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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Alanine aminotransferase increased'. | A randomized phase-I pharmacokinetic trial comparing the potential biosimilar tocilizumab (QX003S) with the reference product (Actemra®) in Chinese healthy subjects.
QX003S is a biosimilar candidate for the reference tocilizumab, Actemra®. We investigated the tolerance, variability, and pharmacokinetics (PK) of QX003S biosimilar in healthy Chinese male subjects.
A randomised, double-blind, two-arm, parallel study was performed to examine the bioequivalence of QX003S (8 mg/kg) with that of Actemra® as a reference drug.
QX003S (N = 40) and Actemra® (N = 40) groups exhibited similar PK properties. The inter-subject variability ranged from 14.95% to 18.78%. The 90% confidence intervals of the ratios for Cmax, AUC0-t andAUC0-∞ in both groups were within the range of 80-125%. After administration, the number of subjects who tested positive for anti-drug antibodies (ADA) in the QX003S group and Actemra® groups was 6 (14.3%) and 14 (34.1%), respectively. Adverse reactions occurred in 100% and 97.6% subjects in the QX003S and Actemra® groups, respectively. The most common adverse reactions were decrease in fibrinogen level and neutrophil and leukocyte counts.
The PK characteristics and immunogenicity exhibited by QX003S were similar to that of the reference product, Actemra®. The safety profile was similar in the two treatment groups with mild-moderate adverse effects.Trial RegistrationThe trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html#CTR20190002)Key pointsThis was the first clinical report of a new proposed tocilizumab biosimilar, QX003S.This phase-I randomized, controlled study compared pharmacokinetics, variability,immunogenicity, and safety of QX003S vs. the approved tocilizumab product (Actemra@).The results demonstrate bioequivalence between BAT1806 and the reference products (Actemra@), as well as comparable immunogenicity, safety and tolerability profiles.
1. Introduction
Biological products are large and complex molecules, usually derived from living cells. Due to the molecular complexity and multifaceted production process, the characteristics of biosimilars differ from those of the traditional small-molecule drugs [1–3]. Despite significant therapeutic advances, biologic therapies, such as monoclonal antibodies, are expensive with limited global access [4].
The US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Medical Products Administration (NMPA) have emphasized a step-by-step approach for the development of biosimilars [1]. Biological functional similarity is assessed in the first step, followed by the assessment of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics; finally, the clinical similarity (efficacy, safety, and immunogenicity) is assessed using the same approved dose and pathway as the reference product [1–3].
Tocilizumab binds to soluble and membrane-bound interleukin (IL)-6 receptors and through these receptors inhibits IL-6-mediated signal transduction. IL-6 is a multipotent pro-inflammatory cytokine produced by a variety of cell types, including T and B cells, lymphocytes, monocytes, and fibroblasts. Synovial cells and endothelial cells also produce IL-6, which induces the inflammatory process in the joints (e.g. rheumatoid arthritis) [5–6]. Tocilizumab is effective against rheumatoid arthritis, giant cell arteritis, and multi-joint juvenile idiopathic arthritis. In a previous study, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or deathin hospitalised patients with Covid-19 pneumonia; however, it did not improve survival of these patients. Tocilizumab is currently under investigation as a potential treatment for COVID-19, with initial contradictory evidence [7].
Consequently, tocilizumab biosimilars have been actively developed around the world, including in China. Tocilizumab biosimilars (QX003S) have the same primary structure, post-translational modification, biochemical characteristics, and biological functions as the reference product, and in addition, these similarities have been tested in mice and monkeys (data not published). All in vivo studies justify the clinical development of QX003S.
PK studies in humans are essential to demonstrate the bioequivalence of biological analogues and reference products [8]. Herein, we conducted a single-dose PK study in healthy Chinese male subjects to evaluate the bioequivalence between QX003S and Actemra@ as the reference product. Use of healthy subjects helps avoid the potential confounding influence of factors such as comorbid diseases and concomitant therapies. The therapeutic dose of the reference drug used in previous studies is 4–8 mg/kg [9–10]. In this study, a dose of 8 mg/kg was used, based on earlier clinical trial plans of the sponsor.
In this study, the PK profiles of the QX003S with Actemra@ were analysed and compared. In addition, the tolerability, safety, and immunogenicity of QX003S were assessed.
2. Methods
2.1. Study design and subjects
This phase-I study was conducted at the Clinical Research Centre of the First Hospital of Jilin University between 14 March 2019 and 18 September 2019 (Chinese Clinical Trial Registry, Registration No. CTR20190002). The study protocol was approved by the ethics committee of the hospital. The study complied with the guidelines of the Declaration of Helsinki and the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP). Written Informed consent was obtained from all subjects prior to their enrolment.
This was a randomized, double-blind, single-dose, two-arm, parallel comparison study to evaluate the PK, safety, and immunogenicity of QX003S and Actemra@ in healthy Chinese male subjects. Overall, 86 eligible subjects were randomly allocated in a 1:1 ratio to receive a single intravenous drip of 8 mg/kg QX003S or Actemra@. Subjects were stratified into two groups based on body weight (50 to < 67.5 kg and ≥ 67.5 to ≤ 85 kg). Individuals in each of the pre-specified groups were equally assigned to the two treatment groups through randomization (Figure 1).
Figure 1. Flow chart of the study.
Sentinel staggered administration was used in this study. Subjects were administered the investigational product (IP) in a staggered cohort: the first and second cohort consisted of two subjects and four subjects, respectively. For safety evaluation, each subject was required to stay at the study centre for at least 96 h after the administration. Based on sentinel safety results, the principal investigator determined whether the subsequent subjects would be monitored in sentinel mode or in routine follow-up mode. All subjects were followed up for 57 days.
The main inclusion criteria were as follows: (1) healthy men in the age group of 18–50 years; (2) body mass index: 18.0–28.0 kg/m2; (3) body weight: 55–85 kg; and (4) normal test outcomes or clinically unremarkable results of routine blood and urine routine investigations including hepatic and renal function tests during enrolment.
The exclusion criteria were as follows: (1) history of clinically significant diseases; (2) C-reactive protein (CRP) levels 1.5 times higher than the upper limit of the normal range; and (3) positive results of T-SPOT® assay or TB interferon-γ-release assay.
All subjects received a single intravenous infusion of the IP (8 mg/kg) administered over a period of 60 min (±6 min). All subjects were randomly allocated to one of the following two groups in a 1:1 ratio in each of the pre-specified weight intervals: QX003S (Jiangsu Quanxin Biomedicine Co. Ltd; Batch number: F20180801); Actemra@ (Chugai Pharmaceutical Company [Japan]; Batch number: B2063B15).
Screening was performed 14 to 2 days prior to the date of administration. All qualified subjects entered the clinical research unit a day prior to the administration of biosimilars. Subjects were required to fast for at least 8 h before administration and were randomly assigned to either the test drug (QX003S) or reference drug group.
2.2. PK evaluations
Blood samples were collected for PK analysis at different time-points: 1 h before administration (before administration) to 1344 h after the initial infusion (day 57). Serum tocilizumab levels were determined by enzyme-linked immunosorbent assay (ELISA) at the Junke Zhengyuan (Beijing) Pharmaceutical Research Co. Ltd. (Supplement material). PK parameters were determined by non-compartmental analysis model. The concentration–time data included the maximum observable serum concentration (Cmax), clearance (CL), half-life (t1/2), the volume of distribution (Vz), and area under the curve (AUC) from zero to the final quantifiable concentration (AUC0–t) and to infinity (AUC0–∞). The actual sampling times were used for PK analyses. An internally validated software system, Phoenix WinNonLin® v8.0 (Pharsight Corporation, Certara, L.P., Princeton, New Jersey, USA), was used to determine PK parameters.
2.3. Immunogenicity evaluations
Blood samples collected at 1 h before and on 15, 29, 43, and 57 days after drug administration were analysed for the presence of anti-drug antibodies (ADAs) using electrochemiluminescence immunoassay (ECLIA). Subjects who test ADA-positive, those who develop antibody-related adverse reactions, or those with significantly abnormal PK value are required to be further examined for the presence of neutralising antibodies (NAbs). NAb test was not performed in this study because the above conditions were not met.
2.4. Safety evaluation
Physical examination, assessment of vital signs, electrocardiogram, and routine laboratory investigations were performed to monitor adverse events (AEs) according to the National Cancer Institute Common Terminology for Adverse Events (CTCAE;V.4.03). Subjects who showed AEs were monitored until they reached normal or acceptable stability (as assessed by the principal investigator and sponsor) or were lost to follow up.
2.5. Estimation of the sample size
According to the recent FDA guidelines, the geometric mean ratio (GMR) was set at 95% to achieve 90% power (1 − β) at a significant level (two-sided α = 5%). Inter-subject variability (inter-CV) is expressed by the coefficient of variation (CV). NQuery 8.3.0.0 (Boston, USA) software was used to determine the sample size (initial: 68; inter-CV for tocilizumab: 24%) [9]. The final sample size was 86, allowing for a 20% drop-out rate.
2.6. Statistical analysis
After logarithmic transformation of PK parameters Cmax, AUC0–t, and AUC0–∞, the least square method was used for analysis of variance. Bioequivalence inferences were drawn if the 90% confidence intervals (CIs) were found to be within the range of 80–125%. PK analysis was performed using the PK analysis set. The safety analysis set included subjects who were administered the study drug. Descriptive statistical estimates of PK parameters and demographic data were calculated. Between-group differences were assessed using the Chi-squared test for categorical variables, t-test for normally distributed continuous variables, and Wilcoxon rank test for non-normally distributed variables. All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
3. Results
3.1. Subjects
The assigned drugs were administered to 83 of the 86 enrolled subjects and included in the safety analysis (Figure 1). One additional subject was included in the QX003S group, whereas one subject was removed from the Actemra® group due to weight stratification. Therefore, the QX003S group comprised of 44 subjects.
Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, had hypertension and fast pulse rate or polycardia; these subjects were excluded from the study. Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, were ADA positive;these were excluded from the study. The final per-protocol analysis population included in the safety, PK, BE, and immunogenicity (ADA) analysis set comprised of 83, 80, 80, and 83 subjects, respectively (Figure 1). The demographic and baseline characteristics of the per-protocol population and the two treatment groups were comparable (p > .05, Table 1).
Table 1. Demographic and baseline characteristics.
QX003S group Actemra® group Total
(n = 44) (n = 42) (n = 86) p Values
Age (year), mean (SD) 35.5 (8.88) 36.1 (8.51) 35.8 (8.66) .75
Ethnicity (Han, n [%]) 41 (93.2) 40 (95.2) 81 (94.2) .68
Weight (kg), mean (SD) 67.45 (9.423) 66.21 (7.621) 66.84 (8.563) .5
BMI (kg/m2), mean (SD) 23.306 (2.5834) 23.234 (2.5210) 23.271 (2.5383) .89
BMI; body mass index; SD: standard deviation.
3.2. PK evaluation
The mean serum concentration–time curve of tocilizumab and its biosimilar decreased with multiphase mode. A rapid decline immediately after the infusion was followed by a slow elimination phase, and, subsequently, by a slightly faster elimination phase at low concentrations (Figure 2). The non-compartmental analysis model showed slow clearance, longer t1/2, and small Vz of tocilizumab and its biosimilar. The median Tmax values were equivalent between the two groups and these were achieved 1.8 h after the intravenous infusion.
Figure 2. Serum drug concentration–time profile of tocilizumab. Mean values (A); log10 mean values (B); log10 mean values within 0–48 h (C); ADA-positive individuals in the QX003S (D) and Actemra@ (E) groups.
The mean value of t1/2 between the test drug and the reference drug was between 160.8155 and 159.9160 h, indicating comparability. The total clearance rate (CL) and Vz values were also similar in the two groups. The differences between the mean concentration–time curve, mean Cmax, AUC0-t, AUC0-∞ estimation, and inter-CVs were similar (p > .05); the coefficient of variation ranged from 14.95% to 18.78% (Table 2, Figure 2).
Table 2. Pharmacokinetic parameters of tocilizumab in each group (Mean ± SD [CV%] or median [min, max]).
QX003S group (n = 40) Actemra® group (n = 40) p Values GMR (90% CI) GMR (90% CI)a Re-estimated size
Tmax*(h) 1.8 (1-4) 1.8 (1-4) >.05
Cmax (μg/mL) 178.8 ± 28.90 (16.16) 178.2 ± 27.43 (15.39) .92 1 (0.95, 1.06) 1.02 (0.95-1.09) 40
AUC0-t (h•μg/mL) 27116.0941 ± 4466.9216 (16.47) 27446.4185 ± 4103.9469 (14.95) .73 0.9859 (0.9311,1.0439) 0.9827 (0.9197-1.0500) 40
AUC0-∞ (h•μg/mL) 28806.7645 ± 5411.8467 (18.78) 29039.7894 ± 4641.0883 (15.98) .83 0.9878 (0.9272, 1.0524) 0.9787 (0.9098-1.0529) 52
t1/2 (h) 160.8155 ± 35.2772 (21.93) 159.9160 ± 29.0054 (18.13) .90
CL (L/h) 0.0192 ± 0.0031 (16.06) 0.0185 ± 0.0025 (13.68) .26
Vd (L) 4.3578 ± 0.7660 (17.57) 4.2322 ± 0.7760 (18.33) .46
*Median [min, max]; aQX003S/ Actemra® after excluding subject with ADA positive after dosing.
The PK parameters were comparable in the QX003S and Actemra@ groups. The ratio of geometric least-squares means for the QX003S versus Actemra@ were 1, 0.9859, and 0.9878 for Cmax, AUC0-t, and AUC0-∞;the 90% CI was 0.9272–1.06. The 90% CIs of the Cmax, AUC0–t, and AUC0–∞ were within the predefined bioequivalence limit, ranging from 80.00% to 125.00%. A larger inter-CV indicated a broader 90% CI. The sample size was re-estimated on the basis of the results of bioequivalence analysis (GMR and inter-CV), which decreased to a number less than the enrolment size (Table 2).
3.3. Immunogenicity evaluation
Before dosing, two and one subjects in the QX003S and Actemra® group respectively, were ADA positive. After dosing, 6 (14.3%) subjects in the QX003S group and 14 (34.1%) subjects in the Actemra® group tested positive for ADA. The ADA-positive rates were found to increase over a period of time, especially by days 43 (1008 h) and 57 (1344 h). Nevertheless, the drug concentration was less than the lower limit of quantitation (LLOQ) during that period. ADA-positivity rates were similar in the two groups at 15 to 29 days after drug administration (6.7–7.1%). However, at 43 and 57 days after drug administration, the positivity rates in the QX003S group were relatively lower than those in the Actemra@ group; however, the between-group differences in this respect were not statistically significant at any of the time-points (p > .05, Table 3).
Table 3. Summary of immunogenicity (anti-drug antibody) assessment (number [%] of subjects with positive antibodies).
Time (day) QX003S group (n = 42) Actemra® group (n = 41) p Values
Pre-dose 2 (4.88) 1 (2.44) .57
15 0 (0) 0 (0) NA
29 0 (0) 1 (2.44) .30
43 3 (7.32) 5 (12.2) .43
57 8 (19.51) 13 (31.71) .18
NA: Not applicable.
Table 4. Adverse reactions (number of reactions, the number [%] of subjects, more than 4%).
QX003S group (n = 42) Actemra® group (n = 41)
n (%) [number of reactions] n (%) [number of reaction] p Values
Total 42 (100) 134 40 (97.6) 148 0.30
Fibrinogen decreased 38 (90.5) 40 34 (82.9) 34 0.31
Reduced neutrophil counts 30 (71.4) 39 24 (58.5) 32 0.21
Reduced leukocyte count 24 (57.1) 28 19 (46.3) 26 0.32
Elevated serum bilirubin 6 (14.3) 6 3 (7.3) 5 0.30
Elevated alanine aminotransferase 0 (0) 0 5 (12.2) 6 0.01
Elevated aspartate aminotransferase 0 (0) 0 4 (9.8) 6 0.03
Reduced lymphocyte count 1 (2.4) 2 2 (4.9) 2 0.54
Urine leucocyte positive 0 (0) 0 2 (4.9) 2 0.14
Oropharyngeal pain 2 (4.8) 2 3 (7.3) 3 0.62
Cough 2 (4.8) 2 2 (4.9) 2 0.98
Cough with expectoration 1 (2.4) 1 2 (4.9) 2 0.54
Runny nose 0 (0) 0 3 (7.3) 3 0.07
Stuffy nose 0 (0) 0 2 (4.9) 2 0.14
Hypertriglyceridaemia 5 (11.9) 5 7 (17.1) 7 0.50
Hyperuricemia 1 (2.4) 1 2 (4.9) 3 0.54
Diarrhea 2 (4.8) 2 1 (2.4) 1 0.57
Oral mucositis 0 (0) 0 2 (4.9) 2 0.14
The serum concentration-time curves of QX003S and Actemra@ for ADA-positive and ADA-negative subjects were found to be similar (Figure 2). Sensitivity analysis of bioequivalence was performed after exclusion of 20 subjects who tested positive for ADA. The 90% CIs for the comparisons of Cmax and AUC were within the predefined range of bioequivalence limits of 80.00%–125.00% (Table 2). Therefore, overall, ADA-positivity rates were similar in the two groups.
3.4. Safety evaluation
No serious AEs (SAEs), deaths, or discontinuations due to AEs were observed. In this study, 282 adverse reactions occurred in 82 (98.8%) subjects. A total of 134 adverse reactions in 42 (100%) subjects were recorded in the QX003S group, while148 adverse reactions in 40 (97.6%) subjects were recorded in the Actemra® group. The incidence of adverse reactions was comparable in the two groups (Table 4). The adverse reactions with an incidence greater than 5% in the QX003S and Actemra® groups, respectively, were as follows: decreased fibrinogen level (90.5% vs 82.9%), decreased neutrophil count (71.4% vs 58.5%), decreased white blood cell (WBC) count (57.1% vs 46.3%), increased bilirubin (14.3% vs 7.3%), and hypertriglyceridaemia (11.9% vs 17.1%). The severity of most adverse reactions was between grade I and II. The incidence rates of elevated alanine aminotransferase and elevated aspartate aminotransferase level in the QX003S group were lower than those in the Actemra® group (0% vs. 12.2%, p = 0.01; 0% vs. 9.8%, p = 0.03); this indicated a lesser effect of QX003S on liver enzyme levels than the reference product. The incidence of other adverse reactions was comparable in the two groups (p > 0.05).
A total of 20 (24.1%) subjects in the two groups experienced 26 grade III–IV adverse reactions. Thirteen (31.0%) subjects in the QX003S group developed 16 adverse reactions, and seven (17.1%) subjects in the Actemra® group developed 10 adverse reactions. The incidence in the QX003S vs Actemra® groups was comparable: decreased neutrophil count (28.6% vs 12.2%), decreased WBC count (7.1% vs 7.3%), decreased fibrinogen (2.4% vs 2.4%), and increased alanine aminotransferase (0 vs 2.4%). All grade III–IV adverse reactions recovered spontaneously without treatment. Very few Grade I-II adverse reactions required drug therapy, such as cefuroxime axetil, levofloxacin, and glycyrrhizin.
There was no association between ADA development and adverse reactions in this study. None of the subjects developed clinically significant or serious hypersensitivity, anaphylaxis, or injection-site reaction after IP administration, except Subject no.105 of the QX003S group who developed ecchymia and mild tenderness at the injection site 48 h after administration; this subject showed spontaneous recovery on day 8 without any treatment. Subject no.001 of the Actemra® group showed bruising at the injection site at 12 h after administration without any tenderness; this subject also showed spontaneous recovery on day 22 without any treatment. All adverse reactions were reported to the Institutional Review Board of The First Hospital of Jilin University.
4. Discussion
This single-dose, phase-I study demonstrated the bioequivalence of QX003S and Actemra@ when administered as intravenous infusion at a dose of 8 mg/kg. The results of ANOVA showed that the 90% CIs of the geometric mean ratios of Cmax and AUC in the two treatment groups ranged from 92.72%–106%, which was within the predefined bioequivalence intervals of 80% to 125%. Other PK parameters of Tmax and t½ were also similar between the two treatment groups. QX003S and Actemra@ showed a similar safety and immunogenicity profile. No serious AEs were reported; all adverse reactions were mild or moderate in severity, and no local reactions were reported except in two subjects. This indicated that the two products were well tolerated in this population of healthy subjects. The above results justify the use of the biosimilars in the next phase clinical studies [1–3].
The pharmacokinetic behaviour of tocilizumab is different from the small-molecule pharmacokinetic behaviour in that it has limited vascular permeability, neonatal Fc receptor circulation, and more frequent receptor-mediated nonlinearity. Its distribution and clearance (CL) are consistent with target-mediated drug disposition (TMDD) [11]. On average, Cmax of tocilizumab decreased approximately 55% in the first 96 h. Subsequently, a slow elimination phase was observed between 96 and 336 h, followed by a relatively fast elimination between 336 and 672 h (Figure 2). In this study, QX003S at a dose of 8 mg/kg [mean weight of the subjects: 67.45 kg, dosage: 539.6 mg (4 × 67.45)] showed a lower clearance and displayed a longer t1/2 (160.8155 vs 39.9 h) than tocilizumab 162 mg (Roche Products Limited, Welwyn Garden City, UK), more exposure (AUC ratio of QX003S vs tocilizumab 162 mg equal to 6.39) than dose ratio (539.6:162 = 3.33), similar Tmax and dose ratio of Cmax with tocilizumab 162 mg, which have been evaluated in other phase-I studies in healthy subjects (Supplement Table 1) [12].
Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies [9,13]. Similarly, ADA had no effect on drug concentration or bioequivalence results in this study (Figure 2, Table 2). In population PK analysis, body weight was identified as a significant covariate impacting the pharmacokinetics of tocilizumab. When administered intravenously on mg/kg basis, individuals with body weight ≥100 kg are predicted to have higher exposures than individuals with body weight <100 kg. Therefore, weight stratification was adopted in this study to reduce variation of parameters, although the weight of subjects in this study was <100 kg. The inter-CV of tocilizumab was small (less than 18.7867%); therefore, the sample size in future studies can be reduced to 52 subjects (26 subjects per arm) [14].
Notably, the incidence of adverse reactions in the QX003S group was similar to that in the Actemra@ group (100% vs 97.6%); most of these were resolved at the final visit in this study. The most common adverse reactions (incidence of at least 5%) are reported in the label, including upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT level, and injection site reactions [9]. In healthy subjects who were administered ACTEMRA in doses of 2–28 mg/kg intravenously and 81–162 mg subcutaneously, the absolute neutrophil counts decreased to the nadir 3 to 5 days following administration. Thereafter, the neutrophil counts recovered towards baseline in a dose-dependent manner over a period of 9–17 days [12]. Patients with rheumatoid arthritis and GCA exhibited a similar pattern of absolute neutrophil counts following the administration of ACTEMRA [9,15]. Similar to previous reports, the incidence of decreased neutrophil counts and decreased white blood cell counts was indeed very high. Neutrophil counts decreased on day 2 to 5; the mean neutrophil count reached nadir on day 2 in both groups. The mean values returned to baseline by day 57 without any treatment (Figure 3). As described by Nishimoto et al. [16], when tocilizumab concentration is maintained above 1 µg/mL, SIL-6R is saturated by tocilizumab leading to complete inhibition of the IL-6 signal; this may affect the distribution of blood cells such as neutrophils and leukocytes. However, these cell counts quickly return to baseline with the drop in the drug concentration.
Figure 3. Absolute values of neutrophil, leukocyte counts, and fibrinogen level over time. Data presented as mean ± standard error of the mean.
In clinical studies, RA patients were treated with 4–8 mg/kg intravenous doses or the 162 mg weekly and every other weekly subcutaneous doses of ACTEMRA; the levels of CRP decreased to within the normal range along with changes in the pharmacodynamic parameters (i.e. decrease in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen; and increase in haemoglobin) [9]. In the present study, fibrinogen level decreased in 82.9–90.5% subjects and the mean fibrinogen level reached the nadir on day 15 to 29 in the QX003S and Actemra® groups; these changes are similar to the above changes in pharmacodynamic indices.
No acute or delayed anaphylactic reactions developed in subjects who were ADA positive, indicating that there was no product-specific immunogenicity. We observed no impact of the immunogenic responses of tocilizumab to drug safety and PK in this study similar to previous reports; however, it may still be necessary to closely monitor the immunogenicity of QX003S and Actemra and its impact on their efficacy in further related Phase-III studies with larger population, multiple doses, as well as longer time frame [17–19]. Overall, this study demonstrated the safety and tolerability of QX003S and reference Actemra@.
Conclusions
This study showed similar PK profile of tocilizumab biosimilar (QX003S) and Actemra@. The tocilizumab biosimilar showed a nearly similar ADA profile and a comparable safety profile versus the reference drug. The inter-CV of tocilizumab was low among Chinese subjects. These data support the clinical development of QX003S as a tocilizumab biosimilar.
Supplementary Material
Supplemental Material
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Acknowledgements
The authors thank the staff of the Phase I Clinical Research Centre, The First Hospital of Jilin University, Jilin, China for data collection in the study.
Disclosure statement
All data related to this study were interpreted by the trial staff with complete independence from the sponsor. Min Fang is employee of the sponsor team. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Data availability statement
The data that support the findings of this study are available on request from the corresponding author, YHD. The data are not publicly available due to their containing information that could compromise the privacy of research participants. | TOCILIZUMAB | DrugsGivenReaction | CC BY | 33629921 | 19,002,940 | 2021-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood fibrinogen decreased'. | A randomized phase-I pharmacokinetic trial comparing the potential biosimilar tocilizumab (QX003S) with the reference product (Actemra®) in Chinese healthy subjects.
QX003S is a biosimilar candidate for the reference tocilizumab, Actemra®. We investigated the tolerance, variability, and pharmacokinetics (PK) of QX003S biosimilar in healthy Chinese male subjects.
A randomised, double-blind, two-arm, parallel study was performed to examine the bioequivalence of QX003S (8 mg/kg) with that of Actemra® as a reference drug.
QX003S (N = 40) and Actemra® (N = 40) groups exhibited similar PK properties. The inter-subject variability ranged from 14.95% to 18.78%. The 90% confidence intervals of the ratios for Cmax, AUC0-t andAUC0-∞ in both groups were within the range of 80-125%. After administration, the number of subjects who tested positive for anti-drug antibodies (ADA) in the QX003S group and Actemra® groups was 6 (14.3%) and 14 (34.1%), respectively. Adverse reactions occurred in 100% and 97.6% subjects in the QX003S and Actemra® groups, respectively. The most common adverse reactions were decrease in fibrinogen level and neutrophil and leukocyte counts.
The PK characteristics and immunogenicity exhibited by QX003S were similar to that of the reference product, Actemra®. The safety profile was similar in the two treatment groups with mild-moderate adverse effects.Trial RegistrationThe trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html#CTR20190002)Key pointsThis was the first clinical report of a new proposed tocilizumab biosimilar, QX003S.This phase-I randomized, controlled study compared pharmacokinetics, variability,immunogenicity, and safety of QX003S vs. the approved tocilizumab product (Actemra@).The results demonstrate bioequivalence between BAT1806 and the reference products (Actemra@), as well as comparable immunogenicity, safety and tolerability profiles.
1. Introduction
Biological products are large and complex molecules, usually derived from living cells. Due to the molecular complexity and multifaceted production process, the characteristics of biosimilars differ from those of the traditional small-molecule drugs [1–3]. Despite significant therapeutic advances, biologic therapies, such as monoclonal antibodies, are expensive with limited global access [4].
The US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Medical Products Administration (NMPA) have emphasized a step-by-step approach for the development of biosimilars [1]. Biological functional similarity is assessed in the first step, followed by the assessment of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics; finally, the clinical similarity (efficacy, safety, and immunogenicity) is assessed using the same approved dose and pathway as the reference product [1–3].
Tocilizumab binds to soluble and membrane-bound interleukin (IL)-6 receptors and through these receptors inhibits IL-6-mediated signal transduction. IL-6 is a multipotent pro-inflammatory cytokine produced by a variety of cell types, including T and B cells, lymphocytes, monocytes, and fibroblasts. Synovial cells and endothelial cells also produce IL-6, which induces the inflammatory process in the joints (e.g. rheumatoid arthritis) [5–6]. Tocilizumab is effective against rheumatoid arthritis, giant cell arteritis, and multi-joint juvenile idiopathic arthritis. In a previous study, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or deathin hospitalised patients with Covid-19 pneumonia; however, it did not improve survival of these patients. Tocilizumab is currently under investigation as a potential treatment for COVID-19, with initial contradictory evidence [7].
Consequently, tocilizumab biosimilars have been actively developed around the world, including in China. Tocilizumab biosimilars (QX003S) have the same primary structure, post-translational modification, biochemical characteristics, and biological functions as the reference product, and in addition, these similarities have been tested in mice and monkeys (data not published). All in vivo studies justify the clinical development of QX003S.
