PDT-induced acute exudative maculopathy (PAEM).[13] PAEM is defined as a massive subretinal serofibrinous exudation with or without acute severe vision impairment.[14] It occurs within days after PDT but has a self-resolving course and favorable prognosis. PAEM is rarely reported after treatment of chronic CSC, with only 3 cases reported in the literature. The pathogenesis includes breakdown of the blood-retinal barrier, RPE pump dysfunction, and inflammatory surge of VEGF occurring after PDT. OCTA is a useful tool to distinguish PAEM from CNV.
To summarize, CNV secondary to half-dose PDT for chronic CSC after a quite short course of treatment is rare. Considering an otherwise favorable prognosis for CSC treatment, patients with chronic CSC who undergo PDT should be warned of this rare complication. Fortunately, it can be successfully treated by intravitreal injection of anti-VEGF agents.
4 Disclosure
The Institutional Review Board of the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University approved the protocol, and our study was performed in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and all accompanying images. There is no conflict of interest exists in the submission of this manuscript, and manuscript is approved by all authors for publication.
Author contributions
ZWZ, XNB and JZ collected the clinical information of the patient, analyzed and interpreted the clinical data. ZWZ wrote the drafting of this manuscript. ZFW and JZ reviewed and edited the manuscript. JZ was responsible for supervision. All authors read and approved the final manuscript.
Conceptualization: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Funding acquisition: Zhengwei Zhang.
Supervision: Jie Zhang.
Validation: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Writing – original draft: Zhengwei Zhang.
Writing – review & editing: Zhifeng Wu, Jie Zhang.
Abbreviations: BCVA = best-corrected visual acuity, CNV = choroidal neovascularization, CSC = central serous chorioretinopathy, FFA = fluorescein fundus angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = optical coherence tomography angiography, PAEM = PDT-induced acute exudative maculopathy, PDT = photodynamic therapy, PED = pigment epithelium detachment, RPE = retinal pigment epithelium, VEGF = vascular endothelial growth factor.
How to cite this article: Zhang Z, Bao X, Wu Z, Zhang J. Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: a case report. Medicine. 2021;100:7(e24790).
This study was supported by the fund of Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (Grant No. HB2020030) and the Development Fund of Wuxi Science and Technology (Grant No. WX18IIAN019).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | Recovered | ReactionOutcome | CC BY | 33607835 | 18,984,537 | 2021-02-19 |
What was the outcome of reaction 'Retinal haemorrhage'? | Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: A case report.
BACKGROUND
Half-dose or reduced-fluence photodynamic therapy (PDT) with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications. However, we report a case of chronic central serous chorioretinopathy (CSC) who developed choroidal neovascularization (CNV) secondary to half-dose PDT within only 3 weeks. Such an occurrence following this short a course of treatment has not been reported previously.
A 46-year-old Chinese man who had been diagnosed as acute more than 1 year ago revisited our department recently and complained of blurred vision again in his left eye.
Fluorescein fundus angiography (FFA) and indocyanine green angiography (ICGA) revealed patchy hyperfluorescent dots and optical coherence tomography (OCT) indicated irregular flat pigment epithelium detachment (PED) in the central macula. The patient was diagnosed with chronic CSC.
METHODS
The patient was treated by half-dose PDT with verteporfin. Three weeks later, the patient complained of sudden blurred vision and fundus examination showed macular hemorrhages with a best-corrected visual acuity (BCVA) of 20/250. OCT angiography (OCTA) showed a distinct area of flower-like CNV located within the deep retinal slab. Secondary CNV had developed after a quite short course of half-dose PDT treatment. Subsequently, the patient was administered by 2 intravitreal injections of aflibercept (2 mg).
RESULTS
Two months after the second intravitreal injection, macular hemorrhages and secondary CNV were completely resolved, and the BCVA improved to 20/25.
CONCLUSIONS
Patients of chronic CSC with irregular PED who undergo PDT should be warned of secondary CNV within a short course after treatment. If happened, it should be treated by intravitreal injections of anti-vascular endothelial growth factor agents as soon as possible.
pmc1 Introduction
Central serous chorioretinopathy (CSC) is a common vision-threatening chorioretinal disease that causes idiopathic serous detachment of the retina, which primarily affects males aged 20 to 60 years.[1] Pathogenesis of CSC is incompletely understood due to its multifactorial etiology and wide systemic associations. However, choroidal hyper-perfusion and hyperpermeability are known to play a major role.[2] Photodynamic therapy (PDT) induces choroidal vascular remodeling and decreases choroidal permeability, and is advocated for the treatment of CSC.[3]
A widely reported complication of standard PDT is secondary choroidal neovascularization (CNV).[4] Its mechanism is attributed to the pro-inflammatory effect, choriocapillaris occlusion, and significant reduction in chorioretinal perfusion caused by PDT. Subsequently, half-dose or reduced-fluence PDT with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications.[5,6] Despite this, some rare but severe complications are inevitable.
Recently, a study reported high rates of CNV, detected using optical coherence tomography angiography (OCTA), associated with chronic CSC after half-dose PDT with a mean period of 39.5 months. [7] However, development of CNV, secondary to half-dose PDT for chronic CSC after a short course of treatment, is rare. Here, we report a patient of chronic CSC with serous pigment epithelium detachment (PED) whose visual acuity decreased abruptly due to CNV and macular hemorrhage, following a half-dose PDT, within 3 weeks of the intervention. Fortunately, this case was treated successfully with 2 intravitreal injections of aflibercept (2 mg).
2 Case presentation
More than 1 year ago, a 46-year-old Chinese man presented to our department with blurred vision in his left eye. At the time, he was diagnosed with acute central serous chorioretinopathy. Oral medications were prescribed; however, he was lost to follow-up. He had excellent uncorrected distance acuity (20/20 in both eyes). Records of optical coherence tomography (OCT) B-scan showed neurosensory detachment at the central macula.
He revisited our department recently and complained of blurred vision again since 1 month. At this visit, he underwent a complete ophthalmic examination, including slitlamp biomicroscopy, best-corrected visual acuity (BCVA), non-contact tonometry, detailed fundus examination, fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA), OCT, and OCTA.
The BCVA was 20/20 OD and 20/25 OS. Intraocular pressure was within normal limits, and anterior segment examination was unremarkable in both eyes. Fundus examination of the right eye was normal, but the left eye showed a shallow sensory detachment in the macula (Fig. 1A). On FFA, the lesion revealed patchy hyperfluorescent dots temporal to the fovea in the early and late phases (Fig. 1B). ICGA also revealed patchy hyperfluorescent dots in the middle and late phases (Fig. 1C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at the first visit (Fig. 1D) and subsequent visit (Fig. 1E). OCTA, reported to be useful for identifying hidden CNVs that could not be found via FA and ICGA, did not show a distinct CNV (Fig. 1F).
Figure 1 Multimodal imaging before treatment Fundus photograph showing a shallow sensory detachment in the macula (yellow arrows) in the left eye (A). The lesion revealed patchy hyperfluorescent dots temporal to the fovea in the late phase of FFA (B) and ICGA (C). OCT B-scan showed a dome-shaped serous detachment of the neurosensory retina and a flat serous PED at both the initial visit (D) and this visit (E). OCTA did not detect a distinct CNV (F).
The patient was diagnosed with chronic CSC. Treatment employed was half-dose PDT with verteporfin. Fifteen minutes after the start of the intravenous infusion of verteporfin (3 mg/m2), a 689 nm laser was delivered (600 mW/cm2; 83 s). The delivered radiation covered the hyperfluorescent area of the corresponding serous subfoveal PED in the middle or late phase of the ICGA. Three weeks later, the patient complained of sudden blurred vision and revisited our department. Fundus examination showed macular hemorrhages (Fig. 2A) with a BCVA of 20/250. OCTA showed a distinct area of flower-like CNV located within the deep retinal slab (Fig. 2B). OCT B-scan revealed subretinal hyperreflective material corresponding to the CNV complex located above the retinal pigment epithelium (RPE) (Fig. 2C). Unfortunately, secondary CNV had developed after half-dose PDT in this case.
Figure 2 Multimodal imaging after half-dose PDT Fundus photograph showing macular hemorrhages approximately 3 weeks after treatment (A). OCTA showing a distinct area of flower-like CNV located within the deep retinal slab (B). OCT B-scan displaying subretinal hyperreflective material corresponding to the CNV complex located above the RPE (C). Three months after two intravitreal injections of aflibercept (2 mg), macular hemorrhages were completely resolved in the fundus (D) and the CNV did not recur in the OCTA image (E), but a small PED was still present on the OCT B-scan (F).
Next day, intravitreal injection of aflibercept (2 mg) was administered. One month later, the patient's symptoms were relieved and his BCVA improved to 20/100. Fundus examination revealed almost complete resolution of macular hemorrhages. OCTA showed the CNV had completely disappeared. To consolidate treatment, a second intravitreal injection of aflibercept (2 mg) was administered. Two months later, the BCVA improved to 20/25. Macular hemorrhages were completely resolved in the fundus (Fig. 2D) The CNV did not recur in the OCTA image (Fig. 2E), but a small PED was present on the OCT B-scan (Fig. 2F).
3 Discussion
Although PDT with verteporfin was originally developed for treating CNV secondary to age-related macular degeneration, it was soon used as an important treatment modality for chronic CSC.[6,8] Full-dose PDT with verteporfin (6 mg/m2 intravenously) used in CSC may sometimes, cause severe complications that are unacceptable for a disease with relatively favorable prognosis. Verteporfin dye might accumulate selectively around the choroidal hyper-permeable area owing to slow blood flow and vascular congestion, which may lead to irreversible occlusion of the choroidal vessels.[9] Additionally, PDT may cause RPE alterations and induce the release of vascular endothelial growth factor (VEGF), contributing to the development of CNV.[10]
Many studies have recommended half-dose or reduced-fluence PDT for treating CSC. [5] More recently, Wu et al[7] reported high rates of CNV associated with chronic CSC after half-dose PDT with a mean period of 39.5 months (range: 4–138 months) from treatment to OCTA examination. However, the development of CNV secondary to half-dose PDT within 1 month of treatment is rare. Hwang et al[11] reported 1 such case of chronic CSC developed secondary CNV and subretinal hemorrhages 1 month after reduced-fluence PDT (30 mJ/cm2). In their case, the PED was small and dome-shaped under the fovea before treatment. Fortunately, their patient recovered his vision after 2 intravitreal bevacizumab injections.
In our case, we employed half-dose PDT (3 mg/m2), reported to result in favorable outcomes with less risk of complications.[5] Unfortunately, secondary CNV developed 3 weeks post-treatment. To the best of our knowledge, such an occurrence following this short a course of treatment has not been reported previously. Although the pathophysiology of CSC is poorly understood, it is reasonable to apply optimized PDT at the area of choroidal congestion and RPE leakage, thus preventing the disease from developing. Choriocapillary thinning secondary to the underlying choroidal congestion, long-standing serous PED, and pre-existing defects in Bruch's membrane due to chronic RPE changes, may be a risk factor for the development of CNV. Demircan et al[12] reported that choriocapillaris perfusion seemed to decrease in the very early period following half-fluence PDT and returned to normal after 1 month of therapy. Therefore, half-dose PDT may further exacerbate the already compromised choriocapillaries and increase the incidence of CNV. Undoubtedly, the risk does not outweigh the benefits of optimized PDT for the treatment of CSC. However, patients undergoing PDT with relatively good vision should be warned of this rare complication.
Another rare complication secondary to PDT, which needs to be distinguished from secondary CNV, is PDT-induced acute exudative maculopathy (PAEM).[13] PAEM is defined as a massive subretinal serofibrinous exudation with or without acute severe vision impairment.[14] It occurs within days after PDT but has a self-resolving course and favorable prognosis. PAEM is rarely reported after treatment of chronic CSC, with only 3 cases reported in the literature. The pathogenesis includes breakdown of the blood-retinal barrier, RPE pump dysfunction, and inflammatory surge of VEGF occurring after PDT. OCTA is a useful tool to distinguish PAEM from CNV.
To summarize, CNV secondary to half-dose PDT for chronic CSC after a quite short course of treatment is rare. Considering an otherwise favorable prognosis for CSC treatment, patients with chronic CSC who undergo PDT should be warned of this rare complication. Fortunately, it can be successfully treated by intravitreal injection of anti-VEGF agents.
4 Disclosure
The Institutional Review Board of the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University approved the protocol, and our study was performed in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and all accompanying images. There is no conflict of interest exists in the submission of this manuscript, and manuscript is approved by all authors for publication.
Author contributions
ZWZ, XNB and JZ collected the clinical information of the patient, analyzed and interpreted the clinical data. ZWZ wrote the drafting of this manuscript. ZFW and JZ reviewed and edited the manuscript. JZ was responsible for supervision. All authors read and approved the final manuscript.
Conceptualization: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Funding acquisition: Zhengwei Zhang.
Supervision: Jie Zhang.
Validation: Zhengwei Zhang, Xiaona Bao, Zhifeng Wu, Jie Zhang.
Writing – original draft: Zhengwei Zhang.
Writing – review & editing: Zhifeng Wu, Jie Zhang.
Abbreviations: BCVA = best-corrected visual acuity, CNV = choroidal neovascularization, CSC = central serous chorioretinopathy, FFA = fluorescein fundus angiography, ICGA = indocyanine green angiography, OCT = optical coherence tomography, OCTA = optical coherence tomography angiography, PAEM = PDT-induced acute exudative maculopathy, PDT = photodynamic therapy, PED = pigment epithelium detachment, RPE = retinal pigment epithelium, VEGF = vascular endothelial growth factor.
How to cite this article: Zhang Z, Bao X, Wu Z, Zhang J. Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: a case report. Medicine. 2021;100:7(e24790).
This study was supported by the fund of Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (Grant No. HB2020030) and the Development Fund of Wuxi Science and Technology (Grant No. WX18IIAN019).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | Recovered | ReactionOutcome | CC BY | 33607835 | 18,984,537 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Enterocolitis'. | Treatment with Ramucirumab-paclitaxel in a metastatic gastric cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Ramucirumab, a human Ig 1 monoclonal antibody against vascular endothelial growth factor receptor-2, in combination with paclitaxel is a second-line chemotherapy for patients with metastatic gastric cancer. Several reports have suggested that dose adjustments of cetuximab, an anti- epidermal growth factor receptor antibody, are not required in patients with renal impairment. However, the combination chemotherapy of ramucirumab and cytotoxic drug for hemodialysis (HD) patients has not been reported.
A 65-year-old man on HD was diagnosed with gastric cancer and underwent a subtotal gastrectomy with D2 lymphadenectomy. Abdominal computed tomography (CT) was examined after completion of 8 cycles of adjuvant chemotherapy with capecitabine combination oxaliplatin.
METHODS
The patient was diagnosed with advanced gastric cancer at stage IIIb (pT3N2M0) 11 months ago. Unfortunately, 9 months after the start of adjuvant chemotherapy, multiple liver metastases from gastric cancer were found by abdominal CT.
METHODS
He began receiving weekly paclitaxel(80 mg/m2) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week.
RESULTS
He was treated with ramucirumab without dose adjustment. The metastatic liver mass had a partial response, after 2 and 4 cycles of chemotherapy and had a stable disease up to 12 cycles of chemotherapy. No obvious adverse effect was observed during treatment. However, after 14 cycles chemotherapy, follow-up abdominal CT revealed progression disease of multiple liver metastasis and lymph nodes invasion.
CONCLUSIONS
The paclitaxel chemotherapy with ramucirumab is effective and safe in HD patients with metastatic gastric cancer. As seen in patients with normal kidney function, ramucirumab can be safely administered without a dose reduction.
pmc1 Introduction
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death and high mortality.[1,2] Currently, chemotherapy based on a combination of fluoropyrimidines and platinum compounds is the standard treatment in first-line therapy.[3] Based on the result of a randomized phase III trials, ramucirumab monotherapy or in combination with paclitaxel was proven safe and effective for patients with metastatic gastric cancer progressed after a first-line of chemotherapy.[4,5]
Ramucirumab is a human IgG 1 monoclonal antibody against vascular endothelial growth factor receptor-2 that prevents ligand binding and receptor-mediated pathway activation in endothelial cells, resulting in the inhibition of angiogenesis.[6].
However, there is no data on ramucirumab therapy in patients undergoing chronic hemodialysis (HD). We herein report the first case of a metastatic gastric cancer patient on HD who was successfully treated with ramucirumab combination paclitaxel.
2 Case presentation
A 65-year-old man was undergoing peritoneal dialysis for chronic renal failure due to Focal segmental glomerulosclerosis 5 years previously and had switched to HD 3 times weekly beginning 3 years previously. He also had coexisting diseases, including hypertension. He complained of melena and hematochezia, and endoscopy identified a Her-2-negative poorly differentiated adenocarcinoma in the gastric body. He underwent subtotal gastrectomy with D2 lymphadenectomy, which led to a diagnosis of stage IIIb (pT3N2M0) gastric adenocarcinoma.
The patient started receiving chemotherapy in our hospital from May 2018. Initially, he received adjuvant chemotherapy with capecitabine 500 mg/m2 (50% of the standard dose of 1000 mg/m2) combination oxaliplatin 65 mg/m2 (50% of the standard dose of 130 mg/m2) every 3weeks. Chemotherapy was administered in the morning and he received HD on same day in the afternoon.
However, after completion of 8 cycles of chemotherapy, abdominal computed tomography (CT) examination revealed multiple liver metastasis. (Fig. 1) In Feb 2019, for progressed disease, second-line chemotherapy was started. At that time, his Eastern Cooperative Oncology Group performance status, body surface area, and body weight was 1, 1.59m2, and 57 kg, respectively. He began receiving weekly paclitaxel (80 mg/m2) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week. Because the patient had HD at another hospital, renal monitoring and drug trough levels monitoring could not be confirmed.
Figure 1 Abdominal computed tomography showed mutiple targetoid masses in both lobe of the liver (arrow). The largest 1 is 2.4 cm in S6 subcapsular area (arrow head).
On day 1 after cycle 2 chemotherapy, he developed grade 3 neutropenia (according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0).[7] The dose of paclitaxel was reduced up to 75% from the next cycle. After cycle 2 and cycle 4 of chemotherapy, abdominal CT was done to confirm the effectiveness of chemotherapy (Fig. 2A, B). While the liver metastatic mass expanded to 24 mm in diameter at beginning of chemotherapy, the mass reduced to 18 mm after 2 cycles of chemotherapy and subcentimeter sized (3 mm) after 4 cycles of chemotherapy. According to the Response Evaluation Criteria in Solid Tumor guidelines, we evaluated the patient as having a partial response.
Figure 2 Computed tomography images show the liver metastasis. (A) At the start of chemotherapy; (B) after 2 cycles; (C) after 4 cycles; (D) after 6 cycles; (E) after 9 cycles; and (F) after 12 cycles of chemotherapy. While the liver metastatic mass expanded to 24 mm in diameter at beginning of chemotherapy, the mass reduced to subcentimeter sized (3 mm) after 4 cycles of chemotherapy.
For the sixth course of chemotherapy, because he developed grade 3 neutropenia despite the 25% reduction in dose, we further reduced the dose of paclitaxel on 60% and paclitaxel was skipped on days 8 from the next cycle in November 2019. After that, his metastatic liver tumor showed a stable disease, (Fig. 2 C–F) and he received 8 cycles of chemotherapy at that dose.
After cycle fourteen chemotherapy in July 2020, the progression of liver metastasis happened 16months after the second-line chemotherapy. Abdominal CT revealed progression disease of multiple liver metastasis and multiple small lymph nodes in the celiac axis, left gastric area, aortocaval area, left paraortic area. In August 2020, third-line chemotherapy was started with irinotecan (180 mg/m2). After cycle 1 chemotherapy, he was admitted to our department for neutropenic fever (ANC 80/uL), finally, he diagnosed enterocolitis and treated with antibiotics. After that, the third-line chemotherapy was stopped and he was received supportive care until October 2020. Since then, the patient has no longer visited our hospital.
3 Discussion
Recently, the phase 3 REGARD trial identified a new agent for second-line chemotherapy – ramucirumab, anti- vascular endothelial growth factor receptor-2 antibody.[4] Follow up phase 3 RAINBOW trial ramucirumab plus paclitaxel significant extended second-line overall survival (OS; medican 9.6 vs 7.4 months; hazard ratio [HR] = 0.807; P = .017) and progression-free survival (PFS; medican 4.4 vs 2.9 months; HR = 0.635; P < .0001) over placebo-paclitaxel.[5] Based on these results, we selected ramucirumab in combination with paclitaxel in second-line treatment for patients with advanced gastric cancer. Although the number of patients undergoing HD has been increasing to date, the guidelines for the management of chemotherapy in cancer patients undergoing HD have not yet been established. Renal dysfunction is not uncommon in cancer patients. However, patients with renal dysfunction are excluded from many clinical trials. Therefore, there is little data on the efficacy of all chemotherapy drugs in patients with renal impairment, and no recommendation for dosage and administration.
To the best of our knowledge, this is the first case of examining a combination of ramucirumab and paclitaxel for a patients undergoing HD.
Table 1 lists the published cases involving therapy with antiepidermal growth factor receptor antibody (ie, cetuximab, panitumumab) or anti VEGF antibody (ie, bevacizumab) in patients receiving HD.[8–11]
Table 1 Summary of data from previous case reports.
Cancer Age Gender Regimen Dose of anti-(V)EGFR antibody Efficacy Adverse events with anti-(V)EGFR antibody Reference
Colorectal cancer 65 Male mFOLFOX6 and bevacizumab Full dose Partial response Not described [8]
Colorectal cancer 71 Male mFOLFOX6 and bevacizumab Full dose Stable disease Not described [8]
Colorectal cancer 71 Female mFOLFOX6 and bevacizumab Full dose Progressive disease Not described [8]
Colorectal cancer 68 Male Cetuximab and irinotecan Full dose Partial response Not described [9]
Colorectal cancer 66 Male Cetuximab monotherapy Full dose Partial response Not described [10]
Colorectal cancer 62 Female mFOLFOX6 and panitumumab Full dose Partial response Grade 1 acneiform rash [11]
The administration of ramucirumab in patients with renal impairment has not yet been reported, but pharmacokinetic behavior appears similar to cetuximab. The previous cases HD cancer patients treated with cetuximab suggested its safety, efficacy and no necessity for dose reduction.[9,10] Another report analyzing the pharmacokinetics of cetuximab has shown that it can be safely used in patients with renal impairment without dose adjustment.[12]
Kobayashi et al[11] showed that chemotherapy with panitumumab, a fully human IgG2 monoclonal antibody against epidermal growth factor receptor, is safe and effective in cancer patient with chronic kidney disease on HD.
Lisa O’brien et al[13] reports about population pharmacokinetic meta-analysis of ramucirumab in cancer patients. This report showed that weight-normalized dosing regimen is appropriate for ramucirumab therapy, and dose adjustment was not required for patients with mild to moderate renal impairment or mild hepatic impairment. However, ramucirumab clearance in HD has not yet been analyzed.
In our case, ramucirumab was administered without a dose reduction and no side effects were observed. Although the mechanism is slightly different, ramucirumab can be safely used in patients with renal impairment, but further investigations involving drug clearance are required.
In terms of the efficacy of combined chemotherapy ramucirumab and paclitaxel, the mPFS and OS were 4.4 months and 9.6 months, respectively, in the RAINBOW trial.[5] For our patient, the PFS was about 17 months, so we believe that combination chemotherapy with ramucirumab and paclitaxel is effective for patient undergoing HD compared to previous reports.
In conclusion, combination chemotherapy with ramucirumab was safe and effective in patients with chronic kidney disease undergoing HD, similar to that seen in patients with normal renal function. However, it is necessary to determine the dosage and administration through additional pharmacodynamic therapy.
Author contributions
Conceptualization: Min Joo Yang, Young Mi Seol, Young Jin Choi, Hyo Jeong Kim, Do Young Kim.
Investigation: Min Joo Yang, Hyo Jeong Kim, Do Young Kim.
Supervision: Young Mi Seol, Young Jin Choi.
Writing – original draft: Min Joo Yang.
Writing – review & editing: Young Mi Seol.
Abbreviations: CT = computed tomography, HD = hemodialysis.
How to cite this article: Yang MJ, Choi YJ, Kim HJ, Kim DY, Seol YM. Treatment with Ramucirumab-paclitaxel in a metastatic gastric cancer patient undergoing hemodialysis: A case report. Medicine. 2021;100:7(e24795).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
Written informed consent was obtained from the patient for publication of the case details and accompanying images. As this is a case report, ethics approval was not required for this document.
The authors have no funding and conflicts of interests to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
EGFR = epidermal growth factor receptor, VEGFR-2 = vascular endothelial growth factor receptor-2. | IRINOTECAN | DrugsGivenReaction | CC BY | 33607838 | 18,995,994 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Febrile neutropenia'. | Treatment with Ramucirumab-paclitaxel in a metastatic gastric cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Ramucirumab, a human Ig 1 monoclonal antibody against vascular endothelial growth factor receptor-2, in combination with paclitaxel is a second-line chemotherapy for patients with metastatic gastric cancer. Several reports have suggested that dose adjustments of cetuximab, an anti- epidermal growth factor receptor antibody, are not required in patients with renal impairment. However, the combination chemotherapy of ramucirumab and cytotoxic drug for hemodialysis (HD) patients has not been reported.
A 65-year-old man on HD was diagnosed with gastric cancer and underwent a subtotal gastrectomy with D2 lymphadenectomy. Abdominal computed tomography (CT) was examined after completion of 8 cycles of adjuvant chemotherapy with capecitabine combination oxaliplatin.
METHODS
The patient was diagnosed with advanced gastric cancer at stage IIIb (pT3N2M0) 11 months ago. Unfortunately, 9 months after the start of adjuvant chemotherapy, multiple liver metastases from gastric cancer were found by abdominal CT.
METHODS
He began receiving weekly paclitaxel(80 mg/m2) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week.
RESULTS
He was treated with ramucirumab without dose adjustment. The metastatic liver mass had a partial response, after 2 and 4 cycles of chemotherapy and had a stable disease up to 12 cycles of chemotherapy. No obvious adverse effect was observed during treatment. However, after 14 cycles chemotherapy, follow-up abdominal CT revealed progression disease of multiple liver metastasis and lymph nodes invasion.
CONCLUSIONS
The paclitaxel chemotherapy with ramucirumab is effective and safe in HD patients with metastatic gastric cancer. As seen in patients with normal kidney function, ramucirumab can be safely administered without a dose reduction.
pmc1 Introduction
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death and high mortality.[1,2] Currently, chemotherapy based on a combination of fluoropyrimidines and platinum compounds is the standard treatment in first-line therapy.[3] Based on the result of a randomized phase III trials, ramucirumab monotherapy or in combination with paclitaxel was proven safe and effective for patients with metastatic gastric cancer progressed after a first-line of chemotherapy.[4,5]
Ramucirumab is a human IgG 1 monoclonal antibody against vascular endothelial growth factor receptor-2 that prevents ligand binding and receptor-mediated pathway activation in endothelial cells, resulting in the inhibition of angiogenesis.[6].
However, there is no data on ramucirumab therapy in patients undergoing chronic hemodialysis (HD). We herein report the first case of a metastatic gastric cancer patient on HD who was successfully treated with ramucirumab combination paclitaxel.
2 Case presentation
A 65-year-old man was undergoing peritoneal dialysis for chronic renal failure due to Focal segmental glomerulosclerosis 5 years previously and had switched to HD 3 times weekly beginning 3 years previously. He also had coexisting diseases, including hypertension. He complained of melena and hematochezia, and endoscopy identified a Her-2-negative poorly differentiated adenocarcinoma in the gastric body. He underwent subtotal gastrectomy with D2 lymphadenectomy, which led to a diagnosis of stage IIIb (pT3N2M0) gastric adenocarcinoma.
The patient started receiving chemotherapy in our hospital from May 2018. Initially, he received adjuvant chemotherapy with capecitabine 500 mg/m2 (50% of the standard dose of 1000 mg/m2) combination oxaliplatin 65 mg/m2 (50% of the standard dose of 130 mg/m2) every 3weeks. Chemotherapy was administered in the morning and he received HD on same day in the afternoon.
However, after completion of 8 cycles of chemotherapy, abdominal computed tomography (CT) examination revealed multiple liver metastasis. (Fig. 1) In Feb 2019, for progressed disease, second-line chemotherapy was started. At that time, his Eastern Cooperative Oncology Group performance status, body surface area, and body weight was 1, 1.59m2, and 57 kg, respectively. He began receiving weekly paclitaxel (80 mg/m2) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week. Because the patient had HD at another hospital, renal monitoring and drug trough levels monitoring could not be confirmed.
Figure 1 Abdominal computed tomography showed mutiple targetoid masses in both lobe of the liver (arrow). The largest 1 is 2.4 cm in S6 subcapsular area (arrow head).
On day 1 after cycle 2 chemotherapy, he developed grade 3 neutropenia (according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0).[7] The dose of paclitaxel was reduced up to 75% from the next cycle. After cycle 2 and cycle 4 of chemotherapy, abdominal CT was done to confirm the effectiveness of chemotherapy (Fig. 2A, B). While the liver metastatic mass expanded to 24 mm in diameter at beginning of chemotherapy, the mass reduced to 18 mm after 2 cycles of chemotherapy and subcentimeter sized (3 mm) after 4 cycles of chemotherapy. According to the Response Evaluation Criteria in Solid Tumor guidelines, we evaluated the patient as having a partial response.
Figure 2 Computed tomography images show the liver metastasis. (A) At the start of chemotherapy; (B) after 2 cycles; (C) after 4 cycles; (D) after 6 cycles; (E) after 9 cycles; and (F) after 12 cycles of chemotherapy. While the liver metastatic mass expanded to 24 mm in diameter at beginning of chemotherapy, the mass reduced to subcentimeter sized (3 mm) after 4 cycles of chemotherapy.
For the sixth course of chemotherapy, because he developed grade 3 neutropenia despite the 25% reduction in dose, we further reduced the dose of paclitaxel on 60% and paclitaxel was skipped on days 8 from the next cycle in November 2019. After that, his metastatic liver tumor showed a stable disease, (Fig. 2 C–F) and he received 8 cycles of chemotherapy at that dose.
After cycle fourteen chemotherapy in July 2020, the progression of liver metastasis happened 16months after the second-line chemotherapy. Abdominal CT revealed progression disease of multiple liver metastasis and multiple small lymph nodes in the celiac axis, left gastric area, aortocaval area, left paraortic area. In August 2020, third-line chemotherapy was started with irinotecan (180 mg/m2). After cycle 1 chemotherapy, he was admitted to our department for neutropenic fever (ANC 80/uL), finally, he diagnosed enterocolitis and treated with antibiotics. After that, the third-line chemotherapy was stopped and he was received supportive care until October 2020. Since then, the patient has no longer visited our hospital.
3 Discussion
Recently, the phase 3 REGARD trial identified a new agent for second-line chemotherapy – ramucirumab, anti- vascular endothelial growth factor receptor-2 antibody.[4] Follow up phase 3 RAINBOW trial ramucirumab plus paclitaxel significant extended second-line overall survival (OS; medican 9.6 vs 7.4 months; hazard ratio [HR] = 0.807; P = .017) and progression-free survival (PFS; medican 4.4 vs 2.9 months; HR = 0.635; P < .0001) over placebo-paclitaxel.[5] Based on these results, we selected ramucirumab in combination with paclitaxel in second-line treatment for patients with advanced gastric cancer. Although the number of patients undergoing HD has been increasing to date, the guidelines for the management of chemotherapy in cancer patients undergoing HD have not yet been established. Renal dysfunction is not uncommon in cancer patients. However, patients with renal dysfunction are excluded from many clinical trials. Therefore, there is little data on the efficacy of all chemotherapy drugs in patients with renal impairment, and no recommendation for dosage and administration.
To the best of our knowledge, this is the first case of examining a combination of ramucirumab and paclitaxel for a patients undergoing HD.
Table 1 lists the published cases involving therapy with antiepidermal growth factor receptor antibody (ie, cetuximab, panitumumab) or anti VEGF antibody (ie, bevacizumab) in patients receiving HD.[8–11]
Table 1 Summary of data from previous case reports.
Cancer Age Gender Regimen Dose of anti-(V)EGFR antibody Efficacy Adverse events with anti-(V)EGFR antibody Reference
Colorectal cancer 65 Male mFOLFOX6 and bevacizumab Full dose Partial response Not described [8]
Colorectal cancer 71 Male mFOLFOX6 and bevacizumab Full dose Stable disease Not described [8]
Colorectal cancer 71 Female mFOLFOX6 and bevacizumab Full dose Progressive disease Not described [8]
Colorectal cancer 68 Male Cetuximab and irinotecan Full dose Partial response Not described [9]
Colorectal cancer 66 Male Cetuximab monotherapy Full dose Partial response Not described [10]
Colorectal cancer 62 Female mFOLFOX6 and panitumumab Full dose Partial response Grade 1 acneiform rash [11]
The administration of ramucirumab in patients with renal impairment has not yet been reported, but pharmacokinetic behavior appears similar to cetuximab. The previous cases HD cancer patients treated with cetuximab suggested its safety, efficacy and no necessity for dose reduction.[9,10] Another report analyzing the pharmacokinetics of cetuximab has shown that it can be safely used in patients with renal impairment without dose adjustment.[12]
Kobayashi et al[11] showed that chemotherapy with panitumumab, a fully human IgG2 monoclonal antibody against epidermal growth factor receptor, is safe and effective in cancer patient with chronic kidney disease on HD.
Lisa O’brien et al[13] reports about population pharmacokinetic meta-analysis of ramucirumab in cancer patients. This report showed that weight-normalized dosing regimen is appropriate for ramucirumab therapy, and dose adjustment was not required for patients with mild to moderate renal impairment or mild hepatic impairment. However, ramucirumab clearance in HD has not yet been analyzed.
In our case, ramucirumab was administered without a dose reduction and no side effects were observed. Although the mechanism is slightly different, ramucirumab can be safely used in patients with renal impairment, but further investigations involving drug clearance are required.
In terms of the efficacy of combined chemotherapy ramucirumab and paclitaxel, the mPFS and OS were 4.4 months and 9.6 months, respectively, in the RAINBOW trial.[5] For our patient, the PFS was about 17 months, so we believe that combination chemotherapy with ramucirumab and paclitaxel is effective for patient undergoing HD compared to previous reports.
In conclusion, combination chemotherapy with ramucirumab was safe and effective in patients with chronic kidney disease undergoing HD, similar to that seen in patients with normal renal function. However, it is necessary to determine the dosage and administration through additional pharmacodynamic therapy.
Author contributions
Conceptualization: Min Joo Yang, Young Mi Seol, Young Jin Choi, Hyo Jeong Kim, Do Young Kim.
Investigation: Min Joo Yang, Hyo Jeong Kim, Do Young Kim.
Supervision: Young Mi Seol, Young Jin Choi.
Writing – original draft: Min Joo Yang.
Writing – review & editing: Young Mi Seol.
Abbreviations: CT = computed tomography, HD = hemodialysis.
How to cite this article: Yang MJ, Choi YJ, Kim HJ, Kim DY, Seol YM. Treatment with Ramucirumab-paclitaxel in a metastatic gastric cancer patient undergoing hemodialysis: A case report. Medicine. 2021;100:7(e24795).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
Written informed consent was obtained from the patient for publication of the case details and accompanying images. As this is a case report, ethics approval was not required for this document.
The authors have no funding and conflicts of interests to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
EGFR = epidermal growth factor receptor, VEGFR-2 = vascular endothelial growth factor receptor-2. | IRINOTECAN | DrugsGivenReaction | CC BY | 33607838 | 18,995,994 | 2021-02-19 |
What is the weight of the patient? | Treatment with Ramucirumab-paclitaxel in a metastatic gastric cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Ramucirumab, a human Ig 1 monoclonal antibody against vascular endothelial growth factor receptor-2, in combination with paclitaxel is a second-line chemotherapy for patients with metastatic gastric cancer. Several reports have suggested that dose adjustments of cetuximab, an anti- epidermal growth factor receptor antibody, are not required in patients with renal impairment. However, the combination chemotherapy of ramucirumab and cytotoxic drug for hemodialysis (HD) patients has not been reported.
A 65-year-old man on HD was diagnosed with gastric cancer and underwent a subtotal gastrectomy with D2 lymphadenectomy. Abdominal computed tomography (CT) was examined after completion of 8 cycles of adjuvant chemotherapy with capecitabine combination oxaliplatin.
METHODS
The patient was diagnosed with advanced gastric cancer at stage IIIb (pT3N2M0) 11 months ago. Unfortunately, 9 months after the start of adjuvant chemotherapy, multiple liver metastases from gastric cancer were found by abdominal CT.
METHODS
He began receiving weekly paclitaxel(80 mg/m2) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week.
RESULTS
He was treated with ramucirumab without dose adjustment. The metastatic liver mass had a partial response, after 2 and 4 cycles of chemotherapy and had a stable disease up to 12 cycles of chemotherapy. No obvious adverse effect was observed during treatment. However, after 14 cycles chemotherapy, follow-up abdominal CT revealed progression disease of multiple liver metastasis and lymph nodes invasion.
CONCLUSIONS
The paclitaxel chemotherapy with ramucirumab is effective and safe in HD patients with metastatic gastric cancer. As seen in patients with normal kidney function, ramucirumab can be safely administered without a dose reduction.
pmc1 Introduction
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death and high mortality.[1,2] Currently, chemotherapy based on a combination of fluoropyrimidines and platinum compounds is the standard treatment in first-line therapy.[3] Based on the result of a randomized phase III trials, ramucirumab monotherapy or in combination with paclitaxel was proven safe and effective for patients with metastatic gastric cancer progressed after a first-line of chemotherapy.[4,5]
Ramucirumab is a human IgG 1 monoclonal antibody against vascular endothelial growth factor receptor-2 that prevents ligand binding and receptor-mediated pathway activation in endothelial cells, resulting in the inhibition of angiogenesis.[6].
However, there is no data on ramucirumab therapy in patients undergoing chronic hemodialysis (HD). We herein report the first case of a metastatic gastric cancer patient on HD who was successfully treated with ramucirumab combination paclitaxel.
2 Case presentation
A 65-year-old man was undergoing peritoneal dialysis for chronic renal failure due to Focal segmental glomerulosclerosis 5 years previously and had switched to HD 3 times weekly beginning 3 years previously. He also had coexisting diseases, including hypertension. He complained of melena and hematochezia, and endoscopy identified a Her-2-negative poorly differentiated adenocarcinoma in the gastric body. He underwent subtotal gastrectomy with D2 lymphadenectomy, which led to a diagnosis of stage IIIb (pT3N2M0) gastric adenocarcinoma.
The patient started receiving chemotherapy in our hospital from May 2018. Initially, he received adjuvant chemotherapy with capecitabine 500 mg/m2 (50% of the standard dose of 1000 mg/m2) combination oxaliplatin 65 mg/m2 (50% of the standard dose of 130 mg/m2) every 3weeks. Chemotherapy was administered in the morning and he received HD on same day in the afternoon.
However, after completion of 8 cycles of chemotherapy, abdominal computed tomography (CT) examination revealed multiple liver metastasis. (Fig. 1) In Feb 2019, for progressed disease, second-line chemotherapy was started. At that time, his Eastern Cooperative Oncology Group performance status, body surface area, and body weight was 1, 1.59m2, and 57 kg, respectively. He began receiving weekly paclitaxel (80 mg/m2) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week. Because the patient had HD at another hospital, renal monitoring and drug trough levels monitoring could not be confirmed.
Figure 1 Abdominal computed tomography showed mutiple targetoid masses in both lobe of the liver (arrow). The largest 1 is 2.4 cm in S6 subcapsular area (arrow head).
On day 1 after cycle 2 chemotherapy, he developed grade 3 neutropenia (according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0).[7] The dose of paclitaxel was reduced up to 75% from the next cycle. After cycle 2 and cycle 4 of chemotherapy, abdominal CT was done to confirm the effectiveness of chemotherapy (Fig. 2A, B). While the liver metastatic mass expanded to 24 mm in diameter at beginning of chemotherapy, the mass reduced to 18 mm after 2 cycles of chemotherapy and subcentimeter sized (3 mm) after 4 cycles of chemotherapy. According to the Response Evaluation Criteria in Solid Tumor guidelines, we evaluated the patient as having a partial response.
Figure 2 Computed tomography images show the liver metastasis. (A) At the start of chemotherapy; (B) after 2 cycles; (C) after 4 cycles; (D) after 6 cycles; (E) after 9 cycles; and (F) after 12 cycles of chemotherapy. While the liver metastatic mass expanded to 24 mm in diameter at beginning of chemotherapy, the mass reduced to subcentimeter sized (3 mm) after 4 cycles of chemotherapy.
For the sixth course of chemotherapy, because he developed grade 3 neutropenia despite the 25% reduction in dose, we further reduced the dose of paclitaxel on 60% and paclitaxel was skipped on days 8 from the next cycle in November 2019. After that, his metastatic liver tumor showed a stable disease, (Fig. 2 C–F) and he received 8 cycles of chemotherapy at that dose.
After cycle fourteen chemotherapy in July 2020, the progression of liver metastasis happened 16months after the second-line chemotherapy. Abdominal CT revealed progression disease of multiple liver metastasis and multiple small lymph nodes in the celiac axis, left gastric area, aortocaval area, left paraortic area. In August 2020, third-line chemotherapy was started with irinotecan (180 mg/m2). After cycle 1 chemotherapy, he was admitted to our department for neutropenic fever (ANC 80/uL), finally, he diagnosed enterocolitis and treated with antibiotics. After that, the third-line chemotherapy was stopped and he was received supportive care until October 2020. Since then, the patient has no longer visited our hospital.
3 Discussion
Recently, the phase 3 REGARD trial identified a new agent for second-line chemotherapy – ramucirumab, anti- vascular endothelial growth factor receptor-2 antibody.[4] Follow up phase 3 RAINBOW trial ramucirumab plus paclitaxel significant extended second-line overall survival (OS; medican 9.6 vs 7.4 months; hazard ratio [HR] = 0.807; P = .017) and progression-free survival (PFS; medican 4.4 vs 2.9 months; HR = 0.635; P < .0001) over placebo-paclitaxel.[5] Based on these results, we selected ramucirumab in combination with paclitaxel in second-line treatment for patients with advanced gastric cancer. Although the number of patients undergoing HD has been increasing to date, the guidelines for the management of chemotherapy in cancer patients undergoing HD have not yet been established. Renal dysfunction is not uncommon in cancer patients. However, patients with renal dysfunction are excluded from many clinical trials. Therefore, there is little data on the efficacy of all chemotherapy drugs in patients with renal impairment, and no recommendation for dosage and administration.
To the best of our knowledge, this is the first case of examining a combination of ramucirumab and paclitaxel for a patients undergoing HD.
Table 1 lists the published cases involving therapy with antiepidermal growth factor receptor antibody (ie, cetuximab, panitumumab) or anti VEGF antibody (ie, bevacizumab) in patients receiving HD.[8–11]
Table 1 Summary of data from previous case reports.
Cancer Age Gender Regimen Dose of anti-(V)EGFR antibody Efficacy Adverse events with anti-(V)EGFR antibody Reference
Colorectal cancer 65 Male mFOLFOX6 and bevacizumab Full dose Partial response Not described [8]
Colorectal cancer 71 Male mFOLFOX6 and bevacizumab Full dose Stable disease Not described [8]
Colorectal cancer 71 Female mFOLFOX6 and bevacizumab Full dose Progressive disease Not described [8]
Colorectal cancer 68 Male Cetuximab and irinotecan Full dose Partial response Not described [9]
Colorectal cancer 66 Male Cetuximab monotherapy Full dose Partial response Not described [10]
Colorectal cancer 62 Female mFOLFOX6 and panitumumab Full dose Partial response Grade 1 acneiform rash [11]
The administration of ramucirumab in patients with renal impairment has not yet been reported, but pharmacokinetic behavior appears similar to cetuximab. The previous cases HD cancer patients treated with cetuximab suggested its safety, efficacy and no necessity for dose reduction.[9,10] Another report analyzing the pharmacokinetics of cetuximab has shown that it can be safely used in patients with renal impairment without dose adjustment.[12]
Kobayashi et al[11] showed that chemotherapy with panitumumab, a fully human IgG2 monoclonal antibody against epidermal growth factor receptor, is safe and effective in cancer patient with chronic kidney disease on HD.
Lisa O’brien et al[13] reports about population pharmacokinetic meta-analysis of ramucirumab in cancer patients. This report showed that weight-normalized dosing regimen is appropriate for ramucirumab therapy, and dose adjustment was not required for patients with mild to moderate renal impairment or mild hepatic impairment. However, ramucirumab clearance in HD has not yet been analyzed.
In our case, ramucirumab was administered without a dose reduction and no side effects were observed. Although the mechanism is slightly different, ramucirumab can be safely used in patients with renal impairment, but further investigations involving drug clearance are required.
In terms of the efficacy of combined chemotherapy ramucirumab and paclitaxel, the mPFS and OS were 4.4 months and 9.6 months, respectively, in the RAINBOW trial.[5] For our patient, the PFS was about 17 months, so we believe that combination chemotherapy with ramucirumab and paclitaxel is effective for patient undergoing HD compared to previous reports.
In conclusion, combination chemotherapy with ramucirumab was safe and effective in patients with chronic kidney disease undergoing HD, similar to that seen in patients with normal renal function. However, it is necessary to determine the dosage and administration through additional pharmacodynamic therapy.
Author contributions
Conceptualization: Min Joo Yang, Young Mi Seol, Young Jin Choi, Hyo Jeong Kim, Do Young Kim.
Investigation: Min Joo Yang, Hyo Jeong Kim, Do Young Kim.
Supervision: Young Mi Seol, Young Jin Choi.
Writing – original draft: Min Joo Yang.
Writing – review & editing: Young Mi Seol.
Abbreviations: CT = computed tomography, HD = hemodialysis.
How to cite this article: Yang MJ, Choi YJ, Kim HJ, Kim DY, Seol YM. Treatment with Ramucirumab-paclitaxel in a metastatic gastric cancer patient undergoing hemodialysis: A case report. Medicine. 2021;100:7(e24795).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
Written informed consent was obtained from the patient for publication of the case details and accompanying images. As this is a case report, ethics approval was not required for this document.
The authors have no funding and conflicts of interests to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
EGFR = epidermal growth factor receptor, VEGFR-2 = vascular endothelial growth factor receptor-2. | 57 kg. | Weight | CC BY | 33607838 | 18,995,994 | 2021-02-19 |
What was the dosage of drug 'IRINOTECAN'? | Treatment with Ramucirumab-paclitaxel in a metastatic gastric cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Ramucirumab, a human Ig 1 monoclonal antibody against vascular endothelial growth factor receptor-2, in combination with paclitaxel is a second-line chemotherapy for patients with metastatic gastric cancer. Several reports have suggested that dose adjustments of cetuximab, an anti- epidermal growth factor receptor antibody, are not required in patients with renal impairment. However, the combination chemotherapy of ramucirumab and cytotoxic drug for hemodialysis (HD) patients has not been reported.
A 65-year-old man on HD was diagnosed with gastric cancer and underwent a subtotal gastrectomy with D2 lymphadenectomy. Abdominal computed tomography (CT) was examined after completion of 8 cycles of adjuvant chemotherapy with capecitabine combination oxaliplatin.
METHODS
The patient was diagnosed with advanced gastric cancer at stage IIIb (pT3N2M0) 11 months ago. Unfortunately, 9 months after the start of adjuvant chemotherapy, multiple liver metastases from gastric cancer were found by abdominal CT.
METHODS
He began receiving weekly paclitaxel(80 mg/m2) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week.
RESULTS
He was treated with ramucirumab without dose adjustment. The metastatic liver mass had a partial response, after 2 and 4 cycles of chemotherapy and had a stable disease up to 12 cycles of chemotherapy. No obvious adverse effect was observed during treatment. However, after 14 cycles chemotherapy, follow-up abdominal CT revealed progression disease of multiple liver metastasis and lymph nodes invasion.
CONCLUSIONS
The paclitaxel chemotherapy with ramucirumab is effective and safe in HD patients with metastatic gastric cancer. As seen in patients with normal kidney function, ramucirumab can be safely administered without a dose reduction.
pmc1 Introduction
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death and high mortality.[1,2] Currently, chemotherapy based on a combination of fluoropyrimidines and platinum compounds is the standard treatment in first-line therapy.[3] Based on the result of a randomized phase III trials, ramucirumab monotherapy or in combination with paclitaxel was proven safe and effective for patients with metastatic gastric cancer progressed after a first-line of chemotherapy.[4,5]
Ramucirumab is a human IgG 1 monoclonal antibody against vascular endothelial growth factor receptor-2 that prevents ligand binding and receptor-mediated pathway activation in endothelial cells, resulting in the inhibition of angiogenesis.[6].
However, there is no data on ramucirumab therapy in patients undergoing chronic hemodialysis (HD). We herein report the first case of a metastatic gastric cancer patient on HD who was successfully treated with ramucirumab combination paclitaxel.
2 Case presentation
A 65-year-old man was undergoing peritoneal dialysis for chronic renal failure due to Focal segmental glomerulosclerosis 5 years previously and had switched to HD 3 times weekly beginning 3 years previously. He also had coexisting diseases, including hypertension. He complained of melena and hematochezia, and endoscopy identified a Her-2-negative poorly differentiated adenocarcinoma in the gastric body. He underwent subtotal gastrectomy with D2 lymphadenectomy, which led to a diagnosis of stage IIIb (pT3N2M0) gastric adenocarcinoma.