PK studies in humans are essential to demonstrate the bioequivalence of biological analogues and reference products [8]. Herein, we conducted a single-dose PK study in healthy Chinese male subjects to evaluate the bioequivalence between QX003S and Actemra@ as the reference product. Use of healthy subjects helps avoid the potential confounding influence of factors such as comorbid diseases and concomitant therapies. The therapeutic dose of the reference drug used in previous studies is 4–8 mg/kg [9–10]. In this study, a dose of 8 mg/kg was used, based on earlier clinical trial plans of the sponsor.
In this study, the PK profiles of the QX003S with Actemra@ were analysed and compared. In addition, the tolerability, safety, and immunogenicity of QX003S were assessed.
2. Methods
2.1. Study design and subjects
This phase-I study was conducted at the Clinical Research Centre of the First Hospital of Jilin University between 14 March 2019 and 18 September 2019 (Chinese Clinical Trial Registry, Registration No. CTR20190002). The study protocol was approved by the ethics committee of the hospital. The study complied with the guidelines of the Declaration of Helsinki and the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP). Written Informed consent was obtained from all subjects prior to their enrolment.
This was a randomized, double-blind, single-dose, two-arm, parallel comparison study to evaluate the PK, safety, and immunogenicity of QX003S and Actemra@ in healthy Chinese male subjects. Overall, 86 eligible subjects were randomly allocated in a 1:1 ratio to receive a single intravenous drip of 8 mg/kg QX003S or Actemra@. Subjects were stratified into two groups based on body weight (50 to < 67.5 kg and ≥ 67.5 to ≤ 85 kg). Individuals in each of the pre-specified groups were equally assigned to the two treatment groups through randomization (Figure 1).
Figure 1. Flow chart of the study.
Sentinel staggered administration was used in this study. Subjects were administered the investigational product (IP) in a staggered cohort: the first and second cohort consisted of two subjects and four subjects, respectively. For safety evaluation, each subject was required to stay at the study centre for at least 96 h after the administration. Based on sentinel safety results, the principal investigator determined whether the subsequent subjects would be monitored in sentinel mode or in routine follow-up mode. All subjects were followed up for 57 days.
The main inclusion criteria were as follows: (1) healthy men in the age group of 18–50 years; (2) body mass index: 18.0–28.0 kg/m2; (3) body weight: 55–85 kg; and (4) normal test outcomes or clinically unremarkable results of routine blood and urine routine investigations including hepatic and renal function tests during enrolment.
The exclusion criteria were as follows: (1) history of clinically significant diseases; (2) C-reactive protein (CRP) levels 1.5 times higher than the upper limit of the normal range; and (3) positive results of T-SPOT® assay or TB interferon-γ-release assay.
All subjects received a single intravenous infusion of the IP (8 mg/kg) administered over a period of 60 min (±6 min). All subjects were randomly allocated to one of the following two groups in a 1:1 ratio in each of the pre-specified weight intervals: QX003S (Jiangsu Quanxin Biomedicine Co. Ltd; Batch number: F20180801); Actemra@ (Chugai Pharmaceutical Company [Japan]; Batch number: B2063B15).
Screening was performed 14 to 2 days prior to the date of administration. All qualified subjects entered the clinical research unit a day prior to the administration of biosimilars. Subjects were required to fast for at least 8 h before administration and were randomly assigned to either the test drug (QX003S) or reference drug group.
2.2. PK evaluations
Blood samples were collected for PK analysis at different time-points: 1 h before administration (before administration) to 1344 h after the initial infusion (day 57). Serum tocilizumab levels were determined by enzyme-linked immunosorbent assay (ELISA) at the Junke Zhengyuan (Beijing) Pharmaceutical Research Co. Ltd. (Supplement material). PK parameters were determined by non-compartmental analysis model. The concentration–time data included the maximum observable serum concentration (Cmax), clearance (CL), half-life (t1/2), the volume of distribution (Vz), and area under the curve (AUC) from zero to the final quantifiable concentration (AUC0–t) and to infinity (AUC0–∞). The actual sampling times were used for PK analyses. An internally validated software system, Phoenix WinNonLin® v8.0 (Pharsight Corporation, Certara, L.P., Princeton, New Jersey, USA), was used to determine PK parameters.
2.3. Immunogenicity evaluations
Blood samples collected at 1 h before and on 15, 29, 43, and 57 days after drug administration were analysed for the presence of anti-drug antibodies (ADAs) using electrochemiluminescence immunoassay (ECLIA). Subjects who test ADA-positive, those who develop antibody-related adverse reactions, or those with significantly abnormal PK value are required to be further examined for the presence of neutralising antibodies (NAbs). NAb test was not performed in this study because the above conditions were not met.
2.4. Safety evaluation
Physical examination, assessment of vital signs, electrocardiogram, and routine laboratory investigations were performed to monitor adverse events (AEs) according to the National Cancer Institute Common Terminology for Adverse Events (CTCAE;V.4.03). Subjects who showed AEs were monitored until they reached normal or acceptable stability (as assessed by the principal investigator and sponsor) or were lost to follow up.
2.5. Estimation of the sample size
According to the recent FDA guidelines, the geometric mean ratio (GMR) was set at 95% to achieve 90% power (1 − β) at a significant level (two-sided α = 5%). Inter-subject variability (inter-CV) is expressed by the coefficient of variation (CV). NQuery 8.3.0.0 (Boston, USA) software was used to determine the sample size (initial: 68; inter-CV for tocilizumab: 24%) [9]. The final sample size was 86, allowing for a 20% drop-out rate.
2.6. Statistical analysis
After logarithmic transformation of PK parameters Cmax, AUC0–t, and AUC0–∞, the least square method was used for analysis of variance. Bioequivalence inferences were drawn if the 90% confidence intervals (CIs) were found to be within the range of 80–125%. PK analysis was performed using the PK analysis set. The safety analysis set included subjects who were administered the study drug. Descriptive statistical estimates of PK parameters and demographic data were calculated. Between-group differences were assessed using the Chi-squared test for categorical variables, t-test for normally distributed continuous variables, and Wilcoxon rank test for non-normally distributed variables. All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
3. Results
3.1. Subjects
The assigned drugs were administered to 83 of the 86 enrolled subjects and included in the safety analysis (Figure 1). One additional subject was included in the QX003S group, whereas one subject was removed from the Actemra® group due to weight stratification. Therefore, the QX003S group comprised of 44 subjects.
Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, had hypertension and fast pulse rate or polycardia; these subjects were excluded from the study. Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, were ADA positive;these were excluded from the study. The final per-protocol analysis population included in the safety, PK, BE, and immunogenicity (ADA) analysis set comprised of 83, 80, 80, and 83 subjects, respectively (Figure 1). The demographic and baseline characteristics of the per-protocol population and the two treatment groups were comparable (p > .05, Table 1).
Table 1. Demographic and baseline characteristics.
QX003S group Actemra® group Total
(n = 44) (n = 42) (n = 86) p Values
Age (year), mean (SD) 35.5 (8.88) 36.1 (8.51) 35.8 (8.66) .75
Ethnicity (Han, n [%]) 41 (93.2) 40 (95.2) 81 (94.2) .68
Weight (kg), mean (SD) 67.45 (9.423) 66.21 (7.621) 66.84 (8.563) .5
BMI (kg/m2), mean (SD) 23.306 (2.5834) 23.234 (2.5210) 23.271 (2.5383) .89
BMI; body mass index; SD: standard deviation.
3.2. PK evaluation
The mean serum concentration–time curve of tocilizumab and its biosimilar decreased with multiphase mode. A rapid decline immediately after the infusion was followed by a slow elimination phase, and, subsequently, by a slightly faster elimination phase at low concentrations (Figure 2). The non-compartmental analysis model showed slow clearance, longer t1/2, and small Vz of tocilizumab and its biosimilar. The median Tmax values were equivalent between the two groups and these were achieved 1.8 h after the intravenous infusion.
Figure 2. Serum drug concentration–time profile of tocilizumab. Mean values (A); log10 mean values (B); log10 mean values within 0–48 h (C); ADA-positive individuals in the QX003S (D) and Actemra@ (E) groups.
The mean value of t1/2 between the test drug and the reference drug was between 160.8155 and 159.9160 h, indicating comparability. The total clearance rate (CL) and Vz values were also similar in the two groups. The differences between the mean concentration–time curve, mean Cmax, AUC0-t, AUC0-∞ estimation, and inter-CVs were similar (p > .05); the coefficient of variation ranged from 14.95% to 18.78% (Table 2, Figure 2).
Table 2. Pharmacokinetic parameters of tocilizumab in each group (Mean ± SD [CV%] or median [min, max]).
QX003S group (n = 40) Actemra® group (n = 40) p Values GMR (90% CI) GMR (90% CI)a Re-estimated size
Tmax*(h) 1.8 (1-4) 1.8 (1-4) >.05
Cmax (μg/mL) 178.8 ± 28.90 (16.16) 178.2 ± 27.43 (15.39) .92 1 (0.95, 1.06) 1.02 (0.95-1.09) 40
AUC0-t (h•μg/mL) 27116.0941 ± 4466.9216 (16.47) 27446.4185 ± 4103.9469 (14.95) .73 0.9859 (0.9311,1.0439) 0.9827 (0.9197-1.0500) 40
AUC0-∞ (h•μg/mL) 28806.7645 ± 5411.8467 (18.78) 29039.7894 ± 4641.0883 (15.98) .83 0.9878 (0.9272, 1.0524) 0.9787 (0.9098-1.0529) 52
t1/2 (h) 160.8155 ± 35.2772 (21.93) 159.9160 ± 29.0054 (18.13) .90
CL (L/h) 0.0192 ± 0.0031 (16.06) 0.0185 ± 0.0025 (13.68) .26
Vd (L) 4.3578 ± 0.7660 (17.57) 4.2322 ± 0.7760 (18.33) .46
*Median [min, max]; aQX003S/ Actemra® after excluding subject with ADA positive after dosing.
The PK parameters were comparable in the QX003S and Actemra@ groups. The ratio of geometric least-squares means for the QX003S versus Actemra@ were 1, 0.9859, and 0.9878 for Cmax, AUC0-t, and AUC0-∞;the 90% CI was 0.9272–1.06. The 90% CIs of the Cmax, AUC0–t, and AUC0–∞ were within the predefined bioequivalence limit, ranging from 80.00% to 125.00%. A larger inter-CV indicated a broader 90% CI. The sample size was re-estimated on the basis of the results of bioequivalence analysis (GMR and inter-CV), which decreased to a number less than the enrolment size (Table 2).
3.3. Immunogenicity evaluation
Before dosing, two and one subjects in the QX003S and Actemra® group respectively, were ADA positive. After dosing, 6 (14.3%) subjects in the QX003S group and 14 (34.1%) subjects in the Actemra® group tested positive for ADA. The ADA-positive rates were found to increase over a period of time, especially by days 43 (1008 h) and 57 (1344 h). Nevertheless, the drug concentration was less than the lower limit of quantitation (LLOQ) during that period. ADA-positivity rates were similar in the two groups at 15 to 29 days after drug administration (6.7–7.1%). However, at 43 and 57 days after drug administration, the positivity rates in the QX003S group were relatively lower than those in the Actemra@ group; however, the between-group differences in this respect were not statistically significant at any of the time-points (p > .05, Table 3).
Table 3. Summary of immunogenicity (anti-drug antibody) assessment (number [%] of subjects with positive antibodies).
Time (day) QX003S group (n = 42) Actemra® group (n = 41) p Values
Pre-dose 2 (4.88) 1 (2.44) .57
15 0 (0) 0 (0) NA
29 0 (0) 1 (2.44) .30
43 3 (7.32) 5 (12.2) .43
57 8 (19.51) 13 (31.71) .18
NA: Not applicable.
Table 4. Adverse reactions (number of reactions, the number [%] of subjects, more than 4%).
QX003S group (n = 42) Actemra® group (n = 41)
n (%) [number of reactions] n (%) [number of reaction] p Values
Total 42 (100) 134 40 (97.6) 148 0.30
Fibrinogen decreased 38 (90.5) 40 34 (82.9) 34 0.31
Reduced neutrophil counts 30 (71.4) 39 24 (58.5) 32 0.21
Reduced leukocyte count 24 (57.1) 28 19 (46.3) 26 0.32
Elevated serum bilirubin 6 (14.3) 6 3 (7.3) 5 0.30
Elevated alanine aminotransferase 0 (0) 0 5 (12.2) 6 0.01
Elevated aspartate aminotransferase 0 (0) 0 4 (9.8) 6 0.03
Reduced lymphocyte count 1 (2.4) 2 2 (4.9) 2 0.54
Urine leucocyte positive 0 (0) 0 2 (4.9) 2 0.14
Oropharyngeal pain 2 (4.8) 2 3 (7.3) 3 0.62
Cough 2 (4.8) 2 2 (4.9) 2 0.98
Cough with expectoration 1 (2.4) 1 2 (4.9) 2 0.54
Runny nose 0 (0) 0 3 (7.3) 3 0.07
Stuffy nose 0 (0) 0 2 (4.9) 2 0.14
Hypertriglyceridaemia 5 (11.9) 5 7 (17.1) 7 0.50
Hyperuricemia 1 (2.4) 1 2 (4.9) 3 0.54
Diarrhea 2 (4.8) 2 1 (2.4) 1 0.57
Oral mucositis 0 (0) 0 2 (4.9) 2 0.14
The serum concentration-time curves of QX003S and Actemra@ for ADA-positive and ADA-negative subjects were found to be similar (Figure 2). Sensitivity analysis of bioequivalence was performed after exclusion of 20 subjects who tested positive for ADA. The 90% CIs for the comparisons of Cmax and AUC were within the predefined range of bioequivalence limits of 80.00%–125.00% (Table 2). Therefore, overall, ADA-positivity rates were similar in the two groups.
3.4. Safety evaluation
No serious AEs (SAEs), deaths, or discontinuations due to AEs were observed. In this study, 282 adverse reactions occurred in 82 (98.8%) subjects. A total of 134 adverse reactions in 42 (100%) subjects were recorded in the QX003S group, while148 adverse reactions in 40 (97.6%) subjects were recorded in the Actemra® group. The incidence of adverse reactions was comparable in the two groups (Table 4). The adverse reactions with an incidence greater than 5% in the QX003S and Actemra® groups, respectively, were as follows: decreased fibrinogen level (90.5% vs 82.9%), decreased neutrophil count (71.4% vs 58.5%), decreased white blood cell (WBC) count (57.1% vs 46.3%), increased bilirubin (14.3% vs 7.3%), and hypertriglyceridaemia (11.9% vs 17.1%). The severity of most adverse reactions was between grade I and II. The incidence rates of elevated alanine aminotransferase and elevated aspartate aminotransferase level in the QX003S group were lower than those in the Actemra® group (0% vs. 12.2%, p = 0.01; 0% vs. 9.8%, p = 0.03); this indicated a lesser effect of QX003S on liver enzyme levels than the reference product. The incidence of other adverse reactions was comparable in the two groups (p > 0.05).
A total of 20 (24.1%) subjects in the two groups experienced 26 grade III–IV adverse reactions. Thirteen (31.0%) subjects in the QX003S group developed 16 adverse reactions, and seven (17.1%) subjects in the Actemra® group developed 10 adverse reactions. The incidence in the QX003S vs Actemra® groups was comparable: decreased neutrophil count (28.6% vs 12.2%), decreased WBC count (7.1% vs 7.3%), decreased fibrinogen (2.4% vs 2.4%), and increased alanine aminotransferase (0 vs 2.4%). All grade III–IV adverse reactions recovered spontaneously without treatment. Very few Grade I-II adverse reactions required drug therapy, such as cefuroxime axetil, levofloxacin, and glycyrrhizin.
There was no association between ADA development and adverse reactions in this study. None of the subjects developed clinically significant or serious hypersensitivity, anaphylaxis, or injection-site reaction after IP administration, except Subject no.105 of the QX003S group who developed ecchymia and mild tenderness at the injection site 48 h after administration; this subject showed spontaneous recovery on day 8 without any treatment. Subject no.001 of the Actemra® group showed bruising at the injection site at 12 h after administration without any tenderness; this subject also showed spontaneous recovery on day 22 without any treatment. All adverse reactions were reported to the Institutional Review Board of The First Hospital of Jilin University.
4. Discussion
This single-dose, phase-I study demonstrated the bioequivalence of QX003S and Actemra@ when administered as intravenous infusion at a dose of 8 mg/kg. The results of ANOVA showed that the 90% CIs of the geometric mean ratios of Cmax and AUC in the two treatment groups ranged from 92.72%–106%, which was within the predefined bioequivalence intervals of 80% to 125%. Other PK parameters of Tmax and t½ were also similar between the two treatment groups. QX003S and Actemra@ showed a similar safety and immunogenicity profile. No serious AEs were reported; all adverse reactions were mild or moderate in severity, and no local reactions were reported except in two subjects. This indicated that the two products were well tolerated in this population of healthy subjects. The above results justify the use of the biosimilars in the next phase clinical studies [1–3].
The pharmacokinetic behaviour of tocilizumab is different from the small-molecule pharmacokinetic behaviour in that it has limited vascular permeability, neonatal Fc receptor circulation, and more frequent receptor-mediated nonlinearity. Its distribution and clearance (CL) are consistent with target-mediated drug disposition (TMDD) [11]. On average, Cmax of tocilizumab decreased approximately 55% in the first 96 h. Subsequently, a slow elimination phase was observed between 96 and 336 h, followed by a relatively fast elimination between 336 and 672 h (Figure 2). In this study, QX003S at a dose of 8 mg/kg [mean weight of the subjects: 67.45 kg, dosage: 539.6 mg (4 × 67.45)] showed a lower clearance and displayed a longer t1/2 (160.8155 vs 39.9 h) than tocilizumab 162 mg (Roche Products Limited, Welwyn Garden City, UK), more exposure (AUC ratio of QX003S vs tocilizumab 162 mg equal to 6.39) than dose ratio (539.6:162 = 3.33), similar Tmax and dose ratio of Cmax with tocilizumab 162 mg, which have been evaluated in other phase-I studies in healthy subjects (Supplement Table 1) [12].
Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies [9,13]. Similarly, ADA had no effect on drug concentration or bioequivalence results in this study (Figure 2, Table 2). In population PK analysis, body weight was identified as a significant covariate impacting the pharmacokinetics of tocilizumab. When administered intravenously on mg/kg basis, individuals with body weight ≥100 kg are predicted to have higher exposures than individuals with body weight <100 kg. Therefore, weight stratification was adopted in this study to reduce variation of parameters, although the weight of subjects in this study was <100 kg. The inter-CV of tocilizumab was small (less than 18.7867%); therefore, the sample size in future studies can be reduced to 52 subjects (26 subjects per arm) [14].
Notably, the incidence of adverse reactions in the QX003S group was similar to that in the Actemra@ group (100% vs 97.6%); most of these were resolved at the final visit in this study. The most common adverse reactions (incidence of at least 5%) are reported in the label, including upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT level, and injection site reactions [9]. In healthy subjects who were administered ACTEMRA in doses of 2–28 mg/kg intravenously and 81–162 mg subcutaneously, the absolute neutrophil counts decreased to the nadir 3 to 5 days following administration. Thereafter, the neutrophil counts recovered towards baseline in a dose-dependent manner over a period of 9–17 days [12]. Patients with rheumatoid arthritis and GCA exhibited a similar pattern of absolute neutrophil counts following the administration of ACTEMRA [9,15]. Similar to previous reports, the incidence of decreased neutrophil counts and decreased white blood cell counts was indeed very high. Neutrophil counts decreased on day 2 to 5; the mean neutrophil count reached nadir on day 2 in both groups. The mean values returned to baseline by day 57 without any treatment (Figure 3). As described by Nishimoto et al. [16], when tocilizumab concentration is maintained above 1 µg/mL, SIL-6R is saturated by tocilizumab leading to complete inhibition of the IL-6 signal; this may affect the distribution of blood cells such as neutrophils and leukocytes. However, these cell counts quickly return to baseline with the drop in the drug concentration.
Figure 3. Absolute values of neutrophil, leukocyte counts, and fibrinogen level over time. Data presented as mean ± standard error of the mean.
In clinical studies, RA patients were treated with 4–8 mg/kg intravenous doses or the 162 mg weekly and every other weekly subcutaneous doses of ACTEMRA; the levels of CRP decreased to within the normal range along with changes in the pharmacodynamic parameters (i.e. decrease in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen; and increase in haemoglobin) [9]. In the present study, fibrinogen level decreased in 82.9–90.5% subjects and the mean fibrinogen level reached the nadir on day 15 to 29 in the QX003S and Actemra® groups; these changes are similar to the above changes in pharmacodynamic indices.
No acute or delayed anaphylactic reactions developed in subjects who were ADA positive, indicating that there was no product-specific immunogenicity. We observed no impact of the immunogenic responses of tocilizumab to drug safety and PK in this study similar to previous reports; however, it may still be necessary to closely monitor the immunogenicity of QX003S and Actemra and its impact on their efficacy in further related Phase-III studies with larger population, multiple doses, as well as longer time frame [17–19]. Overall, this study demonstrated the safety and tolerability of QX003S and reference Actemra@.
Conclusions
This study showed similar PK profile of tocilizumab biosimilar (QX003S) and Actemra@. The tocilizumab biosimilar showed a nearly similar ADA profile and a comparable safety profile versus the reference drug. The inter-CV of tocilizumab was low among Chinese subjects. These data support the clinical development of QX003S as a tocilizumab biosimilar.
Supplementary Material
Supplemental Material
Click here for additional data file.
Acknowledgements
The authors thank the staff of the Phase I Clinical Research Centre, The First Hospital of Jilin University, Jilin, China for data collection in the study.
Disclosure statement
All data related to this study were interpreted by the trial staff with complete independence from the sponsor. Min Fang is employee of the sponsor team. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Data availability statement
The data that support the findings of this study are available on request from the corresponding author, YHD. The data are not publicly available due to their containing information that could compromise the privacy of research participants. | TOCILIZUMAB | DrugsGivenReaction | CC BY | 33629921 | 19,002,940 | 2021-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutrophil count decreased'. | A randomized phase-I pharmacokinetic trial comparing the potential biosimilar tocilizumab (QX003S) with the reference product (Actemra®) in Chinese healthy subjects.
QX003S is a biosimilar candidate for the reference tocilizumab, Actemra®. We investigated the tolerance, variability, and pharmacokinetics (PK) of QX003S biosimilar in healthy Chinese male subjects.
A randomised, double-blind, two-arm, parallel study was performed to examine the bioequivalence of QX003S (8 mg/kg) with that of Actemra® as a reference drug.
QX003S (N = 40) and Actemra® (N = 40) groups exhibited similar PK properties. The inter-subject variability ranged from 14.95% to 18.78%. The 90% confidence intervals of the ratios for Cmax, AUC0-t andAUC0-∞ in both groups were within the range of 80-125%. After administration, the number of subjects who tested positive for anti-drug antibodies (ADA) in the QX003S group and Actemra® groups was 6 (14.3%) and 14 (34.1%), respectively. Adverse reactions occurred in 100% and 97.6% subjects in the QX003S and Actemra® groups, respectively. The most common adverse reactions were decrease in fibrinogen level and neutrophil and leukocyte counts.
The PK characteristics and immunogenicity exhibited by QX003S were similar to that of the reference product, Actemra®. The safety profile was similar in the two treatment groups with mild-moderate adverse effects.Trial RegistrationThe trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html#CTR20190002)Key pointsThis was the first clinical report of a new proposed tocilizumab biosimilar, QX003S.This phase-I randomized, controlled study compared pharmacokinetics, variability,immunogenicity, and safety of QX003S vs. the approved tocilizumab product (Actemra@).The results demonstrate bioequivalence between BAT1806 and the reference products (Actemra@), as well as comparable immunogenicity, safety and tolerability profiles.
1. Introduction
Biological products are large and complex molecules, usually derived from living cells. Due to the molecular complexity and multifaceted production process, the characteristics of biosimilars differ from those of the traditional small-molecule drugs [1–3]. Despite significant therapeutic advances, biologic therapies, such as monoclonal antibodies, are expensive with limited global access [4].
The US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Medical Products Administration (NMPA) have emphasized a step-by-step approach for the development of biosimilars [1]. Biological functional similarity is assessed in the first step, followed by the assessment of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics; finally, the clinical similarity (efficacy, safety, and immunogenicity) is assessed using the same approved dose and pathway as the reference product [1–3].
Tocilizumab binds to soluble and membrane-bound interleukin (IL)-6 receptors and through these receptors inhibits IL-6-mediated signal transduction. IL-6 is a multipotent pro-inflammatory cytokine produced by a variety of cell types, including T and B cells, lymphocytes, monocytes, and fibroblasts. Synovial cells and endothelial cells also produce IL-6, which induces the inflammatory process in the joints (e.g. rheumatoid arthritis) [5–6]. Tocilizumab is effective against rheumatoid arthritis, giant cell arteritis, and multi-joint juvenile idiopathic arthritis. In a previous study, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or deathin hospitalised patients with Covid-19 pneumonia; however, it did not improve survival of these patients. Tocilizumab is currently under investigation as a potential treatment for COVID-19, with initial contradictory evidence [7].
Consequently, tocilizumab biosimilars have been actively developed around the world, including in China. Tocilizumab biosimilars (QX003S) have the same primary structure, post-translational modification, biochemical characteristics, and biological functions as the reference product, and in addition, these similarities have been tested in mice and monkeys (data not published). All in vivo studies justify the clinical development of QX003S.
PK studies in humans are essential to demonstrate the bioequivalence of biological analogues and reference products [8]. Herein, we conducted a single-dose PK study in healthy Chinese male subjects to evaluate the bioequivalence between QX003S and Actemra@ as the reference product. Use of healthy subjects helps avoid the potential confounding influence of factors such as comorbid diseases and concomitant therapies. The therapeutic dose of the reference drug used in previous studies is 4–8 mg/kg [9–10]. In this study, a dose of 8 mg/kg was used, based on earlier clinical trial plans of the sponsor.
In this study, the PK profiles of the QX003S with Actemra@ were analysed and compared. In addition, the tolerability, safety, and immunogenicity of QX003S were assessed.
2. Methods
2.1. Study design and subjects
This phase-I study was conducted at the Clinical Research Centre of the First Hospital of Jilin University between 14 March 2019 and 18 September 2019 (Chinese Clinical Trial Registry, Registration No. CTR20190002). The study protocol was approved by the ethics committee of the hospital. The study complied with the guidelines of the Declaration of Helsinki and the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP). Written Informed consent was obtained from all subjects prior to their enrolment.
This was a randomized, double-blind, single-dose, two-arm, parallel comparison study to evaluate the PK, safety, and immunogenicity of QX003S and Actemra@ in healthy Chinese male subjects. Overall, 86 eligible subjects were randomly allocated in a 1:1 ratio to receive a single intravenous drip of 8 mg/kg QX003S or Actemra@. Subjects were stratified into two groups based on body weight (50 to < 67.5 kg and ≥ 67.5 to ≤ 85 kg). Individuals in each of the pre-specified groups were equally assigned to the two treatment groups through randomization (Figure 1).
Figure 1. Flow chart of the study.
Sentinel staggered administration was used in this study. Subjects were administered the investigational product (IP) in a staggered cohort: the first and second cohort consisted of two subjects and four subjects, respectively. For safety evaluation, each subject was required to stay at the study centre for at least 96 h after the administration. Based on sentinel safety results, the principal investigator determined whether the subsequent subjects would be monitored in sentinel mode or in routine follow-up mode. All subjects were followed up for 57 days.
The main inclusion criteria were as follows: (1) healthy men in the age group of 18–50 years; (2) body mass index: 18.0–28.0 kg/m2; (3) body weight: 55–85 kg; and (4) normal test outcomes or clinically unremarkable results of routine blood and urine routine investigations including hepatic and renal function tests during enrolment.
The exclusion criteria were as follows: (1) history of clinically significant diseases; (2) C-reactive protein (CRP) levels 1.5 times higher than the upper limit of the normal range; and (3) positive results of T-SPOT® assay or TB interferon-γ-release assay.
All subjects received a single intravenous infusion of the IP (8 mg/kg) administered over a period of 60 min (±6 min). All subjects were randomly allocated to one of the following two groups in a 1:1 ratio in each of the pre-specified weight intervals: QX003S (Jiangsu Quanxin Biomedicine Co. Ltd; Batch number: F20180801); Actemra@ (Chugai Pharmaceutical Company [Japan]; Batch number: B2063B15).
Screening was performed 14 to 2 days prior to the date of administration. All qualified subjects entered the clinical research unit a day prior to the administration of biosimilars. Subjects were required to fast for at least 8 h before administration and were randomly assigned to either the test drug (QX003S) or reference drug group.