The patient started receiving chemotherapy in our hospital from May 2018. Initially, he received adjuvant chemotherapy with capecitabine 500 mg/m2 (50% of the standard dose of 1000 mg/m2) combination oxaliplatin 65 mg/m2 (50% of the standard dose of 130 mg/m2) every 3weeks. Chemotherapy was administered in the morning and he received HD on same day in the afternoon.
However, after completion of 8 cycles of chemotherapy, abdominal computed tomography (CT) examination revealed multiple liver metastasis. (Fig. 1) In Feb 2019, for progressed disease, second-line chemotherapy was started. At that time, his Eastern Cooperative Oncology Group performance status, body surface area, and body weight was 1, 1.59m2, and 57 kg, respectively. He began receiving weekly paclitaxel (80 mg/m2) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week. Because the patient had HD at another hospital, renal monitoring and drug trough levels monitoring could not be confirmed.
Figure 1 Abdominal computed tomography showed mutiple targetoid masses in both lobe of the liver (arrow). The largest 1 is 2.4 cm in S6 subcapsular area (arrow head).
On day 1 after cycle 2 chemotherapy, he developed grade 3 neutropenia (according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0).[7] The dose of paclitaxel was reduced up to 75% from the next cycle. After cycle 2 and cycle 4 of chemotherapy, abdominal CT was done to confirm the effectiveness of chemotherapy (Fig. 2A, B). While the liver metastatic mass expanded to 24 mm in diameter at beginning of chemotherapy, the mass reduced to 18 mm after 2 cycles of chemotherapy and subcentimeter sized (3 mm) after 4 cycles of chemotherapy. According to the Response Evaluation Criteria in Solid Tumor guidelines, we evaluated the patient as having a partial response.
Figure 2 Computed tomography images show the liver metastasis. (A) At the start of chemotherapy; (B) after 2 cycles; (C) after 4 cycles; (D) after 6 cycles; (E) after 9 cycles; and (F) after 12 cycles of chemotherapy. While the liver metastatic mass expanded to 24 mm in diameter at beginning of chemotherapy, the mass reduced to subcentimeter sized (3 mm) after 4 cycles of chemotherapy.
For the sixth course of chemotherapy, because he developed grade 3 neutropenia despite the 25% reduction in dose, we further reduced the dose of paclitaxel on 60% and paclitaxel was skipped on days 8 from the next cycle in November 2019. After that, his metastatic liver tumor showed a stable disease, (Fig. 2 C–F) and he received 8 cycles of chemotherapy at that dose.
After cycle fourteen chemotherapy in July 2020, the progression of liver metastasis happened 16months after the second-line chemotherapy. Abdominal CT revealed progression disease of multiple liver metastasis and multiple small lymph nodes in the celiac axis, left gastric area, aortocaval area, left paraortic area. In August 2020, third-line chemotherapy was started with irinotecan (180 mg/m2). After cycle 1 chemotherapy, he was admitted to our department for neutropenic fever (ANC 80/uL), finally, he diagnosed enterocolitis and treated with antibiotics. After that, the third-line chemotherapy was stopped and he was received supportive care until October 2020. Since then, the patient has no longer visited our hospital.
3 Discussion
Recently, the phase 3 REGARD trial identified a new agent for second-line chemotherapy – ramucirumab, anti- vascular endothelial growth factor receptor-2 antibody.[4] Follow up phase 3 RAINBOW trial ramucirumab plus paclitaxel significant extended second-line overall survival (OS; medican 9.6 vs 7.4 months; hazard ratio [HR] = 0.807; P = .017) and progression-free survival (PFS; medican 4.4 vs 2.9 months; HR = 0.635; P < .0001) over placebo-paclitaxel.[5] Based on these results, we selected ramucirumab in combination with paclitaxel in second-line treatment for patients with advanced gastric cancer. Although the number of patients undergoing HD has been increasing to date, the guidelines for the management of chemotherapy in cancer patients undergoing HD have not yet been established. Renal dysfunction is not uncommon in cancer patients. However, patients with renal dysfunction are excluded from many clinical trials. Therefore, there is little data on the efficacy of all chemotherapy drugs in patients with renal impairment, and no recommendation for dosage and administration.
To the best of our knowledge, this is the first case of examining a combination of ramucirumab and paclitaxel for a patients undergoing HD.
Table 1 lists the published cases involving therapy with antiepidermal growth factor receptor antibody (ie, cetuximab, panitumumab) or anti VEGF antibody (ie, bevacizumab) in patients receiving HD.[8–11]
Table 1 Summary of data from previous case reports.
Cancer Age Gender Regimen Dose of anti-(V)EGFR antibody Efficacy Adverse events with anti-(V)EGFR antibody Reference
Colorectal cancer 65 Male mFOLFOX6 and bevacizumab Full dose Partial response Not described [8]
Colorectal cancer 71 Male mFOLFOX6 and bevacizumab Full dose Stable disease Not described [8]
Colorectal cancer 71 Female mFOLFOX6 and bevacizumab Full dose Progressive disease Not described [8]
Colorectal cancer 68 Male Cetuximab and irinotecan Full dose Partial response Not described [9]
Colorectal cancer 66 Male Cetuximab monotherapy Full dose Partial response Not described [10]
Colorectal cancer 62 Female mFOLFOX6 and panitumumab Full dose Partial response Grade 1 acneiform rash [11]
The administration of ramucirumab in patients with renal impairment has not yet been reported, but pharmacokinetic behavior appears similar to cetuximab. The previous cases HD cancer patients treated with cetuximab suggested its safety, efficacy and no necessity for dose reduction.[9,10] Another report analyzing the pharmacokinetics of cetuximab has shown that it can be safely used in patients with renal impairment without dose adjustment.[12]
Kobayashi et al[11] showed that chemotherapy with panitumumab, a fully human IgG2 monoclonal antibody against epidermal growth factor receptor, is safe and effective in cancer patient with chronic kidney disease on HD.
Lisa O’brien et al[13] reports about population pharmacokinetic meta-analysis of ramucirumab in cancer patients. This report showed that weight-normalized dosing regimen is appropriate for ramucirumab therapy, and dose adjustment was not required for patients with mild to moderate renal impairment or mild hepatic impairment. However, ramucirumab clearance in HD has not yet been analyzed.
In our case, ramucirumab was administered without a dose reduction and no side effects were observed. Although the mechanism is slightly different, ramucirumab can be safely used in patients with renal impairment, but further investigations involving drug clearance are required.
In terms of the efficacy of combined chemotherapy ramucirumab and paclitaxel, the mPFS and OS were 4.4 months and 9.6 months, respectively, in the RAINBOW trial.[5] For our patient, the PFS was about 17 months, so we believe that combination chemotherapy with ramucirumab and paclitaxel is effective for patient undergoing HD compared to previous reports.
In conclusion, combination chemotherapy with ramucirumab was safe and effective in patients with chronic kidney disease undergoing HD, similar to that seen in patients with normal renal function. However, it is necessary to determine the dosage and administration through additional pharmacodynamic therapy.
Author contributions
Conceptualization: Min Joo Yang, Young Mi Seol, Young Jin Choi, Hyo Jeong Kim, Do Young Kim.
Investigation: Min Joo Yang, Hyo Jeong Kim, Do Young Kim.
Supervision: Young Mi Seol, Young Jin Choi.
Writing – original draft: Min Joo Yang.
Writing – review & editing: Young Mi Seol.
Abbreviations: CT = computed tomography, HD = hemodialysis.
How to cite this article: Yang MJ, Choi YJ, Kim HJ, Kim DY, Seol YM. Treatment with Ramucirumab-paclitaxel in a metastatic gastric cancer patient undergoing hemodialysis: A case report. Medicine. 2021;100:7(e24795).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
Written informed consent was obtained from the patient for publication of the case details and accompanying images. As this is a case report, ethics approval was not required for this document.
The authors have no funding and conflicts of interests to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
EGFR = epidermal growth factor receptor, VEGFR-2 = vascular endothelial growth factor receptor-2. | CYCLE 1 | DrugDosageText | CC BY | 33607838 | 18,995,994 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myelosuppression'. | Neoadjuvant chemoradiotherapy for patients with unresectable radically locally advanced colon cancer: a potential improvement to overall survival and decrease to multivisceral resection.
BACKGROUND
The management of unresectable locally advanced colon cancer (LACC) remains controversial, as resection is not feasible. The goal of this study was to evaluate the treatment outcomes and toxicity of neoadjuvant chemoradiotherapy (NACRT) followed with surgery and adjuvant chemotherapy in patients with unresectable radically LACC.
METHODS
We included patients who were diagnosed at our institution, 2010-2018. The neoadjuvant regimen consisted of radiotherapy and capecitabine/ 5-fluorouracil-based chemotherapy.
RESULTS
One hundred patients were identified. The median follow-up time was 32 months. The R0 resection rate, adjusted nonmultivisceral resection rate and bladder preservation rate were 83.0, 43.0 and 83.3%, respectively. The pCR and clinical-downstaging rates were 18, and 81.0%%, respectively. The 3-year PFS and OS rates for all patients were 68.6 and 82.1%, respectively. Seventeen patients developed grade 3-4 myelosuppression, which was the most common adverse event observed after NACRT. Tumor perforation occurred in 3 patients during NACRT. The incidence of grade 3-4 surgery-related complications was 7.0%. Postoperative anastomotic leakage was observed in 3 patients.
CONCLUSIONS
NACRT followed by surgery was feasible and safe for selected patients with LACC, and can be used as a conversion treatment to achieve satisfactory downstaging, long-term survival and quality of life, with acceptable toxicities.
Introduction
Colon cancer is one of the most common cancers worldwide and accounted for approximately 6.1% of newly diagnosed cancers and 5.8% cancer-related deaths in 2018 [1]. Approximately 26% of patients with colon cancer present with a locally advanced disease [2]. In patients with locally advanced colon cancer, including patients with high-risk stage II or stage III disease, surgery and adjuvant chemotherapy are the standard treatments [3]. However, R0 resection is unable to be achieved in some patients with T4b, M0 or N2, M0 disease, even after multivisceral resection (MVR) [4]. Incomplete resection has not been shown to be beneficial [5]. Therefore, converting unresectable LACC to achieve radical resection may be essential to improve the quality of life and prolong the survival time of patients.
Neoadjuvant chemoradiotherapy (NACRT) has been well established as the standard therapy for locally advanced rectal cancer (LARC), and is related to a survival benefit and organ preservation [6]. The pathogenesis of colon and rectal cancer is similar. Thus, NACRT is worthy of investigation in patients with unresectable LACC. Actually, several reports with a small sample size have evaluated NACRT followed by radical surgery for LACC [7]. We also previously published several studies with small sample sizes [8, 9]. Results suggest that patients with LACC may benefit from NACRT. In the present study, we described the results of the administration of NACRT to patients with LACC over the last decade at a comprehensive cancer center.
Methods
Patient population and staging system
The study was designed to evaluate the value of the NACRT for patients with unresectable LACC. This observational study was approved by our institutional medical ethics committee (B2020–063-01). One hundred eligible patients were identified who were diagnosed at our hospital from November 1, 2010 to June 31, 2018. Patients were selected to undergo NACRT on a case-by-case basis through a consultation with a multidisciplinary team (MDT). The pretreatment evaluation, the definition of unresectability and key exclusion criteria were described in our previous reports [8, 9]. Patients with LACC (defined as the primary tumor having an inferior margin ≥15 cm from the anal verge, as determined by colonoscopy) were candidates for NACRT if they met the criteria listed in the Fig. 1a. Patients’ medical records were reviewed and demographic, oncological, and pathological information was collected. A Charlson comorbidity index score was generated for each patient after a review of the medical history [10]. All patients have signed the informed consent form before treatment.
Fig. 1 Flowchart of diagnosis of unresectable LACC (a) and Study profile (b). NACRT, Neoadjuvant chemoradiotherapy; EL, exploratory laparotomy; CME, complete mesocolic excision; MVR, multivisceral resection
The pretreatment clinical stage of all patients treated before 2017 were re-evaluated according to the 8th edition of the Union for American Joint Cancer Committee (AJCC) TNM staging system. Then the 8th edition of TNM staging was used for clinical staging in patients who were diagnosed after 2017. Patients with peritoneal carcinomatosis classified as M1c were excluded from this study. Chest/abdomen/pelvic computed tomography (CT), pelvic magnetic resonance image (MRI), serum chemical profile including carcinoembryonic antigen (CEA), and considering colonoscopy were performed after NACRT to assess the response of tumors.
Treatments and follow-up
Chemotherapy and radiotherapy, and surgery were described in detail in our previous reports [8]. Standard complete mesocolic excision (CME) would be performed after NACRT. When tumor infiltration or adhesion to the adjacent organs was detected intraoperatively, MVR was required. Radial margins were evaluated based on the pathological review principles of the NCCN guidelines. The formalin-fixed paraffin-embedded blocks of surgical samples from a portion of patients were tested for the MMR status using immunohistochemical staining for MLH1, MSH2, MSH6, and PMS2. Acute adverse events that occurred during or 30 days after NACRT were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) (version 4.03). Postoperative complications were assessed according to the Clavien-Dindo classification [11].
Follow-up visits were performed by a multidisciplinary team every 3 months in the first 2 years after treatment, every 6 months in the following 3 years, and then yearly thereafter. Afterwards the patients were followed by an outpatient interview or household registration system. The last follow-up time point was December 31, 2019.
Statistical analysis
Descriptive statistics were used to report patient, tumor, and treatment characteristics. Continuous data are presented as medians with interquartile ranges (IQRs). Categorical data are presented as numbers with percentages (%). Progression-free survival (PFS) was calculated from the initial diagnosis to the first disease progression or death. Overall survival (OS) was calculated from the diagnosis to the date of death. Disease-free survival (DFS) was calculated from the initial diagnosis to the first disease progression or death in the R0 group. The local recurrence (LR) rate was calculated in the R0 group. The distant metastasis (DM) rate was evaluated in all patients. The survival analysis was performed using R version 3.6.0. The packages ‘survival’ and ‘survminer’ were used for the survival analysis. Survival curves were also constructed by using R version 3.6.0. The multicollinearity regressions, the correlation matrix analysis, the Cox regression analysis, the Cox proportional hazard regression model were performed using STATA software (version 15). The multicollinearity regressions and a correlation matrix analysis were used to calculate the correlations between variables. Univariate and multivariate analyses were conducted to identify prognostic factors. A Cox regression analysis was used for univariate and multivariate analyses. The Cox proportional hazard regression model was used to estimate the hazard ratio (and corresponding 95% confidence interval [CI]) for each of the potential risk factors. A two-sided P-value < 0.05 was considered statistically significant.
Results
Characteristics and compliance
The study profile is shown in Fig. 1b. Patient characteristics, tumor staging and treatment details of the 100 patients with unresectable LACC are listed in Table 1. The pathological type of all patients was adenocarcinoma. All patients underwent colonoscopy and pathological biopsy at diagnosis. Eighty-four patients (84.0%) were diagnosed with stage cT4b tumors. The most common tumor location was the sigmoid colon (60/100, 60.0%), and bladder was the most commonly invaded organ (42/100, 42.0%). Fourteen (14/100, 14.0%) of these patients had a bladder fistula caused by tumor infiltration prior to the treatments. Meanwhile, 19 (19/100, 19.0%) patients had an intestinal obstruction at diagnosis. All patients received NACRT after the remission of the obstruction. Prophylactic enterostomy was performed in 27 (27/100, 27.0%) patients.
Table 1 Baseline pathological and clinical characteristics of patients
No. (%)
Age, median, years 54 (43–63)
≤65 84 (84.0%)
> 65 16 (16.0%)
Sex
Male 73 (73.0%)
Female 27 (27.0%)
KPS
90 78 (78.0%)
80 22 (22.0%)
BMI, median, 21.4 (19.5–23.6)
Primary tumor length, median, cm 7.4 (1.7–8.9)
Primary tumor location
Sigmoid colon 60 (60.0%)
Descending colon 3 (3.0%)
Transverse colon 10 (10.0%)
Ascending colon 25 (25.0%)
Ileocecus 2 (2.0%)
Tumor differentiation
High 20 (20.0%)
Moderate 65 (65.0%)
Low 15 (15.0%)
CEA pre-CRT, median, ng/ml 6.1 (3.0–21.3)
Complication
No 56 (56.0%)
Yes 44 (44.0%)
cT stage
T3 4 (4.0%)
T4a 12 (12.0%)
T4b 84 (84.0%)
cN stage
N0 1 (1.0%)
N1 36 (36.0%)
N2 63 (63.0%)
Clinical stage
IIC 1 (1.0%)
IIIB 16 (16.0%)
IIIC 83 (83.0%)
Involved organ
Bladder 42 (42.0%)
Ureter 12 (12.0%)
Renal and perirenal fat, prerenal space 6 (6.0%)
Pelvic wall 10 (10.0%)
Presacral space 2 (2.0%)
Abdominal wall 11 (11.0%)
Mesentery 2 (2.0%)
Great vessel 8 (8.0%)
Small intestine 26 (26.0%)
Greater omentum 5 (5.0%)
Gallbladder 6 (6.0%)
Liver 9 (9.0%)
Appendix 1 (1.0%)
Pancreas 2 (2.0%)
Uterus 6 (6.0%)
Vagina 1 (1.0%)
Seminal vesicle gland 3 (3.0%)
Vas deferens 2 (2.0%)
Iliopsoas muscle 1 (1.0%)
Bladder fistula/perforation
Yes 14 (14.0%)
No 86 (86.0%)
Intestinal obstruction
Yes 19 (19.0%)
No 81 (81.0%)
Family history
Yes 20 (20.0%)
No 80 (80.0%)
Charlson Comorbidity Score
0 82 (82.0%)
1 15 (15.0%)
2 2 (2.0%)
3 1 (1.0%)
MMR
dMMR 14 (22.6%)
pMMR 48 (77.4%)
Unknown 38
Abbreviations: KPS Karnofsky Performance Status, BMI Body Mass Index, cT stage Clinical T stage, cN stage Clinical N stage, MMR Mismatch repair phenotype
Neoadjuvant chemotherapy was a capecitabine/ 5FU-based regimen with a median cycles number of 4 (IQR 3–4). The sketching methods of GTV and CTV are described in our previous two articles [8, 9]. The dose of GTV is 46-54Gy/23–27 fractions. The dose of CTV is 41.4–46 Gy/23–27 fractions. Three patients developed colon cancer perforation during NACRT. Ninety-seven patients successfully received the allocated NACRT. 93 (93/100, 93.0%) patients underwent surgical treatment, and the other 7 (7/100, 7.0%) patients abandoned further surgical treatment after NACRT with treatment details shown in Supplementary Table 1.
Short-term efficacy
Among all patients receiving NACRT, 93 (93/100, 93.0%) patients underwent surgery with the goal of a radical operation (Supplementary Figure 1). The details of operations and pathological findings from the 93 patients are presented in the Table 2. In this cohort study, 89.25% (83/93) of the 93 patients who underwent surgery reached R0, and 81.0% (81/100) patients achieved downstaging after NACRT. The pCR rate was 18.0% (18/100).
Table 2 Treatment outcomes of operations and pathological findings
No. (%)
CEA preoperative, median, ng/ml 2.4 (1.5–4.1)
Surgery situation
R0 83 (89.2%)
R2 6 (6.5%)b
ELa 4 (4.3%)
Downstage T
Yes 65 (69.9%)
No 28 (30.1%)c
Downstage N
Yes 84 (90.3%)
No 9 (9.7%)c
Downstage
Yes 81 (87.1%)
No 12 (12.9%)c
MVR
Yes 44 (47.3%)
No 49 (52.7%)c
pCR
Yes 18 (19.4%)
No 75 (80.6%)c
Resection Surgery-Radiotherapy interval Median, d (range) 63.0 (55–76.5)
Abbreviations: ypT stage Postoperative pathological T stage, ypN stage Postoperative pathological N stage, MVR Multivisceral resection, pCR Pathological complete remission
aEL; btwo patients who had perforations during NACRT were included in this group; cfour patients who underwent EL were included in this group
Seventy (83.3%, 70/84) patients with cT4b diseases achieved R0 resection. 34.5% (29/84) patients underwent CME without MVR and 48.8% (41/84) patients required CME with MVR. The changes in the imaging features of cT4b patients after NACRT are shown in Fig. 2.
Fig. 2 Changes in the imaging features of patients with T4b tumors after neoadjuvant radiotherapy and chemotherapy. a Imaging figures presented ascending colon cancer with invasion of ileum (yellow arrow) and lymph node metastasis with invasion of parietal peritoneum (blue arrow). After NACRT, ascending colon cancer and lymph node metastasis were obviously smaller than before NACRT; b Imaging figures showed sigmoid colon cancer with invasion of bladder (brown arrow), small intestinal (yellow arrow) and peritoneum (blue arrow). Sigmoid colon cancer shrank significantly after NACRT
Among the 42 patients with pretreatment bladder invasion (Supplementary Figure 2A), 2 (2/42, 4.8%) and 22 (22/42, 52.4%) patients underwent total cystectomy and partial cystectomy respectively. 13 (13/42, 31.0%) patients did not have bladder resection. Five (5/42, 11.9%) patients did not undergo cystectomy due to unresectability or personal reasons. Therefore, totally 83.3% (35/42) patients retained bladder function.
In addition, the small intestine is the second most common site of adjacent organ invasion in patients with LACC (Supplementary Figure 2B). Nine (9/26, 34.6%) patients with R0 resection avoided small intestine resection. 7 (7/26, 26.9%) patients underwent small bowel resection and 4 (4/26, 15.4%) patients had a Whipple’s procedure. Six (6/26, 23.1%) patients did not received radical surgery because the conversion therapy failed or for personal reasons.
Long-term survival
The median follow-up period of surviving patients was 32 (IQR 24–55) months in the entire group. Using the public security household registration system, we inquired about the survival outcomes of 6 patients who were lost medical follow-up. None of the patients were lost to follow-up.
The estimated PFS rate at 3 years was 68.6% for the whole group (Fig. 3a). The estimated OS rate at 3 years was 82.1% (Fig. 3a). In this study, local control failed in 16 (16/100, 16.0%) patient, and DM occurred in 28 (28/100, 28.0%) patients. Among the patients who underwent R0 surgery, the 3-year PFS, OS, LR and DM rates were 74.0% (Fig. 3b), 89.6% (Fig. 3c), 13.4 and 20.8%, respectively. As expect, the LR rate and DM rate of 17 patients with non-R0 resection were disappointing. The cumulative 3 year PFS, OS, local progression, DM rates for this cohort were 38.1, 45.8, 71.9, and 41.2%, respectively.
Fig. 3 Survival curves. OS and PFS curves of all patients (a). PFS curves (b) and OS curves (c) curves of the patients with unresectable LACC by resection group (R0 vs R2 vs NRS). P values were calculated from the comparison between the groups. NRS: Nonresectable surgery
In the univariate analysis (Supplementary Table 3), low differentiation, non-R0 resection, ypT stage (ypT4a-T4b) and advanced ypTNM stage (ypIIb-IIIc) were significantly associated with poor OS and PFS in the whole group (Supplementary Figure 3A-H), and a low KPS, low differentiation, and VLPNI (vascular or lymphatic or perineural invasion) positively were associated with a poor DFS in the R0 group (Supplementary Figure 3I-K). Both the results of multicollinearity regression (Supplementary Table 4.1) and the correlation matrix (Supplementary Table 4.2) identified strong correlations between two variables (ypT stage group and ypTNM stage group). Then we subjected the ypTNM stage group to the multivariate analysis. In the multivariate analysis, differentiation remained an independent prognostic factor for OS rates (Table 3). However, no difference in survival was observed between patients with different ypN stages, MMR status, genders, ages and nutritional statuses. A Low TRG score seems to be associated with the poor OS but failed to reach the significance (Supplementary Figure 3M). We supposed that the number of each group was small to reach statistical difference.
Table 3 Multivariate Cox analysis of prognostic factors for OS, PFS, DFS. (OS: p = 0·0006, χ2 = 27·27; PFS: p = 0·065, χ2 = 19·35; DFS: p = 0·087, χ2 = 9·62)
OS PFS DFS
HR (95%CI) p HR (95%CI) p HR (95%CI) p
KPS (80a
vs 90) ·· ·· 0.50 (0.20–1.22) 0.13 0.53 (0.21–1.36) 0.2
Complication (yesa
vs no) 1.70 (0.54–5.41) 0.37 1·56 (0·67–3·64) 0.3 ·· ··
Differentiation ·· 0 ·· 0.06 ·· 0.6
Higha 1 ·· 1 ·· 1 ··
Middle 3.07 (0.29–32.59) 0.35 1.60 (0.31–8.18) 0.57 1.48 (0.32–6.82) 0.6
Low 26.87 (2.38–303.60) 0.01 4.75 (0.73–22.74) 0.07 2.39 (0.42–13.51) 0.3
ypN stage (N0a
vs N1 + N2) 0.31 (0.029–3.19) 0.32 0.41 (0.073–2.24) 0.3 ·· ··
ypTNM stage (0-IIBa
vs IIC-IIIC) 3.44 (0.82–14.38) 0.09 1.82 (0.67–4.99) 0.24 1.49 (0.53–4.16) 0.5
pCR (yesa
vs non) 0.40 (0.053–2.99) 0.37 1.18 (0.29–4.84) 0.81 ·· ··
MVR (nona
vs yes) 1.07 (0.28–4.14) 0.92 0.97 (0.40–2.36) 0.95 ·· ··
VLPNI (negativea
vs positive) 3.61 (0.84–15.54) 0.09 2.16 (0.77–6.02) 0.14 2.01 (0.64–6.37) 0.2
R0 resection (non-R0a
vs R0) 0.21 (0.030–1.48) 0.12 0.60 (0.12–3.08) 0.54 ·· ··
Abbreviations: KPS Karnofsky Performance Status, cT stage Clinical T stage, MVR Multivisceral resection, pCR Pathologic complete remission, VLPNI Vascular or lymphatic or perineural invasion
aThe control group of multivariate Cox analysis
The information about the treatment-related toxicities is shown in Table 4. Based on the CTCAE criteria ver. 4.03, the most common grade 3 to 4 NACRT-related toxicities were myelosuppression, gastrointestinal (GI) toxicities and mucositis/dermatitis. The incidence rates were 17.0, 7.0, and 3.0%, respectively. Eight patients developed an intestinal obstruction during NACRT. Seven patients developed diarrhea and abdominal pain in the process of radiotherapy. Only 3 patients did not complete the radiation course due to tumor rupture, of which two patients underwent emergency surgery and one patient requested for supportive treatment instead of the operation as described before. No patients died during NACRT.
Table 4 Toxicities of NACRT and complications of surgery
No. (%)
Myelosuppression
Grade 0–2 83 (83.0%)
Grade 3–4 17 (17.0%)
Mucositis/dermatitis
Grade 0–2 97 (97.0%)
Grade 3–4 3 (3.0%)
GI toxicities
Grade 0–2 93 (93.0%)
Grade 3–4 7 (7.0%)
Intestinal obstruction
Yes 8 (8.0%)
No 92 (92.0%)
Postsurgical complications
Grade 0–2 82 (92.1%)
Grade 3–4 7 (7.9%)
Nonresectable surgerya 11
Anastomotic leakage
Yes 3 (3.2%)
No 86 (96.8%)
Nonresectable surgerya 11
Abbreviation: GI Gastrointestinal
aIncludes 7 patients who abandoned surgery and 4 patients who underwent EL
Among the 93 patients who underwent surgery, grade 3/4 Clavien-Dindo postsurgical complications were observed in 7 patients (7/100, 7.0%). In addition, 3 patients experienced anastomotic leakage after radical surgery, but completely recovered after the enterostomy or the repair of fistula.
Discussion
Worldwide, surgery is the cornerstone of curative treatment for the colorectal cancer. Radical resection is one of the most important predictors of LR and long-term survival in patients with stage III colon cancer [12]. Hence, a crucial question is whether patients with LACC are able to be converted from an unresectable status to resectable status with the goal of a cure. For locally unresectable radically or bulky nodal disease or clinical T4b colon cancer, neoadjuvant chemotherapy is recommended by NCCN guidelines [13]. In the present study, 7 patients with unresectable LACC underwent 3–5 courses of chemotherapy had stable diseases before NACRT and failed to convert to resection surgery. Therefore, more effective treatments are urgently needed.
Previously published studies have showed that NACRT is an effective choice for patient with unresectable LACC. The evidence of the effectiveness of NACRT for colon cancer is still accumulating. Between 2000 and 2010, several single or very small sample size case reports described the use of NACRT for colon cancer [14, 15]. Taylor et al. retrospectively analyzed 25 patients with LACC who were treated with en-bloc surgical resection with radiotherapy and chemotherapy. Those patients had a median survival of 38.2 months and a 5-year survival rate of 49% [16]. Since 2010, a greater number of reports have investigated small sample sizes. The application of NACRT followed by MVR to 33 patients with primary locally advanced adherent colon cancer and 15 patients with locally recurrent adherent colon cancer patients both achieved high rates of R0 resection and excellent LR in studies published in 2012 and 2014, respectively, by Wong et al’ team from Canada [17, 18] (Supplementary Table 2). In Taiwan, Chun-Ming Huang et al. delivered NACRT to 36 patients with potentially incomplete resection of LACC, as defined by the presence of a T3 tumor with extramural extension of > 5 mm or a T4 tumor diagnosed by imaging. Approximately 26.4% of patients achieved pCR and the 2-year estimated OS and DFS rates were 88.7 and 73.6%, respectively [19].
Because the benefits of NACRT for colon cancer are not clear, the MDT of our cancer center began to explore the application of NACRT only in patients with LACC. We have previously also reported the treatment outcomes of 21 and 60 patients with unresectable radically LACC in 2016 and 2018, respectively. The current report describes 100 patients enrolled from 2010 to 2018 and is the largest sample in which NACRT for LACC has been analyzed. Similar to previous studies, NACRT results in downstaging of tumor for patients with LACC, in which the pCR rate is 18%. The low rate of pCR in the Canadian studies [17] may be due to the use of 5FU alone in NACRT, while we used double chemotherapy during NACRT, similar to the study by Huang CM et al. [19]. Doublet chemotherapy was well tolerated in the patients receiving NACRT for LACC and may contribute to better tumor regression, as observed in patients with LARC [20]. The higher R0 resection rate of LACC in our study may translate to long-term survival benefit. The 3-year PFS and OS rates were 68.6 and 82.1%, respectively, similar to two previous studies [8, 9], and significantly higher than rates reported in the literatures for patients undergoing neoadjuvant chemotherapy [21]. Recently, a research team has compared the treatment outcomes of cT4 colon cancers treated with neoadjuvant radiotherapy (NRT) to patients treated without NRT in their tertiary care center and the National Cancer Database [22, 23]. Both studies showed that the 5-year OS rate of the NRT group was 20 to 25% higher than that of the non-NRT group, and even when patients with cT4b tumors received NRT than non-NRT. Thus, the survival benefit of NACRT is plausible for patients with cT4 colon cancer.
Univariate and multivariate survival analyses revealed independent association of pathological grade with OS. The results were consistent with findings from the study by Wang el at, who constructed a prediction model to predict cause-specific death in elderly patients with colorectal cancer after surgery, particularly for patients with colon cancer [24]. By performing subgroup analysis, patients with better T downstaging had higher survival rates in the present study (Supplementary Figure 3E). Similar results were obtained from the analysis of ypTNM staging (Supplementary Figure 3G). Meanwhile, survival was prolonged in the patients who achieved pCR than in the patients who did not achieve pCR after NACRT. However, the difference was not statistically significant and may be caused by the small sample sizes.
The incidence of acute toxicities of NACRT is another important concern. Bone marrow toxicity was the most common adverse event, of which the incidence grade 3–4 adverse events was 17.0%. The incidences of severe gastrointestinal and skin reactions were similar to patients who received neoadjuvant chemotherapy for LACC [25]. According to previous studies, IMRT accurately delivers radiation to tumors and decreases the dose administered to normal tissues [26]. In our study, 97 (97.0%) patients successfully completed the full doses of radiotherapy. Three patients (3.0%) experienced tumor perforation during the course of NACRT. We speculated that the tumor perforation may be attributed to the radiotherapy, which may cause rapid tumor regression. Therefore, based on the results of the present study, NACRT for colon cancer is safe and tolerable.
In Canadian studies, all patients underwent MVR with a relatively high incidence (> 30%) of postoperative complications [17, 18, 27]. The incidence of postsurgical complications in our series was lower, namely, 7.0%. And no significant difference in survival existed between the MVR group and non-MVR group (Supplementary Fig 3L). Hence, we consider that NACRT can reduce the probability of MVR and decrease the incidence of postoperative complications.
As is well known that the preservation of bladder function is of vital importance to patients in terms of quality of life [28]. In our study, the bladder function was retained in 30.95% of patients with primary bladder invasion. Similarly, several adjacent organs avoided surgical resection or the scope of surgical resection was reduced, such as the small intestine, duodenum, kidney, liver, pancreas and large blood vessels. Therefore, this treatment strategy is more conducive to the preservation of organs and functions, with the results of an improvement in the survival rate and an improvement in the quality of life.
Sensitivity of the deficient mismatch repair (dMMR) phenotype to conventional chemotherapy and radiotherapy is still controversial [29]. At the ASCO conference in 2019, Matt et al. presented an oral report stating that the rate of tumor regression after neoadjuvant chemotherapy markedly was reduced in patient with dMMR tumors, while the rate of pCR was similar. In our study, patients with the dMMR phenotype had similar survival rates to patients with the pMMR phenotype (p = 0.880). Notably, dMMR tumors present opportunities for immunotherapy [30]. Further studies are needed to determine whether NACRT combined with immunotherapy improves the prognosis of patients with dMMR tumors, and we initiated a phase II clinical trial (NCT04301557).
The limitations of the study are the nature of nonrandomized study, moderate sample size and the follow-up time was not long enough. In addition, the specific strategies of NACRT for patients with unresectable LACC enrolled in our study were inconsistent. The optimal strategy of NACRT for LACC requires further investigation. Therefore, we are conducting an open multicenter, randomized controlled trial to further validate the results by comparing the efficacy of neoadjuvant chemotherapy and NACRT in patients with unresectable LACC (NCT03970694). To date, 25 patients have been recruited and the prospective data are expected, which may provide the higher levels of evidence.
In conclusion, NACRT might provide an opportunity for patients with unresectable LACC to achieve R0 resection, which might translate into a survival benefit and better quality of life.
Supplementary Information
Additional file 1: Supplementary Figure 1. The flowchart of treatment of unresectable LACC. Abbreviations: MVR, multivisceral resection; EL, exploratory laparotomy; CME, complete mesocolic excision. Supplementary Figure 2. The surgical details of adjacent organs. Bladder (A); Small intestine (B). Supplementary Figure 3. Subgroup analysis of survival. OS analyzed in patients with unresectable LACC treated with NACRT and surgery by differentiation (A), Resection group (C), ypT stage (E), ypTNM stage (G), MVR (L), TRG score (M). PFS analyzed in all patients by differentiation (B), resection group (D), ypT stage (F), ypTNM stage (H). DFS analyzed in patients with radical surgery by KPS (I), Differentiation (J), VPLNI (K). P values in the figure were calculated from the comparison of the groups. NRS: Nonresectable surgery. Supplementary Table 1. Tumor characteristics and treatment of patients who abandoned surgery. Supplementary Table 2. Characteristics of studies included in the discussion. Supplementary Table 3. Univariate Cox analysis of prognostic factors for OS, PFS, DFS. Supplementary Table 4. 1. Multiple linear regression coefficients. 2. Correlation matrix analysis.
Abbreviations
LACCLocally advanced colon cancer
NACRTNeoadjuvant chemoradiotherapy
MVRMultivisceral resection
MDTMultidisciplinary team
AJCCAmerican Joint Cancer Committee
CTComputed tomography
MRIMagnetic resonance image
CEACarcinoembryonic antigen
CMEComplete mesocolic excision
CTCAECommon Terminology Criteria for Adverse Events
IQRsInterquartile ranges
PFSProgression-free survival
OSOverall survival
DFSDisease-free survival
LRLocal recurrence
DMDistant metastasis
CIConfidence interval
GIGastrointestinal
NRTNeoadjuvant radiotherapy
dMMRDeficient mismatch repair
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yan Yuan, Wei-Wei Xiao, Wei-Hao Xie, Rong Zhang and Yuan-Hong Gao contributed equally to this work.
We thank all the clinicians and patients who participated in the study.
Authors’ contributions
R.Z. and Y.H.G. had the original idea for the study. Y.H.G. had access to all data in the study, and were responsible for the integrity of the data and the accuracy of the data analyses. Y.Y., W.W.X. and W.H.X. participated in analysing the data and writing of the manuscript. P.Q.C. reviewed radiologic images of all the patients. Y.H.G., Q.X.W., H.C. and B.Q.C. were involved in the revision of the manuscript. Y.H.G., W.H.Z., Z.F.Z., X.J.W. and L.R.L. were involved in the design of the study and collected the data. Q.L. was responsible for the accuracy of the statistical analysis. All authors have read, edited, and approved the final version of the manuscript.
Funding
This work was supported by National Natural Science Foundation of China (81672987; 82073329), Natural Science Foundation of Guangdong Province (2020A1515011286).
Availability of data and materials
All data are available via the corresponding author.
Ethics approval and consent to participate
This observational study was performed in accordance with the Declaration of Helsinki and approved by the Medical Ethics Committee of Sun Yat-sen University Cancer Center (B2020–063-01). All patients have signed the informed consent form before treatment.
Consent for publication
Not applicable.
Competing interests
The authors report no conflicts of interest. | CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY | 33607964 | 18,966,748 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytokine release syndrome'. | Anti-BCMA CAR T administration in a relapsed and refractory multiple myeloma patient after COVID-19 infection: a case report.
BACKGROUND
Very little is known about the risk that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection poses to cancer patients, many of whom are immune compromised causing them to be more susceptible to a host of infections. As a precautionary measure, many clinical studies halted enrollment during the initial surge of the global Novel Coronavirus Disease (COVID-19) pandemic. In this case report, we detail the successful treatment of a relapsed and refractory multiple myeloma (MM) patient treated with an anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy immediately following clinical recovery from COVID-19.
METHODS
The 57 year old Caucasian male patient had a 4-year history of MM and was considered penta-refractory upon presentation for CAR T cell therapy. He had a history of immunosuppression and received one dose of lymphodepleting chemotherapy (LDC) the day prior to COVID-19 diagnosis; this patient was able to mount a substantial immune response against the SARS-CoV-2 virus, and antiviral antibodies remain detectable 2 months after receiving anti-BCMA CAR T cell therapy. The recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated cytokine release syndrome (CRS) and conversely the CAR T cell therapy did not result in COVID-19-related complications. One month after CAR T cell infusion, the patient was assessed to have an unconfirmed partial response per International Myeloma Working Group (IMWG) criteria.
CONCLUSIONS
Our case adds important context around treatment choice for MM patients in the era of COVID-19 and whether CAR T therapy can be administered to patients who have recovered from COVID-19. As the COVID-19 global pandemic continues, the decision of whether to proceed with CAR T cell therapy will require extensive discussion weighing the potential risks and benefits of therapy. This case suggests that it is possible to successfully complete anti-BCMA CAR T cell therapy after recovery from COVID-19. CRB-402 study registered 6 September 2017 at clinicaltrials.gov (NCT03274219).
Background
The global COVID-19 pandemic represents a worldwide public health crisis and directly impacts cancer care. Patients with multiple myeloma (MM) have cellular and humoral immune dysfunction causing them to be more susceptible to infections [1, 2]. Anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy is emerging as a promising option for relapsed myeloma patients; however, most clinical trials of CAR T therapy for MM were paused during the pandemic because of the possibility of increased morbidity and mortality with COVID-19. Specifically, in MM patients, it is unclear whether the immunosuppression resulting from conditioning regimens used with CAR T cell therapy may pose an increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, COVID-19 may trigger an inflammatory cascade [3-5] similar to the cytokine release syndrome (CRS) seen in some patients treated with CAR T cells [6]. Our experience in MM patients with COVID-19 showed they have a similar mortality compared to the general age-matched COVID-19-infected population [7]. Our practice has therefore been to weigh the risks and benefits of treatment to tailor therapy for individual MM patients during the COVID-19 pandemic. Here, we report the first case to our knowledge of an MM patient safely treated with anti-BCMA CAR T cell therapy immediately after clinical recovery from COVID-19.
Case presentation
A 57-year-old Caucasian male patient with a 4-year history of IgG-kappa MM was referred to Mount Sinai Hospital in New York City in early February 2020 because of disease progression. He was penta-refractory (refractory to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 antibody) and had previously received nine lines of therapy.
In early February 2020, approximately 3.5 weeks prior to the first confirmed case of COVID-19 in New York City, the patient was enrolled in a clinical study (NCT03274219) of bb21217, an investigational BCMA-directed CAR T cell therapy. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines for Good Clinical Practice, and the protocol was approved by local or independent institutional review boards (IRB) at each study center. Informed consent was obtained from each patient. The patient received bridging therapy with melphalan and bortezomib while awaiting CAR T cell manufacturing. He was asymptomatic and screened negative by PCR test for SARS-CoV-2 two days prior to a planned 3-day course of lymphodepleting chemotherapy (LDC). Approximately 24 hours after receiving the first dose of LDC [cyclophosphamide (300 mg/m2)/fludarabine (30 mg/m2)], the patient returned to clinic with fever, cough, and diarrhea. Nasopharyngeal polymerase chain reaction (PCR) test confirmed SARS-CoV-2 infection.
CAR T infusion was held in the setting of active COVID-19 infection, and the patient was admitted to the hospital for observation. He was afebrile upon admission with a mild cough that resolved within 1 day. He was given granulocyte colony stimulating factor (G-CSF) for grade 1 neutropenia and discharged with instructions to self-isolate at home after 3 days of hospitalization.
The patient was monitored weekly, and further therapy was held until SARS-CoV-2 clearance was confirmed by nasopharyngeal PCR test, 39 days after COVID-19 diagnosis. Upon approval by the sponsor and our IRB, the patient reinitiated the full 3-day course of LDC in preparation for CAR T cell administration. At this point, inflammatory markers were normal, and SARS-CoV-2 antibodies were detected at a titer of 1:2880 using an IgG assay developed by Mount Sinai [8]. On the day of CAR T cell infusion, lymphocytes in the peripheral blood were undetectable and the patient showed profound leukopenia (Figure 1). Twelve hours after CAR T cell infusion, clinical signs consistent with Grade 1 CRS developed, including fever and tachycardia [9]. On day 2, CRS escalated to Grade 2 and was accompanied by hypotension (81/52), only transiently responsive to fluids; thus, tocilizumab (8 mg/kg) × 1 was given. The patient experienced 2 more days of low-grade fever (Figure 2) and grade 1 hypotension. CRS resolved by day 6, and cytokines returned to pretreatment levels by day 9 (Figure 2). Blood counts improved by day 12 except lymphopenia, which persisted through day 14 (Figure 1). Based on 1-month follow-up post-CAR T cell infusion, the patient did not experience other complications, remained SARS-CoV-2 negative, and showed normalization of free kappa light chain with a 61% decrease in serum M protein (Figure 1), consistent with partial response per international myeloma working group (IMWG) criteria. Repeat SARS-CoV-2 antibody titer at his 1-month follow up was 1:960 and at 2-month follow up was 1:320.Fig. 1 Clinical course: blood laboratory values from initial baseline assessment through 30 days post CAR T cell administration. LDC was administered on days -47 and days -5 through -3; positive COVID-19 test by PCR day -46, negative COVID-19 test by PCR day -7; CAR T cell administration day 1, anti-viral antibody titer day -7. Repeat anti-viral antibody titers were conducted day 43 and day 73 (not shown)
Fig. 2 Cytokine release syndrome course and recovery: temperature, inflammatory and cytokine values from CAR T cell administration through 30 days post CAR T cell administration, CRS course (shaded) days 1–6
Discussion/Conclusions
Our case adds important context to the evolving literature about treatment of MM patients in the era of COVID-19 [10]. This is the first case report in the published literature to share the experience of successful administration of anti-BCMA CAR T cell treatment to a patient with relapsed and refractory MM who recently recovered from COVID-19. Importantly, the administration of 1 day of LDC immediately prior to SARS-CoV-2 infection did not result in any COVID-19-related complications.
The patient experienced Grade 2 CRS, an expected toxicity associated with CAR T therapy, which resolved within 6 days, and the patient is currently in partial response (unconfirmed), per IMWG assessment [11, 12]. Inflammatory cytokines were elevated during the CRS event; however, levels were in the same range as for CAR T cell-treated patients without COVID-19 who experience CRS [13]. Hence, recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated CRS, even though this is a toxicity known to be associated with COVID-19.
Interestingly, this patient experienced a robust humoral response to viral infection, despite his history of immune suppression. Two months after treatment with a BCMA-directed CAR T therapy, which can ablate normal BCMA expressing plasma cells, the antibody titer decreased from 1:2880 to 1:320 but remained clearly detectable approximately 4 months after infection. Whether this patient developed and retained long-term immunity against COVID-19 remains to be determined.
With the initial surge of COVID-19, many clinical trial sites paused trials of CAR T cell therapy for MM patients. As trials re-start, investigational sites should ensure access to critical care and availability of appropriate drugs to manage CAR T cell-associated toxicities and carefully weigh the potential risks and benefits of therapy prior to proceeding with CAR T cell therapy. Our report, although limited to a single patient experience, suggests that patients who have tested antibody positive for SARS-CoV-2 can proceed with CAR T cell therapy without flare-up of COVID-19-related symptoms. High antibody titers can be generated in myeloma patients; SARS-CoV-2-specific antibodies were retained despite effective anti-BCMA CAR T cell therapy in this patient. Additional studies to determine the effect of BCMA targeting agents on the risk of SARS-CoV-2 re-infection are warranted. As COVID-19 immunity after recovery has not been well characterized, appropriate precautions such as social distancing, facial mask, and good hygiene are recommended to prevent re-infection.
The information available regarding management strategies for MM patients during the COVID-19 pandemic is insufficient to provide evidence-based recommendations; however, several consensus statements have been published that provide guidance. The recommendations included within this report—securing access to supportive care, taking appropriate precautions to avoid SARS-CoV-2 infection, and carefully weighing the potential risks and benefits of CAR T cell therapy—align well with existing consensus statements [14, 15].
Abbreviations
ANCAbsolute neutrophil count
BCMAB-cell maturation antigen
CARChimeric antigen receptor
CRPC reactive protein
CRSCytokine release syndrome
IFNInterferon
ILInterleukin
IMWGInternational Myeloma Working Group
HbHemoglobin
κLCKappa light chain
LDCLymphodepleting chemotherapy
LymLymphocytes
MMMultiple myeloma
TmaxTemperature
TNFTumor necrosis factor
SARS-CoV-2Severe acute respiratory syndrome coronavirus 2
WBCWhite blood cell
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge all the staff and families for the selfless efforts in caring for patients who developed COVID-19 and the strength and courage of all patients affected by the pandemic. Medical writing assistance was provided by Karen Repetny, PhD, of bluebird bio, Cambridge, MA, USA
Authors’ Contributions
DM: collected data, analyzed and interpreted data preparation and review of the manuscript. SP: collected data, analyzed and interpreted data preparation and review of the manuscript. TC: analyzed and interpreted data preparation and review of the manuscript. FP: collected data, analyzed and interpreted data preparation and review of the manuscript. FN: analyzed and interpreted data preparation and review of the manuscript. SJ: collected data, analyzed and interpreted data preparation and review of the manuscript. All authors read and approved the final manuscript.
Funding
The clinical study NCT03274219 is supported by bluebird bio
Availability of data and materials
All data are included in this case report
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines for Good Clinical Practice and the protocol was approved by local or independent institutional review boards at each study center. All patients provided informed consent for participation in this clinical study.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interest
D.M.: Advisory board and consulting fees from Janssen, Celgene, Bristol Myers Squibb, Takeda, Legend, Sanofi Genzyme, GlaxoSmithKline, Kinevant, and Foundation Medicine. S.P.: Consulting fees from Foundation Medicine, research funding from Celgene and Karyopharm. Supported by 1R01CA244899-01A1. T.C.: Employment and ownership of Bristol-Myers Squibb, F.P.: employment and ownership interest of bluebird bio, F.N.: prior employment and ownership interest of bluebird bio. S.J.: Advisory board and consulting fees from Celgene, Bristol‐Myers Squibb, Janssen Pharmaceuticals, and Merck. | BORTEZOMIB, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, INVESTIGATIONAL PRODUCT, MELPHALAN, MEZAGITAMAB | DrugsGivenReaction | CC BY | 33608053 | 19,598,038 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Anti-BCMA CAR T administration in a relapsed and refractory multiple myeloma patient after COVID-19 infection: a case report.
BACKGROUND
Very little is known about the risk that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection poses to cancer patients, many of whom are immune compromised causing them to be more susceptible to a host of infections. As a precautionary measure, many clinical studies halted enrollment during the initial surge of the global Novel Coronavirus Disease (COVID-19) pandemic. In this case report, we detail the successful treatment of a relapsed and refractory multiple myeloma (MM) patient treated with an anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy immediately following clinical recovery from COVID-19.