2.2. PK evaluations
Blood samples were collected for PK analysis at different time-points: 1 h before administration (before administration) to 1344 h after the initial infusion (day 57). Serum tocilizumab levels were determined by enzyme-linked immunosorbent assay (ELISA) at the Junke Zhengyuan (Beijing) Pharmaceutical Research Co. Ltd. (Supplement material). PK parameters were determined by non-compartmental analysis model. The concentration–time data included the maximum observable serum concentration (Cmax), clearance (CL), half-life (t1/2), the volume of distribution (Vz), and area under the curve (AUC) from zero to the final quantifiable concentration (AUC0–t) and to infinity (AUC0–∞). The actual sampling times were used for PK analyses. An internally validated software system, Phoenix WinNonLin® v8.0 (Pharsight Corporation, Certara, L.P., Princeton, New Jersey, USA), was used to determine PK parameters.
2.3. Immunogenicity evaluations
Blood samples collected at 1 h before and on 15, 29, 43, and 57 days after drug administration were analysed for the presence of anti-drug antibodies (ADAs) using electrochemiluminescence immunoassay (ECLIA). Subjects who test ADA-positive, those who develop antibody-related adverse reactions, or those with significantly abnormal PK value are required to be further examined for the presence of neutralising antibodies (NAbs). NAb test was not performed in this study because the above conditions were not met.
2.4. Safety evaluation
Physical examination, assessment of vital signs, electrocardiogram, and routine laboratory investigations were performed to monitor adverse events (AEs) according to the National Cancer Institute Common Terminology for Adverse Events (CTCAE;V.4.03). Subjects who showed AEs were monitored until they reached normal or acceptable stability (as assessed by the principal investigator and sponsor) or were lost to follow up.
2.5. Estimation of the sample size
According to the recent FDA guidelines, the geometric mean ratio (GMR) was set at 95% to achieve 90% power (1 − β) at a significant level (two-sided α = 5%). Inter-subject variability (inter-CV) is expressed by the coefficient of variation (CV). NQuery 8.3.0.0 (Boston, USA) software was used to determine the sample size (initial: 68; inter-CV for tocilizumab: 24%) [9]. The final sample size was 86, allowing for a 20% drop-out rate.
2.6. Statistical analysis
After logarithmic transformation of PK parameters Cmax, AUC0–t, and AUC0–∞, the least square method was used for analysis of variance. Bioequivalence inferences were drawn if the 90% confidence intervals (CIs) were found to be within the range of 80–125%. PK analysis was performed using the PK analysis set. The safety analysis set included subjects who were administered the study drug. Descriptive statistical estimates of PK parameters and demographic data were calculated. Between-group differences were assessed using the Chi-squared test for categorical variables, t-test for normally distributed continuous variables, and Wilcoxon rank test for non-normally distributed variables. All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
3. Results
3.1. Subjects
The assigned drugs were administered to 83 of the 86 enrolled subjects and included in the safety analysis (Figure 1). One additional subject was included in the QX003S group, whereas one subject was removed from the Actemra® group due to weight stratification. Therefore, the QX003S group comprised of 44 subjects.
Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, had hypertension and fast pulse rate or polycardia; these subjects were excluded from the study. Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, were ADA positive;these were excluded from the study. The final per-protocol analysis population included in the safety, PK, BE, and immunogenicity (ADA) analysis set comprised of 83, 80, 80, and 83 subjects, respectively (Figure 1). The demographic and baseline characteristics of the per-protocol population and the two treatment groups were comparable (p > .05, Table 1).
Table 1. Demographic and baseline characteristics.
QX003S group Actemra® group Total
(n = 44) (n = 42) (n = 86) p Values
Age (year), mean (SD) 35.5 (8.88) 36.1 (8.51) 35.8 (8.66) .75
Ethnicity (Han, n [%]) 41 (93.2) 40 (95.2) 81 (94.2) .68
Weight (kg), mean (SD) 67.45 (9.423) 66.21 (7.621) 66.84 (8.563) .5
BMI (kg/m2), mean (SD) 23.306 (2.5834) 23.234 (2.5210) 23.271 (2.5383) .89
BMI; body mass index; SD: standard deviation.
3.2. PK evaluation
The mean serum concentration–time curve of tocilizumab and its biosimilar decreased with multiphase mode. A rapid decline immediately after the infusion was followed by a slow elimination phase, and, subsequently, by a slightly faster elimination phase at low concentrations (Figure 2). The non-compartmental analysis model showed slow clearance, longer t1/2, and small Vz of tocilizumab and its biosimilar. The median Tmax values were equivalent between the two groups and these were achieved 1.8 h after the intravenous infusion.
Figure 2. Serum drug concentration–time profile of tocilizumab. Mean values (A); log10 mean values (B); log10 mean values within 0–48 h (C); ADA-positive individuals in the QX003S (D) and Actemra@ (E) groups.
The mean value of t1/2 between the test drug and the reference drug was between 160.8155 and 159.9160 h, indicating comparability. The total clearance rate (CL) and Vz values were also similar in the two groups. The differences between the mean concentration–time curve, mean Cmax, AUC0-t, AUC0-∞ estimation, and inter-CVs were similar (p > .05); the coefficient of variation ranged from 14.95% to 18.78% (Table 2, Figure 2).
Table 2. Pharmacokinetic parameters of tocilizumab in each group (Mean ± SD [CV%] or median [min, max]).
QX003S group (n = 40) Actemra® group (n = 40) p Values GMR (90% CI) GMR (90% CI)a Re-estimated size
Tmax*(h) 1.8 (1-4) 1.8 (1-4) >.05
Cmax (μg/mL) 178.8 ± 28.90 (16.16) 178.2 ± 27.43 (15.39) .92 1 (0.95, 1.06) 1.02 (0.95-1.09) 40
AUC0-t (h•μg/mL) 27116.0941 ± 4466.9216 (16.47) 27446.4185 ± 4103.9469 (14.95) .73 0.9859 (0.9311,1.0439) 0.9827 (0.9197-1.0500) 40
AUC0-∞ (h•μg/mL) 28806.7645 ± 5411.8467 (18.78) 29039.7894 ± 4641.0883 (15.98) .83 0.9878 (0.9272, 1.0524) 0.9787 (0.9098-1.0529) 52
t1/2 (h) 160.8155 ± 35.2772 (21.93) 159.9160 ± 29.0054 (18.13) .90
CL (L/h) 0.0192 ± 0.0031 (16.06) 0.0185 ± 0.0025 (13.68) .26
Vd (L) 4.3578 ± 0.7660 (17.57) 4.2322 ± 0.7760 (18.33) .46
*Median [min, max]; aQX003S/ Actemra® after excluding subject with ADA positive after dosing.
The PK parameters were comparable in the QX003S and Actemra@ groups. The ratio of geometric least-squares means for the QX003S versus Actemra@ were 1, 0.9859, and 0.9878 for Cmax, AUC0-t, and AUC0-∞;the 90% CI was 0.9272–1.06. The 90% CIs of the Cmax, AUC0–t, and AUC0–∞ were within the predefined bioequivalence limit, ranging from 80.00% to 125.00%. A larger inter-CV indicated a broader 90% CI. The sample size was re-estimated on the basis of the results of bioequivalence analysis (GMR and inter-CV), which decreased to a number less than the enrolment size (Table 2).
3.3. Immunogenicity evaluation
Before dosing, two and one subjects in the QX003S and Actemra® group respectively, were ADA positive. After dosing, 6 (14.3%) subjects in the QX003S group and 14 (34.1%) subjects in the Actemra® group tested positive for ADA. The ADA-positive rates were found to increase over a period of time, especially by days 43 (1008 h) and 57 (1344 h). Nevertheless, the drug concentration was less than the lower limit of quantitation (LLOQ) during that period. ADA-positivity rates were similar in the two groups at 15 to 29 days after drug administration (6.7–7.1%). However, at 43 and 57 days after drug administration, the positivity rates in the QX003S group were relatively lower than those in the Actemra@ group; however, the between-group differences in this respect were not statistically significant at any of the time-points (p > .05, Table 3).
Table 3. Summary of immunogenicity (anti-drug antibody) assessment (number [%] of subjects with positive antibodies).
Time (day) QX003S group (n = 42) Actemra® group (n = 41) p Values
Pre-dose 2 (4.88) 1 (2.44) .57
15 0 (0) 0 (0) NA
29 0 (0) 1 (2.44) .30
43 3 (7.32) 5 (12.2) .43
57 8 (19.51) 13 (31.71) .18
NA: Not applicable.
Table 4. Adverse reactions (number of reactions, the number [%] of subjects, more than 4%).
QX003S group (n = 42) Actemra® group (n = 41)
n (%) [number of reactions] n (%) [number of reaction] p Values
Total 42 (100) 134 40 (97.6) 148 0.30
Fibrinogen decreased 38 (90.5) 40 34 (82.9) 34 0.31
Reduced neutrophil counts 30 (71.4) 39 24 (58.5) 32 0.21
Reduced leukocyte count 24 (57.1) 28 19 (46.3) 26 0.32
Elevated serum bilirubin 6 (14.3) 6 3 (7.3) 5 0.30
Elevated alanine aminotransferase 0 (0) 0 5 (12.2) 6 0.01
Elevated aspartate aminotransferase 0 (0) 0 4 (9.8) 6 0.03
Reduced lymphocyte count 1 (2.4) 2 2 (4.9) 2 0.54
Urine leucocyte positive 0 (0) 0 2 (4.9) 2 0.14
Oropharyngeal pain 2 (4.8) 2 3 (7.3) 3 0.62
Cough 2 (4.8) 2 2 (4.9) 2 0.98
Cough with expectoration 1 (2.4) 1 2 (4.9) 2 0.54
Runny nose 0 (0) 0 3 (7.3) 3 0.07
Stuffy nose 0 (0) 0 2 (4.9) 2 0.14
Hypertriglyceridaemia 5 (11.9) 5 7 (17.1) 7 0.50
Hyperuricemia 1 (2.4) 1 2 (4.9) 3 0.54
Diarrhea 2 (4.8) 2 1 (2.4) 1 0.57
Oral mucositis 0 (0) 0 2 (4.9) 2 0.14
The serum concentration-time curves of QX003S and Actemra@ for ADA-positive and ADA-negative subjects were found to be similar (Figure 2). Sensitivity analysis of bioequivalence was performed after exclusion of 20 subjects who tested positive for ADA. The 90% CIs for the comparisons of Cmax and AUC were within the predefined range of bioequivalence limits of 80.00%–125.00% (Table 2). Therefore, overall, ADA-positivity rates were similar in the two groups.
3.4. Safety evaluation
No serious AEs (SAEs), deaths, or discontinuations due to AEs were observed. In this study, 282 adverse reactions occurred in 82 (98.8%) subjects. A total of 134 adverse reactions in 42 (100%) subjects were recorded in the QX003S group, while148 adverse reactions in 40 (97.6%) subjects were recorded in the Actemra® group. The incidence of adverse reactions was comparable in the two groups (Table 4). The adverse reactions with an incidence greater than 5% in the QX003S and Actemra® groups, respectively, were as follows: decreased fibrinogen level (90.5% vs 82.9%), decreased neutrophil count (71.4% vs 58.5%), decreased white blood cell (WBC) count (57.1% vs 46.3%), increased bilirubin (14.3% vs 7.3%), and hypertriglyceridaemia (11.9% vs 17.1%). The severity of most adverse reactions was between grade I and II. The incidence rates of elevated alanine aminotransferase and elevated aspartate aminotransferase level in the QX003S group were lower than those in the Actemra® group (0% vs. 12.2%, p = 0.01; 0% vs. 9.8%, p = 0.03); this indicated a lesser effect of QX003S on liver enzyme levels than the reference product. The incidence of other adverse reactions was comparable in the two groups (p > 0.05).
A total of 20 (24.1%) subjects in the two groups experienced 26 grade III–IV adverse reactions. Thirteen (31.0%) subjects in the QX003S group developed 16 adverse reactions, and seven (17.1%) subjects in the Actemra® group developed 10 adverse reactions. The incidence in the QX003S vs Actemra® groups was comparable: decreased neutrophil count (28.6% vs 12.2%), decreased WBC count (7.1% vs 7.3%), decreased fibrinogen (2.4% vs 2.4%), and increased alanine aminotransferase (0 vs 2.4%). All grade III–IV adverse reactions recovered spontaneously without treatment. Very few Grade I-II adverse reactions required drug therapy, such as cefuroxime axetil, levofloxacin, and glycyrrhizin.
There was no association between ADA development and adverse reactions in this study. None of the subjects developed clinically significant or serious hypersensitivity, anaphylaxis, or injection-site reaction after IP administration, except Subject no.105 of the QX003S group who developed ecchymia and mild tenderness at the injection site 48 h after administration; this subject showed spontaneous recovery on day 8 without any treatment. Subject no.001 of the Actemra® group showed bruising at the injection site at 12 h after administration without any tenderness; this subject also showed spontaneous recovery on day 22 without any treatment. All adverse reactions were reported to the Institutional Review Board of The First Hospital of Jilin University.
4. Discussion
This single-dose, phase-I study demonstrated the bioequivalence of QX003S and Actemra@ when administered as intravenous infusion at a dose of 8 mg/kg. The results of ANOVA showed that the 90% CIs of the geometric mean ratios of Cmax and AUC in the two treatment groups ranged from 92.72%–106%, which was within the predefined bioequivalence intervals of 80% to 125%. Other PK parameters of Tmax and t½ were also similar between the two treatment groups. QX003S and Actemra@ showed a similar safety and immunogenicity profile. No serious AEs were reported; all adverse reactions were mild or moderate in severity, and no local reactions were reported except in two subjects. This indicated that the two products were well tolerated in this population of healthy subjects. The above results justify the use of the biosimilars in the next phase clinical studies [1–3].
The pharmacokinetic behaviour of tocilizumab is different from the small-molecule pharmacokinetic behaviour in that it has limited vascular permeability, neonatal Fc receptor circulation, and more frequent receptor-mediated nonlinearity. Its distribution and clearance (CL) are consistent with target-mediated drug disposition (TMDD) [11]. On average, Cmax of tocilizumab decreased approximately 55% in the first 96 h. Subsequently, a slow elimination phase was observed between 96 and 336 h, followed by a relatively fast elimination between 336 and 672 h (Figure 2). In this study, QX003S at a dose of 8 mg/kg [mean weight of the subjects: 67.45 kg, dosage: 539.6 mg (4 × 67.45)] showed a lower clearance and displayed a longer t1/2 (160.8155 vs 39.9 h) than tocilizumab 162 mg (Roche Products Limited, Welwyn Garden City, UK), more exposure (AUC ratio of QX003S vs tocilizumab 162 mg equal to 6.39) than dose ratio (539.6:162 = 3.33), similar Tmax and dose ratio of Cmax with tocilizumab 162 mg, which have been evaluated in other phase-I studies in healthy subjects (Supplement Table 1) [12].
Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies [9,13]. Similarly, ADA had no effect on drug concentration or bioequivalence results in this study (Figure 2, Table 2). In population PK analysis, body weight was identified as a significant covariate impacting the pharmacokinetics of tocilizumab. When administered intravenously on mg/kg basis, individuals with body weight ≥100 kg are predicted to have higher exposures than individuals with body weight <100 kg. Therefore, weight stratification was adopted in this study to reduce variation of parameters, although the weight of subjects in this study was <100 kg. The inter-CV of tocilizumab was small (less than 18.7867%); therefore, the sample size in future studies can be reduced to 52 subjects (26 subjects per arm) [14].
Notably, the incidence of adverse reactions in the QX003S group was similar to that in the Actemra@ group (100% vs 97.6%); most of these were resolved at the final visit in this study. The most common adverse reactions (incidence of at least 5%) are reported in the label, including upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT level, and injection site reactions [9]. In healthy subjects who were administered ACTEMRA in doses of 2–28 mg/kg intravenously and 81–162 mg subcutaneously, the absolute neutrophil counts decreased to the nadir 3 to 5 days following administration. Thereafter, the neutrophil counts recovered towards baseline in a dose-dependent manner over a period of 9–17 days [12]. Patients with rheumatoid arthritis and GCA exhibited a similar pattern of absolute neutrophil counts following the administration of ACTEMRA [9,15]. Similar to previous reports, the incidence of decreased neutrophil counts and decreased white blood cell counts was indeed very high. Neutrophil counts decreased on day 2 to 5; the mean neutrophil count reached nadir on day 2 in both groups. The mean values returned to baseline by day 57 without any treatment (Figure 3). As described by Nishimoto et al. [16], when tocilizumab concentration is maintained above 1 µg/mL, SIL-6R is saturated by tocilizumab leading to complete inhibition of the IL-6 signal; this may affect the distribution of blood cells such as neutrophils and leukocytes. However, these cell counts quickly return to baseline with the drop in the drug concentration.
Figure 3. Absolute values of neutrophil, leukocyte counts, and fibrinogen level over time. Data presented as mean ± standard error of the mean.
In clinical studies, RA patients were treated with 4–8 mg/kg intravenous doses or the 162 mg weekly and every other weekly subcutaneous doses of ACTEMRA; the levels of CRP decreased to within the normal range along with changes in the pharmacodynamic parameters (i.e. decrease in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen; and increase in haemoglobin) [9]. In the present study, fibrinogen level decreased in 82.9–90.5% subjects and the mean fibrinogen level reached the nadir on day 15 to 29 in the QX003S and Actemra® groups; these changes are similar to the above changes in pharmacodynamic indices.
No acute or delayed anaphylactic reactions developed in subjects who were ADA positive, indicating that there was no product-specific immunogenicity. We observed no impact of the immunogenic responses of tocilizumab to drug safety and PK in this study similar to previous reports; however, it may still be necessary to closely monitor the immunogenicity of QX003S and Actemra and its impact on their efficacy in further related Phase-III studies with larger population, multiple doses, as well as longer time frame [17–19]. Overall, this study demonstrated the safety and tolerability of QX003S and reference Actemra@.
Conclusions
This study showed similar PK profile of tocilizumab biosimilar (QX003S) and Actemra@. The tocilizumab biosimilar showed a nearly similar ADA profile and a comparable safety profile versus the reference drug. The inter-CV of tocilizumab was low among Chinese subjects. These data support the clinical development of QX003S as a tocilizumab biosimilar.
Supplementary Material
Supplemental Material
Click here for additional data file.
Acknowledgements
The authors thank the staff of the Phase I Clinical Research Centre, The First Hospital of Jilin University, Jilin, China for data collection in the study.
Disclosure statement
All data related to this study were interpreted by the trial staff with complete independence from the sponsor. Min Fang is employee of the sponsor team. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Data availability statement
The data that support the findings of this study are available on request from the corresponding author, YHD. The data are not publicly available due to their containing information that could compromise the privacy of research participants. | TOCILIZUMAB | DrugsGivenReaction | CC BY | 33629921 | 19,002,940 | 2021-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'White blood cell count decreased'. | A randomized phase-I pharmacokinetic trial comparing the potential biosimilar tocilizumab (QX003S) with the reference product (Actemra®) in Chinese healthy subjects.
QX003S is a biosimilar candidate for the reference tocilizumab, Actemra®. We investigated the tolerance, variability, and pharmacokinetics (PK) of QX003S biosimilar in healthy Chinese male subjects.
A randomised, double-blind, two-arm, parallel study was performed to examine the bioequivalence of QX003S (8 mg/kg) with that of Actemra® as a reference drug.
QX003S (N = 40) and Actemra® (N = 40) groups exhibited similar PK properties. The inter-subject variability ranged from 14.95% to 18.78%. The 90% confidence intervals of the ratios for Cmax, AUC0-t andAUC0-∞ in both groups were within the range of 80-125%. After administration, the number of subjects who tested positive for anti-drug antibodies (ADA) in the QX003S group and Actemra® groups was 6 (14.3%) and 14 (34.1%), respectively. Adverse reactions occurred in 100% and 97.6% subjects in the QX003S and Actemra® groups, respectively. The most common adverse reactions were decrease in fibrinogen level and neutrophil and leukocyte counts.
The PK characteristics and immunogenicity exhibited by QX003S were similar to that of the reference product, Actemra®. The safety profile was similar in the two treatment groups with mild-moderate adverse effects.Trial RegistrationThe trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html#CTR20190002)Key pointsThis was the first clinical report of a new proposed tocilizumab biosimilar, QX003S.This phase-I randomized, controlled study compared pharmacokinetics, variability,immunogenicity, and safety of QX003S vs. the approved tocilizumab product (Actemra@).The results demonstrate bioequivalence between BAT1806 and the reference products (Actemra@), as well as comparable immunogenicity, safety and tolerability profiles.
1. Introduction
Biological products are large and complex molecules, usually derived from living cells. Due to the molecular complexity and multifaceted production process, the characteristics of biosimilars differ from those of the traditional small-molecule drugs [1–3]. Despite significant therapeutic advances, biologic therapies, such as monoclonal antibodies, are expensive with limited global access [4].
The US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Medical Products Administration (NMPA) have emphasized a step-by-step approach for the development of biosimilars [1]. Biological functional similarity is assessed in the first step, followed by the assessment of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics; finally, the clinical similarity (efficacy, safety, and immunogenicity) is assessed using the same approved dose and pathway as the reference product [1–3].
Tocilizumab binds to soluble and membrane-bound interleukin (IL)-6 receptors and through these receptors inhibits IL-6-mediated signal transduction. IL-6 is a multipotent pro-inflammatory cytokine produced by a variety of cell types, including T and B cells, lymphocytes, monocytes, and fibroblasts. Synovial cells and endothelial cells also produce IL-6, which induces the inflammatory process in the joints (e.g. rheumatoid arthritis) [5–6]. Tocilizumab is effective against rheumatoid arthritis, giant cell arteritis, and multi-joint juvenile idiopathic arthritis. In a previous study, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or deathin hospitalised patients with Covid-19 pneumonia; however, it did not improve survival of these patients. Tocilizumab is currently under investigation as a potential treatment for COVID-19, with initial contradictory evidence [7].
Consequently, tocilizumab biosimilars have been actively developed around the world, including in China. Tocilizumab biosimilars (QX003S) have the same primary structure, post-translational modification, biochemical characteristics, and biological functions as the reference product, and in addition, these similarities have been tested in mice and monkeys (data not published). All in vivo studies justify the clinical development of QX003S.
PK studies in humans are essential to demonstrate the bioequivalence of biological analogues and reference products [8]. Herein, we conducted a single-dose PK study in healthy Chinese male subjects to evaluate the bioequivalence between QX003S and Actemra@ as the reference product. Use of healthy subjects helps avoid the potential confounding influence of factors such as comorbid diseases and concomitant therapies. The therapeutic dose of the reference drug used in previous studies is 4–8 mg/kg [9–10]. In this study, a dose of 8 mg/kg was used, based on earlier clinical trial plans of the sponsor.
In this study, the PK profiles of the QX003S with Actemra@ were analysed and compared. In addition, the tolerability, safety, and immunogenicity of QX003S were assessed.
2. Methods
2.1. Study design and subjects
This phase-I study was conducted at the Clinical Research Centre of the First Hospital of Jilin University between 14 March 2019 and 18 September 2019 (Chinese Clinical Trial Registry, Registration No. CTR20190002). The study protocol was approved by the ethics committee of the hospital. The study complied with the guidelines of the Declaration of Helsinki and the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP). Written Informed consent was obtained from all subjects prior to their enrolment.
This was a randomized, double-blind, single-dose, two-arm, parallel comparison study to evaluate the PK, safety, and immunogenicity of QX003S and Actemra@ in healthy Chinese male subjects. Overall, 86 eligible subjects were randomly allocated in a 1:1 ratio to receive a single intravenous drip of 8 mg/kg QX003S or Actemra@. Subjects were stratified into two groups based on body weight (50 to < 67.5 kg and ≥ 67.5 to ≤ 85 kg). Individuals in each of the pre-specified groups were equally assigned to the two treatment groups through randomization (Figure 1).
Figure 1. Flow chart of the study.
Sentinel staggered administration was used in this study. Subjects were administered the investigational product (IP) in a staggered cohort: the first and second cohort consisted of two subjects and four subjects, respectively. For safety evaluation, each subject was required to stay at the study centre for at least 96 h after the administration. Based on sentinel safety results, the principal investigator determined whether the subsequent subjects would be monitored in sentinel mode or in routine follow-up mode. All subjects were followed up for 57 days.
The main inclusion criteria were as follows: (1) healthy men in the age group of 18–50 years; (2) body mass index: 18.0–28.0 kg/m2; (3) body weight: 55–85 kg; and (4) normal test outcomes or clinically unremarkable results of routine blood and urine routine investigations including hepatic and renal function tests during enrolment.
The exclusion criteria were as follows: (1) history of clinically significant diseases; (2) C-reactive protein (CRP) levels 1.5 times higher than the upper limit of the normal range; and (3) positive results of T-SPOT® assay or TB interferon-γ-release assay.
All subjects received a single intravenous infusion of the IP (8 mg/kg) administered over a period of 60 min (±6 min). All subjects were randomly allocated to one of the following two groups in a 1:1 ratio in each of the pre-specified weight intervals: QX003S (Jiangsu Quanxin Biomedicine Co. Ltd; Batch number: F20180801); Actemra@ (Chugai Pharmaceutical Company [Japan]; Batch number: B2063B15).
Screening was performed 14 to 2 days prior to the date of administration. All qualified subjects entered the clinical research unit a day prior to the administration of biosimilars. Subjects were required to fast for at least 8 h before administration and were randomly assigned to either the test drug (QX003S) or reference drug group.
2.2. PK evaluations
Blood samples were collected for PK analysis at different time-points: 1 h before administration (before administration) to 1344 h after the initial infusion (day 57). Serum tocilizumab levels were determined by enzyme-linked immunosorbent assay (ELISA) at the Junke Zhengyuan (Beijing) Pharmaceutical Research Co. Ltd. (Supplement material). PK parameters were determined by non-compartmental analysis model. The concentration–time data included the maximum observable serum concentration (Cmax), clearance (CL), half-life (t1/2), the volume of distribution (Vz), and area under the curve (AUC) from zero to the final quantifiable concentration (AUC0–t) and to infinity (AUC0–∞). The actual sampling times were used for PK analyses. An internally validated software system, Phoenix WinNonLin® v8.0 (Pharsight Corporation, Certara, L.P., Princeton, New Jersey, USA), was used to determine PK parameters.
2.3. Immunogenicity evaluations
Blood samples collected at 1 h before and on 15, 29, 43, and 57 days after drug administration were analysed for the presence of anti-drug antibodies (ADAs) using electrochemiluminescence immunoassay (ECLIA). Subjects who test ADA-positive, those who develop antibody-related adverse reactions, or those with significantly abnormal PK value are required to be further examined for the presence of neutralising antibodies (NAbs). NAb test was not performed in this study because the above conditions were not met.
2.4. Safety evaluation
Physical examination, assessment of vital signs, electrocardiogram, and routine laboratory investigations were performed to monitor adverse events (AEs) according to the National Cancer Institute Common Terminology for Adverse Events (CTCAE;V.4.03). Subjects who showed AEs were monitored until they reached normal or acceptable stability (as assessed by the principal investigator and sponsor) or were lost to follow up.
2.5. Estimation of the sample size
According to the recent FDA guidelines, the geometric mean ratio (GMR) was set at 95% to achieve 90% power (1 − β) at a significant level (two-sided α = 5%). Inter-subject variability (inter-CV) is expressed by the coefficient of variation (CV). NQuery 8.3.0.0 (Boston, USA) software was used to determine the sample size (initial: 68; inter-CV for tocilizumab: 24%) [9]. The final sample size was 86, allowing for a 20% drop-out rate.
2.6. Statistical analysis
After logarithmic transformation of PK parameters Cmax, AUC0–t, and AUC0–∞, the least square method was used for analysis of variance. Bioequivalence inferences were drawn if the 90% confidence intervals (CIs) were found to be within the range of 80–125%. PK analysis was performed using the PK analysis set. The safety analysis set included subjects who were administered the study drug. Descriptive statistical estimates of PK parameters and demographic data were calculated. Between-group differences were assessed using the Chi-squared test for categorical variables, t-test for normally distributed continuous variables, and Wilcoxon rank test for non-normally distributed variables. All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
3. Results
3.1. Subjects
The assigned drugs were administered to 83 of the 86 enrolled subjects and included in the safety analysis (Figure 1). One additional subject was included in the QX003S group, whereas one subject was removed from the Actemra® group due to weight stratification. Therefore, the QX003S group comprised of 44 subjects.
Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, had hypertension and fast pulse rate or polycardia; these subjects were excluded from the study. Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, were ADA positive;these were excluded from the study. The final per-protocol analysis population included in the safety, PK, BE, and immunogenicity (ADA) analysis set comprised of 83, 80, 80, and 83 subjects, respectively (Figure 1). The demographic and baseline characteristics of the per-protocol population and the two treatment groups were comparable (p > .05, Table 1).