METHODS
The 57 year old Caucasian male patient had a 4-year history of MM and was considered penta-refractory upon presentation for CAR T cell therapy. He had a history of immunosuppression and received one dose of lymphodepleting chemotherapy (LDC) the day prior to COVID-19 diagnosis; this patient was able to mount a substantial immune response against the SARS-CoV-2 virus, and antiviral antibodies remain detectable 2 months after receiving anti-BCMA CAR T cell therapy. The recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated cytokine release syndrome (CRS) and conversely the CAR T cell therapy did not result in COVID-19-related complications. One month after CAR T cell infusion, the patient was assessed to have an unconfirmed partial response per International Myeloma Working Group (IMWG) criteria.
CONCLUSIONS
Our case adds important context around treatment choice for MM patients in the era of COVID-19 and whether CAR T therapy can be administered to patients who have recovered from COVID-19. As the COVID-19 global pandemic continues, the decision of whether to proceed with CAR T cell therapy will require extensive discussion weighing the potential risks and benefits of therapy. This case suggests that it is possible to successfully complete anti-BCMA CAR T cell therapy after recovery from COVID-19. CRB-402 study registered 6 September 2017 at clinicaltrials.gov (NCT03274219).
Background
The global COVID-19 pandemic represents a worldwide public health crisis and directly impacts cancer care. Patients with multiple myeloma (MM) have cellular and humoral immune dysfunction causing them to be more susceptible to infections [1, 2]. Anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy is emerging as a promising option for relapsed myeloma patients; however, most clinical trials of CAR T therapy for MM were paused during the pandemic because of the possibility of increased morbidity and mortality with COVID-19. Specifically, in MM patients, it is unclear whether the immunosuppression resulting from conditioning regimens used with CAR T cell therapy may pose an increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, COVID-19 may trigger an inflammatory cascade [3-5] similar to the cytokine release syndrome (CRS) seen in some patients treated with CAR T cells [6]. Our experience in MM patients with COVID-19 showed they have a similar mortality compared to the general age-matched COVID-19-infected population [7]. Our practice has therefore been to weigh the risks and benefits of treatment to tailor therapy for individual MM patients during the COVID-19 pandemic. Here, we report the first case to our knowledge of an MM patient safely treated with anti-BCMA CAR T cell therapy immediately after clinical recovery from COVID-19.
Case presentation
A 57-year-old Caucasian male patient with a 4-year history of IgG-kappa MM was referred to Mount Sinai Hospital in New York City in early February 2020 because of disease progression. He was penta-refractory (refractory to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 antibody) and had previously received nine lines of therapy.
In early February 2020, approximately 3.5 weeks prior to the first confirmed case of COVID-19 in New York City, the patient was enrolled in a clinical study (NCT03274219) of bb21217, an investigational BCMA-directed CAR T cell therapy. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines for Good Clinical Practice, and the protocol was approved by local or independent institutional review boards (IRB) at each study center. Informed consent was obtained from each patient. The patient received bridging therapy with melphalan and bortezomib while awaiting CAR T cell manufacturing. He was asymptomatic and screened negative by PCR test for SARS-CoV-2 two days prior to a planned 3-day course of lymphodepleting chemotherapy (LDC). Approximately 24 hours after receiving the first dose of LDC [cyclophosphamide (300 mg/m2)/fludarabine (30 mg/m2)], the patient returned to clinic with fever, cough, and diarrhea. Nasopharyngeal polymerase chain reaction (PCR) test confirmed SARS-CoV-2 infection.
CAR T infusion was held in the setting of active COVID-19 infection, and the patient was admitted to the hospital for observation. He was afebrile upon admission with a mild cough that resolved within 1 day. He was given granulocyte colony stimulating factor (G-CSF) for grade 1 neutropenia and discharged with instructions to self-isolate at home after 3 days of hospitalization.
The patient was monitored weekly, and further therapy was held until SARS-CoV-2 clearance was confirmed by nasopharyngeal PCR test, 39 days after COVID-19 diagnosis. Upon approval by the sponsor and our IRB, the patient reinitiated the full 3-day course of LDC in preparation for CAR T cell administration. At this point, inflammatory markers were normal, and SARS-CoV-2 antibodies were detected at a titer of 1:2880 using an IgG assay developed by Mount Sinai [8]. On the day of CAR T cell infusion, lymphocytes in the peripheral blood were undetectable and the patient showed profound leukopenia (Figure 1). Twelve hours after CAR T cell infusion, clinical signs consistent with Grade 1 CRS developed, including fever and tachycardia [9]. On day 2, CRS escalated to Grade 2 and was accompanied by hypotension (81/52), only transiently responsive to fluids; thus, tocilizumab (8 mg/kg) × 1 was given. The patient experienced 2 more days of low-grade fever (Figure 2) and grade 1 hypotension. CRS resolved by day 6, and cytokines returned to pretreatment levels by day 9 (Figure 2). Blood counts improved by day 12 except lymphopenia, which persisted through day 14 (Figure 1). Based on 1-month follow-up post-CAR T cell infusion, the patient did not experience other complications, remained SARS-CoV-2 negative, and showed normalization of free kappa light chain with a 61% decrease in serum M protein (Figure 1), consistent with partial response per international myeloma working group (IMWG) criteria. Repeat SARS-CoV-2 antibody titer at his 1-month follow up was 1:960 and at 2-month follow up was 1:320.Fig. 1 Clinical course: blood laboratory values from initial baseline assessment through 30 days post CAR T cell administration. LDC was administered on days -47 and days -5 through -3; positive COVID-19 test by PCR day -46, negative COVID-19 test by PCR day -7; CAR T cell administration day 1, anti-viral antibody titer day -7. Repeat anti-viral antibody titers were conducted day 43 and day 73 (not shown)
Fig. 2 Cytokine release syndrome course and recovery: temperature, inflammatory and cytokine values from CAR T cell administration through 30 days post CAR T cell administration, CRS course (shaded) days 1–6
Discussion/Conclusions
Our case adds important context to the evolving literature about treatment of MM patients in the era of COVID-19 [10]. This is the first case report in the published literature to share the experience of successful administration of anti-BCMA CAR T cell treatment to a patient with relapsed and refractory MM who recently recovered from COVID-19. Importantly, the administration of 1 day of LDC immediately prior to SARS-CoV-2 infection did not result in any COVID-19-related complications.
The patient experienced Grade 2 CRS, an expected toxicity associated with CAR T therapy, which resolved within 6 days, and the patient is currently in partial response (unconfirmed), per IMWG assessment [11, 12]. Inflammatory cytokines were elevated during the CRS event; however, levels were in the same range as for CAR T cell-treated patients without COVID-19 who experience CRS [13]. Hence, recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated CRS, even though this is a toxicity known to be associated with COVID-19.
Interestingly, this patient experienced a robust humoral response to viral infection, despite his history of immune suppression. Two months after treatment with a BCMA-directed CAR T therapy, which can ablate normal BCMA expressing plasma cells, the antibody titer decreased from 1:2880 to 1:320 but remained clearly detectable approximately 4 months after infection. Whether this patient developed and retained long-term immunity against COVID-19 remains to be determined.
With the initial surge of COVID-19, many clinical trial sites paused trials of CAR T cell therapy for MM patients. As trials re-start, investigational sites should ensure access to critical care and availability of appropriate drugs to manage CAR T cell-associated toxicities and carefully weigh the potential risks and benefits of therapy prior to proceeding with CAR T cell therapy. Our report, although limited to a single patient experience, suggests that patients who have tested antibody positive for SARS-CoV-2 can proceed with CAR T cell therapy without flare-up of COVID-19-related symptoms. High antibody titers can be generated in myeloma patients; SARS-CoV-2-specific antibodies were retained despite effective anti-BCMA CAR T cell therapy in this patient. Additional studies to determine the effect of BCMA targeting agents on the risk of SARS-CoV-2 re-infection are warranted. As COVID-19 immunity after recovery has not been well characterized, appropriate precautions such as social distancing, facial mask, and good hygiene are recommended to prevent re-infection.
The information available regarding management strategies for MM patients during the COVID-19 pandemic is insufficient to provide evidence-based recommendations; however, several consensus statements have been published that provide guidance. The recommendations included within this report—securing access to supportive care, taking appropriate precautions to avoid SARS-CoV-2 infection, and carefully weighing the potential risks and benefits of CAR T cell therapy—align well with existing consensus statements [14, 15].
Abbreviations
ANCAbsolute neutrophil count
BCMAB-cell maturation antigen
CARChimeric antigen receptor
CRPC reactive protein
CRSCytokine release syndrome
IFNInterferon
ILInterleukin
IMWGInternational Myeloma Working Group
HbHemoglobin
κLCKappa light chain
LDCLymphodepleting chemotherapy
LymLymphocytes
MMMultiple myeloma
TmaxTemperature
TNFTumor necrosis factor
SARS-CoV-2Severe acute respiratory syndrome coronavirus 2
WBCWhite blood cell
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge all the staff and families for the selfless efforts in caring for patients who developed COVID-19 and the strength and courage of all patients affected by the pandemic. Medical writing assistance was provided by Karen Repetny, PhD, of bluebird bio, Cambridge, MA, USA
Authors’ Contributions
DM: collected data, analyzed and interpreted data preparation and review of the manuscript. SP: collected data, analyzed and interpreted data preparation and review of the manuscript. TC: analyzed and interpreted data preparation and review of the manuscript. FP: collected data, analyzed and interpreted data preparation and review of the manuscript. FN: analyzed and interpreted data preparation and review of the manuscript. SJ: collected data, analyzed and interpreted data preparation and review of the manuscript. All authors read and approved the final manuscript.
Funding
The clinical study NCT03274219 is supported by bluebird bio
Availability of data and materials
All data are included in this case report
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines for Good Clinical Practice and the protocol was approved by local or independent institutional review boards at each study center. All patients provided informed consent for participation in this clinical study.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interest
D.M.: Advisory board and consulting fees from Janssen, Celgene, Bristol Myers Squibb, Takeda, Legend, Sanofi Genzyme, GlaxoSmithKline, Kinevant, and Foundation Medicine. S.P.: Consulting fees from Foundation Medicine, research funding from Celgene and Karyopharm. Supported by 1R01CA244899-01A1. T.C.: Employment and ownership of Bristol-Myers Squibb, F.P.: employment and ownership interest of bluebird bio, F.N.: prior employment and ownership interest of bluebird bio. S.J.: Advisory board and consulting fees from Celgene, Bristol‐Myers Squibb, Janssen Pharmaceuticals, and Merck. | BORTEZOMIB, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, INVESTIGATIONAL PRODUCT, MELPHALAN, MEZAGITAMAB | DrugsGivenReaction | CC BY | 33608053 | 19,598,038 | 2021-02-19 |
What was the administration route of drug 'INVESTIGATIONAL PRODUCT'? | Anti-BCMA CAR T administration in a relapsed and refractory multiple myeloma patient after COVID-19 infection: a case report.
BACKGROUND
Very little is known about the risk that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection poses to cancer patients, many of whom are immune compromised causing them to be more susceptible to a host of infections. As a precautionary measure, many clinical studies halted enrollment during the initial surge of the global Novel Coronavirus Disease (COVID-19) pandemic. In this case report, we detail the successful treatment of a relapsed and refractory multiple myeloma (MM) patient treated with an anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy immediately following clinical recovery from COVID-19.
METHODS
The 57 year old Caucasian male patient had a 4-year history of MM and was considered penta-refractory upon presentation for CAR T cell therapy. He had a history of immunosuppression and received one dose of lymphodepleting chemotherapy (LDC) the day prior to COVID-19 diagnosis; this patient was able to mount a substantial immune response against the SARS-CoV-2 virus, and antiviral antibodies remain detectable 2 months after receiving anti-BCMA CAR T cell therapy. The recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated cytokine release syndrome (CRS) and conversely the CAR T cell therapy did not result in COVID-19-related complications. One month after CAR T cell infusion, the patient was assessed to have an unconfirmed partial response per International Myeloma Working Group (IMWG) criteria.
CONCLUSIONS
Our case adds important context around treatment choice for MM patients in the era of COVID-19 and whether CAR T therapy can be administered to patients who have recovered from COVID-19. As the COVID-19 global pandemic continues, the decision of whether to proceed with CAR T cell therapy will require extensive discussion weighing the potential risks and benefits of therapy. This case suggests that it is possible to successfully complete anti-BCMA CAR T cell therapy after recovery from COVID-19. CRB-402 study registered 6 September 2017 at clinicaltrials.gov (NCT03274219).
Background
The global COVID-19 pandemic represents a worldwide public health crisis and directly impacts cancer care. Patients with multiple myeloma (MM) have cellular and humoral immune dysfunction causing them to be more susceptible to infections [1, 2]. Anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy is emerging as a promising option for relapsed myeloma patients; however, most clinical trials of CAR T therapy for MM were paused during the pandemic because of the possibility of increased morbidity and mortality with COVID-19. Specifically, in MM patients, it is unclear whether the immunosuppression resulting from conditioning regimens used with CAR T cell therapy may pose an increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, COVID-19 may trigger an inflammatory cascade [3-5] similar to the cytokine release syndrome (CRS) seen in some patients treated with CAR T cells [6]. Our experience in MM patients with COVID-19 showed they have a similar mortality compared to the general age-matched COVID-19-infected population [7]. Our practice has therefore been to weigh the risks and benefits of treatment to tailor therapy for individual MM patients during the COVID-19 pandemic. Here, we report the first case to our knowledge of an MM patient safely treated with anti-BCMA CAR T cell therapy immediately after clinical recovery from COVID-19.
Case presentation
A 57-year-old Caucasian male patient with a 4-year history of IgG-kappa MM was referred to Mount Sinai Hospital in New York City in early February 2020 because of disease progression. He was penta-refractory (refractory to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 antibody) and had previously received nine lines of therapy.
In early February 2020, approximately 3.5 weeks prior to the first confirmed case of COVID-19 in New York City, the patient was enrolled in a clinical study (NCT03274219) of bb21217, an investigational BCMA-directed CAR T cell therapy. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines for Good Clinical Practice, and the protocol was approved by local or independent institutional review boards (IRB) at each study center. Informed consent was obtained from each patient. The patient received bridging therapy with melphalan and bortezomib while awaiting CAR T cell manufacturing. He was asymptomatic and screened negative by PCR test for SARS-CoV-2 two days prior to a planned 3-day course of lymphodepleting chemotherapy (LDC). Approximately 24 hours after receiving the first dose of LDC [cyclophosphamide (300 mg/m2)/fludarabine (30 mg/m2)], the patient returned to clinic with fever, cough, and diarrhea. Nasopharyngeal polymerase chain reaction (PCR) test confirmed SARS-CoV-2 infection.
CAR T infusion was held in the setting of active COVID-19 infection, and the patient was admitted to the hospital for observation. He was afebrile upon admission with a mild cough that resolved within 1 day. He was given granulocyte colony stimulating factor (G-CSF) for grade 1 neutropenia and discharged with instructions to self-isolate at home after 3 days of hospitalization.
The patient was monitored weekly, and further therapy was held until SARS-CoV-2 clearance was confirmed by nasopharyngeal PCR test, 39 days after COVID-19 diagnosis. Upon approval by the sponsor and our IRB, the patient reinitiated the full 3-day course of LDC in preparation for CAR T cell administration. At this point, inflammatory markers were normal, and SARS-CoV-2 antibodies were detected at a titer of 1:2880 using an IgG assay developed by Mount Sinai [8]. On the day of CAR T cell infusion, lymphocytes in the peripheral blood were undetectable and the patient showed profound leukopenia (Figure 1). Twelve hours after CAR T cell infusion, clinical signs consistent with Grade 1 CRS developed, including fever and tachycardia [9]. On day 2, CRS escalated to Grade 2 and was accompanied by hypotension (81/52), only transiently responsive to fluids; thus, tocilizumab (8 mg/kg) × 1 was given. The patient experienced 2 more days of low-grade fever (Figure 2) and grade 1 hypotension. CRS resolved by day 6, and cytokines returned to pretreatment levels by day 9 (Figure 2). Blood counts improved by day 12 except lymphopenia, which persisted through day 14 (Figure 1). Based on 1-month follow-up post-CAR T cell infusion, the patient did not experience other complications, remained SARS-CoV-2 negative, and showed normalization of free kappa light chain with a 61% decrease in serum M protein (Figure 1), consistent with partial response per international myeloma working group (IMWG) criteria. Repeat SARS-CoV-2 antibody titer at his 1-month follow up was 1:960 and at 2-month follow up was 1:320.Fig. 1 Clinical course: blood laboratory values from initial baseline assessment through 30 days post CAR T cell administration. LDC was administered on days -47 and days -5 through -3; positive COVID-19 test by PCR day -46, negative COVID-19 test by PCR day -7; CAR T cell administration day 1, anti-viral antibody titer day -7. Repeat anti-viral antibody titers were conducted day 43 and day 73 (not shown)
Fig. 2 Cytokine release syndrome course and recovery: temperature, inflammatory and cytokine values from CAR T cell administration through 30 days post CAR T cell administration, CRS course (shaded) days 1–6
Discussion/Conclusions
Our case adds important context to the evolving literature about treatment of MM patients in the era of COVID-19 [10]. This is the first case report in the published literature to share the experience of successful administration of anti-BCMA CAR T cell treatment to a patient with relapsed and refractory MM who recently recovered from COVID-19. Importantly, the administration of 1 day of LDC immediately prior to SARS-CoV-2 infection did not result in any COVID-19-related complications.
The patient experienced Grade 2 CRS, an expected toxicity associated with CAR T therapy, which resolved within 6 days, and the patient is currently in partial response (unconfirmed), per IMWG assessment [11, 12]. Inflammatory cytokines were elevated during the CRS event; however, levels were in the same range as for CAR T cell-treated patients without COVID-19 who experience CRS [13]. Hence, recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated CRS, even though this is a toxicity known to be associated with COVID-19.
Interestingly, this patient experienced a robust humoral response to viral infection, despite his history of immune suppression. Two months after treatment with a BCMA-directed CAR T therapy, which can ablate normal BCMA expressing plasma cells, the antibody titer decreased from 1:2880 to 1:320 but remained clearly detectable approximately 4 months after infection. Whether this patient developed and retained long-term immunity against COVID-19 remains to be determined.
With the initial surge of COVID-19, many clinical trial sites paused trials of CAR T cell therapy for MM patients. As trials re-start, investigational sites should ensure access to critical care and availability of appropriate drugs to manage CAR T cell-associated toxicities and carefully weigh the potential risks and benefits of therapy prior to proceeding with CAR T cell therapy. Our report, although limited to a single patient experience, suggests that patients who have tested antibody positive for SARS-CoV-2 can proceed with CAR T cell therapy without flare-up of COVID-19-related symptoms. High antibody titers can be generated in myeloma patients; SARS-CoV-2-specific antibodies were retained despite effective anti-BCMA CAR T cell therapy in this patient. Additional studies to determine the effect of BCMA targeting agents on the risk of SARS-CoV-2 re-infection are warranted. As COVID-19 immunity after recovery has not been well characterized, appropriate precautions such as social distancing, facial mask, and good hygiene are recommended to prevent re-infection.
The information available regarding management strategies for MM patients during the COVID-19 pandemic is insufficient to provide evidence-based recommendations; however, several consensus statements have been published that provide guidance. The recommendations included within this report—securing access to supportive care, taking appropriate precautions to avoid SARS-CoV-2 infection, and carefully weighing the potential risks and benefits of CAR T cell therapy—align well with existing consensus statements [14, 15].
Abbreviations
ANCAbsolute neutrophil count
BCMAB-cell maturation antigen
CARChimeric antigen receptor
CRPC reactive protein
CRSCytokine release syndrome
IFNInterferon
ILInterleukin
IMWGInternational Myeloma Working Group
HbHemoglobin
κLCKappa light chain
LDCLymphodepleting chemotherapy
LymLymphocytes
MMMultiple myeloma
TmaxTemperature
TNFTumor necrosis factor
SARS-CoV-2Severe acute respiratory syndrome coronavirus 2
WBCWhite blood cell
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge all the staff and families for the selfless efforts in caring for patients who developed COVID-19 and the strength and courage of all patients affected by the pandemic. Medical writing assistance was provided by Karen Repetny, PhD, of bluebird bio, Cambridge, MA, USA
Authors’ Contributions
DM: collected data, analyzed and interpreted data preparation and review of the manuscript. SP: collected data, analyzed and interpreted data preparation and review of the manuscript. TC: analyzed and interpreted data preparation and review of the manuscript. FP: collected data, analyzed and interpreted data preparation and review of the manuscript. FN: analyzed and interpreted data preparation and review of the manuscript. SJ: collected data, analyzed and interpreted data preparation and review of the manuscript. All authors read and approved the final manuscript.
Funding
The clinical study NCT03274219 is supported by bluebird bio
Availability of data and materials
All data are included in this case report
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines for Good Clinical Practice and the protocol was approved by local or independent institutional review boards at each study center. All patients provided informed consent for participation in this clinical study.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interest
D.M.: Advisory board and consulting fees from Janssen, Celgene, Bristol Myers Squibb, Takeda, Legend, Sanofi Genzyme, GlaxoSmithKline, Kinevant, and Foundation Medicine. S.P.: Consulting fees from Foundation Medicine, research funding from Celgene and Karyopharm. Supported by 1R01CA244899-01A1. T.C.: Employment and ownership of Bristol-Myers Squibb, F.P.: employment and ownership interest of bluebird bio, F.N.: prior employment and ownership interest of bluebird bio. S.J.: Advisory board and consulting fees from Celgene, Bristol‐Myers Squibb, Janssen Pharmaceuticals, and Merck. | Other | DrugAdministrationRoute | CC BY | 33608053 | 19,598,038 | 2021-02-19 |
What was the outcome of reaction 'COVID-19'? | Anti-BCMA CAR T administration in a relapsed and refractory multiple myeloma patient after COVID-19 infection: a case report.
BACKGROUND
Very little is known about the risk that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection poses to cancer patients, many of whom are immune compromised causing them to be more susceptible to a host of infections. As a precautionary measure, many clinical studies halted enrollment during the initial surge of the global Novel Coronavirus Disease (COVID-19) pandemic. In this case report, we detail the successful treatment of a relapsed and refractory multiple myeloma (MM) patient treated with an anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy immediately following clinical recovery from COVID-19.
METHODS
The 57 year old Caucasian male patient had a 4-year history of MM and was considered penta-refractory upon presentation for CAR T cell therapy. He had a history of immunosuppression and received one dose of lymphodepleting chemotherapy (LDC) the day prior to COVID-19 diagnosis; this patient was able to mount a substantial immune response against the SARS-CoV-2 virus, and antiviral antibodies remain detectable 2 months after receiving anti-BCMA CAR T cell therapy. The recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated cytokine release syndrome (CRS) and conversely the CAR T cell therapy did not result in COVID-19-related complications. One month after CAR T cell infusion, the patient was assessed to have an unconfirmed partial response per International Myeloma Working Group (IMWG) criteria.
CONCLUSIONS
Our case adds important context around treatment choice for MM patients in the era of COVID-19 and whether CAR T therapy can be administered to patients who have recovered from COVID-19. As the COVID-19 global pandemic continues, the decision of whether to proceed with CAR T cell therapy will require extensive discussion weighing the potential risks and benefits of therapy. This case suggests that it is possible to successfully complete anti-BCMA CAR T cell therapy after recovery from COVID-19. CRB-402 study registered 6 September 2017 at clinicaltrials.gov (NCT03274219).
Background
The global COVID-19 pandemic represents a worldwide public health crisis and directly impacts cancer care. Patients with multiple myeloma (MM) have cellular and humoral immune dysfunction causing them to be more susceptible to infections [1, 2]. Anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy is emerging as a promising option for relapsed myeloma patients; however, most clinical trials of CAR T therapy for MM were paused during the pandemic because of the possibility of increased morbidity and mortality with COVID-19. Specifically, in MM patients, it is unclear whether the immunosuppression resulting from conditioning regimens used with CAR T cell therapy may pose an increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, COVID-19 may trigger an inflammatory cascade [3-5] similar to the cytokine release syndrome (CRS) seen in some patients treated with CAR T cells [6]. Our experience in MM patients with COVID-19 showed they have a similar mortality compared to the general age-matched COVID-19-infected population [7]. Our practice has therefore been to weigh the risks and benefits of treatment to tailor therapy for individual MM patients during the COVID-19 pandemic. Here, we report the first case to our knowledge of an MM patient safely treated with anti-BCMA CAR T cell therapy immediately after clinical recovery from COVID-19.
Case presentation
A 57-year-old Caucasian male patient with a 4-year history of IgG-kappa MM was referred to Mount Sinai Hospital in New York City in early February 2020 because of disease progression. He was penta-refractory (refractory to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 antibody) and had previously received nine lines of therapy.
In early February 2020, approximately 3.5 weeks prior to the first confirmed case of COVID-19 in New York City, the patient was enrolled in a clinical study (NCT03274219) of bb21217, an investigational BCMA-directed CAR T cell therapy. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines for Good Clinical Practice, and the protocol was approved by local or independent institutional review boards (IRB) at each study center. Informed consent was obtained from each patient. The patient received bridging therapy with melphalan and bortezomib while awaiting CAR T cell manufacturing. He was asymptomatic and screened negative by PCR test for SARS-CoV-2 two days prior to a planned 3-day course of lymphodepleting chemotherapy (LDC). Approximately 24 hours after receiving the first dose of LDC [cyclophosphamide (300 mg/m2)/fludarabine (30 mg/m2)], the patient returned to clinic with fever, cough, and diarrhea. Nasopharyngeal polymerase chain reaction (PCR) test confirmed SARS-CoV-2 infection.
CAR T infusion was held in the setting of active COVID-19 infection, and the patient was admitted to the hospital for observation. He was afebrile upon admission with a mild cough that resolved within 1 day. He was given granulocyte colony stimulating factor (G-CSF) for grade 1 neutropenia and discharged with instructions to self-isolate at home after 3 days of hospitalization.
The patient was monitored weekly, and further therapy was held until SARS-CoV-2 clearance was confirmed by nasopharyngeal PCR test, 39 days after COVID-19 diagnosis. Upon approval by the sponsor and our IRB, the patient reinitiated the full 3-day course of LDC in preparation for CAR T cell administration. At this point, inflammatory markers were normal, and SARS-CoV-2 antibodies were detected at a titer of 1:2880 using an IgG assay developed by Mount Sinai [8]. On the day of CAR T cell infusion, lymphocytes in the peripheral blood were undetectable and the patient showed profound leukopenia (Figure 1). Twelve hours after CAR T cell infusion, clinical signs consistent with Grade 1 CRS developed, including fever and tachycardia [9]. On day 2, CRS escalated to Grade 2 and was accompanied by hypotension (81/52), only transiently responsive to fluids; thus, tocilizumab (8 mg/kg) × 1 was given. The patient experienced 2 more days of low-grade fever (Figure 2) and grade 1 hypotension. CRS resolved by day 6, and cytokines returned to pretreatment levels by day 9 (Figure 2). Blood counts improved by day 12 except lymphopenia, which persisted through day 14 (Figure 1). Based on 1-month follow-up post-CAR T cell infusion, the patient did not experience other complications, remained SARS-CoV-2 negative, and showed normalization of free kappa light chain with a 61% decrease in serum M protein (Figure 1), consistent with partial response per international myeloma working group (IMWG) criteria. Repeat SARS-CoV-2 antibody titer at his 1-month follow up was 1:960 and at 2-month follow up was 1:320.Fig. 1 Clinical course: blood laboratory values from initial baseline assessment through 30 days post CAR T cell administration. LDC was administered on days -47 and days -5 through -3; positive COVID-19 test by PCR day -46, negative COVID-19 test by PCR day -7; CAR T cell administration day 1, anti-viral antibody titer day -7. Repeat anti-viral antibody titers were conducted day 43 and day 73 (not shown)
Fig. 2 Cytokine release syndrome course and recovery: temperature, inflammatory and cytokine values from CAR T cell administration through 30 days post CAR T cell administration, CRS course (shaded) days 1–6
Discussion/Conclusions
Our case adds important context to the evolving literature about treatment of MM patients in the era of COVID-19 [10]. This is the first case report in the published literature to share the experience of successful administration of anti-BCMA CAR T cell treatment to a patient with relapsed and refractory MM who recently recovered from COVID-19. Importantly, the administration of 1 day of LDC immediately prior to SARS-CoV-2 infection did not result in any COVID-19-related complications.
The patient experienced Grade 2 CRS, an expected toxicity associated with CAR T therapy, which resolved within 6 days, and the patient is currently in partial response (unconfirmed), per IMWG assessment [11, 12]. Inflammatory cytokines were elevated during the CRS event; however, levels were in the same range as for CAR T cell-treated patients without COVID-19 who experience CRS [13]. Hence, recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated CRS, even though this is a toxicity known to be associated with COVID-19.
Interestingly, this patient experienced a robust humoral response to viral infection, despite his history of immune suppression. Two months after treatment with a BCMA-directed CAR T therapy, which can ablate normal BCMA expressing plasma cells, the antibody titer decreased from 1:2880 to 1:320 but remained clearly detectable approximately 4 months after infection. Whether this patient developed and retained long-term immunity against COVID-19 remains to be determined.
With the initial surge of COVID-19, many clinical trial sites paused trials of CAR T cell therapy for MM patients. As trials re-start, investigational sites should ensure access to critical care and availability of appropriate drugs to manage CAR T cell-associated toxicities and carefully weigh the potential risks and benefits of therapy prior to proceeding with CAR T cell therapy. Our report, although limited to a single patient experience, suggests that patients who have tested antibody positive for SARS-CoV-2 can proceed with CAR T cell therapy without flare-up of COVID-19-related symptoms. High antibody titers can be generated in myeloma patients; SARS-CoV-2-specific antibodies were retained despite effective anti-BCMA CAR T cell therapy in this patient. Additional studies to determine the effect of BCMA targeting agents on the risk of SARS-CoV-2 re-infection are warranted. As COVID-19 immunity after recovery has not been well characterized, appropriate precautions such as social distancing, facial mask, and good hygiene are recommended to prevent re-infection.
The information available regarding management strategies for MM patients during the COVID-19 pandemic is insufficient to provide evidence-based recommendations; however, several consensus statements have been published that provide guidance. The recommendations included within this report—securing access to supportive care, taking appropriate precautions to avoid SARS-CoV-2 infection, and carefully weighing the potential risks and benefits of CAR T cell therapy—align well with existing consensus statements [14, 15].
Abbreviations
ANCAbsolute neutrophil count
BCMAB-cell maturation antigen
CARChimeric antigen receptor
CRPC reactive protein
CRSCytokine release syndrome
IFNInterferon
ILInterleukin
IMWGInternational Myeloma Working Group
HbHemoglobin
κLCKappa light chain
LDCLymphodepleting chemotherapy
LymLymphocytes
MMMultiple myeloma
TmaxTemperature
TNFTumor necrosis factor
SARS-CoV-2Severe acute respiratory syndrome coronavirus 2
WBCWhite blood cell
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge all the staff and families for the selfless efforts in caring for patients who developed COVID-19 and the strength and courage of all patients affected by the pandemic. Medical writing assistance was provided by Karen Repetny, PhD, of bluebird bio, Cambridge, MA, USA
Authors’ Contributions
DM: collected data, analyzed and interpreted data preparation and review of the manuscript. SP: collected data, analyzed and interpreted data preparation and review of the manuscript. TC: analyzed and interpreted data preparation and review of the manuscript. FP: collected data, analyzed and interpreted data preparation and review of the manuscript. FN: analyzed and interpreted data preparation and review of the manuscript. SJ: collected data, analyzed and interpreted data preparation and review of the manuscript. All authors read and approved the final manuscript.
Funding
The clinical study NCT03274219 is supported by bluebird bio
Availability of data and materials
All data are included in this case report
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines for Good Clinical Practice and the protocol was approved by local or independent institutional review boards at each study center. All patients provided informed consent for participation in this clinical study.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interest
D.M.: Advisory board and consulting fees from Janssen, Celgene, Bristol Myers Squibb, Takeda, Legend, Sanofi Genzyme, GlaxoSmithKline, Kinevant, and Foundation Medicine. S.P.: Consulting fees from Foundation Medicine, research funding from Celgene and Karyopharm. Supported by 1R01CA244899-01A1. T.C.: Employment and ownership of Bristol-Myers Squibb, F.P.: employment and ownership interest of bluebird bio, F.N.: prior employment and ownership interest of bluebird bio. S.J.: Advisory board and consulting fees from Celgene, Bristol‐Myers Squibb, Janssen Pharmaceuticals, and Merck. | Recovered | ReactionOutcome | CC BY | 33608053 | 19,573,417 | 2021-02-19 |
What was the outcome of reaction 'Cytokine release syndrome'? | Anti-BCMA CAR T administration in a relapsed and refractory multiple myeloma patient after COVID-19 infection: a case report.
BACKGROUND
Very little is known about the risk that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection poses to cancer patients, many of whom are immune compromised causing them to be more susceptible to a host of infections. As a precautionary measure, many clinical studies halted enrollment during the initial surge of the global Novel Coronavirus Disease (COVID-19) pandemic. In this case report, we detail the successful treatment of a relapsed and refractory multiple myeloma (MM) patient treated with an anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy immediately following clinical recovery from COVID-19.
METHODS
The 57 year old Caucasian male patient had a 4-year history of MM and was considered penta-refractory upon presentation for CAR T cell therapy. He had a history of immunosuppression and received one dose of lymphodepleting chemotherapy (LDC) the day prior to COVID-19 diagnosis; this patient was able to mount a substantial immune response against the SARS-CoV-2 virus, and antiviral antibodies remain detectable 2 months after receiving anti-BCMA CAR T cell therapy. The recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated cytokine release syndrome (CRS) and conversely the CAR T cell therapy did not result in COVID-19-related complications. One month after CAR T cell infusion, the patient was assessed to have an unconfirmed partial response per International Myeloma Working Group (IMWG) criteria.
CONCLUSIONS
Our case adds important context around treatment choice for MM patients in the era of COVID-19 and whether CAR T therapy can be administered to patients who have recovered from COVID-19. As the COVID-19 global pandemic continues, the decision of whether to proceed with CAR T cell therapy will require extensive discussion weighing the potential risks and benefits of therapy. This case suggests that it is possible to successfully complete anti-BCMA CAR T cell therapy after recovery from COVID-19. CRB-402 study registered 6 September 2017 at clinicaltrials.gov (NCT03274219).
Background
The global COVID-19 pandemic represents a worldwide public health crisis and directly impacts cancer care. Patients with multiple myeloma (MM) have cellular and humoral immune dysfunction causing them to be more susceptible to infections [1, 2]. Anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy is emerging as a promising option for relapsed myeloma patients; however, most clinical trials of CAR T therapy for MM were paused during the pandemic because of the possibility of increased morbidity and mortality with COVID-19. Specifically, in MM patients, it is unclear whether the immunosuppression resulting from conditioning regimens used with CAR T cell therapy may pose an increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, COVID-19 may trigger an inflammatory cascade [3-5] similar to the cytokine release syndrome (CRS) seen in some patients treated with CAR T cells [6]. Our experience in MM patients with COVID-19 showed they have a similar mortality compared to the general age-matched COVID-19-infected population [7]. Our practice has therefore been to weigh the risks and benefits of treatment to tailor therapy for individual MM patients during the COVID-19 pandemic. Here, we report the first case to our knowledge of an MM patient safely treated with anti-BCMA CAR T cell therapy immediately after clinical recovery from COVID-19.
Case presentation
A 57-year-old Caucasian male patient with a 4-year history of IgG-kappa MM was referred to Mount Sinai Hospital in New York City in early February 2020 because of disease progression. He was penta-refractory (refractory to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 antibody) and had previously received nine lines of therapy.
In early February 2020, approximately 3.5 weeks prior to the first confirmed case of COVID-19 in New York City, the patient was enrolled in a clinical study (NCT03274219) of bb21217, an investigational BCMA-directed CAR T cell therapy. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines for Good Clinical Practice, and the protocol was approved by local or independent institutional review boards (IRB) at each study center. Informed consent was obtained from each patient. The patient received bridging therapy with melphalan and bortezomib while awaiting CAR T cell manufacturing. He was asymptomatic and screened negative by PCR test for SARS-CoV-2 two days prior to a planned 3-day course of lymphodepleting chemotherapy (LDC). Approximately 24 hours after receiving the first dose of LDC [cyclophosphamide (300 mg/m2)/fludarabine (30 mg/m2)], the patient returned to clinic with fever, cough, and diarrhea. Nasopharyngeal polymerase chain reaction (PCR) test confirmed SARS-CoV-2 infection.
CAR T infusion was held in the setting of active COVID-19 infection, and the patient was admitted to the hospital for observation. He was afebrile upon admission with a mild cough that resolved within 1 day. He was given granulocyte colony stimulating factor (G-CSF) for grade 1 neutropenia and discharged with instructions to self-isolate at home after 3 days of hospitalization.
The patient was monitored weekly, and further therapy was held until SARS-CoV-2 clearance was confirmed by nasopharyngeal PCR test, 39 days after COVID-19 diagnosis. Upon approval by the sponsor and our IRB, the patient reinitiated the full 3-day course of LDC in preparation for CAR T cell administration. At this point, inflammatory markers were normal, and SARS-CoV-2 antibodies were detected at a titer of 1:2880 using an IgG assay developed by Mount Sinai [8]. On the day of CAR T cell infusion, lymphocytes in the peripheral blood were undetectable and the patient showed profound leukopenia (Figure 1). Twelve hours after CAR T cell infusion, clinical signs consistent with Grade 1 CRS developed, including fever and tachycardia [9]. On day 2, CRS escalated to Grade 2 and was accompanied by hypotension (81/52), only transiently responsive to fluids; thus, tocilizumab (8 mg/kg) × 1 was given. The patient experienced 2 more days of low-grade fever (Figure 2) and grade 1 hypotension. CRS resolved by day 6, and cytokines returned to pretreatment levels by day 9 (Figure 2). Blood counts improved by day 12 except lymphopenia, which persisted through day 14 (Figure 1). Based on 1-month follow-up post-CAR T cell infusion, the patient did not experience other complications, remained SARS-CoV-2 negative, and showed normalization of free kappa light chain with a 61% decrease in serum M protein (Figure 1), consistent with partial response per international myeloma working group (IMWG) criteria. Repeat SARS-CoV-2 antibody titer at his 1-month follow up was 1:960 and at 2-month follow up was 1:320.Fig. 1 Clinical course: blood laboratory values from initial baseline assessment through 30 days post CAR T cell administration. LDC was administered on days -47 and days -5 through -3; positive COVID-19 test by PCR day -46, negative COVID-19 test by PCR day -7; CAR T cell administration day 1, anti-viral antibody titer day -7. Repeat anti-viral antibody titers were conducted day 43 and day 73 (not shown)
Fig. 2 Cytokine release syndrome course and recovery: temperature, inflammatory and cytokine values from CAR T cell administration through 30 days post CAR T cell administration, CRS course (shaded) days 1–6
Discussion/Conclusions
Our case adds important context to the evolving literature about treatment of MM patients in the era of COVID-19 [10]. This is the first case report in the published literature to share the experience of successful administration of anti-BCMA CAR T cell treatment to a patient with relapsed and refractory MM who recently recovered from COVID-19. Importantly, the administration of 1 day of LDC immediately prior to SARS-CoV-2 infection did not result in any COVID-19-related complications.
The patient experienced Grade 2 CRS, an expected toxicity associated with CAR T therapy, which resolved within 6 days, and the patient is currently in partial response (unconfirmed), per IMWG assessment [11, 12]. Inflammatory cytokines were elevated during the CRS event; however, levels were in the same range as for CAR T cell-treated patients without COVID-19 who experience CRS [13]. Hence, recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated CRS, even though this is a toxicity known to be associated with COVID-19.
Interestingly, this patient experienced a robust humoral response to viral infection, despite his history of immune suppression. Two months after treatment with a BCMA-directed CAR T therapy, which can ablate normal BCMA expressing plasma cells, the antibody titer decreased from 1:2880 to 1:320 but remained clearly detectable approximately 4 months after infection. Whether this patient developed and retained long-term immunity against COVID-19 remains to be determined.
With the initial surge of COVID-19, many clinical trial sites paused trials of CAR T cell therapy for MM patients. As trials re-start, investigational sites should ensure access to critical care and availability of appropriate drugs to manage CAR T cell-associated toxicities and carefully weigh the potential risks and benefits of therapy prior to proceeding with CAR T cell therapy. Our report, although limited to a single patient experience, suggests that patients who have tested antibody positive for SARS-CoV-2 can proceed with CAR T cell therapy without flare-up of COVID-19-related symptoms. High antibody titers can be generated in myeloma patients; SARS-CoV-2-specific antibodies were retained despite effective anti-BCMA CAR T cell therapy in this patient. Additional studies to determine the effect of BCMA targeting agents on the risk of SARS-CoV-2 re-infection are warranted. As COVID-19 immunity after recovery has not been well characterized, appropriate precautions such as social distancing, facial mask, and good hygiene are recommended to prevent re-infection.
The information available regarding management strategies for MM patients during the COVID-19 pandemic is insufficient to provide evidence-based recommendations; however, several consensus statements have been published that provide guidance. The recommendations included within this report—securing access to supportive care, taking appropriate precautions to avoid SARS-CoV-2 infection, and carefully weighing the potential risks and benefits of CAR T cell therapy—align well with existing consensus statements [14, 15].
Abbreviations
ANCAbsolute neutrophil count
BCMAB-cell maturation antigen
CARChimeric antigen receptor
CRPC reactive protein
CRSCytokine release syndrome
IFNInterferon
ILInterleukin
IMWGInternational Myeloma Working Group
HbHemoglobin
κLCKappa light chain
LDCLymphodepleting chemotherapy
LymLymphocytes
MMMultiple myeloma
TmaxTemperature
TNFTumor necrosis factor
SARS-CoV-2Severe acute respiratory syndrome coronavirus 2
WBCWhite blood cell
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge all the staff and families for the selfless efforts in caring for patients who developed COVID-19 and the strength and courage of all patients affected by the pandemic. Medical writing assistance was provided by Karen Repetny, PhD, of bluebird bio, Cambridge, MA, USA
Authors’ Contributions
DM: collected data, analyzed and interpreted data preparation and review of the manuscript. SP: collected data, analyzed and interpreted data preparation and review of the manuscript. TC: analyzed and interpreted data preparation and review of the manuscript. FP: collected data, analyzed and interpreted data preparation and review of the manuscript. FN: analyzed and interpreted data preparation and review of the manuscript. SJ: collected data, analyzed and interpreted data preparation and review of the manuscript. All authors read and approved the final manuscript.
Funding
The clinical study NCT03274219 is supported by bluebird bio
Availability of data and materials
All data are included in this case report
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines for Good Clinical Practice and the protocol was approved by local or independent institutional review boards at each study center. All patients provided informed consent for participation in this clinical study.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interest
D.M.: Advisory board and consulting fees from Janssen, Celgene, Bristol Myers Squibb, Takeda, Legend, Sanofi Genzyme, GlaxoSmithKline, Kinevant, and Foundation Medicine. S.P.: Consulting fees from Foundation Medicine, research funding from Celgene and Karyopharm. Supported by 1R01CA244899-01A1. T.C.: Employment and ownership of Bristol-Myers Squibb, F.P.: employment and ownership interest of bluebird bio, F.N.: prior employment and ownership interest of bluebird bio. S.J.: Advisory board and consulting fees from Celgene, Bristol‐Myers Squibb, Janssen Pharmaceuticals, and Merck. | Recovered | ReactionOutcome | CC BY | 33608053 | 19,598,038 | 2021-02-19 |
What was the outcome of reaction 'Lymphopenia'? | Anti-BCMA CAR T administration in a relapsed and refractory multiple myeloma patient after COVID-19 infection: a case report.
BACKGROUND
Very little is known about the risk that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection poses to cancer patients, many of whom are immune compromised causing them to be more susceptible to a host of infections. As a precautionary measure, many clinical studies halted enrollment during the initial surge of the global Novel Coronavirus Disease (COVID-19) pandemic. In this case report, we detail the successful treatment of a relapsed and refractory multiple myeloma (MM) patient treated with an anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy immediately following clinical recovery from COVID-19.
METHODS
The 57 year old Caucasian male patient had a 4-year history of MM and was considered penta-refractory upon presentation for CAR T cell therapy. He had a history of immunosuppression and received one dose of lymphodepleting chemotherapy (LDC) the day prior to COVID-19 diagnosis; this patient was able to mount a substantial immune response against the SARS-CoV-2 virus, and antiviral antibodies remain detectable 2 months after receiving anti-BCMA CAR T cell therapy. The recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated cytokine release syndrome (CRS) and conversely the CAR T cell therapy did not result in COVID-19-related complications. One month after CAR T cell infusion, the patient was assessed to have an unconfirmed partial response per International Myeloma Working Group (IMWG) criteria.
CONCLUSIONS
Our case adds important context around treatment choice for MM patients in the era of COVID-19 and whether CAR T therapy can be administered to patients who have recovered from COVID-19. As the COVID-19 global pandemic continues, the decision of whether to proceed with CAR T cell therapy will require extensive discussion weighing the potential risks and benefits of therapy. This case suggests that it is possible to successfully complete anti-BCMA CAR T cell therapy after recovery from COVID-19. CRB-402 study registered 6 September 2017 at clinicaltrials.gov (NCT03274219).
Background
The global COVID-19 pandemic represents a worldwide public health crisis and directly impacts cancer care. Patients with multiple myeloma (MM) have cellular and humoral immune dysfunction causing them to be more susceptible to infections [1, 2]. Anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy is emerging as a promising option for relapsed myeloma patients; however, most clinical trials of CAR T therapy for MM were paused during the pandemic because of the possibility of increased morbidity and mortality with COVID-19. Specifically, in MM patients, it is unclear whether the immunosuppression resulting from conditioning regimens used with CAR T cell therapy may pose an increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, COVID-19 may trigger an inflammatory cascade [3-5] similar to the cytokine release syndrome (CRS) seen in some patients treated with CAR T cells [6]. Our experience in MM patients with COVID-19 showed they have a similar mortality compared to the general age-matched COVID-19-infected population [7]. Our practice has therefore been to weigh the risks and benefits of treatment to tailor therapy for individual MM patients during the COVID-19 pandemic. Here, we report the first case to our knowledge of an MM patient safely treated with anti-BCMA CAR T cell therapy immediately after clinical recovery from COVID-19.
Case presentation
A 57-year-old Caucasian male patient with a 4-year history of IgG-kappa MM was referred to Mount Sinai Hospital in New York City in early February 2020 because of disease progression. He was penta-refractory (refractory to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 antibody) and had previously received nine lines of therapy.
In early February 2020, approximately 3.5 weeks prior to the first confirmed case of COVID-19 in New York City, the patient was enrolled in a clinical study (NCT03274219) of bb21217, an investigational BCMA-directed CAR T cell therapy. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines for Good Clinical Practice, and the protocol was approved by local or independent institutional review boards (IRB) at each study center. Informed consent was obtained from each patient. The patient received bridging therapy with melphalan and bortezomib while awaiting CAR T cell manufacturing. He was asymptomatic and screened negative by PCR test for SARS-CoV-2 two days prior to a planned 3-day course of lymphodepleting chemotherapy (LDC). Approximately 24 hours after receiving the first dose of LDC [cyclophosphamide (300 mg/m2)/fludarabine (30 mg/m2)], the patient returned to clinic with fever, cough, and diarrhea. Nasopharyngeal polymerase chain reaction (PCR) test confirmed SARS-CoV-2 infection.
CAR T infusion was held in the setting of active COVID-19 infection, and the patient was admitted to the hospital for observation. He was afebrile upon admission with a mild cough that resolved within 1 day. He was given granulocyte colony stimulating factor (G-CSF) for grade 1 neutropenia and discharged with instructions to self-isolate at home after 3 days of hospitalization.
The patient was monitored weekly, and further therapy was held until SARS-CoV-2 clearance was confirmed by nasopharyngeal PCR test, 39 days after COVID-19 diagnosis. Upon approval by the sponsor and our IRB, the patient reinitiated the full 3-day course of LDC in preparation for CAR T cell administration. At this point, inflammatory markers were normal, and SARS-CoV-2 antibodies were detected at a titer of 1:2880 using an IgG assay developed by Mount Sinai [8]. On the day of CAR T cell infusion, lymphocytes in the peripheral blood were undetectable and the patient showed profound leukopenia (Figure 1). Twelve hours after CAR T cell infusion, clinical signs consistent with Grade 1 CRS developed, including fever and tachycardia [9]. On day 2, CRS escalated to Grade 2 and was accompanied by hypotension (81/52), only transiently responsive to fluids; thus, tocilizumab (8 mg/kg) × 1 was given. The patient experienced 2 more days of low-grade fever (Figure 2) and grade 1 hypotension. CRS resolved by day 6, and cytokines returned to pretreatment levels by day 9 (Figure 2). Blood counts improved by day 12 except lymphopenia, which persisted through day 14 (Figure 1). Based on 1-month follow-up post-CAR T cell infusion, the patient did not experience other complications, remained SARS-CoV-2 negative, and showed normalization of free kappa light chain with a 61% decrease in serum M protein (Figure 1), consistent with partial response per international myeloma working group (IMWG) criteria. Repeat SARS-CoV-2 antibody titer at his 1-month follow up was 1:960 and at 2-month follow up was 1:320.Fig. 1 Clinical course: blood laboratory values from initial baseline assessment through 30 days post CAR T cell administration. LDC was administered on days -47 and days -5 through -3; positive COVID-19 test by PCR day -46, negative COVID-19 test by PCR day -7; CAR T cell administration day 1, anti-viral antibody titer day -7. Repeat anti-viral antibody titers were conducted day 43 and day 73 (not shown)
Fig. 2 Cytokine release syndrome course and recovery: temperature, inflammatory and cytokine values from CAR T cell administration through 30 days post CAR T cell administration, CRS course (shaded) days 1–6
Discussion/Conclusions
Our case adds important context to the evolving literature about treatment of MM patients in the era of COVID-19 [10]. This is the first case report in the published literature to share the experience of successful administration of anti-BCMA CAR T cell treatment to a patient with relapsed and refractory MM who recently recovered from COVID-19. Importantly, the administration of 1 day of LDC immediately prior to SARS-CoV-2 infection did not result in any COVID-19-related complications.