Table 1. Demographic and baseline characteristics.
QX003S group Actemra® group Total
(n = 44) (n = 42) (n = 86) p Values
Age (year), mean (SD) 35.5 (8.88) 36.1 (8.51) 35.8 (8.66) .75
Ethnicity (Han, n [%]) 41 (93.2) 40 (95.2) 81 (94.2) .68
Weight (kg), mean (SD) 67.45 (9.423) 66.21 (7.621) 66.84 (8.563) .5
BMI (kg/m2), mean (SD) 23.306 (2.5834) 23.234 (2.5210) 23.271 (2.5383) .89
BMI; body mass index; SD: standard deviation.
3.2. PK evaluation
The mean serum concentration–time curve of tocilizumab and its biosimilar decreased with multiphase mode. A rapid decline immediately after the infusion was followed by a slow elimination phase, and, subsequently, by a slightly faster elimination phase at low concentrations (Figure 2). The non-compartmental analysis model showed slow clearance, longer t1/2, and small Vz of tocilizumab and its biosimilar. The median Tmax values were equivalent between the two groups and these were achieved 1.8 h after the intravenous infusion.
Figure 2. Serum drug concentration–time profile of tocilizumab. Mean values (A); log10 mean values (B); log10 mean values within 0–48 h (C); ADA-positive individuals in the QX003S (D) and Actemra@ (E) groups.
The mean value of t1/2 between the test drug and the reference drug was between 160.8155 and 159.9160 h, indicating comparability. The total clearance rate (CL) and Vz values were also similar in the two groups. The differences between the mean concentration–time curve, mean Cmax, AUC0-t, AUC0-∞ estimation, and inter-CVs were similar (p > .05); the coefficient of variation ranged from 14.95% to 18.78% (Table 2, Figure 2).
Table 2. Pharmacokinetic parameters of tocilizumab in each group (Mean ± SD [CV%] or median [min, max]).
QX003S group (n = 40) Actemra® group (n = 40) p Values GMR (90% CI) GMR (90% CI)a Re-estimated size
Tmax*(h) 1.8 (1-4) 1.8 (1-4) >.05
Cmax (μg/mL) 178.8 ± 28.90 (16.16) 178.2 ± 27.43 (15.39) .92 1 (0.95, 1.06) 1.02 (0.95-1.09) 40
AUC0-t (h•μg/mL) 27116.0941 ± 4466.9216 (16.47) 27446.4185 ± 4103.9469 (14.95) .73 0.9859 (0.9311,1.0439) 0.9827 (0.9197-1.0500) 40
AUC0-∞ (h•μg/mL) 28806.7645 ± 5411.8467 (18.78) 29039.7894 ± 4641.0883 (15.98) .83 0.9878 (0.9272, 1.0524) 0.9787 (0.9098-1.0529) 52
t1/2 (h) 160.8155 ± 35.2772 (21.93) 159.9160 ± 29.0054 (18.13) .90
CL (L/h) 0.0192 ± 0.0031 (16.06) 0.0185 ± 0.0025 (13.68) .26
Vd (L) 4.3578 ± 0.7660 (17.57) 4.2322 ± 0.7760 (18.33) .46
*Median [min, max]; aQX003S/ Actemra® after excluding subject with ADA positive after dosing.
The PK parameters were comparable in the QX003S and Actemra@ groups. The ratio of geometric least-squares means for the QX003S versus Actemra@ were 1, 0.9859, and 0.9878 for Cmax, AUC0-t, and AUC0-∞;the 90% CI was 0.9272–1.06. The 90% CIs of the Cmax, AUC0–t, and AUC0–∞ were within the predefined bioequivalence limit, ranging from 80.00% to 125.00%. A larger inter-CV indicated a broader 90% CI. The sample size was re-estimated on the basis of the results of bioequivalence analysis (GMR and inter-CV), which decreased to a number less than the enrolment size (Table 2).
3.3. Immunogenicity evaluation
Before dosing, two and one subjects in the QX003S and Actemra® group respectively, were ADA positive. After dosing, 6 (14.3%) subjects in the QX003S group and 14 (34.1%) subjects in the Actemra® group tested positive for ADA. The ADA-positive rates were found to increase over a period of time, especially by days 43 (1008 h) and 57 (1344 h). Nevertheless, the drug concentration was less than the lower limit of quantitation (LLOQ) during that period. ADA-positivity rates were similar in the two groups at 15 to 29 days after drug administration (6.7–7.1%). However, at 43 and 57 days after drug administration, the positivity rates in the QX003S group were relatively lower than those in the Actemra@ group; however, the between-group differences in this respect were not statistically significant at any of the time-points (p > .05, Table 3).
Table 3. Summary of immunogenicity (anti-drug antibody) assessment (number [%] of subjects with positive antibodies).
Time (day) QX003S group (n = 42) Actemra® group (n = 41) p Values
Pre-dose 2 (4.88) 1 (2.44) .57
15 0 (0) 0 (0) NA
29 0 (0) 1 (2.44) .30
43 3 (7.32) 5 (12.2) .43
57 8 (19.51) 13 (31.71) .18
NA: Not applicable.
Table 4. Adverse reactions (number of reactions, the number [%] of subjects, more than 4%).
QX003S group (n = 42) Actemra® group (n = 41)
n (%) [number of reactions] n (%) [number of reaction] p Values
Total 42 (100) 134 40 (97.6) 148 0.30
Fibrinogen decreased 38 (90.5) 40 34 (82.9) 34 0.31
Reduced neutrophil counts 30 (71.4) 39 24 (58.5) 32 0.21
Reduced leukocyte count 24 (57.1) 28 19 (46.3) 26 0.32
Elevated serum bilirubin 6 (14.3) 6 3 (7.3) 5 0.30
Elevated alanine aminotransferase 0 (0) 0 5 (12.2) 6 0.01
Elevated aspartate aminotransferase 0 (0) 0 4 (9.8) 6 0.03
Reduced lymphocyte count 1 (2.4) 2 2 (4.9) 2 0.54
Urine leucocyte positive 0 (0) 0 2 (4.9) 2 0.14
Oropharyngeal pain 2 (4.8) 2 3 (7.3) 3 0.62
Cough 2 (4.8) 2 2 (4.9) 2 0.98
Cough with expectoration 1 (2.4) 1 2 (4.9) 2 0.54
Runny nose 0 (0) 0 3 (7.3) 3 0.07
Stuffy nose 0 (0) 0 2 (4.9) 2 0.14
Hypertriglyceridaemia 5 (11.9) 5 7 (17.1) 7 0.50
Hyperuricemia 1 (2.4) 1 2 (4.9) 3 0.54
Diarrhea 2 (4.8) 2 1 (2.4) 1 0.57
Oral mucositis 0 (0) 0 2 (4.9) 2 0.14
The serum concentration-time curves of QX003S and Actemra@ for ADA-positive and ADA-negative subjects were found to be similar (Figure 2). Sensitivity analysis of bioequivalence was performed after exclusion of 20 subjects who tested positive for ADA. The 90% CIs for the comparisons of Cmax and AUC were within the predefined range of bioequivalence limits of 80.00%–125.00% (Table 2). Therefore, overall, ADA-positivity rates were similar in the two groups.
3.4. Safety evaluation
No serious AEs (SAEs), deaths, or discontinuations due to AEs were observed. In this study, 282 adverse reactions occurred in 82 (98.8%) subjects. A total of 134 adverse reactions in 42 (100%) subjects were recorded in the QX003S group, while148 adverse reactions in 40 (97.6%) subjects were recorded in the Actemra® group. The incidence of adverse reactions was comparable in the two groups (Table 4). The adverse reactions with an incidence greater than 5% in the QX003S and Actemra® groups, respectively, were as follows: decreased fibrinogen level (90.5% vs 82.9%), decreased neutrophil count (71.4% vs 58.5%), decreased white blood cell (WBC) count (57.1% vs 46.3%), increased bilirubin (14.3% vs 7.3%), and hypertriglyceridaemia (11.9% vs 17.1%). The severity of most adverse reactions was between grade I and II. The incidence rates of elevated alanine aminotransferase and elevated aspartate aminotransferase level in the QX003S group were lower than those in the Actemra® group (0% vs. 12.2%, p = 0.01; 0% vs. 9.8%, p = 0.03); this indicated a lesser effect of QX003S on liver enzyme levels than the reference product. The incidence of other adverse reactions was comparable in the two groups (p > 0.05).
A total of 20 (24.1%) subjects in the two groups experienced 26 grade III–IV adverse reactions. Thirteen (31.0%) subjects in the QX003S group developed 16 adverse reactions, and seven (17.1%) subjects in the Actemra® group developed 10 adverse reactions. The incidence in the QX003S vs Actemra® groups was comparable: decreased neutrophil count (28.6% vs 12.2%), decreased WBC count (7.1% vs 7.3%), decreased fibrinogen (2.4% vs 2.4%), and increased alanine aminotransferase (0 vs 2.4%). All grade III–IV adverse reactions recovered spontaneously without treatment. Very few Grade I-II adverse reactions required drug therapy, such as cefuroxime axetil, levofloxacin, and glycyrrhizin.
There was no association between ADA development and adverse reactions in this study. None of the subjects developed clinically significant or serious hypersensitivity, anaphylaxis, or injection-site reaction after IP administration, except Subject no.105 of the QX003S group who developed ecchymia and mild tenderness at the injection site 48 h after administration; this subject showed spontaneous recovery on day 8 without any treatment. Subject no.001 of the Actemra® group showed bruising at the injection site at 12 h after administration without any tenderness; this subject also showed spontaneous recovery on day 22 without any treatment. All adverse reactions were reported to the Institutional Review Board of The First Hospital of Jilin University.
4. Discussion
This single-dose, phase-I study demonstrated the bioequivalence of QX003S and Actemra@ when administered as intravenous infusion at a dose of 8 mg/kg. The results of ANOVA showed that the 90% CIs of the geometric mean ratios of Cmax and AUC in the two treatment groups ranged from 92.72%–106%, which was within the predefined bioequivalence intervals of 80% to 125%. Other PK parameters of Tmax and t½ were also similar between the two treatment groups. QX003S and Actemra@ showed a similar safety and immunogenicity profile. No serious AEs were reported; all adverse reactions were mild or moderate in severity, and no local reactions were reported except in two subjects. This indicated that the two products were well tolerated in this population of healthy subjects. The above results justify the use of the biosimilars in the next phase clinical studies [1–3].
The pharmacokinetic behaviour of tocilizumab is different from the small-molecule pharmacokinetic behaviour in that it has limited vascular permeability, neonatal Fc receptor circulation, and more frequent receptor-mediated nonlinearity. Its distribution and clearance (CL) are consistent with target-mediated drug disposition (TMDD) [11]. On average, Cmax of tocilizumab decreased approximately 55% in the first 96 h. Subsequently, a slow elimination phase was observed between 96 and 336 h, followed by a relatively fast elimination between 336 and 672 h (Figure 2). In this study, QX003S at a dose of 8 mg/kg [mean weight of the subjects: 67.45 kg, dosage: 539.6 mg (4 × 67.45)] showed a lower clearance and displayed a longer t1/2 (160.8155 vs 39.9 h) than tocilizumab 162 mg (Roche Products Limited, Welwyn Garden City, UK), more exposure (AUC ratio of QX003S vs tocilizumab 162 mg equal to 6.39) than dose ratio (539.6:162 = 3.33), similar Tmax and dose ratio of Cmax with tocilizumab 162 mg, which have been evaluated in other phase-I studies in healthy subjects (Supplement Table 1) [12].
Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies [9,13]. Similarly, ADA had no effect on drug concentration or bioequivalence results in this study (Figure 2, Table 2). In population PK analysis, body weight was identified as a significant covariate impacting the pharmacokinetics of tocilizumab. When administered intravenously on mg/kg basis, individuals with body weight ≥100 kg are predicted to have higher exposures than individuals with body weight <100 kg. Therefore, weight stratification was adopted in this study to reduce variation of parameters, although the weight of subjects in this study was <100 kg. The inter-CV of tocilizumab was small (less than 18.7867%); therefore, the sample size in future studies can be reduced to 52 subjects (26 subjects per arm) [14].
Notably, the incidence of adverse reactions in the QX003S group was similar to that in the Actemra@ group (100% vs 97.6%); most of these were resolved at the final visit in this study. The most common adverse reactions (incidence of at least 5%) are reported in the label, including upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT level, and injection site reactions [9]. In healthy subjects who were administered ACTEMRA in doses of 2–28 mg/kg intravenously and 81–162 mg subcutaneously, the absolute neutrophil counts decreased to the nadir 3 to 5 days following administration. Thereafter, the neutrophil counts recovered towards baseline in a dose-dependent manner over a period of 9–17 days [12]. Patients with rheumatoid arthritis and GCA exhibited a similar pattern of absolute neutrophil counts following the administration of ACTEMRA [9,15]. Similar to previous reports, the incidence of decreased neutrophil counts and decreased white blood cell counts was indeed very high. Neutrophil counts decreased on day 2 to 5; the mean neutrophil count reached nadir on day 2 in both groups. The mean values returned to baseline by day 57 without any treatment (Figure 3). As described by Nishimoto et al. [16], when tocilizumab concentration is maintained above 1 µg/mL, SIL-6R is saturated by tocilizumab leading to complete inhibition of the IL-6 signal; this may affect the distribution of blood cells such as neutrophils and leukocytes. However, these cell counts quickly return to baseline with the drop in the drug concentration.
Figure 3. Absolute values of neutrophil, leukocyte counts, and fibrinogen level over time. Data presented as mean ± standard error of the mean.
In clinical studies, RA patients were treated with 4–8 mg/kg intravenous doses or the 162 mg weekly and every other weekly subcutaneous doses of ACTEMRA; the levels of CRP decreased to within the normal range along with changes in the pharmacodynamic parameters (i.e. decrease in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen; and increase in haemoglobin) [9]. In the present study, fibrinogen level decreased in 82.9–90.5% subjects and the mean fibrinogen level reached the nadir on day 15 to 29 in the QX003S and Actemra® groups; these changes are similar to the above changes in pharmacodynamic indices.
No acute or delayed anaphylactic reactions developed in subjects who were ADA positive, indicating that there was no product-specific immunogenicity. We observed no impact of the immunogenic responses of tocilizumab to drug safety and PK in this study similar to previous reports; however, it may still be necessary to closely monitor the immunogenicity of QX003S and Actemra and its impact on their efficacy in further related Phase-III studies with larger population, multiple doses, as well as longer time frame [17–19]. Overall, this study demonstrated the safety and tolerability of QX003S and reference Actemra@.
Conclusions
This study showed similar PK profile of tocilizumab biosimilar (QX003S) and Actemra@. The tocilizumab biosimilar showed a nearly similar ADA profile and a comparable safety profile versus the reference drug. The inter-CV of tocilizumab was low among Chinese subjects. These data support the clinical development of QX003S as a tocilizumab biosimilar.
Supplementary Material
Supplemental Material
Click here for additional data file.
Acknowledgements
The authors thank the staff of the Phase I Clinical Research Centre, The First Hospital of Jilin University, Jilin, China for data collection in the study.
Disclosure statement
All data related to this study were interpreted by the trial staff with complete independence from the sponsor. Min Fang is employee of the sponsor team. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Data availability statement
The data that support the findings of this study are available on request from the corresponding author, YHD. The data are not publicly available due to their containing information that could compromise the privacy of research participants. | TOCILIZUMAB | DrugsGivenReaction | CC BY | 33629921 | 19,002,940 | 2021-12 |
What was the administration route of drug 'TOCILIZUMAB'? | A randomized phase-I pharmacokinetic trial comparing the potential biosimilar tocilizumab (QX003S) with the reference product (Actemra®) in Chinese healthy subjects.
QX003S is a biosimilar candidate for the reference tocilizumab, Actemra®. We investigated the tolerance, variability, and pharmacokinetics (PK) of QX003S biosimilar in healthy Chinese male subjects.
A randomised, double-blind, two-arm, parallel study was performed to examine the bioequivalence of QX003S (8 mg/kg) with that of Actemra® as a reference drug.
QX003S (N = 40) and Actemra® (N = 40) groups exhibited similar PK properties. The inter-subject variability ranged from 14.95% to 18.78%. The 90% confidence intervals of the ratios for Cmax, AUC0-t andAUC0-∞ in both groups were within the range of 80-125%. After administration, the number of subjects who tested positive for anti-drug antibodies (ADA) in the QX003S group and Actemra® groups was 6 (14.3%) and 14 (34.1%), respectively. Adverse reactions occurred in 100% and 97.6% subjects in the QX003S and Actemra® groups, respectively. The most common adverse reactions were decrease in fibrinogen level and neutrophil and leukocyte counts.
The PK characteristics and immunogenicity exhibited by QX003S were similar to that of the reference product, Actemra®. The safety profile was similar in the two treatment groups with mild-moderate adverse effects.Trial RegistrationThe trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html#CTR20190002)Key pointsThis was the first clinical report of a new proposed tocilizumab biosimilar, QX003S.This phase-I randomized, controlled study compared pharmacokinetics, variability,immunogenicity, and safety of QX003S vs. the approved tocilizumab product (Actemra@).The results demonstrate bioequivalence between BAT1806 and the reference products (Actemra@), as well as comparable immunogenicity, safety and tolerability profiles.
1. Introduction
Biological products are large and complex molecules, usually derived from living cells. Due to the molecular complexity and multifaceted production process, the characteristics of biosimilars differ from those of the traditional small-molecule drugs [1–3]. Despite significant therapeutic advances, biologic therapies, such as monoclonal antibodies, are expensive with limited global access [4].
The US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Medical Products Administration (NMPA) have emphasized a step-by-step approach for the development of biosimilars [1]. Biological functional similarity is assessed in the first step, followed by the assessment of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics; finally, the clinical similarity (efficacy, safety, and immunogenicity) is assessed using the same approved dose and pathway as the reference product [1–3].
Tocilizumab binds to soluble and membrane-bound interleukin (IL)-6 receptors and through these receptors inhibits IL-6-mediated signal transduction. IL-6 is a multipotent pro-inflammatory cytokine produced by a variety of cell types, including T and B cells, lymphocytes, monocytes, and fibroblasts. Synovial cells and endothelial cells also produce IL-6, which induces the inflammatory process in the joints (e.g. rheumatoid arthritis) [5–6]. Tocilizumab is effective against rheumatoid arthritis, giant cell arteritis, and multi-joint juvenile idiopathic arthritis. In a previous study, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or deathin hospitalised patients with Covid-19 pneumonia; however, it did not improve survival of these patients. Tocilizumab is currently under investigation as a potential treatment for COVID-19, with initial contradictory evidence [7].
Consequently, tocilizumab biosimilars have been actively developed around the world, including in China. Tocilizumab biosimilars (QX003S) have the same primary structure, post-translational modification, biochemical characteristics, and biological functions as the reference product, and in addition, these similarities have been tested in mice and monkeys (data not published). All in vivo studies justify the clinical development of QX003S.
PK studies in humans are essential to demonstrate the bioequivalence of biological analogues and reference products [8]. Herein, we conducted a single-dose PK study in healthy Chinese male subjects to evaluate the bioequivalence between QX003S and Actemra@ as the reference product. Use of healthy subjects helps avoid the potential confounding influence of factors such as comorbid diseases and concomitant therapies. The therapeutic dose of the reference drug used in previous studies is 4–8 mg/kg [9–10]. In this study, a dose of 8 mg/kg was used, based on earlier clinical trial plans of the sponsor.
In this study, the PK profiles of the QX003S with Actemra@ were analysed and compared. In addition, the tolerability, safety, and immunogenicity of QX003S were assessed.
2. Methods
2.1. Study design and subjects
This phase-I study was conducted at the Clinical Research Centre of the First Hospital of Jilin University between 14 March 2019 and 18 September 2019 (Chinese Clinical Trial Registry, Registration No. CTR20190002). The study protocol was approved by the ethics committee of the hospital. The study complied with the guidelines of the Declaration of Helsinki and the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP). Written Informed consent was obtained from all subjects prior to their enrolment.
This was a randomized, double-blind, single-dose, two-arm, parallel comparison study to evaluate the PK, safety, and immunogenicity of QX003S and Actemra@ in healthy Chinese male subjects. Overall, 86 eligible subjects were randomly allocated in a 1:1 ratio to receive a single intravenous drip of 8 mg/kg QX003S or Actemra@. Subjects were stratified into two groups based on body weight (50 to < 67.5 kg and ≥ 67.5 to ≤ 85 kg). Individuals in each of the pre-specified groups were equally assigned to the two treatment groups through randomization (Figure 1).
Figure 1. Flow chart of the study.
Sentinel staggered administration was used in this study. Subjects were administered the investigational product (IP) in a staggered cohort: the first and second cohort consisted of two subjects and four subjects, respectively. For safety evaluation, each subject was required to stay at the study centre for at least 96 h after the administration. Based on sentinel safety results, the principal investigator determined whether the subsequent subjects would be monitored in sentinel mode or in routine follow-up mode. All subjects were followed up for 57 days.
The main inclusion criteria were as follows: (1) healthy men in the age group of 18–50 years; (2) body mass index: 18.0–28.0 kg/m2; (3) body weight: 55–85 kg; and (4) normal test outcomes or clinically unremarkable results of routine blood and urine routine investigations including hepatic and renal function tests during enrolment.
The exclusion criteria were as follows: (1) history of clinically significant diseases; (2) C-reactive protein (CRP) levels 1.5 times higher than the upper limit of the normal range; and (3) positive results of T-SPOT® assay or TB interferon-γ-release assay.
All subjects received a single intravenous infusion of the IP (8 mg/kg) administered over a period of 60 min (±6 min). All subjects were randomly allocated to one of the following two groups in a 1:1 ratio in each of the pre-specified weight intervals: QX003S (Jiangsu Quanxin Biomedicine Co. Ltd; Batch number: F20180801); Actemra@ (Chugai Pharmaceutical Company [Japan]; Batch number: B2063B15).
Screening was performed 14 to 2 days prior to the date of administration. All qualified subjects entered the clinical research unit a day prior to the administration of biosimilars. Subjects were required to fast for at least 8 h before administration and were randomly assigned to either the test drug (QX003S) or reference drug group.
2.2. PK evaluations
Blood samples were collected for PK analysis at different time-points: 1 h before administration (before administration) to 1344 h after the initial infusion (day 57). Serum tocilizumab levels were determined by enzyme-linked immunosorbent assay (ELISA) at the Junke Zhengyuan (Beijing) Pharmaceutical Research Co. Ltd. (Supplement material). PK parameters were determined by non-compartmental analysis model. The concentration–time data included the maximum observable serum concentration (Cmax), clearance (CL), half-life (t1/2), the volume of distribution (Vz), and area under the curve (AUC) from zero to the final quantifiable concentration (AUC0–t) and to infinity (AUC0–∞). The actual sampling times were used for PK analyses. An internally validated software system, Phoenix WinNonLin® v8.0 (Pharsight Corporation, Certara, L.P., Princeton, New Jersey, USA), was used to determine PK parameters.
2.3. Immunogenicity evaluations
Blood samples collected at 1 h before and on 15, 29, 43, and 57 days after drug administration were analysed for the presence of anti-drug antibodies (ADAs) using electrochemiluminescence immunoassay (ECLIA). Subjects who test ADA-positive, those who develop antibody-related adverse reactions, or those with significantly abnormal PK value are required to be further examined for the presence of neutralising antibodies (NAbs). NAb test was not performed in this study because the above conditions were not met.
2.4. Safety evaluation
Physical examination, assessment of vital signs, electrocardiogram, and routine laboratory investigations were performed to monitor adverse events (AEs) according to the National Cancer Institute Common Terminology for Adverse Events (CTCAE;V.4.03). Subjects who showed AEs were monitored until they reached normal or acceptable stability (as assessed by the principal investigator and sponsor) or were lost to follow up.
2.5. Estimation of the sample size
According to the recent FDA guidelines, the geometric mean ratio (GMR) was set at 95% to achieve 90% power (1 − β) at a significant level (two-sided α = 5%). Inter-subject variability (inter-CV) is expressed by the coefficient of variation (CV). NQuery 8.3.0.0 (Boston, USA) software was used to determine the sample size (initial: 68; inter-CV for tocilizumab: 24%) [9]. The final sample size was 86, allowing for a 20% drop-out rate.
2.6. Statistical analysis
After logarithmic transformation of PK parameters Cmax, AUC0–t, and AUC0–∞, the least square method was used for analysis of variance. Bioequivalence inferences were drawn if the 90% confidence intervals (CIs) were found to be within the range of 80–125%. PK analysis was performed using the PK analysis set. The safety analysis set included subjects who were administered the study drug. Descriptive statistical estimates of PK parameters and demographic data were calculated. Between-group differences were assessed using the Chi-squared test for categorical variables, t-test for normally distributed continuous variables, and Wilcoxon rank test for non-normally distributed variables. All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
3. Results
3.1. Subjects
The assigned drugs were administered to 83 of the 86 enrolled subjects and included in the safety analysis (Figure 1). One additional subject was included in the QX003S group, whereas one subject was removed from the Actemra® group due to weight stratification. Therefore, the QX003S group comprised of 44 subjects.
Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, had hypertension and fast pulse rate or polycardia; these subjects were excluded from the study. Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, were ADA positive;these were excluded from the study. The final per-protocol analysis population included in the safety, PK, BE, and immunogenicity (ADA) analysis set comprised of 83, 80, 80, and 83 subjects, respectively (Figure 1). The demographic and baseline characteristics of the per-protocol population and the two treatment groups were comparable (p > .05, Table 1).
Table 1. Demographic and baseline characteristics.
QX003S group Actemra® group Total
(n = 44) (n = 42) (n = 86) p Values
Age (year), mean (SD) 35.5 (8.88) 36.1 (8.51) 35.8 (8.66) .75
Ethnicity (Han, n [%]) 41 (93.2) 40 (95.2) 81 (94.2) .68
Weight (kg), mean (SD) 67.45 (9.423) 66.21 (7.621) 66.84 (8.563) .5
BMI (kg/m2), mean (SD) 23.306 (2.5834) 23.234 (2.5210) 23.271 (2.5383) .89
BMI; body mass index; SD: standard deviation.
3.2. PK evaluation
The mean serum concentration–time curve of tocilizumab and its biosimilar decreased with multiphase mode. A rapid decline immediately after the infusion was followed by a slow elimination phase, and, subsequently, by a slightly faster elimination phase at low concentrations (Figure 2). The non-compartmental analysis model showed slow clearance, longer t1/2, and small Vz of tocilizumab and its biosimilar. The median Tmax values were equivalent between the two groups and these were achieved 1.8 h after the intravenous infusion.
Figure 2. Serum drug concentration–time profile of tocilizumab. Mean values (A); log10 mean values (B); log10 mean values within 0–48 h (C); ADA-positive individuals in the QX003S (D) and Actemra@ (E) groups.
The mean value of t1/2 between the test drug and the reference drug was between 160.8155 and 159.9160 h, indicating comparability. The total clearance rate (CL) and Vz values were also similar in the two groups. The differences between the mean concentration–time curve, mean Cmax, AUC0-t, AUC0-∞ estimation, and inter-CVs were similar (p > .05); the coefficient of variation ranged from 14.95% to 18.78% (Table 2, Figure 2).
Table 2. Pharmacokinetic parameters of tocilizumab in each group (Mean ± SD [CV%] or median [min, max]).
QX003S group (n = 40) Actemra® group (n = 40) p Values GMR (90% CI) GMR (90% CI)a Re-estimated size
Tmax*(h) 1.8 (1-4) 1.8 (1-4) >.05
Cmax (μg/mL) 178.8 ± 28.90 (16.16) 178.2 ± 27.43 (15.39) .92 1 (0.95, 1.06) 1.02 (0.95-1.09) 40
AUC0-t (h•μg/mL) 27116.0941 ± 4466.9216 (16.47) 27446.4185 ± 4103.9469 (14.95) .73 0.9859 (0.9311,1.0439) 0.9827 (0.9197-1.0500) 40
AUC0-∞ (h•μg/mL) 28806.7645 ± 5411.8467 (18.78) 29039.7894 ± 4641.0883 (15.98) .83 0.9878 (0.9272, 1.0524) 0.9787 (0.9098-1.0529) 52
t1/2 (h) 160.8155 ± 35.2772 (21.93) 159.9160 ± 29.0054 (18.13) .90
CL (L/h) 0.0192 ± 0.0031 (16.06) 0.0185 ± 0.0025 (13.68) .26
Vd (L) 4.3578 ± 0.7660 (17.57) 4.2322 ± 0.7760 (18.33) .46
*Median [min, max]; aQX003S/ Actemra® after excluding subject with ADA positive after dosing.