The patient experienced Grade 2 CRS, an expected toxicity associated with CAR T therapy, which resolved within 6 days, and the patient is currently in partial response (unconfirmed), per IMWG assessment [11, 12]. Inflammatory cytokines were elevated during the CRS event; however, levels were in the same range as for CAR T cell-treated patients without COVID-19 who experience CRS [13]. Hence, recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated CRS, even though this is a toxicity known to be associated with COVID-19.
Interestingly, this patient experienced a robust humoral response to viral infection, despite his history of immune suppression. Two months after treatment with a BCMA-directed CAR T therapy, which can ablate normal BCMA expressing plasma cells, the antibody titer decreased from 1:2880 to 1:320 but remained clearly detectable approximately 4 months after infection. Whether this patient developed and retained long-term immunity against COVID-19 remains to be determined.
With the initial surge of COVID-19, many clinical trial sites paused trials of CAR T cell therapy for MM patients. As trials re-start, investigational sites should ensure access to critical care and availability of appropriate drugs to manage CAR T cell-associated toxicities and carefully weigh the potential risks and benefits of therapy prior to proceeding with CAR T cell therapy. Our report, although limited to a single patient experience, suggests that patients who have tested antibody positive for SARS-CoV-2 can proceed with CAR T cell therapy without flare-up of COVID-19-related symptoms. High antibody titers can be generated in myeloma patients; SARS-CoV-2-specific antibodies were retained despite effective anti-BCMA CAR T cell therapy in this patient. Additional studies to determine the effect of BCMA targeting agents on the risk of SARS-CoV-2 re-infection are warranted. As COVID-19 immunity after recovery has not been well characterized, appropriate precautions such as social distancing, facial mask, and good hygiene are recommended to prevent re-infection.
The information available regarding management strategies for MM patients during the COVID-19 pandemic is insufficient to provide evidence-based recommendations; however, several consensus statements have been published that provide guidance. The recommendations included within this report—securing access to supportive care, taking appropriate precautions to avoid SARS-CoV-2 infection, and carefully weighing the potential risks and benefits of CAR T cell therapy—align well with existing consensus statements [14, 15].
Abbreviations
ANCAbsolute neutrophil count
BCMAB-cell maturation antigen
CARChimeric antigen receptor
CRPC reactive protein
CRSCytokine release syndrome
IFNInterferon
ILInterleukin
IMWGInternational Myeloma Working Group
HbHemoglobin
κLCKappa light chain
LDCLymphodepleting chemotherapy
LymLymphocytes
MMMultiple myeloma
TmaxTemperature
TNFTumor necrosis factor
SARS-CoV-2Severe acute respiratory syndrome coronavirus 2
WBCWhite blood cell
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge all the staff and families for the selfless efforts in caring for patients who developed COVID-19 and the strength and courage of all patients affected by the pandemic. Medical writing assistance was provided by Karen Repetny, PhD, of bluebird bio, Cambridge, MA, USA
Authors’ Contributions
DM: collected data, analyzed and interpreted data preparation and review of the manuscript. SP: collected data, analyzed and interpreted data preparation and review of the manuscript. TC: analyzed and interpreted data preparation and review of the manuscript. FP: collected data, analyzed and interpreted data preparation and review of the manuscript. FN: analyzed and interpreted data preparation and review of the manuscript. SJ: collected data, analyzed and interpreted data preparation and review of the manuscript. All authors read and approved the final manuscript.
Funding
The clinical study NCT03274219 is supported by bluebird bio
Availability of data and materials
All data are included in this case report
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines for Good Clinical Practice and the protocol was approved by local or independent institutional review boards at each study center. All patients provided informed consent for participation in this clinical study.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interest
D.M.: Advisory board and consulting fees from Janssen, Celgene, Bristol Myers Squibb, Takeda, Legend, Sanofi Genzyme, GlaxoSmithKline, Kinevant, and Foundation Medicine. S.P.: Consulting fees from Foundation Medicine, research funding from Celgene and Karyopharm. Supported by 1R01CA244899-01A1. T.C.: Employment and ownership of Bristol-Myers Squibb, F.P.: employment and ownership interest of bluebird bio, F.N.: prior employment and ownership interest of bluebird bio. S.J.: Advisory board and consulting fees from Celgene, Bristol‐Myers Squibb, Janssen Pharmaceuticals, and Merck. | Not recovered | ReactionOutcome | CC BY | 33608053 | 19,573,417 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure'. | SRP-positive necrotising myopathy: takes more than just the muscles.
Necrotising myopathy is an autoimmune disease that commonly affects muscles. Here we examine a case of a middle-aged women presenting with a chief report of shortness of breath, who subsequently developed muscle weakness. Her clinical course was complicated by respiratory failure and pulmonary hypertension likely due to the underlying pathology of signal recognition particle-positive necrotising myopathy. After further evaluation, her shortness of breath was thought to be secondary to muscle pathology rather than cardiopulmonary pathology. She was transferred to our institution for workup by rheumatology. At the time of admission, 6 months after initial presentation, her weakness progressed, so that she was unable to lift her arms and legs against gravity. Furthermore, neurological examination revealed mild facial and nuchal weakness, severe proximal weakness, more moderate distal weakness and global areflexia.
Background
Necrotising myopathy is a rare autoimmune disease that is thought to primarily affect muscles and commonly presents as weakness; it has been reported that there are associated effects on the heart and lungs. This case describes a middle-aged woman presenting with a chief report of shortness of breath, who was subsequently found to have muscle weakness and respiratory failure due to signal recognition particle (SRP)-positive myopathy. In this case, we evaluate her clinical course, review the literature regarding SRP-positive myopathy and strengthen the case that due to the ubiquitous nature of the SRP autoantibodies; patient presentations can extend beyond proximal muscle weakness.
Case presentation
A previously independently functioning 52-year-old obese African American woman initially presented to her primary care office with a chief report of unresolving shortness of breath, which seemed to be incited after she tripped over a broom at work. Previous medical history was significant for hyperlipidaemia treated with simvastatin 40 mg for primary prevention from 2013 to 2020, morbid obesity, congestive heart failure and coronary artery disease.
Patient’s primary care doctor sent the patient for a CT angiogram that was significant for pulmonary hypertension and hepatic inflammation. In the following weeks, she was admitted for progressive muscle weakness.
Patient was found to have a creatine kinase (CK) elevation that peaked at 25 295 U/L. MRI of the lumbar spine revealed diffuse oedema of the pelvic muscles. Left quadriceps muscle biopsy was interpreted with ‘rare’ necrotic fibres, ‘occasional’ cytochrome c oxidase-intermediate (COX)-negative fibres, without deposits of complement macrophage antigens (MAC), and major histocompatibility (MHC) class I staining. SRP and -hydroxy-3-methyl-glutaryl-coenzymereductase (HMGCR) antibodies were negative. Antinuclear antibodies (ANA), nuclear ribonucleoprotein (RNP), Sjögren’s syndrome antibody (SSA), double-stranded DNA and myeloperoxidase antibodies were positive. Her home simvastatin was held, she was treated with prednisone and intravenous immunoglobulin. Her CK gradually decreased to the 2000–4000 U/L.
She continued to experience shortness of breath and was found to have a non-ST elevation myocardial infarction treated with medical management and stent placement for left anterior descending lesion. Further evaluation with an electromyography showed a diffuse, proximal-predominant, irritable myopathy and distal axonal polyneuropathy.
Laboratory workup was consistent with elevated erythrocyte sedimentation rate (ESR) and positive ANA with a homogeneous pattern, which is typically seen in lupus, RNP as well as SSA antibodies as noted at the outside hospital. SRP 54 was now positive. CT C/A/P did not identify any malignancy. Muscle biopsy was significant for highly active and chronic necrotising myopathy with inflammation, mild mitochondrial dysfunction, preferential type 2 atrophy, increased type 2C fibres, occasional rounded atrophic fibres and mild denervation atrophy, indicative of highly active and possibly chronic necrotising myopathy.
Treatment
Patient was treated with prednisone, IVIG and mycophenolate mofetil.
Outcome and follow-up
Patient initially failed to improve. Her course was complicated by worsening heart failure, respiratory failure requiring intubation with transition to tracheostomy and dysphagia requiring nasogastric tube for nutrition. She continued to slowly decline and was evaluated for placement at a long-term care facility. After a course at a long-term acute care, the patient returned home with continued needs for assistance with activities of daily living.
Discussion
Immune-mediated necrotising myopathy (IMNM) is characterised by minimal infiltration on muscle biopsy and is one of the most severe and progressive myopathies.1 2 In our case, the patient was SRP 54 positive, a subunit of the SRP protein complex, presenting with shortness of breath, followed by weakness, then dysphagia. It is commonly thought that the type of autoantibody will predict the course of the myopathy and the associated extra muscular manifestations. SRP is a ribonuclear protein that regulates translocation of protein across the endoplasmic reticulum. It is not specific to muscle tissue but is ubiquitously found in all protein processing cells.2 Myopathies associated with SRP antibodies were thought to have a similar clinical presentation; however, the literature suggests the presentation of SRP associated myopathy can vary greatly. Anti-SRP-related myopathy is now considered a subset of IMNM, also known as necrotising autoimmune myopathy. Symptoms of anti-SRP myopathy are range from weakness, dysphagia and cardiovascular involvement, with some studies showing lower association with interstitial lung disease (ILD).3 While limb weakness is the most common manifestation of myositis, there are reports of the SRP protein antibodies leading to different presenting symptoms involving the lungs and heart.2 4Involvement of the haematologic system with neutropenia and other alterations in proliferation were also identified.2 5 The ubiquitous nature of the SRP protein leads to multiple different manifestations when attacked by the immune system, from pulmonary, cardiac and haematologic.6 7 Myocardial involvement in anti-SRP myopathy can be severe and is considered a poor prognostic factor. Extramuscular manifestations such as ILD, Raynaud’s and arthralgia have been reported, though these features are typically mild. Some authors have suggested that radiographic suggestion of ILD in these patients may in fact arise from respiratory insufficiency due to musculoskeletal weakness.8
Other autoimmune conditions may have been at play in our patient and her dramatic hospital course. It has been shown that patients positive for ANA in a homogeneous pattern, consistent with SLE, is potentially associated with an overlap syndrome of SLE and necrotising myopathy. While this may have been present in our patient, the likelihood is low as there was no history of SLE in our patient. Furthermore, the overlap between SLE and necrotising myopathy has only been described in one case report to date.9 With this knowledge, clinicians should be aware of the complications of dysphagia, respiratory and cardiac failure and initiate prompt treatment to avoid further complications in the patient’s clinical course.
In fact, involvement of muscles with a symptom of weakness may not be as prominent as other symptoms such as shortness of breath or dysphagia. This is logical given the ubiquity of SRP and the ability of the antibody to cause dysfunction in different tissues.2
Patient’s perspective
As this was during the COVID pandemic, it was extremely difficult for me to adjust to the situation and the loss of the ability to care for myself. I often felt alone and was very scared. As I was in the hospital for over 6 months, I feel that I missed out a lot with my family. We lost my son to a gunshot wound before my sickness and I was also grieving that loss.
Learning points
Necrotising myopathy is a rare but fatal aetiology in patient’s presenting with weakness and shortness of breath.
Patients can have variable presentations and may initially present with symptoms other than skeletal muscle weakness.
Treatment of the condition should not be delayed while workup is undertaken as it can result in pulmonary hypertension and serious pulmonary and cardiac manifestations.
It is imperative to know a patient’s functional baseline to set expectations for the clinical course of a myopathy pathology
Contributors: MB: served as scientific advisor. SB: wrote and researched case.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed. | MYCOPHENOLATE MOFETIL, PREDNISONE, SIMVASTATIN | DrugsGivenReaction | CC BY-NC | 33608334 | 19,753,479 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | SRP-positive necrotising myopathy: takes more than just the muscles.
Necrotising myopathy is an autoimmune disease that commonly affects muscles. Here we examine a case of a middle-aged women presenting with a chief report of shortness of breath, who subsequently developed muscle weakness. Her clinical course was complicated by respiratory failure and pulmonary hypertension likely due to the underlying pathology of signal recognition particle-positive necrotising myopathy. After further evaluation, her shortness of breath was thought to be secondary to muscle pathology rather than cardiopulmonary pathology. She was transferred to our institution for workup by rheumatology. At the time of admission, 6 months after initial presentation, her weakness progressed, so that she was unable to lift her arms and legs against gravity. Furthermore, neurological examination revealed mild facial and nuchal weakness, severe proximal weakness, more moderate distal weakness and global areflexia.
Background
Necrotising myopathy is a rare autoimmune disease that is thought to primarily affect muscles and commonly presents as weakness; it has been reported that there are associated effects on the heart and lungs. This case describes a middle-aged woman presenting with a chief report of shortness of breath, who was subsequently found to have muscle weakness and respiratory failure due to signal recognition particle (SRP)-positive myopathy. In this case, we evaluate her clinical course, review the literature regarding SRP-positive myopathy and strengthen the case that due to the ubiquitous nature of the SRP autoantibodies; patient presentations can extend beyond proximal muscle weakness.
Case presentation
A previously independently functioning 52-year-old obese African American woman initially presented to her primary care office with a chief report of unresolving shortness of breath, which seemed to be incited after she tripped over a broom at work. Previous medical history was significant for hyperlipidaemia treated with simvastatin 40 mg for primary prevention from 2013 to 2020, morbid obesity, congestive heart failure and coronary artery disease.
Patient’s primary care doctor sent the patient for a CT angiogram that was significant for pulmonary hypertension and hepatic inflammation. In the following weeks, she was admitted for progressive muscle weakness.
Patient was found to have a creatine kinase (CK) elevation that peaked at 25 295 U/L. MRI of the lumbar spine revealed diffuse oedema of the pelvic muscles. Left quadriceps muscle biopsy was interpreted with ‘rare’ necrotic fibres, ‘occasional’ cytochrome c oxidase-intermediate (COX)-negative fibres, without deposits of complement macrophage antigens (MAC), and major histocompatibility (MHC) class I staining. SRP and -hydroxy-3-methyl-glutaryl-coenzymereductase (HMGCR) antibodies were negative. Antinuclear antibodies (ANA), nuclear ribonucleoprotein (RNP), Sjögren’s syndrome antibody (SSA), double-stranded DNA and myeloperoxidase antibodies were positive. Her home simvastatin was held, she was treated with prednisone and intravenous immunoglobulin. Her CK gradually decreased to the 2000–4000 U/L.
She continued to experience shortness of breath and was found to have a non-ST elevation myocardial infarction treated with medical management and stent placement for left anterior descending lesion. Further evaluation with an electromyography showed a diffuse, proximal-predominant, irritable myopathy and distal axonal polyneuropathy.
Laboratory workup was consistent with elevated erythrocyte sedimentation rate (ESR) and positive ANA with a homogeneous pattern, which is typically seen in lupus, RNP as well as SSA antibodies as noted at the outside hospital. SRP 54 was now positive. CT C/A/P did not identify any malignancy. Muscle biopsy was significant for highly active and chronic necrotising myopathy with inflammation, mild mitochondrial dysfunction, preferential type 2 atrophy, increased type 2C fibres, occasional rounded atrophic fibres and mild denervation atrophy, indicative of highly active and possibly chronic necrotising myopathy.
Treatment
Patient was treated with prednisone, IVIG and mycophenolate mofetil.
Outcome and follow-up
Patient initially failed to improve. Her course was complicated by worsening heart failure, respiratory failure requiring intubation with transition to tracheostomy and dysphagia requiring nasogastric tube for nutrition. She continued to slowly decline and was evaluated for placement at a long-term care facility. After a course at a long-term acute care, the patient returned home with continued needs for assistance with activities of daily living.
Discussion
Immune-mediated necrotising myopathy (IMNM) is characterised by minimal infiltration on muscle biopsy and is one of the most severe and progressive myopathies.1 2 In our case, the patient was SRP 54 positive, a subunit of the SRP protein complex, presenting with shortness of breath, followed by weakness, then dysphagia. It is commonly thought that the type of autoantibody will predict the course of the myopathy and the associated extra muscular manifestations. SRP is a ribonuclear protein that regulates translocation of protein across the endoplasmic reticulum. It is not specific to muscle tissue but is ubiquitously found in all protein processing cells.2 Myopathies associated with SRP antibodies were thought to have a similar clinical presentation; however, the literature suggests the presentation of SRP associated myopathy can vary greatly. Anti-SRP-related myopathy is now considered a subset of IMNM, also known as necrotising autoimmune myopathy. Symptoms of anti-SRP myopathy are range from weakness, dysphagia and cardiovascular involvement, with some studies showing lower association with interstitial lung disease (ILD).3 While limb weakness is the most common manifestation of myositis, there are reports of the SRP protein antibodies leading to different presenting symptoms involving the lungs and heart.2 4Involvement of the haematologic system with neutropenia and other alterations in proliferation were also identified.2 5 The ubiquitous nature of the SRP protein leads to multiple different manifestations when attacked by the immune system, from pulmonary, cardiac and haematologic.6 7 Myocardial involvement in anti-SRP myopathy can be severe and is considered a poor prognostic factor. Extramuscular manifestations such as ILD, Raynaud’s and arthralgia have been reported, though these features are typically mild. Some authors have suggested that radiographic suggestion of ILD in these patients may in fact arise from respiratory insufficiency due to musculoskeletal weakness.8
Other autoimmune conditions may have been at play in our patient and her dramatic hospital course. It has been shown that patients positive for ANA in a homogeneous pattern, consistent with SLE, is potentially associated with an overlap syndrome of SLE and necrotising myopathy. While this may have been present in our patient, the likelihood is low as there was no history of SLE in our patient. Furthermore, the overlap between SLE and necrotising myopathy has only been described in one case report to date.9 With this knowledge, clinicians should be aware of the complications of dysphagia, respiratory and cardiac failure and initiate prompt treatment to avoid further complications in the patient’s clinical course.
In fact, involvement of muscles with a symptom of weakness may not be as prominent as other symptoms such as shortness of breath or dysphagia. This is logical given the ubiquity of SRP and the ability of the antibody to cause dysfunction in different tissues.2
Patient’s perspective
As this was during the COVID pandemic, it was extremely difficult for me to adjust to the situation and the loss of the ability to care for myself. I often felt alone and was very scared. As I was in the hospital for over 6 months, I feel that I missed out a lot with my family. We lost my son to a gunshot wound before my sickness and I was also grieving that loss.
Learning points
Necrotising myopathy is a rare but fatal aetiology in patient’s presenting with weakness and shortness of breath.
Patients can have variable presentations and may initially present with symptoms other than skeletal muscle weakness.
Treatment of the condition should not be delayed while workup is undertaken as it can result in pulmonary hypertension and serious pulmonary and cardiac manifestations.
It is imperative to know a patient’s functional baseline to set expectations for the clinical course of a myopathy pathology
Contributors: MB: served as scientific advisor. SB: wrote and researched case.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed. | MYCOPHENOLATE MOFETIL, PREDNISONE, SIMVASTATIN | DrugsGivenReaction | CC BY-NC | 33608334 | 19,753,479 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | SRP-positive necrotising myopathy: takes more than just the muscles.
Necrotising myopathy is an autoimmune disease that commonly affects muscles. Here we examine a case of a middle-aged women presenting with a chief report of shortness of breath, who subsequently developed muscle weakness. Her clinical course was complicated by respiratory failure and pulmonary hypertension likely due to the underlying pathology of signal recognition particle-positive necrotising myopathy. After further evaluation, her shortness of breath was thought to be secondary to muscle pathology rather than cardiopulmonary pathology. She was transferred to our institution for workup by rheumatology. At the time of admission, 6 months after initial presentation, her weakness progressed, so that she was unable to lift her arms and legs against gravity. Furthermore, neurological examination revealed mild facial and nuchal weakness, severe proximal weakness, more moderate distal weakness and global areflexia.
Background
Necrotising myopathy is a rare autoimmune disease that is thought to primarily affect muscles and commonly presents as weakness; it has been reported that there are associated effects on the heart and lungs. This case describes a middle-aged woman presenting with a chief report of shortness of breath, who was subsequently found to have muscle weakness and respiratory failure due to signal recognition particle (SRP)-positive myopathy. In this case, we evaluate her clinical course, review the literature regarding SRP-positive myopathy and strengthen the case that due to the ubiquitous nature of the SRP autoantibodies; patient presentations can extend beyond proximal muscle weakness.
Case presentation
A previously independently functioning 52-year-old obese African American woman initially presented to her primary care office with a chief report of unresolving shortness of breath, which seemed to be incited after she tripped over a broom at work. Previous medical history was significant for hyperlipidaemia treated with simvastatin 40 mg for primary prevention from 2013 to 2020, morbid obesity, congestive heart failure and coronary artery disease.
Patient’s primary care doctor sent the patient for a CT angiogram that was significant for pulmonary hypertension and hepatic inflammation. In the following weeks, she was admitted for progressive muscle weakness.
Patient was found to have a creatine kinase (CK) elevation that peaked at 25 295 U/L. MRI of the lumbar spine revealed diffuse oedema of the pelvic muscles. Left quadriceps muscle biopsy was interpreted with ‘rare’ necrotic fibres, ‘occasional’ cytochrome c oxidase-intermediate (COX)-negative fibres, without deposits of complement macrophage antigens (MAC), and major histocompatibility (MHC) class I staining. SRP and -hydroxy-3-methyl-glutaryl-coenzymereductase (HMGCR) antibodies were negative. Antinuclear antibodies (ANA), nuclear ribonucleoprotein (RNP), Sjögren’s syndrome antibody (SSA), double-stranded DNA and myeloperoxidase antibodies were positive. Her home simvastatin was held, she was treated with prednisone and intravenous immunoglobulin. Her CK gradually decreased to the 2000–4000 U/L.
She continued to experience shortness of breath and was found to have a non-ST elevation myocardial infarction treated with medical management and stent placement for left anterior descending lesion. Further evaluation with an electromyography showed a diffuse, proximal-predominant, irritable myopathy and distal axonal polyneuropathy.
Laboratory workup was consistent with elevated erythrocyte sedimentation rate (ESR) and positive ANA with a homogeneous pattern, which is typically seen in lupus, RNP as well as SSA antibodies as noted at the outside hospital. SRP 54 was now positive. CT C/A/P did not identify any malignancy. Muscle biopsy was significant for highly active and chronic necrotising myopathy with inflammation, mild mitochondrial dysfunction, preferential type 2 atrophy, increased type 2C fibres, occasional rounded atrophic fibres and mild denervation atrophy, indicative of highly active and possibly chronic necrotising myopathy.
Treatment
Patient was treated with prednisone, IVIG and mycophenolate mofetil.
Outcome and follow-up
Patient initially failed to improve. Her course was complicated by worsening heart failure, respiratory failure requiring intubation with transition to tracheostomy and dysphagia requiring nasogastric tube for nutrition. She continued to slowly decline and was evaluated for placement at a long-term care facility. After a course at a long-term acute care, the patient returned home with continued needs for assistance with activities of daily living.