The PK parameters were comparable in the QX003S and Actemra@ groups. The ratio of geometric least-squares means for the QX003S versus Actemra@ were 1, 0.9859, and 0.9878 for Cmax, AUC0-t, and AUC0-∞;the 90% CI was 0.9272–1.06. The 90% CIs of the Cmax, AUC0–t, and AUC0–∞ were within the predefined bioequivalence limit, ranging from 80.00% to 125.00%. A larger inter-CV indicated a broader 90% CI. The sample size was re-estimated on the basis of the results of bioequivalence analysis (GMR and inter-CV), which decreased to a number less than the enrolment size (Table 2).
3.3. Immunogenicity evaluation
Before dosing, two and one subjects in the QX003S and Actemra® group respectively, were ADA positive. After dosing, 6 (14.3%) subjects in the QX003S group and 14 (34.1%) subjects in the Actemra® group tested positive for ADA. The ADA-positive rates were found to increase over a period of time, especially by days 43 (1008 h) and 57 (1344 h). Nevertheless, the drug concentration was less than the lower limit of quantitation (LLOQ) during that period. ADA-positivity rates were similar in the two groups at 15 to 29 days after drug administration (6.7–7.1%). However, at 43 and 57 days after drug administration, the positivity rates in the QX003S group were relatively lower than those in the Actemra@ group; however, the between-group differences in this respect were not statistically significant at any of the time-points (p > .05, Table 3).
Table 3. Summary of immunogenicity (anti-drug antibody) assessment (number [%] of subjects with positive antibodies).
Time (day) QX003S group (n = 42) Actemra® group (n = 41) p Values
Pre-dose 2 (4.88) 1 (2.44) .57
15 0 (0) 0 (0) NA
29 0 (0) 1 (2.44) .30
43 3 (7.32) 5 (12.2) .43
57 8 (19.51) 13 (31.71) .18
NA: Not applicable.
Table 4. Adverse reactions (number of reactions, the number [%] of subjects, more than 4%).
QX003S group (n = 42) Actemra® group (n = 41)
n (%) [number of reactions] n (%) [number of reaction] p Values
Total 42 (100) 134 40 (97.6) 148 0.30
Fibrinogen decreased 38 (90.5) 40 34 (82.9) 34 0.31
Reduced neutrophil counts 30 (71.4) 39 24 (58.5) 32 0.21
Reduced leukocyte count 24 (57.1) 28 19 (46.3) 26 0.32
Elevated serum bilirubin 6 (14.3) 6 3 (7.3) 5 0.30
Elevated alanine aminotransferase 0 (0) 0 5 (12.2) 6 0.01
Elevated aspartate aminotransferase 0 (0) 0 4 (9.8) 6 0.03
Reduced lymphocyte count 1 (2.4) 2 2 (4.9) 2 0.54
Urine leucocyte positive 0 (0) 0 2 (4.9) 2 0.14
Oropharyngeal pain 2 (4.8) 2 3 (7.3) 3 0.62
Cough 2 (4.8) 2 2 (4.9) 2 0.98
Cough with expectoration 1 (2.4) 1 2 (4.9) 2 0.54
Runny nose 0 (0) 0 3 (7.3) 3 0.07
Stuffy nose 0 (0) 0 2 (4.9) 2 0.14
Hypertriglyceridaemia 5 (11.9) 5 7 (17.1) 7 0.50
Hyperuricemia 1 (2.4) 1 2 (4.9) 3 0.54
Diarrhea 2 (4.8) 2 1 (2.4) 1 0.57
Oral mucositis 0 (0) 0 2 (4.9) 2 0.14
The serum concentration-time curves of QX003S and Actemra@ for ADA-positive and ADA-negative subjects were found to be similar (Figure 2). Sensitivity analysis of bioequivalence was performed after exclusion of 20 subjects who tested positive for ADA. The 90% CIs for the comparisons of Cmax and AUC were within the predefined range of bioequivalence limits of 80.00%–125.00% (Table 2). Therefore, overall, ADA-positivity rates were similar in the two groups.
3.4. Safety evaluation
No serious AEs (SAEs), deaths, or discontinuations due to AEs were observed. In this study, 282 adverse reactions occurred in 82 (98.8%) subjects. A total of 134 adverse reactions in 42 (100%) subjects were recorded in the QX003S group, while148 adverse reactions in 40 (97.6%) subjects were recorded in the Actemra® group. The incidence of adverse reactions was comparable in the two groups (Table 4). The adverse reactions with an incidence greater than 5% in the QX003S and Actemra® groups, respectively, were as follows: decreased fibrinogen level (90.5% vs 82.9%), decreased neutrophil count (71.4% vs 58.5%), decreased white blood cell (WBC) count (57.1% vs 46.3%), increased bilirubin (14.3% vs 7.3%), and hypertriglyceridaemia (11.9% vs 17.1%). The severity of most adverse reactions was between grade I and II. The incidence rates of elevated alanine aminotransferase and elevated aspartate aminotransferase level in the QX003S group were lower than those in the Actemra® group (0% vs. 12.2%, p = 0.01; 0% vs. 9.8%, p = 0.03); this indicated a lesser effect of QX003S on liver enzyme levels than the reference product. The incidence of other adverse reactions was comparable in the two groups (p > 0.05).
A total of 20 (24.1%) subjects in the two groups experienced 26 grade III–IV adverse reactions. Thirteen (31.0%) subjects in the QX003S group developed 16 adverse reactions, and seven (17.1%) subjects in the Actemra® group developed 10 adverse reactions. The incidence in the QX003S vs Actemra® groups was comparable: decreased neutrophil count (28.6% vs 12.2%), decreased WBC count (7.1% vs 7.3%), decreased fibrinogen (2.4% vs 2.4%), and increased alanine aminotransferase (0 vs 2.4%). All grade III–IV adverse reactions recovered spontaneously without treatment. Very few Grade I-II adverse reactions required drug therapy, such as cefuroxime axetil, levofloxacin, and glycyrrhizin.
There was no association between ADA development and adverse reactions in this study. None of the subjects developed clinically significant or serious hypersensitivity, anaphylaxis, or injection-site reaction after IP administration, except Subject no.105 of the QX003S group who developed ecchymia and mild tenderness at the injection site 48 h after administration; this subject showed spontaneous recovery on day 8 without any treatment. Subject no.001 of the Actemra® group showed bruising at the injection site at 12 h after administration without any tenderness; this subject also showed spontaneous recovery on day 22 without any treatment. All adverse reactions were reported to the Institutional Review Board of The First Hospital of Jilin University.
4. Discussion
This single-dose, phase-I study demonstrated the bioequivalence of QX003S and Actemra@ when administered as intravenous infusion at a dose of 8 mg/kg. The results of ANOVA showed that the 90% CIs of the geometric mean ratios of Cmax and AUC in the two treatment groups ranged from 92.72%–106%, which was within the predefined bioequivalence intervals of 80% to 125%. Other PK parameters of Tmax and t½ were also similar between the two treatment groups. QX003S and Actemra@ showed a similar safety and immunogenicity profile. No serious AEs were reported; all adverse reactions were mild or moderate in severity, and no local reactions were reported except in two subjects. This indicated that the two products were well tolerated in this population of healthy subjects. The above results justify the use of the biosimilars in the next phase clinical studies [1–3].
The pharmacokinetic behaviour of tocilizumab is different from the small-molecule pharmacokinetic behaviour in that it has limited vascular permeability, neonatal Fc receptor circulation, and more frequent receptor-mediated nonlinearity. Its distribution and clearance (CL) are consistent with target-mediated drug disposition (TMDD) [11]. On average, Cmax of tocilizumab decreased approximately 55% in the first 96 h. Subsequently, a slow elimination phase was observed between 96 and 336 h, followed by a relatively fast elimination between 336 and 672 h (Figure 2). In this study, QX003S at a dose of 8 mg/kg [mean weight of the subjects: 67.45 kg, dosage: 539.6 mg (4 × 67.45)] showed a lower clearance and displayed a longer t1/2 (160.8155 vs 39.9 h) than tocilizumab 162 mg (Roche Products Limited, Welwyn Garden City, UK), more exposure (AUC ratio of QX003S vs tocilizumab 162 mg equal to 6.39) than dose ratio (539.6:162 = 3.33), similar Tmax and dose ratio of Cmax with tocilizumab 162 mg, which have been evaluated in other phase-I studies in healthy subjects (Supplement Table 1) [12].
Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies [9,13]. Similarly, ADA had no effect on drug concentration or bioequivalence results in this study (Figure 2, Table 2). In population PK analysis, body weight was identified as a significant covariate impacting the pharmacokinetics of tocilizumab. When administered intravenously on mg/kg basis, individuals with body weight ≥100 kg are predicted to have higher exposures than individuals with body weight <100 kg. Therefore, weight stratification was adopted in this study to reduce variation of parameters, although the weight of subjects in this study was <100 kg. The inter-CV of tocilizumab was small (less than 18.7867%); therefore, the sample size in future studies can be reduced to 52 subjects (26 subjects per arm) [14].
Notably, the incidence of adverse reactions in the QX003S group was similar to that in the Actemra@ group (100% vs 97.6%); most of these were resolved at the final visit in this study. The most common adverse reactions (incidence of at least 5%) are reported in the label, including upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT level, and injection site reactions [9]. In healthy subjects who were administered ACTEMRA in doses of 2–28 mg/kg intravenously and 81–162 mg subcutaneously, the absolute neutrophil counts decreased to the nadir 3 to 5 days following administration. Thereafter, the neutrophil counts recovered towards baseline in a dose-dependent manner over a period of 9–17 days [12]. Patients with rheumatoid arthritis and GCA exhibited a similar pattern of absolute neutrophil counts following the administration of ACTEMRA [9,15]. Similar to previous reports, the incidence of decreased neutrophil counts and decreased white blood cell counts was indeed very high. Neutrophil counts decreased on day 2 to 5; the mean neutrophil count reached nadir on day 2 in both groups. The mean values returned to baseline by day 57 without any treatment (Figure 3). As described by Nishimoto et al. [16], when tocilizumab concentration is maintained above 1 µg/mL, SIL-6R is saturated by tocilizumab leading to complete inhibition of the IL-6 signal; this may affect the distribution of blood cells such as neutrophils and leukocytes. However, these cell counts quickly return to baseline with the drop in the drug concentration.
Figure 3. Absolute values of neutrophil, leukocyte counts, and fibrinogen level over time. Data presented as mean ± standard error of the mean.
In clinical studies, RA patients were treated with 4–8 mg/kg intravenous doses or the 162 mg weekly and every other weekly subcutaneous doses of ACTEMRA; the levels of CRP decreased to within the normal range along with changes in the pharmacodynamic parameters (i.e. decrease in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen; and increase in haemoglobin) [9]. In the present study, fibrinogen level decreased in 82.9–90.5% subjects and the mean fibrinogen level reached the nadir on day 15 to 29 in the QX003S and Actemra® groups; these changes are similar to the above changes in pharmacodynamic indices.
No acute or delayed anaphylactic reactions developed in subjects who were ADA positive, indicating that there was no product-specific immunogenicity. We observed no impact of the immunogenic responses of tocilizumab to drug safety and PK in this study similar to previous reports; however, it may still be necessary to closely monitor the immunogenicity of QX003S and Actemra and its impact on their efficacy in further related Phase-III studies with larger population, multiple doses, as well as longer time frame [17–19]. Overall, this study demonstrated the safety and tolerability of QX003S and reference Actemra@.
Conclusions
This study showed similar PK profile of tocilizumab biosimilar (QX003S) and Actemra@. The tocilizumab biosimilar showed a nearly similar ADA profile and a comparable safety profile versus the reference drug. The inter-CV of tocilizumab was low among Chinese subjects. These data support the clinical development of QX003S as a tocilizumab biosimilar.
Supplementary Material
Supplemental Material
Click here for additional data file.
Acknowledgements
The authors thank the staff of the Phase I Clinical Research Centre, The First Hospital of Jilin University, Jilin, China for data collection in the study.
Disclosure statement
All data related to this study were interpreted by the trial staff with complete independence from the sponsor. Min Fang is employee of the sponsor team. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Data availability statement
The data that support the findings of this study are available on request from the corresponding author, YHD. The data are not publicly available due to their containing information that could compromise the privacy of research participants. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33629921 | 19,002,940 | 2021-12 |
What was the outcome of reaction 'Alanine aminotransferase increased'? | A randomized phase-I pharmacokinetic trial comparing the potential biosimilar tocilizumab (QX003S) with the reference product (Actemra®) in Chinese healthy subjects.
QX003S is a biosimilar candidate for the reference tocilizumab, Actemra®. We investigated the tolerance, variability, and pharmacokinetics (PK) of QX003S biosimilar in healthy Chinese male subjects.
A randomised, double-blind, two-arm, parallel study was performed to examine the bioequivalence of QX003S (8 mg/kg) with that of Actemra® as a reference drug.
QX003S (N = 40) and Actemra® (N = 40) groups exhibited similar PK properties. The inter-subject variability ranged from 14.95% to 18.78%. The 90% confidence intervals of the ratios for Cmax, AUC0-t andAUC0-∞ in both groups were within the range of 80-125%. After administration, the number of subjects who tested positive for anti-drug antibodies (ADA) in the QX003S group and Actemra® groups was 6 (14.3%) and 14 (34.1%), respectively. Adverse reactions occurred in 100% and 97.6% subjects in the QX003S and Actemra® groups, respectively. The most common adverse reactions were decrease in fibrinogen level and neutrophil and leukocyte counts.
The PK characteristics and immunogenicity exhibited by QX003S were similar to that of the reference product, Actemra®. The safety profile was similar in the two treatment groups with mild-moderate adverse effects.Trial RegistrationThe trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html#CTR20190002)Key pointsThis was the first clinical report of a new proposed tocilizumab biosimilar, QX003S.This phase-I randomized, controlled study compared pharmacokinetics, variability,immunogenicity, and safety of QX003S vs. the approved tocilizumab product (Actemra@).The results demonstrate bioequivalence between BAT1806 and the reference products (Actemra@), as well as comparable immunogenicity, safety and tolerability profiles.
1. Introduction
Biological products are large and complex molecules, usually derived from living cells. Due to the molecular complexity and multifaceted production process, the characteristics of biosimilars differ from those of the traditional small-molecule drugs [1–3]. Despite significant therapeutic advances, biologic therapies, such as monoclonal antibodies, are expensive with limited global access [4].
The US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Medical Products Administration (NMPA) have emphasized a step-by-step approach for the development of biosimilars [1]. Biological functional similarity is assessed in the first step, followed by the assessment of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics; finally, the clinical similarity (efficacy, safety, and immunogenicity) is assessed using the same approved dose and pathway as the reference product [1–3].
Tocilizumab binds to soluble and membrane-bound interleukin (IL)-6 receptors and through these receptors inhibits IL-6-mediated signal transduction. IL-6 is a multipotent pro-inflammatory cytokine produced by a variety of cell types, including T and B cells, lymphocytes, monocytes, and fibroblasts. Synovial cells and endothelial cells also produce IL-6, which induces the inflammatory process in the joints (e.g. rheumatoid arthritis) [5–6]. Tocilizumab is effective against rheumatoid arthritis, giant cell arteritis, and multi-joint juvenile idiopathic arthritis. In a previous study, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or deathin hospitalised patients with Covid-19 pneumonia; however, it did not improve survival of these patients. Tocilizumab is currently under investigation as a potential treatment for COVID-19, with initial contradictory evidence [7].
Consequently, tocilizumab biosimilars have been actively developed around the world, including in China. Tocilizumab biosimilars (QX003S) have the same primary structure, post-translational modification, biochemical characteristics, and biological functions as the reference product, and in addition, these similarities have been tested in mice and monkeys (data not published). All in vivo studies justify the clinical development of QX003S.
PK studies in humans are essential to demonstrate the bioequivalence of biological analogues and reference products [8]. Herein, we conducted a single-dose PK study in healthy Chinese male subjects to evaluate the bioequivalence between QX003S and Actemra@ as the reference product. Use of healthy subjects helps avoid the potential confounding influence of factors such as comorbid diseases and concomitant therapies. The therapeutic dose of the reference drug used in previous studies is 4–8 mg/kg [9–10]. In this study, a dose of 8 mg/kg was used, based on earlier clinical trial plans of the sponsor.
In this study, the PK profiles of the QX003S with Actemra@ were analysed and compared. In addition, the tolerability, safety, and immunogenicity of QX003S were assessed.
2. Methods
2.1. Study design and subjects
This phase-I study was conducted at the Clinical Research Centre of the First Hospital of Jilin University between 14 March 2019 and 18 September 2019 (Chinese Clinical Trial Registry, Registration No. CTR20190002). The study protocol was approved by the ethics committee of the hospital. The study complied with the guidelines of the Declaration of Helsinki and the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP). Written Informed consent was obtained from all subjects prior to their enrolment.
This was a randomized, double-blind, single-dose, two-arm, parallel comparison study to evaluate the PK, safety, and immunogenicity of QX003S and Actemra@ in healthy Chinese male subjects. Overall, 86 eligible subjects were randomly allocated in a 1:1 ratio to receive a single intravenous drip of 8 mg/kg QX003S or Actemra@. Subjects were stratified into two groups based on body weight (50 to < 67.5 kg and ≥ 67.5 to ≤ 85 kg). Individuals in each of the pre-specified groups were equally assigned to the two treatment groups through randomization (Figure 1).
Figure 1. Flow chart of the study.
Sentinel staggered administration was used in this study. Subjects were administered the investigational product (IP) in a staggered cohort: the first and second cohort consisted of two subjects and four subjects, respectively. For safety evaluation, each subject was required to stay at the study centre for at least 96 h after the administration. Based on sentinel safety results, the principal investigator determined whether the subsequent subjects would be monitored in sentinel mode or in routine follow-up mode. All subjects were followed up for 57 days.
The main inclusion criteria were as follows: (1) healthy men in the age group of 18–50 years; (2) body mass index: 18.0–28.0 kg/m2; (3) body weight: 55–85 kg; and (4) normal test outcomes or clinically unremarkable results of routine blood and urine routine investigations including hepatic and renal function tests during enrolment.
The exclusion criteria were as follows: (1) history of clinically significant diseases; (2) C-reactive protein (CRP) levels 1.5 times higher than the upper limit of the normal range; and (3) positive results of T-SPOT® assay or TB interferon-γ-release assay.
All subjects received a single intravenous infusion of the IP (8 mg/kg) administered over a period of 60 min (±6 min). All subjects were randomly allocated to one of the following two groups in a 1:1 ratio in each of the pre-specified weight intervals: QX003S (Jiangsu Quanxin Biomedicine Co. Ltd; Batch number: F20180801); Actemra@ (Chugai Pharmaceutical Company [Japan]; Batch number: B2063B15).
Screening was performed 14 to 2 days prior to the date of administration. All qualified subjects entered the clinical research unit a day prior to the administration of biosimilars. Subjects were required to fast for at least 8 h before administration and were randomly assigned to either the test drug (QX003S) or reference drug group.
2.2. PK evaluations
Blood samples were collected for PK analysis at different time-points: 1 h before administration (before administration) to 1344 h after the initial infusion (day 57). Serum tocilizumab levels were determined by enzyme-linked immunosorbent assay (ELISA) at the Junke Zhengyuan (Beijing) Pharmaceutical Research Co. Ltd. (Supplement material). PK parameters were determined by non-compartmental analysis model. The concentration–time data included the maximum observable serum concentration (Cmax), clearance (CL), half-life (t1/2), the volume of distribution (Vz), and area under the curve (AUC) from zero to the final quantifiable concentration (AUC0–t) and to infinity (AUC0–∞). The actual sampling times were used for PK analyses. An internally validated software system, Phoenix WinNonLin® v8.0 (Pharsight Corporation, Certara, L.P., Princeton, New Jersey, USA), was used to determine PK parameters.
2.3. Immunogenicity evaluations
Blood samples collected at 1 h before and on 15, 29, 43, and 57 days after drug administration were analysed for the presence of anti-drug antibodies (ADAs) using electrochemiluminescence immunoassay (ECLIA). Subjects who test ADA-positive, those who develop antibody-related adverse reactions, or those with significantly abnormal PK value are required to be further examined for the presence of neutralising antibodies (NAbs). NAb test was not performed in this study because the above conditions were not met.
2.4. Safety evaluation
Physical examination, assessment of vital signs, electrocardiogram, and routine laboratory investigations were performed to monitor adverse events (AEs) according to the National Cancer Institute Common Terminology for Adverse Events (CTCAE;V.4.03). Subjects who showed AEs were monitored until they reached normal or acceptable stability (as assessed by the principal investigator and sponsor) or were lost to follow up.
2.5. Estimation of the sample size
According to the recent FDA guidelines, the geometric mean ratio (GMR) was set at 95% to achieve 90% power (1 − β) at a significant level (two-sided α = 5%). Inter-subject variability (inter-CV) is expressed by the coefficient of variation (CV). NQuery 8.3.0.0 (Boston, USA) software was used to determine the sample size (initial: 68; inter-CV for tocilizumab: 24%) [9]. The final sample size was 86, allowing for a 20% drop-out rate.
2.6. Statistical analysis
After logarithmic transformation of PK parameters Cmax, AUC0–t, and AUC0–∞, the least square method was used for analysis of variance. Bioequivalence inferences were drawn if the 90% confidence intervals (CIs) were found to be within the range of 80–125%. PK analysis was performed using the PK analysis set. The safety analysis set included subjects who were administered the study drug. Descriptive statistical estimates of PK parameters and demographic data were calculated. Between-group differences were assessed using the Chi-squared test for categorical variables, t-test for normally distributed continuous variables, and Wilcoxon rank test for non-normally distributed variables. All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
3. Results
3.1. Subjects
The assigned drugs were administered to 83 of the 86 enrolled subjects and included in the safety analysis (Figure 1). One additional subject was included in the QX003S group, whereas one subject was removed from the Actemra® group due to weight stratification. Therefore, the QX003S group comprised of 44 subjects.
Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, had hypertension and fast pulse rate or polycardia; these subjects were excluded from the study. Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, were ADA positive;these were excluded from the study. The final per-protocol analysis population included in the safety, PK, BE, and immunogenicity (ADA) analysis set comprised of 83, 80, 80, and 83 subjects, respectively (Figure 1). The demographic and baseline characteristics of the per-protocol population and the two treatment groups were comparable (p > .05, Table 1).
Table 1. Demographic and baseline characteristics.
QX003S group Actemra® group Total
(n = 44) (n = 42) (n = 86) p Values
Age (year), mean (SD) 35.5 (8.88) 36.1 (8.51) 35.8 (8.66) .75
Ethnicity (Han, n [%]) 41 (93.2) 40 (95.2) 81 (94.2) .68
Weight (kg), mean (SD) 67.45 (9.423) 66.21 (7.621) 66.84 (8.563) .5
BMI (kg/m2), mean (SD) 23.306 (2.5834) 23.234 (2.5210) 23.271 (2.5383) .89
BMI; body mass index; SD: standard deviation.
3.2. PK evaluation
The mean serum concentration–time curve of tocilizumab and its biosimilar decreased with multiphase mode. A rapid decline immediately after the infusion was followed by a slow elimination phase, and, subsequently, by a slightly faster elimination phase at low concentrations (Figure 2). The non-compartmental analysis model showed slow clearance, longer t1/2, and small Vz of tocilizumab and its biosimilar. The median Tmax values were equivalent between the two groups and these were achieved 1.8 h after the intravenous infusion.
Figure 2. Serum drug concentration–time profile of tocilizumab. Mean values (A); log10 mean values (B); log10 mean values within 0–48 h (C); ADA-positive individuals in the QX003S (D) and Actemra@ (E) groups.
The mean value of t1/2 between the test drug and the reference drug was between 160.8155 and 159.9160 h, indicating comparability. The total clearance rate (CL) and Vz values were also similar in the two groups. The differences between the mean concentration–time curve, mean Cmax, AUC0-t, AUC0-∞ estimation, and inter-CVs were similar (p > .05); the coefficient of variation ranged from 14.95% to 18.78% (Table 2, Figure 2).
Table 2. Pharmacokinetic parameters of tocilizumab in each group (Mean ± SD [CV%] or median [min, max]).
QX003S group (n = 40) Actemra® group (n = 40) p Values GMR (90% CI) GMR (90% CI)a Re-estimated size
Tmax*(h) 1.8 (1-4) 1.8 (1-4) >.05
Cmax (μg/mL) 178.8 ± 28.90 (16.16) 178.2 ± 27.43 (15.39) .92 1 (0.95, 1.06) 1.02 (0.95-1.09) 40
AUC0-t (h•μg/mL) 27116.0941 ± 4466.9216 (16.47) 27446.4185 ± 4103.9469 (14.95) .73 0.9859 (0.9311,1.0439) 0.9827 (0.9197-1.0500) 40
AUC0-∞ (h•μg/mL) 28806.7645 ± 5411.8467 (18.78) 29039.7894 ± 4641.0883 (15.98) .83 0.9878 (0.9272, 1.0524) 0.9787 (0.9098-1.0529) 52
t1/2 (h) 160.8155 ± 35.2772 (21.93) 159.9160 ± 29.0054 (18.13) .90
CL (L/h) 0.0192 ± 0.0031 (16.06) 0.0185 ± 0.0025 (13.68) .26
Vd (L) 4.3578 ± 0.7660 (17.57) 4.2322 ± 0.7760 (18.33) .46
*Median [min, max]; aQX003S/ Actemra® after excluding subject with ADA positive after dosing.
The PK parameters were comparable in the QX003S and Actemra@ groups. The ratio of geometric least-squares means for the QX003S versus Actemra@ were 1, 0.9859, and 0.9878 for Cmax, AUC0-t, and AUC0-∞;the 90% CI was 0.9272–1.06. The 90% CIs of the Cmax, AUC0–t, and AUC0–∞ were within the predefined bioequivalence limit, ranging from 80.00% to 125.00%. A larger inter-CV indicated a broader 90% CI. The sample size was re-estimated on the basis of the results of bioequivalence analysis (GMR and inter-CV), which decreased to a number less than the enrolment size (Table 2).
3.3. Immunogenicity evaluation
Before dosing, two and one subjects in the QX003S and Actemra® group respectively, were ADA positive. After dosing, 6 (14.3%) subjects in the QX003S group and 14 (34.1%) subjects in the Actemra® group tested positive for ADA. The ADA-positive rates were found to increase over a period of time, especially by days 43 (1008 h) and 57 (1344 h). Nevertheless, the drug concentration was less than the lower limit of quantitation (LLOQ) during that period. ADA-positivity rates were similar in the two groups at 15 to 29 days after drug administration (6.7–7.1%). However, at 43 and 57 days after drug administration, the positivity rates in the QX003S group were relatively lower than those in the Actemra@ group; however, the between-group differences in this respect were not statistically significant at any of the time-points (p > .05, Table 3).
Table 3. Summary of immunogenicity (anti-drug antibody) assessment (number [%] of subjects with positive antibodies).
Time (day) QX003S group (n = 42) Actemra® group (n = 41) p Values
Pre-dose 2 (4.88) 1 (2.44) .57
15 0 (0) 0 (0) NA
29 0 (0) 1 (2.44) .30
43 3 (7.32) 5 (12.2) .43
57 8 (19.51) 13 (31.71) .18
NA: Not applicable.
Table 4. Adverse reactions (number of reactions, the number [%] of subjects, more than 4%).
QX003S group (n = 42) Actemra® group (n = 41)
n (%) [number of reactions] n (%) [number of reaction] p Values
Total 42 (100) 134 40 (97.6) 148 0.30
Fibrinogen decreased 38 (90.5) 40 34 (82.9) 34 0.31
Reduced neutrophil counts 30 (71.4) 39 24 (58.5) 32 0.21
Reduced leukocyte count 24 (57.1) 28 19 (46.3) 26 0.32
Elevated serum bilirubin 6 (14.3) 6 3 (7.3) 5 0.30
Elevated alanine aminotransferase 0 (0) 0 5 (12.2) 6 0.01
Elevated aspartate aminotransferase 0 (0) 0 4 (9.8) 6 0.03
Reduced lymphocyte count 1 (2.4) 2 2 (4.9) 2 0.54
Urine leucocyte positive 0 (0) 0 2 (4.9) 2 0.14
Oropharyngeal pain 2 (4.8) 2 3 (7.3) 3 0.62
Cough 2 (4.8) 2 2 (4.9) 2 0.98
Cough with expectoration 1 (2.4) 1 2 (4.9) 2 0.54
Runny nose 0 (0) 0 3 (7.3) 3 0.07
Stuffy nose 0 (0) 0 2 (4.9) 2 0.14
Hypertriglyceridaemia 5 (11.9) 5 7 (17.1) 7 0.50
Hyperuricemia 1 (2.4) 1 2 (4.9) 3 0.54
Diarrhea 2 (4.8) 2 1 (2.4) 1 0.57
Oral mucositis 0 (0) 0 2 (4.9) 2 0.14
The serum concentration-time curves of QX003S and Actemra@ for ADA-positive and ADA-negative subjects were found to be similar (Figure 2). Sensitivity analysis of bioequivalence was performed after exclusion of 20 subjects who tested positive for ADA. The 90% CIs for the comparisons of Cmax and AUC were within the predefined range of bioequivalence limits of 80.00%–125.00% (Table 2). Therefore, overall, ADA-positivity rates were similar in the two groups.