Discussion
Immune-mediated necrotising myopathy (IMNM) is characterised by minimal infiltration on muscle biopsy and is one of the most severe and progressive myopathies.1 2 In our case, the patient was SRP 54 positive, a subunit of the SRP protein complex, presenting with shortness of breath, followed by weakness, then dysphagia. It is commonly thought that the type of autoantibody will predict the course of the myopathy and the associated extra muscular manifestations. SRP is a ribonuclear protein that regulates translocation of protein across the endoplasmic reticulum. It is not specific to muscle tissue but is ubiquitously found in all protein processing cells.2 Myopathies associated with SRP antibodies were thought to have a similar clinical presentation; however, the literature suggests the presentation of SRP associated myopathy can vary greatly. Anti-SRP-related myopathy is now considered a subset of IMNM, also known as necrotising autoimmune myopathy. Symptoms of anti-SRP myopathy are range from weakness, dysphagia and cardiovascular involvement, with some studies showing lower association with interstitial lung disease (ILD).3 While limb weakness is the most common manifestation of myositis, there are reports of the SRP protein antibodies leading to different presenting symptoms involving the lungs and heart.2 4Involvement of the haematologic system with neutropenia and other alterations in proliferation were also identified.2 5 The ubiquitous nature of the SRP protein leads to multiple different manifestations when attacked by the immune system, from pulmonary, cardiac and haematologic.6 7 Myocardial involvement in anti-SRP myopathy can be severe and is considered a poor prognostic factor. Extramuscular manifestations such as ILD, Raynaud’s and arthralgia have been reported, though these features are typically mild. Some authors have suggested that radiographic suggestion of ILD in these patients may in fact arise from respiratory insufficiency due to musculoskeletal weakness.8
Other autoimmune conditions may have been at play in our patient and her dramatic hospital course. It has been shown that patients positive for ANA in a homogeneous pattern, consistent with SLE, is potentially associated with an overlap syndrome of SLE and necrotising myopathy. While this may have been present in our patient, the likelihood is low as there was no history of SLE in our patient. Furthermore, the overlap between SLE and necrotising myopathy has only been described in one case report to date.9 With this knowledge, clinicians should be aware of the complications of dysphagia, respiratory and cardiac failure and initiate prompt treatment to avoid further complications in the patient’s clinical course.
In fact, involvement of muscles with a symptom of weakness may not be as prominent as other symptoms such as shortness of breath or dysphagia. This is logical given the ubiquity of SRP and the ability of the antibody to cause dysfunction in different tissues.2
Patient’s perspective
As this was during the COVID pandemic, it was extremely difficult for me to adjust to the situation and the loss of the ability to care for myself. I often felt alone and was very scared. As I was in the hospital for over 6 months, I feel that I missed out a lot with my family. We lost my son to a gunshot wound before my sickness and I was also grieving that loss.
Learning points
Necrotising myopathy is a rare but fatal aetiology in patient’s presenting with weakness and shortness of breath.
Patients can have variable presentations and may initially present with symptoms other than skeletal muscle weakness.
Treatment of the condition should not be delayed while workup is undertaken as it can result in pulmonary hypertension and serious pulmonary and cardiac manifestations.
It is imperative to know a patient’s functional baseline to set expectations for the clinical course of a myopathy pathology
Contributors: MB: served as scientific advisor. SB: wrote and researched case.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed. | MYCOPHENOLATE MOFETIL, PREDNISONE, SIMVASTATIN | DrugsGivenReaction | CC BY-NC | 33608334 | 19,753,479 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dysphagia'. | SRP-positive necrotising myopathy: takes more than just the muscles.
Necrotising myopathy is an autoimmune disease that commonly affects muscles. Here we examine a case of a middle-aged women presenting with a chief report of shortness of breath, who subsequently developed muscle weakness. Her clinical course was complicated by respiratory failure and pulmonary hypertension likely due to the underlying pathology of signal recognition particle-positive necrotising myopathy. After further evaluation, her shortness of breath was thought to be secondary to muscle pathology rather than cardiopulmonary pathology. She was transferred to our institution for workup by rheumatology. At the time of admission, 6 months after initial presentation, her weakness progressed, so that she was unable to lift her arms and legs against gravity. Furthermore, neurological examination revealed mild facial and nuchal weakness, severe proximal weakness, more moderate distal weakness and global areflexia.
Background
Necrotising myopathy is a rare autoimmune disease that is thought to primarily affect muscles and commonly presents as weakness; it has been reported that there are associated effects on the heart and lungs. This case describes a middle-aged woman presenting with a chief report of shortness of breath, who was subsequently found to have muscle weakness and respiratory failure due to signal recognition particle (SRP)-positive myopathy. In this case, we evaluate her clinical course, review the literature regarding SRP-positive myopathy and strengthen the case that due to the ubiquitous nature of the SRP autoantibodies; patient presentations can extend beyond proximal muscle weakness.
Case presentation
A previously independently functioning 52-year-old obese African American woman initially presented to her primary care office with a chief report of unresolving shortness of breath, which seemed to be incited after she tripped over a broom at work. Previous medical history was significant for hyperlipidaemia treated with simvastatin 40 mg for primary prevention from 2013 to 2020, morbid obesity, congestive heart failure and coronary artery disease.
Patient’s primary care doctor sent the patient for a CT angiogram that was significant for pulmonary hypertension and hepatic inflammation. In the following weeks, she was admitted for progressive muscle weakness.
Patient was found to have a creatine kinase (CK) elevation that peaked at 25 295 U/L. MRI of the lumbar spine revealed diffuse oedema of the pelvic muscles. Left quadriceps muscle biopsy was interpreted with ‘rare’ necrotic fibres, ‘occasional’ cytochrome c oxidase-intermediate (COX)-negative fibres, without deposits of complement macrophage antigens (MAC), and major histocompatibility (MHC) class I staining. SRP and -hydroxy-3-methyl-glutaryl-coenzymereductase (HMGCR) antibodies were negative. Antinuclear antibodies (ANA), nuclear ribonucleoprotein (RNP), Sjögren’s syndrome antibody (SSA), double-stranded DNA and myeloperoxidase antibodies were positive. Her home simvastatin was held, she was treated with prednisone and intravenous immunoglobulin. Her CK gradually decreased to the 2000–4000 U/L.
She continued to experience shortness of breath and was found to have a non-ST elevation myocardial infarction treated with medical management and stent placement for left anterior descending lesion. Further evaluation with an electromyography showed a diffuse, proximal-predominant, irritable myopathy and distal axonal polyneuropathy.
Laboratory workup was consistent with elevated erythrocyte sedimentation rate (ESR) and positive ANA with a homogeneous pattern, which is typically seen in lupus, RNP as well as SSA antibodies as noted at the outside hospital. SRP 54 was now positive. CT C/A/P did not identify any malignancy. Muscle biopsy was significant for highly active and chronic necrotising myopathy with inflammation, mild mitochondrial dysfunction, preferential type 2 atrophy, increased type 2C fibres, occasional rounded atrophic fibres and mild denervation atrophy, indicative of highly active and possibly chronic necrotising myopathy.
Treatment
Patient was treated with prednisone, IVIG and mycophenolate mofetil.
Outcome and follow-up
Patient initially failed to improve. Her course was complicated by worsening heart failure, respiratory failure requiring intubation with transition to tracheostomy and dysphagia requiring nasogastric tube for nutrition. She continued to slowly decline and was evaluated for placement at a long-term care facility. After a course at a long-term acute care, the patient returned home with continued needs for assistance with activities of daily living.
Discussion
Immune-mediated necrotising myopathy (IMNM) is characterised by minimal infiltration on muscle biopsy and is one of the most severe and progressive myopathies.1 2 In our case, the patient was SRP 54 positive, a subunit of the SRP protein complex, presenting with shortness of breath, followed by weakness, then dysphagia. It is commonly thought that the type of autoantibody will predict the course of the myopathy and the associated extra muscular manifestations. SRP is a ribonuclear protein that regulates translocation of protein across the endoplasmic reticulum. It is not specific to muscle tissue but is ubiquitously found in all protein processing cells.2 Myopathies associated with SRP antibodies were thought to have a similar clinical presentation; however, the literature suggests the presentation of SRP associated myopathy can vary greatly. Anti-SRP-related myopathy is now considered a subset of IMNM, also known as necrotising autoimmune myopathy. Symptoms of anti-SRP myopathy are range from weakness, dysphagia and cardiovascular involvement, with some studies showing lower association with interstitial lung disease (ILD).3 While limb weakness is the most common manifestation of myositis, there are reports of the SRP protein antibodies leading to different presenting symptoms involving the lungs and heart.2 4Involvement of the haematologic system with neutropenia and other alterations in proliferation were also identified.2 5 The ubiquitous nature of the SRP protein leads to multiple different manifestations when attacked by the immune system, from pulmonary, cardiac and haematologic.6 7 Myocardial involvement in anti-SRP myopathy can be severe and is considered a poor prognostic factor. Extramuscular manifestations such as ILD, Raynaud’s and arthralgia have been reported, though these features are typically mild. Some authors have suggested that radiographic suggestion of ILD in these patients may in fact arise from respiratory insufficiency due to musculoskeletal weakness.8
Other autoimmune conditions may have been at play in our patient and her dramatic hospital course. It has been shown that patients positive for ANA in a homogeneous pattern, consistent with SLE, is potentially associated with an overlap syndrome of SLE and necrotising myopathy. While this may have been present in our patient, the likelihood is low as there was no history of SLE in our patient. Furthermore, the overlap between SLE and necrotising myopathy has only been described in one case report to date.9 With this knowledge, clinicians should be aware of the complications of dysphagia, respiratory and cardiac failure and initiate prompt treatment to avoid further complications in the patient’s clinical course.
In fact, involvement of muscles with a symptom of weakness may not be as prominent as other symptoms such as shortness of breath or dysphagia. This is logical given the ubiquity of SRP and the ability of the antibody to cause dysfunction in different tissues.2
Patient’s perspective
As this was during the COVID pandemic, it was extremely difficult for me to adjust to the situation and the loss of the ability to care for myself. I often felt alone and was very scared. As I was in the hospital for over 6 months, I feel that I missed out a lot with my family. We lost my son to a gunshot wound before my sickness and I was also grieving that loss.
Learning points
Necrotising myopathy is a rare but fatal aetiology in patient’s presenting with weakness and shortness of breath.
Patients can have variable presentations and may initially present with symptoms other than skeletal muscle weakness.
Treatment of the condition should not be delayed while workup is undertaken as it can result in pulmonary hypertension and serious pulmonary and cardiac manifestations.
It is imperative to know a patient’s functional baseline to set expectations for the clinical course of a myopathy pathology
Contributors: MB: served as scientific advisor. SB: wrote and researched case.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed. | MYCOPHENOLATE MOFETIL, PREDNISONE, SIMVASTATIN | DrugsGivenReaction | CC BY-NC | 33608334 | 19,753,479 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory failure'. | SRP-positive necrotising myopathy: takes more than just the muscles.
Necrotising myopathy is an autoimmune disease that commonly affects muscles. Here we examine a case of a middle-aged women presenting with a chief report of shortness of breath, who subsequently developed muscle weakness. Her clinical course was complicated by respiratory failure and pulmonary hypertension likely due to the underlying pathology of signal recognition particle-positive necrotising myopathy. After further evaluation, her shortness of breath was thought to be secondary to muscle pathology rather than cardiopulmonary pathology. She was transferred to our institution for workup by rheumatology. At the time of admission, 6 months after initial presentation, her weakness progressed, so that she was unable to lift her arms and legs against gravity. Furthermore, neurological examination revealed mild facial and nuchal weakness, severe proximal weakness, more moderate distal weakness and global areflexia.
Background
Necrotising myopathy is a rare autoimmune disease that is thought to primarily affect muscles and commonly presents as weakness; it has been reported that there are associated effects on the heart and lungs. This case describes a middle-aged woman presenting with a chief report of shortness of breath, who was subsequently found to have muscle weakness and respiratory failure due to signal recognition particle (SRP)-positive myopathy. In this case, we evaluate her clinical course, review the literature regarding SRP-positive myopathy and strengthen the case that due to the ubiquitous nature of the SRP autoantibodies; patient presentations can extend beyond proximal muscle weakness.
Case presentation
A previously independently functioning 52-year-old obese African American woman initially presented to her primary care office with a chief report of unresolving shortness of breath, which seemed to be incited after she tripped over a broom at work. Previous medical history was significant for hyperlipidaemia treated with simvastatin 40 mg for primary prevention from 2013 to 2020, morbid obesity, congestive heart failure and coronary artery disease.
Patient’s primary care doctor sent the patient for a CT angiogram that was significant for pulmonary hypertension and hepatic inflammation. In the following weeks, she was admitted for progressive muscle weakness.
Patient was found to have a creatine kinase (CK) elevation that peaked at 25 295 U/L. MRI of the lumbar spine revealed diffuse oedema of the pelvic muscles. Left quadriceps muscle biopsy was interpreted with ‘rare’ necrotic fibres, ‘occasional’ cytochrome c oxidase-intermediate (COX)-negative fibres, without deposits of complement macrophage antigens (MAC), and major histocompatibility (MHC) class I staining. SRP and -hydroxy-3-methyl-glutaryl-coenzymereductase (HMGCR) antibodies were negative. Antinuclear antibodies (ANA), nuclear ribonucleoprotein (RNP), Sjögren’s syndrome antibody (SSA), double-stranded DNA and myeloperoxidase antibodies were positive. Her home simvastatin was held, she was treated with prednisone and intravenous immunoglobulin. Her CK gradually decreased to the 2000–4000 U/L.
She continued to experience shortness of breath and was found to have a non-ST elevation myocardial infarction treated with medical management and stent placement for left anterior descending lesion. Further evaluation with an electromyography showed a diffuse, proximal-predominant, irritable myopathy and distal axonal polyneuropathy.
Laboratory workup was consistent with elevated erythrocyte sedimentation rate (ESR) and positive ANA with a homogeneous pattern, which is typically seen in lupus, RNP as well as SSA antibodies as noted at the outside hospital. SRP 54 was now positive. CT C/A/P did not identify any malignancy. Muscle biopsy was significant for highly active and chronic necrotising myopathy with inflammation, mild mitochondrial dysfunction, preferential type 2 atrophy, increased type 2C fibres, occasional rounded atrophic fibres and mild denervation atrophy, indicative of highly active and possibly chronic necrotising myopathy.
Treatment
Patient was treated with prednisone, IVIG and mycophenolate mofetil.
Outcome and follow-up
Patient initially failed to improve. Her course was complicated by worsening heart failure, respiratory failure requiring intubation with transition to tracheostomy and dysphagia requiring nasogastric tube for nutrition. She continued to slowly decline and was evaluated for placement at a long-term care facility. After a course at a long-term acute care, the patient returned home with continued needs for assistance with activities of daily living.
Discussion
Immune-mediated necrotising myopathy (IMNM) is characterised by minimal infiltration on muscle biopsy and is one of the most severe and progressive myopathies.1 2 In our case, the patient was SRP 54 positive, a subunit of the SRP protein complex, presenting with shortness of breath, followed by weakness, then dysphagia. It is commonly thought that the type of autoantibody will predict the course of the myopathy and the associated extra muscular manifestations. SRP is a ribonuclear protein that regulates translocation of protein across the endoplasmic reticulum. It is not specific to muscle tissue but is ubiquitously found in all protein processing cells.2 Myopathies associated with SRP antibodies were thought to have a similar clinical presentation; however, the literature suggests the presentation of SRP associated myopathy can vary greatly. Anti-SRP-related myopathy is now considered a subset of IMNM, also known as necrotising autoimmune myopathy. Symptoms of anti-SRP myopathy are range from weakness, dysphagia and cardiovascular involvement, with some studies showing lower association with interstitial lung disease (ILD).3 While limb weakness is the most common manifestation of myositis, there are reports of the SRP protein antibodies leading to different presenting symptoms involving the lungs and heart.2 4Involvement of the haematologic system with neutropenia and other alterations in proliferation were also identified.2 5 The ubiquitous nature of the SRP protein leads to multiple different manifestations when attacked by the immune system, from pulmonary, cardiac and haematologic.6 7 Myocardial involvement in anti-SRP myopathy can be severe and is considered a poor prognostic factor. Extramuscular manifestations such as ILD, Raynaud’s and arthralgia have been reported, though these features are typically mild. Some authors have suggested that radiographic suggestion of ILD in these patients may in fact arise from respiratory insufficiency due to musculoskeletal weakness.8
Other autoimmune conditions may have been at play in our patient and her dramatic hospital course. It has been shown that patients positive for ANA in a homogeneous pattern, consistent with SLE, is potentially associated with an overlap syndrome of SLE and necrotising myopathy. While this may have been present in our patient, the likelihood is low as there was no history of SLE in our patient. Furthermore, the overlap between SLE and necrotising myopathy has only been described in one case report to date.9 With this knowledge, clinicians should be aware of the complications of dysphagia, respiratory and cardiac failure and initiate prompt treatment to avoid further complications in the patient’s clinical course.
In fact, involvement of muscles with a symptom of weakness may not be as prominent as other symptoms such as shortness of breath or dysphagia. This is logical given the ubiquity of SRP and the ability of the antibody to cause dysfunction in different tissues.2
Patient’s perspective
As this was during the COVID pandemic, it was extremely difficult for me to adjust to the situation and the loss of the ability to care for myself. I often felt alone and was very scared. As I was in the hospital for over 6 months, I feel that I missed out a lot with my family. We lost my son to a gunshot wound before my sickness and I was also grieving that loss.
Learning points
Necrotising myopathy is a rare but fatal aetiology in patient’s presenting with weakness and shortness of breath.
Patients can have variable presentations and may initially present with symptoms other than skeletal muscle weakness.
Treatment of the condition should not be delayed while workup is undertaken as it can result in pulmonary hypertension and serious pulmonary and cardiac manifestations.
It is imperative to know a patient’s functional baseline to set expectations for the clinical course of a myopathy pathology
Contributors: MB: served as scientific advisor. SB: wrote and researched case.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed. | MYCOPHENOLATE MOFETIL, PREDNISONE, SIMVASTATIN | DrugsGivenReaction | CC BY-NC | 33608334 | 19,753,479 | 2021-02-19 |
What was the dosage of drug 'MYCOPHENOLATE MOFETIL'? | SRP-positive necrotising myopathy: takes more than just the muscles.
Necrotising myopathy is an autoimmune disease that commonly affects muscles. Here we examine a case of a middle-aged women presenting with a chief report of shortness of breath, who subsequently developed muscle weakness. Her clinical course was complicated by respiratory failure and pulmonary hypertension likely due to the underlying pathology of signal recognition particle-positive necrotising myopathy. After further evaluation, her shortness of breath was thought to be secondary to muscle pathology rather than cardiopulmonary pathology. She was transferred to our institution for workup by rheumatology. At the time of admission, 6 months after initial presentation, her weakness progressed, so that she was unable to lift her arms and legs against gravity. Furthermore, neurological examination revealed mild facial and nuchal weakness, severe proximal weakness, more moderate distal weakness and global areflexia.
Background
Necrotising myopathy is a rare autoimmune disease that is thought to primarily affect muscles and commonly presents as weakness; it has been reported that there are associated effects on the heart and lungs. This case describes a middle-aged woman presenting with a chief report of shortness of breath, who was subsequently found to have muscle weakness and respiratory failure due to signal recognition particle (SRP)-positive myopathy. In this case, we evaluate her clinical course, review the literature regarding SRP-positive myopathy and strengthen the case that due to the ubiquitous nature of the SRP autoantibodies; patient presentations can extend beyond proximal muscle weakness.
Case presentation
A previously independently functioning 52-year-old obese African American woman initially presented to her primary care office with a chief report of unresolving shortness of breath, which seemed to be incited after she tripped over a broom at work. Previous medical history was significant for hyperlipidaemia treated with simvastatin 40 mg for primary prevention from 2013 to 2020, morbid obesity, congestive heart failure and coronary artery disease.
Patient’s primary care doctor sent the patient for a CT angiogram that was significant for pulmonary hypertension and hepatic inflammation. In the following weeks, she was admitted for progressive muscle weakness.
Patient was found to have a creatine kinase (CK) elevation that peaked at 25 295 U/L. MRI of the lumbar spine revealed diffuse oedema of the pelvic muscles. Left quadriceps muscle biopsy was interpreted with ‘rare’ necrotic fibres, ‘occasional’ cytochrome c oxidase-intermediate (COX)-negative fibres, without deposits of complement macrophage antigens (MAC), and major histocompatibility (MHC) class I staining. SRP and -hydroxy-3-methyl-glutaryl-coenzymereductase (HMGCR) antibodies were negative. Antinuclear antibodies (ANA), nuclear ribonucleoprotein (RNP), Sjögren’s syndrome antibody (SSA), double-stranded DNA and myeloperoxidase antibodies were positive. Her home simvastatin was held, she was treated with prednisone and intravenous immunoglobulin. Her CK gradually decreased to the 2000–4000 U/L.
She continued to experience shortness of breath and was found to have a non-ST elevation myocardial infarction treated with medical management and stent placement for left anterior descending lesion. Further evaluation with an electromyography showed a diffuse, proximal-predominant, irritable myopathy and distal axonal polyneuropathy.
Laboratory workup was consistent with elevated erythrocyte sedimentation rate (ESR) and positive ANA with a homogeneous pattern, which is typically seen in lupus, RNP as well as SSA antibodies as noted at the outside hospital. SRP 54 was now positive. CT C/A/P did not identify any malignancy. Muscle biopsy was significant for highly active and chronic necrotising myopathy with inflammation, mild mitochondrial dysfunction, preferential type 2 atrophy, increased type 2C fibres, occasional rounded atrophic fibres and mild denervation atrophy, indicative of highly active and possibly chronic necrotising myopathy.
Treatment
Patient was treated with prednisone, IVIG and mycophenolate mofetil.
Outcome and follow-up
Patient initially failed to improve. Her course was complicated by worsening heart failure, respiratory failure requiring intubation with transition to tracheostomy and dysphagia requiring nasogastric tube for nutrition. She continued to slowly decline and was evaluated for placement at a long-term care facility. After a course at a long-term acute care, the patient returned home with continued needs for assistance with activities of daily living.
Discussion
Immune-mediated necrotising myopathy (IMNM) is characterised by minimal infiltration on muscle biopsy and is one of the most severe and progressive myopathies.1 2 In our case, the patient was SRP 54 positive, a subunit of the SRP protein complex, presenting with shortness of breath, followed by weakness, then dysphagia. It is commonly thought that the type of autoantibody will predict the course of the myopathy and the associated extra muscular manifestations. SRP is a ribonuclear protein that regulates translocation of protein across the endoplasmic reticulum. It is not specific to muscle tissue but is ubiquitously found in all protein processing cells.2 Myopathies associated with SRP antibodies were thought to have a similar clinical presentation; however, the literature suggests the presentation of SRP associated myopathy can vary greatly. Anti-SRP-related myopathy is now considered a subset of IMNM, also known as necrotising autoimmune myopathy. Symptoms of anti-SRP myopathy are range from weakness, dysphagia and cardiovascular involvement, with some studies showing lower association with interstitial lung disease (ILD).3 While limb weakness is the most common manifestation of myositis, there are reports of the SRP protein antibodies leading to different presenting symptoms involving the lungs and heart.2 4Involvement of the haematologic system with neutropenia and other alterations in proliferation were also identified.2 5 The ubiquitous nature of the SRP protein leads to multiple different manifestations when attacked by the immune system, from pulmonary, cardiac and haematologic.6 7 Myocardial involvement in anti-SRP myopathy can be severe and is considered a poor prognostic factor. Extramuscular manifestations such as ILD, Raynaud’s and arthralgia have been reported, though these features are typically mild. Some authors have suggested that radiographic suggestion of ILD in these patients may in fact arise from respiratory insufficiency due to musculoskeletal weakness.8
Other autoimmune conditions may have been at play in our patient and her dramatic hospital course. It has been shown that patients positive for ANA in a homogeneous pattern, consistent with SLE, is potentially associated with an overlap syndrome of SLE and necrotising myopathy. While this may have been present in our patient, the likelihood is low as there was no history of SLE in our patient. Furthermore, the overlap between SLE and necrotising myopathy has only been described in one case report to date.9 With this knowledge, clinicians should be aware of the complications of dysphagia, respiratory and cardiac failure and initiate prompt treatment to avoid further complications in the patient’s clinical course.
In fact, involvement of muscles with a symptom of weakness may not be as prominent as other symptoms such as shortness of breath or dysphagia. This is logical given the ubiquity of SRP and the ability of the antibody to cause dysfunction in different tissues.2
Patient’s perspective
As this was during the COVID pandemic, it was extremely difficult for me to adjust to the situation and the loss of the ability to care for myself. I often felt alone and was very scared. As I was in the hospital for over 6 months, I feel that I missed out a lot with my family. We lost my son to a gunshot wound before my sickness and I was also grieving that loss.
Learning points
Necrotising myopathy is a rare but fatal aetiology in patient’s presenting with weakness and shortness of breath.
Patients can have variable presentations and may initially present with symptoms other than skeletal muscle weakness.
Treatment of the condition should not be delayed while workup is undertaken as it can result in pulmonary hypertension and serious pulmonary and cardiac manifestations.
It is imperative to know a patient’s functional baseline to set expectations for the clinical course of a myopathy pathology
Contributors: MB: served as scientific advisor. SB: wrote and researched case.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed. | UNKNOWN | DrugDosageText | CC BY-NC | 33608334 | 19,753,479 | 2021-02-19 |
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