3.4. Safety evaluation
No serious AEs (SAEs), deaths, or discontinuations due to AEs were observed. In this study, 282 adverse reactions occurred in 82 (98.8%) subjects. A total of 134 adverse reactions in 42 (100%) subjects were recorded in the QX003S group, while148 adverse reactions in 40 (97.6%) subjects were recorded in the Actemra® group. The incidence of adverse reactions was comparable in the two groups (Table 4). The adverse reactions with an incidence greater than 5% in the QX003S and Actemra® groups, respectively, were as follows: decreased fibrinogen level (90.5% vs 82.9%), decreased neutrophil count (71.4% vs 58.5%), decreased white blood cell (WBC) count (57.1% vs 46.3%), increased bilirubin (14.3% vs 7.3%), and hypertriglyceridaemia (11.9% vs 17.1%). The severity of most adverse reactions was between grade I and II. The incidence rates of elevated alanine aminotransferase and elevated aspartate aminotransferase level in the QX003S group were lower than those in the Actemra® group (0% vs. 12.2%, p = 0.01; 0% vs. 9.8%, p = 0.03); this indicated a lesser effect of QX003S on liver enzyme levels than the reference product. The incidence of other adverse reactions was comparable in the two groups (p > 0.05).
A total of 20 (24.1%) subjects in the two groups experienced 26 grade III–IV adverse reactions. Thirteen (31.0%) subjects in the QX003S group developed 16 adverse reactions, and seven (17.1%) subjects in the Actemra® group developed 10 adverse reactions. The incidence in the QX003S vs Actemra® groups was comparable: decreased neutrophil count (28.6% vs 12.2%), decreased WBC count (7.1% vs 7.3%), decreased fibrinogen (2.4% vs 2.4%), and increased alanine aminotransferase (0 vs 2.4%). All grade III–IV adverse reactions recovered spontaneously without treatment. Very few Grade I-II adverse reactions required drug therapy, such as cefuroxime axetil, levofloxacin, and glycyrrhizin.
There was no association between ADA development and adverse reactions in this study. None of the subjects developed clinically significant or serious hypersensitivity, anaphylaxis, or injection-site reaction after IP administration, except Subject no.105 of the QX003S group who developed ecchymia and mild tenderness at the injection site 48 h after administration; this subject showed spontaneous recovery on day 8 without any treatment. Subject no.001 of the Actemra® group showed bruising at the injection site at 12 h after administration without any tenderness; this subject also showed spontaneous recovery on day 22 without any treatment. All adverse reactions were reported to the Institutional Review Board of The First Hospital of Jilin University.
4. Discussion
This single-dose, phase-I study demonstrated the bioequivalence of QX003S and Actemra@ when administered as intravenous infusion at a dose of 8 mg/kg. The results of ANOVA showed that the 90% CIs of the geometric mean ratios of Cmax and AUC in the two treatment groups ranged from 92.72%–106%, which was within the predefined bioequivalence intervals of 80% to 125%. Other PK parameters of Tmax and t½ were also similar between the two treatment groups. QX003S and Actemra@ showed a similar safety and immunogenicity profile. No serious AEs were reported; all adverse reactions were mild or moderate in severity, and no local reactions were reported except in two subjects. This indicated that the two products were well tolerated in this population of healthy subjects. The above results justify the use of the biosimilars in the next phase clinical studies [1–3].
The pharmacokinetic behaviour of tocilizumab is different from the small-molecule pharmacokinetic behaviour in that it has limited vascular permeability, neonatal Fc receptor circulation, and more frequent receptor-mediated nonlinearity. Its distribution and clearance (CL) are consistent with target-mediated drug disposition (TMDD) [11]. On average, Cmax of tocilizumab decreased approximately 55% in the first 96 h. Subsequently, a slow elimination phase was observed between 96 and 336 h, followed by a relatively fast elimination between 336 and 672 h (Figure 2). In this study, QX003S at a dose of 8 mg/kg [mean weight of the subjects: 67.45 kg, dosage: 539.6 mg (4 × 67.45)] showed a lower clearance and displayed a longer t1/2 (160.8155 vs 39.9 h) than tocilizumab 162 mg (Roche Products Limited, Welwyn Garden City, UK), more exposure (AUC ratio of QX003S vs tocilizumab 162 mg equal to 6.39) than dose ratio (539.6:162 = 3.33), similar Tmax and dose ratio of Cmax with tocilizumab 162 mg, which have been evaluated in other phase-I studies in healthy subjects (Supplement Table 1) [12].
Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies [9,13]. Similarly, ADA had no effect on drug concentration or bioequivalence results in this study (Figure 2, Table 2). In population PK analysis, body weight was identified as a significant covariate impacting the pharmacokinetics of tocilizumab. When administered intravenously on mg/kg basis, individuals with body weight ≥100 kg are predicted to have higher exposures than individuals with body weight <100 kg. Therefore, weight stratification was adopted in this study to reduce variation of parameters, although the weight of subjects in this study was <100 kg. The inter-CV of tocilizumab was small (less than 18.7867%); therefore, the sample size in future studies can be reduced to 52 subjects (26 subjects per arm) [14].
Notably, the incidence of adverse reactions in the QX003S group was similar to that in the Actemra@ group (100% vs 97.6%); most of these were resolved at the final visit in this study. The most common adverse reactions (incidence of at least 5%) are reported in the label, including upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT level, and injection site reactions [9]. In healthy subjects who were administered ACTEMRA in doses of 2–28 mg/kg intravenously and 81–162 mg subcutaneously, the absolute neutrophil counts decreased to the nadir 3 to 5 days following administration. Thereafter, the neutrophil counts recovered towards baseline in a dose-dependent manner over a period of 9–17 days [12]. Patients with rheumatoid arthritis and GCA exhibited a similar pattern of absolute neutrophil counts following the administration of ACTEMRA [9,15]. Similar to previous reports, the incidence of decreased neutrophil counts and decreased white blood cell counts was indeed very high. Neutrophil counts decreased on day 2 to 5; the mean neutrophil count reached nadir on day 2 in both groups. The mean values returned to baseline by day 57 without any treatment (Figure 3). As described by Nishimoto et al. [16], when tocilizumab concentration is maintained above 1 µg/mL, SIL-6R is saturated by tocilizumab leading to complete inhibition of the IL-6 signal; this may affect the distribution of blood cells such as neutrophils and leukocytes. However, these cell counts quickly return to baseline with the drop in the drug concentration.
Figure 3. Absolute values of neutrophil, leukocyte counts, and fibrinogen level over time. Data presented as mean ± standard error of the mean.
In clinical studies, RA patients were treated with 4–8 mg/kg intravenous doses or the 162 mg weekly and every other weekly subcutaneous doses of ACTEMRA; the levels of CRP decreased to within the normal range along with changes in the pharmacodynamic parameters (i.e. decrease in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen; and increase in haemoglobin) [9]. In the present study, fibrinogen level decreased in 82.9–90.5% subjects and the mean fibrinogen level reached the nadir on day 15 to 29 in the QX003S and Actemra® groups; these changes are similar to the above changes in pharmacodynamic indices.
No acute or delayed anaphylactic reactions developed in subjects who were ADA positive, indicating that there was no product-specific immunogenicity. We observed no impact of the immunogenic responses of tocilizumab to drug safety and PK in this study similar to previous reports; however, it may still be necessary to closely monitor the immunogenicity of QX003S and Actemra and its impact on their efficacy in further related Phase-III studies with larger population, multiple doses, as well as longer time frame [17–19]. Overall, this study demonstrated the safety and tolerability of QX003S and reference Actemra@.
Conclusions
This study showed similar PK profile of tocilizumab biosimilar (QX003S) and Actemra@. The tocilizumab biosimilar showed a nearly similar ADA profile and a comparable safety profile versus the reference drug. The inter-CV of tocilizumab was low among Chinese subjects. These data support the clinical development of QX003S as a tocilizumab biosimilar.
Supplementary Material
Supplemental Material
Click here for additional data file.
Acknowledgements
The authors thank the staff of the Phase I Clinical Research Centre, The First Hospital of Jilin University, Jilin, China for data collection in the study.
Disclosure statement
All data related to this study were interpreted by the trial staff with complete independence from the sponsor. Min Fang is employee of the sponsor team. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Data availability statement
The data that support the findings of this study are available on request from the corresponding author, YHD. The data are not publicly available due to their containing information that could compromise the privacy of research participants. | Recovered | ReactionOutcome | CC BY | 33629921 | 19,002,940 | 2021-12 |
What was the outcome of reaction 'Blood fibrinogen decreased'? | A randomized phase-I pharmacokinetic trial comparing the potential biosimilar tocilizumab (QX003S) with the reference product (Actemra®) in Chinese healthy subjects.
QX003S is a biosimilar candidate for the reference tocilizumab, Actemra®. We investigated the tolerance, variability, and pharmacokinetics (PK) of QX003S biosimilar in healthy Chinese male subjects.
A randomised, double-blind, two-arm, parallel study was performed to examine the bioequivalence of QX003S (8 mg/kg) with that of Actemra® as a reference drug.
QX003S (N = 40) and Actemra® (N = 40) groups exhibited similar PK properties. The inter-subject variability ranged from 14.95% to 18.78%. The 90% confidence intervals of the ratios for Cmax, AUC0-t andAUC0-∞ in both groups were within the range of 80-125%. After administration, the number of subjects who tested positive for anti-drug antibodies (ADA) in the QX003S group and Actemra® groups was 6 (14.3%) and 14 (34.1%), respectively. Adverse reactions occurred in 100% and 97.6% subjects in the QX003S and Actemra® groups, respectively. The most common adverse reactions were decrease in fibrinogen level and neutrophil and leukocyte counts.
The PK characteristics and immunogenicity exhibited by QX003S were similar to that of the reference product, Actemra®. The safety profile was similar in the two treatment groups with mild-moderate adverse effects.Trial RegistrationThe trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html#CTR20190002)Key pointsThis was the first clinical report of a new proposed tocilizumab biosimilar, QX003S.This phase-I randomized, controlled study compared pharmacokinetics, variability,immunogenicity, and safety of QX003S vs. the approved tocilizumab product (Actemra@).The results demonstrate bioequivalence between BAT1806 and the reference products (Actemra@), as well as comparable immunogenicity, safety and tolerability profiles.
1. Introduction
Biological products are large and complex molecules, usually derived from living cells. Due to the molecular complexity and multifaceted production process, the characteristics of biosimilars differ from those of the traditional small-molecule drugs [1–3]. Despite significant therapeutic advances, biologic therapies, such as monoclonal antibodies, are expensive with limited global access [4].
The US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Medical Products Administration (NMPA) have emphasized a step-by-step approach for the development of biosimilars [1]. Biological functional similarity is assessed in the first step, followed by the assessment of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics; finally, the clinical similarity (efficacy, safety, and immunogenicity) is assessed using the same approved dose and pathway as the reference product [1–3].
Tocilizumab binds to soluble and membrane-bound interleukin (IL)-6 receptors and through these receptors inhibits IL-6-mediated signal transduction. IL-6 is a multipotent pro-inflammatory cytokine produced by a variety of cell types, including T and B cells, lymphocytes, monocytes, and fibroblasts. Synovial cells and endothelial cells also produce IL-6, which induces the inflammatory process in the joints (e.g. rheumatoid arthritis) [5–6]. Tocilizumab is effective against rheumatoid arthritis, giant cell arteritis, and multi-joint juvenile idiopathic arthritis. In a previous study, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or deathin hospitalised patients with Covid-19 pneumonia; however, it did not improve survival of these patients. Tocilizumab is currently under investigation as a potential treatment for COVID-19, with initial contradictory evidence [7].
Consequently, tocilizumab biosimilars have been actively developed around the world, including in China. Tocilizumab biosimilars (QX003S) have the same primary structure, post-translational modification, biochemical characteristics, and biological functions as the reference product, and in addition, these similarities have been tested in mice and monkeys (data not published). All in vivo studies justify the clinical development of QX003S.
PK studies in humans are essential to demonstrate the bioequivalence of biological analogues and reference products [8]. Herein, we conducted a single-dose PK study in healthy Chinese male subjects to evaluate the bioequivalence between QX003S and Actemra@ as the reference product. Use of healthy subjects helps avoid the potential confounding influence of factors such as comorbid diseases and concomitant therapies. The therapeutic dose of the reference drug used in previous studies is 4–8 mg/kg [9–10]. In this study, a dose of 8 mg/kg was used, based on earlier clinical trial plans of the sponsor.
In this study, the PK profiles of the QX003S with Actemra@ were analysed and compared. In addition, the tolerability, safety, and immunogenicity of QX003S were assessed.
2. Methods
2.1. Study design and subjects
This phase-I study was conducted at the Clinical Research Centre of the First Hospital of Jilin University between 14 March 2019 and 18 September 2019 (Chinese Clinical Trial Registry, Registration No. CTR20190002). The study protocol was approved by the ethics committee of the hospital. The study complied with the guidelines of the Declaration of Helsinki and the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP). Written Informed consent was obtained from all subjects prior to their enrolment.
This was a randomized, double-blind, single-dose, two-arm, parallel comparison study to evaluate the PK, safety, and immunogenicity of QX003S and Actemra@ in healthy Chinese male subjects. Overall, 86 eligible subjects were randomly allocated in a 1:1 ratio to receive a single intravenous drip of 8 mg/kg QX003S or Actemra@. Subjects were stratified into two groups based on body weight (50 to < 67.5 kg and ≥ 67.5 to ≤ 85 kg). Individuals in each of the pre-specified groups were equally assigned to the two treatment groups through randomization (Figure 1).
Figure 1. Flow chart of the study.
Sentinel staggered administration was used in this study. Subjects were administered the investigational product (IP) in a staggered cohort: the first and second cohort consisted of two subjects and four subjects, respectively. For safety evaluation, each subject was required to stay at the study centre for at least 96 h after the administration. Based on sentinel safety results, the principal investigator determined whether the subsequent subjects would be monitored in sentinel mode or in routine follow-up mode. All subjects were followed up for 57 days.
The main inclusion criteria were as follows: (1) healthy men in the age group of 18–50 years; (2) body mass index: 18.0–28.0 kg/m2; (3) body weight: 55–85 kg; and (4) normal test outcomes or clinically unremarkable results of routine blood and urine routine investigations including hepatic and renal function tests during enrolment.
The exclusion criteria were as follows: (1) history of clinically significant diseases; (2) C-reactive protein (CRP) levels 1.5 times higher than the upper limit of the normal range; and (3) positive results of T-SPOT® assay or TB interferon-γ-release assay.
All subjects received a single intravenous infusion of the IP (8 mg/kg) administered over a period of 60 min (±6 min). All subjects were randomly allocated to one of the following two groups in a 1:1 ratio in each of the pre-specified weight intervals: QX003S (Jiangsu Quanxin Biomedicine Co. Ltd; Batch number: F20180801); Actemra@ (Chugai Pharmaceutical Company [Japan]; Batch number: B2063B15).
Screening was performed 14 to 2 days prior to the date of administration. All qualified subjects entered the clinical research unit a day prior to the administration of biosimilars. Subjects were required to fast for at least 8 h before administration and were randomly assigned to either the test drug (QX003S) or reference drug group.
2.2. PK evaluations
Blood samples were collected for PK analysis at different time-points: 1 h before administration (before administration) to 1344 h after the initial infusion (day 57). Serum tocilizumab levels were determined by enzyme-linked immunosorbent assay (ELISA) at the Junke Zhengyuan (Beijing) Pharmaceutical Research Co. Ltd. (Supplement material). PK parameters were determined by non-compartmental analysis model. The concentration–time data included the maximum observable serum concentration (Cmax), clearance (CL), half-life (t1/2), the volume of distribution (Vz), and area under the curve (AUC) from zero to the final quantifiable concentration (AUC0–t) and to infinity (AUC0–∞). The actual sampling times were used for PK analyses. An internally validated software system, Phoenix WinNonLin® v8.0 (Pharsight Corporation, Certara, L.P., Princeton, New Jersey, USA), was used to determine PK parameters.
2.3. Immunogenicity evaluations
Blood samples collected at 1 h before and on 15, 29, 43, and 57 days after drug administration were analysed for the presence of anti-drug antibodies (ADAs) using electrochemiluminescence immunoassay (ECLIA). Subjects who test ADA-positive, those who develop antibody-related adverse reactions, or those with significantly abnormal PK value are required to be further examined for the presence of neutralising antibodies (NAbs). NAb test was not performed in this study because the above conditions were not met.
2.4. Safety evaluation
Physical examination, assessment of vital signs, electrocardiogram, and routine laboratory investigations were performed to monitor adverse events (AEs) according to the National Cancer Institute Common Terminology for Adverse Events (CTCAE;V.4.03). Subjects who showed AEs were monitored until they reached normal or acceptable stability (as assessed by the principal investigator and sponsor) or were lost to follow up.
2.5. Estimation of the sample size
According to the recent FDA guidelines, the geometric mean ratio (GMR) was set at 95% to achieve 90% power (1 − β) at a significant level (two-sided α = 5%). Inter-subject variability (inter-CV) is expressed by the coefficient of variation (CV). NQuery 8.3.0.0 (Boston, USA) software was used to determine the sample size (initial: 68; inter-CV for tocilizumab: 24%) [9]. The final sample size was 86, allowing for a 20% drop-out rate.
2.6. Statistical analysis
After logarithmic transformation of PK parameters Cmax, AUC0–t, and AUC0–∞, the least square method was used for analysis of variance. Bioequivalence inferences were drawn if the 90% confidence intervals (CIs) were found to be within the range of 80–125%. PK analysis was performed using the PK analysis set. The safety analysis set included subjects who were administered the study drug. Descriptive statistical estimates of PK parameters and demographic data were calculated. Between-group differences were assessed using the Chi-squared test for categorical variables, t-test for normally distributed continuous variables, and Wilcoxon rank test for non-normally distributed variables. All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
3. Results
3.1. Subjects
The assigned drugs were administered to 83 of the 86 enrolled subjects and included in the safety analysis (Figure 1). One additional subject was included in the QX003S group, whereas one subject was removed from the Actemra® group due to weight stratification. Therefore, the QX003S group comprised of 44 subjects.
Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, had hypertension and fast pulse rate or polycardia; these subjects were excluded from the study. Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, were ADA positive;these were excluded from the study. The final per-protocol analysis population included in the safety, PK, BE, and immunogenicity (ADA) analysis set comprised of 83, 80, 80, and 83 subjects, respectively (Figure 1). The demographic and baseline characteristics of the per-protocol population and the two treatment groups were comparable (p > .05, Table 1).
Table 1. Demographic and baseline characteristics.
QX003S group Actemra® group Total
(n = 44) (n = 42) (n = 86) p Values
Age (year), mean (SD) 35.5 (8.88) 36.1 (8.51) 35.8 (8.66) .75
Ethnicity (Han, n [%]) 41 (93.2) 40 (95.2) 81 (94.2) .68
Weight (kg), mean (SD) 67.45 (9.423) 66.21 (7.621) 66.84 (8.563) .5
BMI (kg/m2), mean (SD) 23.306 (2.5834) 23.234 (2.5210) 23.271 (2.5383) .89
BMI; body mass index; SD: standard deviation.
3.2. PK evaluation
The mean serum concentration–time curve of tocilizumab and its biosimilar decreased with multiphase mode. A rapid decline immediately after the infusion was followed by a slow elimination phase, and, subsequently, by a slightly faster elimination phase at low concentrations (Figure 2). The non-compartmental analysis model showed slow clearance, longer t1/2, and small Vz of tocilizumab and its biosimilar. The median Tmax values were equivalent between the two groups and these were achieved 1.8 h after the intravenous infusion.
Figure 2. Serum drug concentration–time profile of tocilizumab. Mean values (A); log10 mean values (B); log10 mean values within 0–48 h (C); ADA-positive individuals in the QX003S (D) and Actemra@ (E) groups.
The mean value of t1/2 between the test drug and the reference drug was between 160.8155 and 159.9160 h, indicating comparability. The total clearance rate (CL) and Vz values were also similar in the two groups. The differences between the mean concentration–time curve, mean Cmax, AUC0-t, AUC0-∞ estimation, and inter-CVs were similar (p > .05); the coefficient of variation ranged from 14.95% to 18.78% (Table 2, Figure 2).
Table 2. Pharmacokinetic parameters of tocilizumab in each group (Mean ± SD [CV%] or median [min, max]).
QX003S group (n = 40) Actemra® group (n = 40) p Values GMR (90% CI) GMR (90% CI)a Re-estimated size
Tmax*(h) 1.8 (1-4) 1.8 (1-4) >.05
Cmax (μg/mL) 178.8 ± 28.90 (16.16) 178.2 ± 27.43 (15.39) .92 1 (0.95, 1.06) 1.02 (0.95-1.09) 40
AUC0-t (h•μg/mL) 27116.0941 ± 4466.9216 (16.47) 27446.4185 ± 4103.9469 (14.95) .73 0.9859 (0.9311,1.0439) 0.9827 (0.9197-1.0500) 40
AUC0-∞ (h•μg/mL) 28806.7645 ± 5411.8467 (18.78) 29039.7894 ± 4641.0883 (15.98) .83 0.9878 (0.9272, 1.0524) 0.9787 (0.9098-1.0529) 52
t1/2 (h) 160.8155 ± 35.2772 (21.93) 159.9160 ± 29.0054 (18.13) .90
CL (L/h) 0.0192 ± 0.0031 (16.06) 0.0185 ± 0.0025 (13.68) .26
Vd (L) 4.3578 ± 0.7660 (17.57) 4.2322 ± 0.7760 (18.33) .46
*Median [min, max]; aQX003S/ Actemra® after excluding subject with ADA positive after dosing.
The PK parameters were comparable in the QX003S and Actemra@ groups. The ratio of geometric least-squares means for the QX003S versus Actemra@ were 1, 0.9859, and 0.9878 for Cmax, AUC0-t, and AUC0-∞;the 90% CI was 0.9272–1.06. The 90% CIs of the Cmax, AUC0–t, and AUC0–∞ were within the predefined bioequivalence limit, ranging from 80.00% to 125.00%. A larger inter-CV indicated a broader 90% CI. The sample size was re-estimated on the basis of the results of bioequivalence analysis (GMR and inter-CV), which decreased to a number less than the enrolment size (Table 2).
3.3. Immunogenicity evaluation
Before dosing, two and one subjects in the QX003S and Actemra® group respectively, were ADA positive. After dosing, 6 (14.3%) subjects in the QX003S group and 14 (34.1%) subjects in the Actemra® group tested positive for ADA. The ADA-positive rates were found to increase over a period of time, especially by days 43 (1008 h) and 57 (1344 h). Nevertheless, the drug concentration was less than the lower limit of quantitation (LLOQ) during that period. ADA-positivity rates were similar in the two groups at 15 to 29 days after drug administration (6.7–7.1%). However, at 43 and 57 days after drug administration, the positivity rates in the QX003S group were relatively lower than those in the Actemra@ group; however, the between-group differences in this respect were not statistically significant at any of the time-points (p > .05, Table 3).
Table 3. Summary of immunogenicity (anti-drug antibody) assessment (number [%] of subjects with positive antibodies).
Time (day) QX003S group (n = 42) Actemra® group (n = 41) p Values
Pre-dose 2 (4.88) 1 (2.44) .57
15 0 (0) 0 (0) NA
29 0 (0) 1 (2.44) .30
43 3 (7.32) 5 (12.2) .43
57 8 (19.51) 13 (31.71) .18
NA: Not applicable.
Table 4. Adverse reactions (number of reactions, the number [%] of subjects, more than 4%).
QX003S group (n = 42) Actemra® group (n = 41)
n (%) [number of reactions] n (%) [number of reaction] p Values
Total 42 (100) 134 40 (97.6) 148 0.30
Fibrinogen decreased 38 (90.5) 40 34 (82.9) 34 0.31
Reduced neutrophil counts 30 (71.4) 39 24 (58.5) 32 0.21
Reduced leukocyte count 24 (57.1) 28 19 (46.3) 26 0.32
Elevated serum bilirubin 6 (14.3) 6 3 (7.3) 5 0.30
Elevated alanine aminotransferase 0 (0) 0 5 (12.2) 6 0.01
Elevated aspartate aminotransferase 0 (0) 0 4 (9.8) 6 0.03
Reduced lymphocyte count 1 (2.4) 2 2 (4.9) 2 0.54
Urine leucocyte positive 0 (0) 0 2 (4.9) 2 0.14
Oropharyngeal pain 2 (4.8) 2 3 (7.3) 3 0.62
Cough 2 (4.8) 2 2 (4.9) 2 0.98
Cough with expectoration 1 (2.4) 1 2 (4.9) 2 0.54
Runny nose 0 (0) 0 3 (7.3) 3 0.07
Stuffy nose 0 (0) 0 2 (4.9) 2 0.14
Hypertriglyceridaemia 5 (11.9) 5 7 (17.1) 7 0.50
Hyperuricemia 1 (2.4) 1 2 (4.9) 3 0.54
Diarrhea 2 (4.8) 2 1 (2.4) 1 0.57
Oral mucositis 0 (0) 0 2 (4.9) 2 0.14
The serum concentration-time curves of QX003S and Actemra@ for ADA-positive and ADA-negative subjects were found to be similar (Figure 2). Sensitivity analysis of bioequivalence was performed after exclusion of 20 subjects who tested positive for ADA. The 90% CIs for the comparisons of Cmax and AUC were within the predefined range of bioequivalence limits of 80.00%–125.00% (Table 2). Therefore, overall, ADA-positivity rates were similar in the two groups.
3.4. Safety evaluation
No serious AEs (SAEs), deaths, or discontinuations due to AEs were observed. In this study, 282 adverse reactions occurred in 82 (98.8%) subjects. A total of 134 adverse reactions in 42 (100%) subjects were recorded in the QX003S group, while148 adverse reactions in 40 (97.6%) subjects were recorded in the Actemra® group. The incidence of adverse reactions was comparable in the two groups (Table 4). The adverse reactions with an incidence greater than 5% in the QX003S and Actemra® groups, respectively, were as follows: decreased fibrinogen level (90.5% vs 82.9%), decreased neutrophil count (71.4% vs 58.5%), decreased white blood cell (WBC) count (57.1% vs 46.3%), increased bilirubin (14.3% vs 7.3%), and hypertriglyceridaemia (11.9% vs 17.1%). The severity of most adverse reactions was between grade I and II. The incidence rates of elevated alanine aminotransferase and elevated aspartate aminotransferase level in the QX003S group were lower than those in the Actemra® group (0% vs. 12.2%, p = 0.01; 0% vs. 9.8%, p = 0.03); this indicated a lesser effect of QX003S on liver enzyme levels than the reference product. The incidence of other adverse reactions was comparable in the two groups (p > 0.05).
A total of 20 (24.1%) subjects in the two groups experienced 26 grade III–IV adverse reactions. Thirteen (31.0%) subjects in the QX003S group developed 16 adverse reactions, and seven (17.1%) subjects in the Actemra® group developed 10 adverse reactions. The incidence in the QX003S vs Actemra® groups was comparable: decreased neutrophil count (28.6% vs 12.2%), decreased WBC count (7.1% vs 7.3%), decreased fibrinogen (2.4% vs 2.4%), and increased alanine aminotransferase (0 vs 2.4%). All grade III–IV adverse reactions recovered spontaneously without treatment. Very few Grade I-II adverse reactions required drug therapy, such as cefuroxime axetil, levofloxacin, and glycyrrhizin.
There was no association between ADA development and adverse reactions in this study. None of the subjects developed clinically significant or serious hypersensitivity, anaphylaxis, or injection-site reaction after IP administration, except Subject no.105 of the QX003S group who developed ecchymia and mild tenderness at the injection site 48 h after administration; this subject showed spontaneous recovery on day 8 without any treatment. Subject no.001 of the Actemra® group showed bruising at the injection site at 12 h after administration without any tenderness; this subject also showed spontaneous recovery on day 22 without any treatment. All adverse reactions were reported to the Institutional Review Board of The First Hospital of Jilin University.
4. Discussion
This single-dose, phase-I study demonstrated the bioequivalence of QX003S and Actemra@ when administered as intravenous infusion at a dose of 8 mg/kg. The results of ANOVA showed that the 90% CIs of the geometric mean ratios of Cmax and AUC in the two treatment groups ranged from 92.72%–106%, which was within the predefined bioequivalence intervals of 80% to 125%. Other PK parameters of Tmax and t½ were also similar between the two treatment groups. QX003S and Actemra@ showed a similar safety and immunogenicity profile. No serious AEs were reported; all adverse reactions were mild or moderate in severity, and no local reactions were reported except in two subjects. This indicated that the two products were well tolerated in this population of healthy subjects. The above results justify the use of the biosimilars in the next phase clinical studies [1–3].
The pharmacokinetic behaviour of tocilizumab is different from the small-molecule pharmacokinetic behaviour in that it has limited vascular permeability, neonatal Fc receptor circulation, and more frequent receptor-mediated nonlinearity. Its distribution and clearance (CL) are consistent with target-mediated drug disposition (TMDD) [11]. On average, Cmax of tocilizumab decreased approximately 55% in the first 96 h. Subsequently, a slow elimination phase was observed between 96 and 336 h, followed by a relatively fast elimination between 336 and 672 h (Figure 2). In this study, QX003S at a dose of 8 mg/kg [mean weight of the subjects: 67.45 kg, dosage: 539.6 mg (4 × 67.45)] showed a lower clearance and displayed a longer t1/2 (160.8155 vs 39.9 h) than tocilizumab 162 mg (Roche Products Limited, Welwyn Garden City, UK), more exposure (AUC ratio of QX003S vs tocilizumab 162 mg equal to 6.39) than dose ratio (539.6:162 = 3.33), similar Tmax and dose ratio of Cmax with tocilizumab 162 mg, which have been evaluated in other phase-I studies in healthy subjects (Supplement Table 1) [12].
Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies [9,13]. Similarly, ADA had no effect on drug concentration or bioequivalence results in this study (Figure 2, Table 2). In population PK analysis, body weight was identified as a significant covariate impacting the pharmacokinetics of tocilizumab. When administered intravenously on mg/kg basis, individuals with body weight ≥100 kg are predicted to have higher exposures than individuals with body weight <100 kg. Therefore, weight stratification was adopted in this study to reduce variation of parameters, although the weight of subjects in this study was <100 kg. The inter-CV of tocilizumab was small (less than 18.7867%); therefore, the sample size in future studies can be reduced to 52 subjects (26 subjects per arm) [14].
Notably, the incidence of adverse reactions in the QX003S group was similar to that in the Actemra@ group (100% vs 97.6%); most of these were resolved at the final visit in this study. The most common adverse reactions (incidence of at least 5%) are reported in the label, including upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT level, and injection site reactions [9]. In healthy subjects who were administered ACTEMRA in doses of 2–28 mg/kg intravenously and 81–162 mg subcutaneously, the absolute neutrophil counts decreased to the nadir 3 to 5 days following administration. Thereafter, the neutrophil counts recovered towards baseline in a dose-dependent manner over a period of 9–17 days [12]. Patients with rheumatoid arthritis and GCA exhibited a similar pattern of absolute neutrophil counts following the administration of ACTEMRA [9,15]. Similar to previous reports, the incidence of decreased neutrophil counts and decreased white blood cell counts was indeed very high. Neutrophil counts decreased on day 2 to 5; the mean neutrophil count reached nadir on day 2 in both groups. The mean values returned to baseline by day 57 without any treatment (Figure 3). As described by Nishimoto et al. [16], when tocilizumab concentration is maintained above 1 µg/mL, SIL-6R is saturated by tocilizumab leading to complete inhibition of the IL-6 signal; this may affect the distribution of blood cells such as neutrophils and leukocytes. However, these cell counts quickly return to baseline with the drop in the drug concentration.
Figure 3. Absolute values of neutrophil, leukocyte counts, and fibrinogen level over time. Data presented as mean ± standard error of the mean.
In clinical studies, RA patients were treated with 4–8 mg/kg intravenous doses or the 162 mg weekly and every other weekly subcutaneous doses of ACTEMRA; the levels of CRP decreased to within the normal range along with changes in the pharmacodynamic parameters (i.e. decrease in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen; and increase in haemoglobin) [9]. In the present study, fibrinogen level decreased in 82.9–90.5% subjects and the mean fibrinogen level reached the nadir on day 15 to 29 in the QX003S and Actemra® groups; these changes are similar to the above changes in pharmacodynamic indices.
No acute or delayed anaphylactic reactions developed in subjects who were ADA positive, indicating that there was no product-specific immunogenicity. We observed no impact of the immunogenic responses of tocilizumab to drug safety and PK in this study similar to previous reports; however, it may still be necessary to closely monitor the immunogenicity of QX003S and Actemra and its impact on their efficacy in further related Phase-III studies with larger population, multiple doses, as well as longer time frame [17–19]. Overall, this study demonstrated the safety and tolerability of QX003S and reference Actemra@.
Conclusions
This study showed similar PK profile of tocilizumab biosimilar (QX003S) and Actemra@. The tocilizumab biosimilar showed a nearly similar ADA profile and a comparable safety profile versus the reference drug. The inter-CV of tocilizumab was low among Chinese subjects. These data support the clinical development of QX003S as a tocilizumab biosimilar.
Supplementary Material
Supplemental Material
Click here for additional data file.
Acknowledgements
The authors thank the staff of the Phase I Clinical Research Centre, The First Hospital of Jilin University, Jilin, China for data collection in the study.
Disclosure statement
All data related to this study were interpreted by the trial staff with complete independence from the sponsor. Min Fang is employee of the sponsor team. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Data availability statement
The data that support the findings of this study are available on request from the corresponding author, YHD. The data are not publicly available due to their containing information that could compromise the privacy of research participants. | Recovered | ReactionOutcome | CC BY | 33629921 | 19,002,940 | 2021-12 |
What was the outcome of reaction 'Neutrophil count decreased'? | A randomized phase-I pharmacokinetic trial comparing the potential biosimilar tocilizumab (QX003S) with the reference product (Actemra®) in Chinese healthy subjects.
QX003S is a biosimilar candidate for the reference tocilizumab, Actemra®. We investigated the tolerance, variability, and pharmacokinetics (PK) of QX003S biosimilar in healthy Chinese male subjects.
A randomised, double-blind, two-arm, parallel study was performed to examine the bioequivalence of QX003S (8 mg/kg) with that of Actemra® as a reference drug.
QX003S (N = 40) and Actemra® (N = 40) groups exhibited similar PK properties. The inter-subject variability ranged from 14.95% to 18.78%. The 90% confidence intervals of the ratios for Cmax, AUC0-t andAUC0-∞ in both groups were within the range of 80-125%. After administration, the number of subjects who tested positive for anti-drug antibodies (ADA) in the QX003S group and Actemra® groups was 6 (14.3%) and 14 (34.1%), respectively. Adverse reactions occurred in 100% and 97.6% subjects in the QX003S and Actemra® groups, respectively. The most common adverse reactions were decrease in fibrinogen level and neutrophil and leukocyte counts.
The PK characteristics and immunogenicity exhibited by QX003S were similar to that of the reference product, Actemra®. The safety profile was similar in the two treatment groups with mild-moderate adverse effects.Trial RegistrationThe trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html#CTR20190002)Key pointsThis was the first clinical report of a new proposed tocilizumab biosimilar, QX003S.This phase-I randomized, controlled study compared pharmacokinetics, variability,immunogenicity, and safety of QX003S vs. the approved tocilizumab product (Actemra@).The results demonstrate bioequivalence between BAT1806 and the reference products (Actemra@), as well as comparable immunogenicity, safety and tolerability profiles.
1. Introduction
Biological products are large and complex molecules, usually derived from living cells. Due to the molecular complexity and multifaceted production process, the characteristics of biosimilars differ from those of the traditional small-molecule drugs [1–3]. Despite significant therapeutic advances, biologic therapies, such as monoclonal antibodies, are expensive with limited global access [4].
The US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Medical Products Administration (NMPA) have emphasized a step-by-step approach for the development of biosimilars [1]. Biological functional similarity is assessed in the first step, followed by the assessment of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics; finally, the clinical similarity (efficacy, safety, and immunogenicity) is assessed using the same approved dose and pathway as the reference product [1–3].
Tocilizumab binds to soluble and membrane-bound interleukin (IL)-6 receptors and through these receptors inhibits IL-6-mediated signal transduction. IL-6 is a multipotent pro-inflammatory cytokine produced by a variety of cell types, including T and B cells, lymphocytes, monocytes, and fibroblasts. Synovial cells and endothelial cells also produce IL-6, which induces the inflammatory process in the joints (e.g. rheumatoid arthritis) [5–6]. Tocilizumab is effective against rheumatoid arthritis, giant cell arteritis, and multi-joint juvenile idiopathic arthritis. In a previous study, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or deathin hospitalised patients with Covid-19 pneumonia; however, it did not improve survival of these patients. Tocilizumab is currently under investigation as a potential treatment for COVID-19, with initial contradictory evidence [7].
Consequently, tocilizumab biosimilars have been actively developed around the world, including in China. Tocilizumab biosimilars (QX003S) have the same primary structure, post-translational modification, biochemical characteristics, and biological functions as the reference product, and in addition, these similarities have been tested in mice and monkeys (data not published). All in vivo studies justify the clinical development of QX003S.
PK studies in humans are essential to demonstrate the bioequivalence of biological analogues and reference products [8]. Herein, we conducted a single-dose PK study in healthy Chinese male subjects to evaluate the bioequivalence between QX003S and Actemra@ as the reference product. Use of healthy subjects helps avoid the potential confounding influence of factors such as comorbid diseases and concomitant therapies. The therapeutic dose of the reference drug used in previous studies is 4–8 mg/kg [9–10]. In this study, a dose of 8 mg/kg was used, based on earlier clinical trial plans of the sponsor.
In this study, the PK profiles of the QX003S with Actemra@ were analysed and compared. In addition, the tolerability, safety, and immunogenicity of QX003S were assessed.
2. Methods
2.1. Study design and subjects
This phase-I study was conducted at the Clinical Research Centre of the First Hospital of Jilin University between 14 March 2019 and 18 September 2019 (Chinese Clinical Trial Registry, Registration No. CTR20190002). The study protocol was approved by the ethics committee of the hospital. The study complied with the guidelines of the Declaration of Helsinki and the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP). Written Informed consent was obtained from all subjects prior to their enrolment.
This was a randomized, double-blind, single-dose, two-arm, parallel comparison study to evaluate the PK, safety, and immunogenicity of QX003S and Actemra@ in healthy Chinese male subjects. Overall, 86 eligible subjects were randomly allocated in a 1:1 ratio to receive a single intravenous drip of 8 mg/kg QX003S or Actemra@. Subjects were stratified into two groups based on body weight (50 to < 67.5 kg and ≥ 67.5 to ≤ 85 kg). Individuals in each of the pre-specified groups were equally assigned to the two treatment groups through randomization (Figure 1).
Figure 1. Flow chart of the study.
Sentinel staggered administration was used in this study. Subjects were administered the investigational product (IP) in a staggered cohort: the first and second cohort consisted of two subjects and four subjects, respectively. For safety evaluation, each subject was required to stay at the study centre for at least 96 h after the administration. Based on sentinel safety results, the principal investigator determined whether the subsequent subjects would be monitored in sentinel mode or in routine follow-up mode. All subjects were followed up for 57 days.
The main inclusion criteria were as follows: (1) healthy men in the age group of 18–50 years; (2) body mass index: 18.0–28.0 kg/m2; (3) body weight: 55–85 kg; and (4) normal test outcomes or clinically unremarkable results of routine blood and urine routine investigations including hepatic and renal function tests during enrolment.
The exclusion criteria were as follows: (1) history of clinically significant diseases; (2) C-reactive protein (CRP) levels 1.5 times higher than the upper limit of the normal range; and (3) positive results of T-SPOT® assay or TB interferon-γ-release assay.
All subjects received a single intravenous infusion of the IP (8 mg/kg) administered over a period of 60 min (±6 min). All subjects were randomly allocated to one of the following two groups in a 1:1 ratio in each of the pre-specified weight intervals: QX003S (Jiangsu Quanxin Biomedicine Co. Ltd; Batch number: F20180801); Actemra@ (Chugai Pharmaceutical Company [Japan]; Batch number: B2063B15).
Screening was performed 14 to 2 days prior to the date of administration. All qualified subjects entered the clinical research unit a day prior to the administration of biosimilars. Subjects were required to fast for at least 8 h before administration and were randomly assigned to either the test drug (QX003S) or reference drug group.
2.2. PK evaluations
Blood samples were collected for PK analysis at different time-points: 1 h before administration (before administration) to 1344 h after the initial infusion (day 57). Serum tocilizumab levels were determined by enzyme-linked immunosorbent assay (ELISA) at the Junke Zhengyuan (Beijing) Pharmaceutical Research Co. Ltd. (Supplement material). PK parameters were determined by non-compartmental analysis model. The concentration–time data included the maximum observable serum concentration (Cmax), clearance (CL), half-life (t1/2), the volume of distribution (Vz), and area under the curve (AUC) from zero to the final quantifiable concentration (AUC0–t) and to infinity (AUC0–∞). The actual sampling times were used for PK analyses. An internally validated software system, Phoenix WinNonLin® v8.0 (Pharsight Corporation, Certara, L.P., Princeton, New Jersey, USA), was used to determine PK parameters.
2.3. Immunogenicity evaluations
Blood samples collected at 1 h before and on 15, 29, 43, and 57 days after drug administration were analysed for the presence of anti-drug antibodies (ADAs) using electrochemiluminescence immunoassay (ECLIA). Subjects who test ADA-positive, those who develop antibody-related adverse reactions, or those with significantly abnormal PK value are required to be further examined for the presence of neutralising antibodies (NAbs). NAb test was not performed in this study because the above conditions were not met.
2.4. Safety evaluation
Physical examination, assessment of vital signs, electrocardiogram, and routine laboratory investigations were performed to monitor adverse events (AEs) according to the National Cancer Institute Common Terminology for Adverse Events (CTCAE;V.4.03). Subjects who showed AEs were monitored until they reached normal or acceptable stability (as assessed by the principal investigator and sponsor) or were lost to follow up.
2.5. Estimation of the sample size
According to the recent FDA guidelines, the geometric mean ratio (GMR) was set at 95% to achieve 90% power (1 − β) at a significant level (two-sided α = 5%). Inter-subject variability (inter-CV) is expressed by the coefficient of variation (CV). NQuery 8.3.0.0 (Boston, USA) software was used to determine the sample size (initial: 68; inter-CV for tocilizumab: 24%) [9]. The final sample size was 86, allowing for a 20% drop-out rate.
2.6. Statistical analysis
After logarithmic transformation of PK parameters Cmax, AUC0–t, and AUC0–∞, the least square method was used for analysis of variance. Bioequivalence inferences were drawn if the 90% confidence intervals (CIs) were found to be within the range of 80–125%. PK analysis was performed using the PK analysis set. The safety analysis set included subjects who were administered the study drug. Descriptive statistical estimates of PK parameters and demographic data were calculated. Between-group differences were assessed using the Chi-squared test for categorical variables, t-test for normally distributed continuous variables, and Wilcoxon rank test for non-normally distributed variables. All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
3. Results
3.1. Subjects
The assigned drugs were administered to 83 of the 86 enrolled subjects and included in the safety analysis (Figure 1). One additional subject was included in the QX003S group, whereas one subject was removed from the Actemra® group due to weight stratification. Therefore, the QX003S group comprised of 44 subjects.
Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, had hypertension and fast pulse rate or polycardia; these subjects were excluded from the study. Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, were ADA positive;these were excluded from the study. The final per-protocol analysis population included in the safety, PK, BE, and immunogenicity (ADA) analysis set comprised of 83, 80, 80, and 83 subjects, respectively (Figure 1). The demographic and baseline characteristics of the per-protocol population and the two treatment groups were comparable (p > .05, Table 1).
Table 1. Demographic and baseline characteristics.
QX003S group Actemra® group Total
(n = 44) (n = 42) (n = 86) p Values
Age (year), mean (SD) 35.5 (8.88) 36.1 (8.51) 35.8 (8.66) .75
Ethnicity (Han, n [%]) 41 (93.2) 40 (95.2) 81 (94.2) .68
Weight (kg), mean (SD) 67.45 (9.423) 66.21 (7.621) 66.84 (8.563) .5
BMI (kg/m2), mean (SD) 23.306 (2.5834) 23.234 (2.5210) 23.271 (2.5383) .89
BMI; body mass index; SD: standard deviation.
3.2. PK evaluation
The mean serum concentration–time curve of tocilizumab and its biosimilar decreased with multiphase mode. A rapid decline immediately after the infusion was followed by a slow elimination phase, and, subsequently, by a slightly faster elimination phase at low concentrations (Figure 2). The non-compartmental analysis model showed slow clearance, longer t1/2, and small Vz of tocilizumab and its biosimilar. The median Tmax values were equivalent between the two groups and these were achieved 1.8 h after the intravenous infusion.
Figure 2. Serum drug concentration–time profile of tocilizumab. Mean values (A); log10 mean values (B); log10 mean values within 0–48 h (C); ADA-positive individuals in the QX003S (D) and Actemra@ (E) groups.
The mean value of t1/2 between the test drug and the reference drug was between 160.8155 and 159.9160 h, indicating comparability. The total clearance rate (CL) and Vz values were also similar in the two groups. The differences between the mean concentration–time curve, mean Cmax, AUC0-t, AUC0-∞ estimation, and inter-CVs were similar (p > .05); the coefficient of variation ranged from 14.95% to 18.78% (Table 2, Figure 2).
Table 2. Pharmacokinetic parameters of tocilizumab in each group (Mean ± SD [CV%] or median [min, max]).
QX003S group (n = 40) Actemra® group (n = 40) p Values GMR (90% CI) GMR (90% CI)a Re-estimated size
Tmax*(h) 1.8 (1-4) 1.8 (1-4) >.05
Cmax (μg/mL) 178.8 ± 28.90 (16.16) 178.2 ± 27.43 (15.39) .92 1 (0.95, 1.06) 1.02 (0.95-1.09) 40
AUC0-t (h•μg/mL) 27116.0941 ± 4466.9216 (16.47) 27446.4185 ± 4103.9469 (14.95) .73 0.9859 (0.9311,1.0439) 0.9827 (0.9197-1.0500) 40
AUC0-∞ (h•μg/mL) 28806.7645 ± 5411.8467 (18.78) 29039.7894 ± 4641.0883 (15.98) .83 0.9878 (0.9272, 1.0524) 0.9787 (0.9098-1.0529) 52
t1/2 (h) 160.8155 ± 35.2772 (21.93) 159.9160 ± 29.0054 (18.13) .90
CL (L/h) 0.0192 ± 0.0031 (16.06) 0.0185 ± 0.0025 (13.68) .26
Vd (L) 4.3578 ± 0.7660 (17.57) 4.2322 ± 0.7760 (18.33) .46
*Median [min, max]; aQX003S/ Actemra® after excluding subject with ADA positive after dosing.
The PK parameters were comparable in the QX003S and Actemra@ groups. The ratio of geometric least-squares means for the QX003S versus Actemra@ were 1, 0.9859, and 0.9878 for Cmax, AUC0-t, and AUC0-∞;the 90% CI was 0.9272–1.06. The 90% CIs of the Cmax, AUC0–t, and AUC0–∞ were within the predefined bioequivalence limit, ranging from 80.00% to 125.00%. A larger inter-CV indicated a broader 90% CI. The sample size was re-estimated on the basis of the results of bioequivalence analysis (GMR and inter-CV), which decreased to a number less than the enrolment size (Table 2).
3.3. Immunogenicity evaluation
Before dosing, two and one subjects in the QX003S and Actemra® group respectively, were ADA positive. After dosing, 6 (14.3%) subjects in the QX003S group and 14 (34.1%) subjects in the Actemra® group tested positive for ADA. The ADA-positive rates were found to increase over a period of time, especially by days 43 (1008 h) and 57 (1344 h). Nevertheless, the drug concentration was less than the lower limit of quantitation (LLOQ) during that period. ADA-positivity rates were similar in the two groups at 15 to 29 days after drug administration (6.7–7.1%). However, at 43 and 57 days after drug administration, the positivity rates in the QX003S group were relatively lower than those in the Actemra@ group; however, the between-group differences in this respect were not statistically significant at any of the time-points (p > .05, Table 3).
Table 3. Summary of immunogenicity (anti-drug antibody) assessment (number [%] of subjects with positive antibodies).
Time (day) QX003S group (n = 42) Actemra® group (n = 41) p Values
Pre-dose 2 (4.88) 1 (2.44) .57
15 0 (0) 0 (0) NA
29 0 (0) 1 (2.44) .30
43 3 (7.32) 5 (12.2) .43
57 8 (19.51) 13 (31.71) .18
NA: Not applicable.
Table 4. Adverse reactions (number of reactions, the number [%] of subjects, more than 4%).
QX003S group (n = 42) Actemra® group (n = 41)
n (%) [number of reactions] n (%) [number of reaction] p Values
Total 42 (100) 134 40 (97.6) 148 0.30
Fibrinogen decreased 38 (90.5) 40 34 (82.9) 34 0.31
Reduced neutrophil counts 30 (71.4) 39 24 (58.5) 32 0.21
Reduced leukocyte count 24 (57.1) 28 19 (46.3) 26 0.32
Elevated serum bilirubin 6 (14.3) 6 3 (7.3) 5 0.30
Elevated alanine aminotransferase 0 (0) 0 5 (12.2) 6 0.01
Elevated aspartate aminotransferase 0 (0) 0 4 (9.8) 6 0.03
Reduced lymphocyte count 1 (2.4) 2 2 (4.9) 2 0.54
Urine leucocyte positive 0 (0) 0 2 (4.9) 2 0.14
Oropharyngeal pain 2 (4.8) 2 3 (7.3) 3 0.62
Cough 2 (4.8) 2 2 (4.9) 2 0.98
Cough with expectoration 1 (2.4) 1 2 (4.9) 2 0.54
Runny nose 0 (0) 0 3 (7.3) 3 0.07
Stuffy nose 0 (0) 0 2 (4.9) 2 0.14
Hypertriglyceridaemia 5 (11.9) 5 7 (17.1) 7 0.50
Hyperuricemia 1 (2.4) 1 2 (4.9) 3 0.54
Diarrhea 2 (4.8) 2 1 (2.4) 1 0.57
Oral mucositis 0 (0) 0 2 (4.9) 2 0.14
The serum concentration-time curves of QX003S and Actemra@ for ADA-positive and ADA-negative subjects were found to be similar (Figure 2). Sensitivity analysis of bioequivalence was performed after exclusion of 20 subjects who tested positive for ADA. The 90% CIs for the comparisons of Cmax and AUC were within the predefined range of bioequivalence limits of 80.00%–125.00% (Table 2). Therefore, overall, ADA-positivity rates were similar in the two groups.
3.4. Safety evaluation
No serious AEs (SAEs), deaths, or discontinuations due to AEs were observed. In this study, 282 adverse reactions occurred in 82 (98.8%) subjects. A total of 134 adverse reactions in 42 (100%) subjects were recorded in the QX003S group, while148 adverse reactions in 40 (97.6%) subjects were recorded in the Actemra® group. The incidence of adverse reactions was comparable in the two groups (Table 4). The adverse reactions with an incidence greater than 5% in the QX003S and Actemra® groups, respectively, were as follows: decreased fibrinogen level (90.5% vs 82.9%), decreased neutrophil count (71.4% vs 58.5%), decreased white blood cell (WBC) count (57.1% vs 46.3%), increased bilirubin (14.3% vs 7.3%), and hypertriglyceridaemia (11.9% vs 17.1%). The severity of most adverse reactions was between grade I and II. The incidence rates of elevated alanine aminotransferase and elevated aspartate aminotransferase level in the QX003S group were lower than those in the Actemra® group (0% vs. 12.2%, p = 0.01; 0% vs. 9.8%, p = 0.03); this indicated a lesser effect of QX003S on liver enzyme levels than the reference product. The incidence of other adverse reactions was comparable in the two groups (p > 0.05).
A total of 20 (24.1%) subjects in the two groups experienced 26 grade III–IV adverse reactions. Thirteen (31.0%) subjects in the QX003S group developed 16 adverse reactions, and seven (17.1%) subjects in the Actemra® group developed 10 adverse reactions. The incidence in the QX003S vs Actemra® groups was comparable: decreased neutrophil count (28.6% vs 12.2%), decreased WBC count (7.1% vs 7.3%), decreased fibrinogen (2.4% vs 2.4%), and increased alanine aminotransferase (0 vs 2.4%). All grade III–IV adverse reactions recovered spontaneously without treatment. Very few Grade I-II adverse reactions required drug therapy, such as cefuroxime axetil, levofloxacin, and glycyrrhizin.
There was no association between ADA development and adverse reactions in this study. None of the subjects developed clinically significant or serious hypersensitivity, anaphylaxis, or injection-site reaction after IP administration, except Subject no.105 of the QX003S group who developed ecchymia and mild tenderness at the injection site 48 h after administration; this subject showed spontaneous recovery on day 8 without any treatment. Subject no.001 of the Actemra® group showed bruising at the injection site at 12 h after administration without any tenderness; this subject also showed spontaneous recovery on day 22 without any treatment. All adverse reactions were reported to the Institutional Review Board of The First Hospital of Jilin University.
4. Discussion
This single-dose, phase-I study demonstrated the bioequivalence of QX003S and Actemra@ when administered as intravenous infusion at a dose of 8 mg/kg. The results of ANOVA showed that the 90% CIs of the geometric mean ratios of Cmax and AUC in the two treatment groups ranged from 92.72%–106%, which was within the predefined bioequivalence intervals of 80% to 125%. Other PK parameters of Tmax and t½ were also similar between the two treatment groups. QX003S and Actemra@ showed a similar safety and immunogenicity profile. No serious AEs were reported; all adverse reactions were mild or moderate in severity, and no local reactions were reported except in two subjects. This indicated that the two products were well tolerated in this population of healthy subjects. The above results justify the use of the biosimilars in the next phase clinical studies [1–3].
The pharmacokinetic behaviour of tocilizumab is different from the small-molecule pharmacokinetic behaviour in that it has limited vascular permeability, neonatal Fc receptor circulation, and more frequent receptor-mediated nonlinearity. Its distribution and clearance (CL) are consistent with target-mediated drug disposition (TMDD) [11]. On average, Cmax of tocilizumab decreased approximately 55% in the first 96 h. Subsequently, a slow elimination phase was observed between 96 and 336 h, followed by a relatively fast elimination between 336 and 672 h (Figure 2). In this study, QX003S at a dose of 8 mg/kg [mean weight of the subjects: 67.45 kg, dosage: 539.6 mg (4 × 67.45)] showed a lower clearance and displayed a longer t1/2 (160.8155 vs 39.9 h) than tocilizumab 162 mg (Roche Products Limited, Welwyn Garden City, UK), more exposure (AUC ratio of QX003S vs tocilizumab 162 mg equal to 6.39) than dose ratio (539.6:162 = 3.33), similar Tmax and dose ratio of Cmax with tocilizumab 162 mg, which have been evaluated in other phase-I studies in healthy subjects (Supplement Table 1) [12].
Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies [9,13]. Similarly, ADA had no effect on drug concentration or bioequivalence results in this study (Figure 2, Table 2). In population PK analysis, body weight was identified as a significant covariate impacting the pharmacokinetics of tocilizumab. When administered intravenously on mg/kg basis, individuals with body weight ≥100 kg are predicted to have higher exposures than individuals with body weight <100 kg. Therefore, weight stratification was adopted in this study to reduce variation of parameters, although the weight of subjects in this study was <100 kg. The inter-CV of tocilizumab was small (less than 18.7867%); therefore, the sample size in future studies can be reduced to 52 subjects (26 subjects per arm) [14].
Notably, the incidence of adverse reactions in the QX003S group was similar to that in the Actemra@ group (100% vs 97.6%); most of these were resolved at the final visit in this study. The most common adverse reactions (incidence of at least 5%) are reported in the label, including upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT level, and injection site reactions [9]. In healthy subjects who were administered ACTEMRA in doses of 2–28 mg/kg intravenously and 81–162 mg subcutaneously, the absolute neutrophil counts decreased to the nadir 3 to 5 days following administration. Thereafter, the neutrophil counts recovered towards baseline in a dose-dependent manner over a period of 9–17 days [12]. Patients with rheumatoid arthritis and GCA exhibited a similar pattern of absolute neutrophil counts following the administration of ACTEMRA [9,15]. Similar to previous reports, the incidence of decreased neutrophil counts and decreased white blood cell counts was indeed very high. Neutrophil counts decreased on day 2 to 5; the mean neutrophil count reached nadir on day 2 in both groups. The mean values returned to baseline by day 57 without any treatment (Figure 3). As described by Nishimoto et al. [16], when tocilizumab concentration is maintained above 1 µg/mL, SIL-6R is saturated by tocilizumab leading to complete inhibition of the IL-6 signal; this may affect the distribution of blood cells such as neutrophils and leukocytes. However, these cell counts quickly return to baseline with the drop in the drug concentration.
Figure 3. Absolute values of neutrophil, leukocyte counts, and fibrinogen level over time. Data presented as mean ± standard error of the mean.
In clinical studies, RA patients were treated with 4–8 mg/kg intravenous doses or the 162 mg weekly and every other weekly subcutaneous doses of ACTEMRA; the levels of CRP decreased to within the normal range along with changes in the pharmacodynamic parameters (i.e. decrease in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen; and increase in haemoglobin) [9]. In the present study, fibrinogen level decreased in 82.9–90.5% subjects and the mean fibrinogen level reached the nadir on day 15 to 29 in the QX003S and Actemra® groups; these changes are similar to the above changes in pharmacodynamic indices.
No acute or delayed anaphylactic reactions developed in subjects who were ADA positive, indicating that there was no product-specific immunogenicity. We observed no impact of the immunogenic responses of tocilizumab to drug safety and PK in this study similar to previous reports; however, it may still be necessary to closely monitor the immunogenicity of QX003S and Actemra and its impact on their efficacy in further related Phase-III studies with larger population, multiple doses, as well as longer time frame [17–19]. Overall, this study demonstrated the safety and tolerability of QX003S and reference Actemra@.
Conclusions
This study showed similar PK profile of tocilizumab biosimilar (QX003S) and Actemra@. The tocilizumab biosimilar showed a nearly similar ADA profile and a comparable safety profile versus the reference drug. The inter-CV of tocilizumab was low among Chinese subjects. These data support the clinical development of QX003S as a tocilizumab biosimilar.
Supplementary Material
Supplemental Material
Click here for additional data file.
Acknowledgements
The authors thank the staff of the Phase I Clinical Research Centre, The First Hospital of Jilin University, Jilin, China for data collection in the study.
Disclosure statement
All data related to this study were interpreted by the trial staff with complete independence from the sponsor. Min Fang is employee of the sponsor team. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Data availability statement
The data that support the findings of this study are available on request from the corresponding author, YHD. The data are not publicly available due to their containing information that could compromise the privacy of research participants. | Recovered | ReactionOutcome | CC BY | 33629921 | 19,002,940 | 2021-12 |
What was the outcome of reaction 'White blood cell count decreased'? | A randomized phase-I pharmacokinetic trial comparing the potential biosimilar tocilizumab (QX003S) with the reference product (Actemra®) in Chinese healthy subjects.
QX003S is a biosimilar candidate for the reference tocilizumab, Actemra®. We investigated the tolerance, variability, and pharmacokinetics (PK) of QX003S biosimilar in healthy Chinese male subjects.
A randomised, double-blind, two-arm, parallel study was performed to examine the bioequivalence of QX003S (8 mg/kg) with that of Actemra® as a reference drug.
QX003S (N = 40) and Actemra® (N = 40) groups exhibited similar PK properties. The inter-subject variability ranged from 14.95% to 18.78%. The 90% confidence intervals of the ratios for Cmax, AUC0-t andAUC0-∞ in both groups were within the range of 80-125%. After administration, the number of subjects who tested positive for anti-drug antibodies (ADA) in the QX003S group and Actemra® groups was 6 (14.3%) and 14 (34.1%), respectively. Adverse reactions occurred in 100% and 97.6% subjects in the QX003S and Actemra® groups, respectively. The most common adverse reactions were decrease in fibrinogen level and neutrophil and leukocyte counts.
The PK characteristics and immunogenicity exhibited by QX003S were similar to that of the reference product, Actemra®. The safety profile was similar in the two treatment groups with mild-moderate adverse effects.Trial RegistrationThe trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html#CTR20190002)Key pointsThis was the first clinical report of a new proposed tocilizumab biosimilar, QX003S.This phase-I randomized, controlled study compared pharmacokinetics, variability,immunogenicity, and safety of QX003S vs. the approved tocilizumab product (Actemra@).The results demonstrate bioequivalence between BAT1806 and the reference products (Actemra@), as well as comparable immunogenicity, safety and tolerability profiles.
1. Introduction
Biological products are large and complex molecules, usually derived from living cells. Due to the molecular complexity and multifaceted production process, the characteristics of biosimilars differ from those of the traditional small-molecule drugs [1–3]. Despite significant therapeutic advances, biologic therapies, such as monoclonal antibodies, are expensive with limited global access [4].
The US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Medical Products Administration (NMPA) have emphasized a step-by-step approach for the development of biosimilars [1]. Biological functional similarity is assessed in the first step, followed by the assessment of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics; finally, the clinical similarity (efficacy, safety, and immunogenicity) is assessed using the same approved dose and pathway as the reference product [1–3].
Tocilizumab binds to soluble and membrane-bound interleukin (IL)-6 receptors and through these receptors inhibits IL-6-mediated signal transduction. IL-6 is a multipotent pro-inflammatory cytokine produced by a variety of cell types, including T and B cells, lymphocytes, monocytes, and fibroblasts. Synovial cells and endothelial cells also produce IL-6, which induces the inflammatory process in the joints (e.g. rheumatoid arthritis) [5–6]. Tocilizumab is effective against rheumatoid arthritis, giant cell arteritis, and multi-joint juvenile idiopathic arthritis. In a previous study, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or deathin hospitalised patients with Covid-19 pneumonia; however, it did not improve survival of these patients. Tocilizumab is currently under investigation as a potential treatment for COVID-19, with initial contradictory evidence [7].
Consequently, tocilizumab biosimilars have been actively developed around the world, including in China. Tocilizumab biosimilars (QX003S) have the same primary structure, post-translational modification, biochemical characteristics, and biological functions as the reference product, and in addition, these similarities have been tested in mice and monkeys (data not published). All in vivo studies justify the clinical development of QX003S.
PK studies in humans are essential to demonstrate the bioequivalence of biological analogues and reference products [8]. Herein, we conducted a single-dose PK study in healthy Chinese male subjects to evaluate the bioequivalence between QX003S and Actemra@ as the reference product. Use of healthy subjects helps avoid the potential confounding influence of factors such as comorbid diseases and concomitant therapies. The therapeutic dose of the reference drug used in previous studies is 4–8 mg/kg [9–10]. In this study, a dose of 8 mg/kg was used, based on earlier clinical trial plans of the sponsor.
In this study, the PK profiles of the QX003S with Actemra@ were analysed and compared. In addition, the tolerability, safety, and immunogenicity of QX003S were assessed.
2. Methods
2.1. Study design and subjects
This phase-I study was conducted at the Clinical Research Centre of the First Hospital of Jilin University between 14 March 2019 and 18 September 2019 (Chinese Clinical Trial Registry, Registration No. CTR20190002). The study protocol was approved by the ethics committee of the hospital. The study complied with the guidelines of the Declaration of Helsinki and the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP). Written Informed consent was obtained from all subjects prior to their enrolment.
This was a randomized, double-blind, single-dose, two-arm, parallel comparison study to evaluate the PK, safety, and immunogenicity of QX003S and Actemra@ in healthy Chinese male subjects. Overall, 86 eligible subjects were randomly allocated in a 1:1 ratio to receive a single intravenous drip of 8 mg/kg QX003S or Actemra@. Subjects were stratified into two groups based on body weight (50 to < 67.5 kg and ≥ 67.5 to ≤ 85 kg). Individuals in each of the pre-specified groups were equally assigned to the two treatment groups through randomization (Figure 1).
Figure 1. Flow chart of the study.
Sentinel staggered administration was used in this study. Subjects were administered the investigational product (IP) in a staggered cohort: the first and second cohort consisted of two subjects and four subjects, respectively. For safety evaluation, each subject was required to stay at the study centre for at least 96 h after the administration. Based on sentinel safety results, the principal investigator determined whether the subsequent subjects would be monitored in sentinel mode or in routine follow-up mode. All subjects were followed up for 57 days.
The main inclusion criteria were as follows: (1) healthy men in the age group of 18–50 years; (2) body mass index: 18.0–28.0 kg/m2; (3) body weight: 55–85 kg; and (4) normal test outcomes or clinically unremarkable results of routine blood and urine routine investigations including hepatic and renal function tests during enrolment.
The exclusion criteria were as follows: (1) history of clinically significant diseases; (2) C-reactive protein (CRP) levels 1.5 times higher than the upper limit of the normal range; and (3) positive results of T-SPOT® assay or TB interferon-γ-release assay.
All subjects received a single intravenous infusion of the IP (8 mg/kg) administered over a period of 60 min (±6 min). All subjects were randomly allocated to one of the following two groups in a 1:1 ratio in each of the pre-specified weight intervals: QX003S (Jiangsu Quanxin Biomedicine Co. Ltd; Batch number: F20180801); Actemra@ (Chugai Pharmaceutical Company [Japan]; Batch number: B2063B15).
Screening was performed 14 to 2 days prior to the date of administration. All qualified subjects entered the clinical research unit a day prior to the administration of biosimilars. Subjects were required to fast for at least 8 h before administration and were randomly assigned to either the test drug (QX003S) or reference drug group.
2.2. PK evaluations
Blood samples were collected for PK analysis at different time-points: 1 h before administration (before administration) to 1344 h after the initial infusion (day 57). Serum tocilizumab levels were determined by enzyme-linked immunosorbent assay (ELISA) at the Junke Zhengyuan (Beijing) Pharmaceutical Research Co. Ltd. (Supplement material). PK parameters were determined by non-compartmental analysis model. The concentration–time data included the maximum observable serum concentration (Cmax), clearance (CL), half-life (t1/2), the volume of distribution (Vz), and area under the curve (AUC) from zero to the final quantifiable concentration (AUC0–t) and to infinity (AUC0–∞). The actual sampling times were used for PK analyses. An internally validated software system, Phoenix WinNonLin® v8.0 (Pharsight Corporation, Certara, L.P., Princeton, New Jersey, USA), was used to determine PK parameters.
2.3. Immunogenicity evaluations
Blood samples collected at 1 h before and on 15, 29, 43, and 57 days after drug administration were analysed for the presence of anti-drug antibodies (ADAs) using electrochemiluminescence immunoassay (ECLIA). Subjects who test ADA-positive, those who develop antibody-related adverse reactions, or those with significantly abnormal PK value are required to be further examined for the presence of neutralising antibodies (NAbs). NAb test was not performed in this study because the above conditions were not met.
2.4. Safety evaluation
Physical examination, assessment of vital signs, electrocardiogram, and routine laboratory investigations were performed to monitor adverse events (AEs) according to the National Cancer Institute Common Terminology for Adverse Events (CTCAE;V.4.03). Subjects who showed AEs were monitored until they reached normal or acceptable stability (as assessed by the principal investigator and sponsor) or were lost to follow up.
2.5. Estimation of the sample size
According to the recent FDA guidelines, the geometric mean ratio (GMR) was set at 95% to achieve 90% power (1 − β) at a significant level (two-sided α = 5%). Inter-subject variability (inter-CV) is expressed by the coefficient of variation (CV). NQuery 8.3.0.0 (Boston, USA) software was used to determine the sample size (initial: 68; inter-CV for tocilizumab: 24%) [9]. The final sample size was 86, allowing for a 20% drop-out rate.
2.6. Statistical analysis
After logarithmic transformation of PK parameters Cmax, AUC0–t, and AUC0–∞, the least square method was used for analysis of variance. Bioequivalence inferences were drawn if the 90% confidence intervals (CIs) were found to be within the range of 80–125%. PK analysis was performed using the PK analysis set. The safety analysis set included subjects who were administered the study drug. Descriptive statistical estimates of PK parameters and demographic data were calculated. Between-group differences were assessed using the Chi-squared test for categorical variables, t-test for normally distributed continuous variables, and Wilcoxon rank test for non-normally distributed variables. All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
3. Results
3.1. Subjects
The assigned drugs were administered to 83 of the 86 enrolled subjects and included in the safety analysis (Figure 1). One additional subject was included in the QX003S group, whereas one subject was removed from the Actemra® group due to weight stratification. Therefore, the QX003S group comprised of 44 subjects.
Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, had hypertension and fast pulse rate or polycardia; these subjects were excluded from the study. Before dosing, two and one subjects in the QX003S and Actemra® groups, respectively, were ADA positive;these were excluded from the study. The final per-protocol analysis population included in the safety, PK, BE, and immunogenicity (ADA) analysis set comprised of 83, 80, 80, and 83 subjects, respectively (Figure 1). The demographic and baseline characteristics of the per-protocol population and the two treatment groups were comparable (p > .05, Table 1).
Table 1. Demographic and baseline characteristics.
QX003S group Actemra® group Total
(n = 44) (n = 42) (n = 86) p Values
Age (year), mean (SD) 35.5 (8.88) 36.1 (8.51) 35.8 (8.66) .75
Ethnicity (Han, n [%]) 41 (93.2) 40 (95.2) 81 (94.2) .68
Weight (kg), mean (SD) 67.45 (9.423) 66.21 (7.621) 66.84 (8.563) .5
BMI (kg/m2), mean (SD) 23.306 (2.5834) 23.234 (2.5210) 23.271 (2.5383) .89
BMI; body mass index; SD: standard deviation.
3.2. PK evaluation
The mean serum concentration–time curve of tocilizumab and its biosimilar decreased with multiphase mode. A rapid decline immediately after the infusion was followed by a slow elimination phase, and, subsequently, by a slightly faster elimination phase at low concentrations (Figure 2). The non-compartmental analysis model showed slow clearance, longer t1/2, and small Vz of tocilizumab and its biosimilar. The median Tmax values were equivalent between the two groups and these were achieved 1.8 h after the intravenous infusion.
Figure 2. Serum drug concentration–time profile of tocilizumab. Mean values (A); log10 mean values (B); log10 mean values within 0–48 h (C); ADA-positive individuals in the QX003S (D) and Actemra@ (E) groups.
The mean value of t1/2 between the test drug and the reference drug was between 160.8155 and 159.9160 h, indicating comparability. The total clearance rate (CL) and Vz values were also similar in the two groups. The differences between the mean concentration–time curve, mean Cmax, AUC0-t, AUC0-∞ estimation, and inter-CVs were similar (p > .05); the coefficient of variation ranged from 14.95% to 18.78% (Table 2, Figure 2).
Table 2. Pharmacokinetic parameters of tocilizumab in each group (Mean ± SD [CV%] or median [min, max]).
QX003S group (n = 40) Actemra® group (n = 40) p Values GMR (90% CI) GMR (90% CI)a Re-estimated size
Tmax*(h) 1.8 (1-4) 1.8 (1-4) >.05
Cmax (μg/mL) 178.8 ± 28.90 (16.16) 178.2 ± 27.43 (15.39) .92 1 (0.95, 1.06) 1.02 (0.95-1.09) 40
AUC0-t (h•μg/mL) 27116.0941 ± 4466.9216 (16.47) 27446.4185 ± 4103.9469 (14.95) .73 0.9859 (0.9311,1.0439) 0.9827 (0.9197-1.0500) 40
AUC0-∞ (h•μg/mL) 28806.7645 ± 5411.8467 (18.78) 29039.7894 ± 4641.0883 (15.98) .83 0.9878 (0.9272, 1.0524) 0.9787 (0.9098-1.0529) 52
t1/2 (h) 160.8155 ± 35.2772 (21.93) 159.9160 ± 29.0054 (18.13) .90
CL (L/h) 0.0192 ± 0.0031 (16.06) 0.0185 ± 0.0025 (13.68) .26
Vd (L) 4.3578 ± 0.7660 (17.57) 4.2322 ± 0.7760 (18.33) .46
*Median [min, max]; aQX003S/ Actemra® after excluding subject with ADA positive after dosing.
The PK parameters were comparable in the QX003S and Actemra@ groups. The ratio of geometric least-squares means for the QX003S versus Actemra@ were 1, 0.9859, and 0.9878 for Cmax, AUC0-t, and AUC0-∞;the 90% CI was 0.9272–1.06. The 90% CIs of the Cmax, AUC0–t, and AUC0–∞ were within the predefined bioequivalence limit, ranging from 80.00% to 125.00%. A larger inter-CV indicated a broader 90% CI. The sample size was re-estimated on the basis of the results of bioequivalence analysis (GMR and inter-CV), which decreased to a number less than the enrolment size (Table 2).
3.3. Immunogenicity evaluation
Before dosing, two and one subjects in the QX003S and Actemra® group respectively, were ADA positive. After dosing, 6 (14.3%) subjects in the QX003S group and 14 (34.1%) subjects in the Actemra® group tested positive for ADA. The ADA-positive rates were found to increase over a period of time, especially by days 43 (1008 h) and 57 (1344 h). Nevertheless, the drug concentration was less than the lower limit of quantitation (LLOQ) during that period. ADA-positivity rates were similar in the two groups at 15 to 29 days after drug administration (6.7–7.1%). However, at 43 and 57 days after drug administration, the positivity rates in the QX003S group were relatively lower than those in the Actemra@ group; however, the between-group differences in this respect were not statistically significant at any of the time-points (p > .05, Table 3).
Table 3. Summary of immunogenicity (anti-drug antibody) assessment (number [%] of subjects with positive antibodies).
Time (day) QX003S group (n = 42) Actemra® group (n = 41) p Values
Pre-dose 2 (4.88) 1 (2.44) .57
15 0 (0) 0 (0) NA
29 0 (0) 1 (2.44) .30
43 3 (7.32) 5 (12.2) .43
57 8 (19.51) 13 (31.71) .18
NA: Not applicable.
Table 4. Adverse reactions (number of reactions, the number [%] of subjects, more than 4%).
QX003S group (n = 42) Actemra® group (n = 41)
n (%) [number of reactions] n (%) [number of reaction] p Values
Total 42 (100) 134 40 (97.6) 148 0.30
Fibrinogen decreased 38 (90.5) 40 34 (82.9) 34 0.31
Reduced neutrophil counts 30 (71.4) 39 24 (58.5) 32 0.21
Reduced leukocyte count 24 (57.1) 28 19 (46.3) 26 0.32
Elevated serum bilirubin 6 (14.3) 6 3 (7.3) 5 0.30
Elevated alanine aminotransferase 0 (0) 0 5 (12.2) 6 0.01
Elevated aspartate aminotransferase 0 (0) 0 4 (9.8) 6 0.03
Reduced lymphocyte count 1 (2.4) 2 2 (4.9) 2 0.54
Urine leucocyte positive 0 (0) 0 2 (4.9) 2 0.14
Oropharyngeal pain 2 (4.8) 2 3 (7.3) 3 0.62
Cough 2 (4.8) 2 2 (4.9) 2 0.98
Cough with expectoration 1 (2.4) 1 2 (4.9) 2 0.54
Runny nose 0 (0) 0 3 (7.3) 3 0.07
Stuffy nose 0 (0) 0 2 (4.9) 2 0.14
Hypertriglyceridaemia 5 (11.9) 5 7 (17.1) 7 0.50
Hyperuricemia 1 (2.4) 1 2 (4.9) 3 0.54
Diarrhea 2 (4.8) 2 1 (2.4) 1 0.57
Oral mucositis 0 (0) 0 2 (4.9) 2 0.14
The serum concentration-time curves of QX003S and Actemra@ for ADA-positive and ADA-negative subjects were found to be similar (Figure 2). Sensitivity analysis of bioequivalence was performed after exclusion of 20 subjects who tested positive for ADA. The 90% CIs for the comparisons of Cmax and AUC were within the predefined range of bioequivalence limits of 80.00%–125.00% (Table 2). Therefore, overall, ADA-positivity rates were similar in the two groups.
3.4. Safety evaluation
No serious AEs (SAEs), deaths, or discontinuations due to AEs were observed. In this study, 282 adverse reactions occurred in 82 (98.8%) subjects. A total of 134 adverse reactions in 42 (100%) subjects were recorded in the QX003S group, while148 adverse reactions in 40 (97.6%) subjects were recorded in the Actemra® group. The incidence of adverse reactions was comparable in the two groups (Table 4). The adverse reactions with an incidence greater than 5% in the QX003S and Actemra® groups, respectively, were as follows: decreased fibrinogen level (90.5% vs 82.9%), decreased neutrophil count (71.4% vs 58.5%), decreased white blood cell (WBC) count (57.1% vs 46.3%), increased bilirubin (14.3% vs 7.3%), and hypertriglyceridaemia (11.9% vs 17.1%). The severity of most adverse reactions was between grade I and II. The incidence rates of elevated alanine aminotransferase and elevated aspartate aminotransferase level in the QX003S group were lower than those in the Actemra® group (0% vs. 12.2%, p = 0.01; 0% vs. 9.8%, p = 0.03); this indicated a lesser effect of QX003S on liver enzyme levels than the reference product. The incidence of other adverse reactions was comparable in the two groups (p > 0.05).
A total of 20 (24.1%) subjects in the two groups experienced 26 grade III–IV adverse reactions. Thirteen (31.0%) subjects in the QX003S group developed 16 adverse reactions, and seven (17.1%) subjects in the Actemra® group developed 10 adverse reactions. The incidence in the QX003S vs Actemra® groups was comparable: decreased neutrophil count (28.6% vs 12.2%), decreased WBC count (7.1% vs 7.3%), decreased fibrinogen (2.4% vs 2.4%), and increased alanine aminotransferase (0 vs 2.4%). All grade III–IV adverse reactions recovered spontaneously without treatment. Very few Grade I-II adverse reactions required drug therapy, such as cefuroxime axetil, levofloxacin, and glycyrrhizin.
There was no association between ADA development and adverse reactions in this study. None of the subjects developed clinically significant or serious hypersensitivity, anaphylaxis, or injection-site reaction after IP administration, except Subject no.105 of the QX003S group who developed ecchymia and mild tenderness at the injection site 48 h after administration; this subject showed spontaneous recovery on day 8 without any treatment. Subject no.001 of the Actemra® group showed bruising at the injection site at 12 h after administration without any tenderness; this subject also showed spontaneous recovery on day 22 without any treatment. All adverse reactions were reported to the Institutional Review Board of The First Hospital of Jilin University.
4. Discussion
This single-dose, phase-I study demonstrated the bioequivalence of QX003S and Actemra@ when administered as intravenous infusion at a dose of 8 mg/kg. The results of ANOVA showed that the 90% CIs of the geometric mean ratios of Cmax and AUC in the two treatment groups ranged from 92.72%–106%, which was within the predefined bioequivalence intervals of 80% to 125%. Other PK parameters of Tmax and t½ were also similar between the two treatment groups. QX003S and Actemra@ showed a similar safety and immunogenicity profile. No serious AEs were reported; all adverse reactions were mild or moderate in severity, and no local reactions were reported except in two subjects. This indicated that the two products were well tolerated in this population of healthy subjects. The above results justify the use of the biosimilars in the next phase clinical studies [1–3].
The pharmacokinetic behaviour of tocilizumab is different from the small-molecule pharmacokinetic behaviour in that it has limited vascular permeability, neonatal Fc receptor circulation, and more frequent receptor-mediated nonlinearity. Its distribution and clearance (CL) are consistent with target-mediated drug disposition (TMDD) [11]. On average, Cmax of tocilizumab decreased approximately 55% in the first 96 h. Subsequently, a slow elimination phase was observed between 96 and 336 h, followed by a relatively fast elimination between 336 and 672 h (Figure 2). In this study, QX003S at a dose of 8 mg/kg [mean weight of the subjects: 67.45 kg, dosage: 539.6 mg (4 × 67.45)] showed a lower clearance and displayed a longer t1/2 (160.8155 vs 39.9 h) than tocilizumab 162 mg (Roche Products Limited, Welwyn Garden City, UK), more exposure (AUC ratio of QX003S vs tocilizumab 162 mg equal to 6.39) than dose ratio (539.6:162 = 3.33), similar Tmax and dose ratio of Cmax with tocilizumab 162 mg, which have been evaluated in other phase-I studies in healthy subjects (Supplement Table 1) [12].
Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies [9,13]. Similarly, ADA had no effect on drug concentration or bioequivalence results in this study (Figure 2, Table 2). In population PK analysis, body weight was identified as a significant covariate impacting the pharmacokinetics of tocilizumab. When administered intravenously on mg/kg basis, individuals with body weight ≥100 kg are predicted to have higher exposures than individuals with body weight <100 kg. Therefore, weight stratification was adopted in this study to reduce variation of parameters, although the weight of subjects in this study was <100 kg. The inter-CV of tocilizumab was small (less than 18.7867%); therefore, the sample size in future studies can be reduced to 52 subjects (26 subjects per arm) [14].
Notably, the incidence of adverse reactions in the QX003S group was similar to that in the Actemra@ group (100% vs 97.6%); most of these were resolved at the final visit in this study. The most common adverse reactions (incidence of at least 5%) are reported in the label, including upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT level, and injection site reactions [9]. In healthy subjects who were administered ACTEMRA in doses of 2–28 mg/kg intravenously and 81–162 mg subcutaneously, the absolute neutrophil counts decreased to the nadir 3 to 5 days following administration. Thereafter, the neutrophil counts recovered towards baseline in a dose-dependent manner over a period of 9–17 days [12]. Patients with rheumatoid arthritis and GCA exhibited a similar pattern of absolute neutrophil counts following the administration of ACTEMRA [9,15]. Similar to previous reports, the incidence of decreased neutrophil counts and decreased white blood cell counts was indeed very high. Neutrophil counts decreased on day 2 to 5; the mean neutrophil count reached nadir on day 2 in both groups. The mean values returned to baseline by day 57 without any treatment (Figure 3). As described by Nishimoto et al. [16], when tocilizumab concentration is maintained above 1 µg/mL, SIL-6R is saturated by tocilizumab leading to complete inhibition of the IL-6 signal; this may affect the distribution of blood cells such as neutrophils and leukocytes. However, these cell counts quickly return to baseline with the drop in the drug concentration.
Figure 3. Absolute values of neutrophil, leukocyte counts, and fibrinogen level over time. Data presented as mean ± standard error of the mean.
In clinical studies, RA patients were treated with 4–8 mg/kg intravenous doses or the 162 mg weekly and every other weekly subcutaneous doses of ACTEMRA; the levels of CRP decreased to within the normal range along with changes in the pharmacodynamic parameters (i.e. decrease in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen; and increase in haemoglobin) [9]. In the present study, fibrinogen level decreased in 82.9–90.5% subjects and the mean fibrinogen level reached the nadir on day 15 to 29 in the QX003S and Actemra® groups; these changes are similar to the above changes in pharmacodynamic indices.
No acute or delayed anaphylactic reactions developed in subjects who were ADA positive, indicating that there was no product-specific immunogenicity. We observed no impact of the immunogenic responses of tocilizumab to drug safety and PK in this study similar to previous reports; however, it may still be necessary to closely monitor the immunogenicity of QX003S and Actemra and its impact on their efficacy in further related Phase-III studies with larger population, multiple doses, as well as longer time frame [17–19]. Overall, this study demonstrated the safety and tolerability of QX003S and reference Actemra@.
Conclusions
This study showed similar PK profile of tocilizumab biosimilar (QX003S) and Actemra@. The tocilizumab biosimilar showed a nearly similar ADA profile and a comparable safety profile versus the reference drug. The inter-CV of tocilizumab was low among Chinese subjects. These data support the clinical development of QX003S as a tocilizumab biosimilar.
Supplementary Material
Supplemental Material
Click here for additional data file.
Acknowledgements
The authors thank the staff of the Phase I Clinical Research Centre, The First Hospital of Jilin University, Jilin, China for data collection in the study.
Disclosure statement
All data related to this study were interpreted by the trial staff with complete independence from the sponsor. Min Fang is employee of the sponsor team. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Data availability statement
The data that support the findings of this study are available on request from the corresponding author, YHD. The data are not publicly available due to their containing information that could compromise the privacy of research participants. | Recovered | ReactionOutcome | CC BY | 33629921 | 19,002,940 | 2021-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abortion spontaneous'. | Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.
OBJECTIVE
To assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.
METHODS
Pregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.
RESULTS
The incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183).
CONCLUSIONS
This observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.
Introduction
Domperidone is an antidopaminergic benzimidazolone compound first synthesized by Janssen Pharmaceutica (Belgium) in 1974. Originally approved in Belgium in 1978, it has since been approved in over 100 countries, including in Japan in 1982. In Japan, domperidone has been widely used for the treatment of gastrointestinal symptoms such as nausea, vomiting, and anorexia.
In a study of domperidone administration during organogenesis in rats, skeletal and visceral malformations were observed in fetuses following an oral dose of 200 mg/kg or an intraperitoneal dose of ≥15 mg/kg. These observed malformations in rats occurred at approximately 300 times the daily oral dose for humans based on body weight. Due to these results, the package insert for domperidone in Japan states that it is contraindicated for use in pregnant women or women suspected of being pregnant.
In some cases, however, domperidone is prescribed for gastrointestinal symptoms such as nausea and vomiting to women who do not yet know they are pregnant due to the pregnancy being unplanned. In such cases, patients often become anxious when they find out they are pregnant and learn that domperidone is contraindicated.
Domperidone and metoclopramide are commonly used as antiemetic drugs in general clinical practice in Japan. Large‐scale epidemiological studies have shown that metoclopramide does not increase the risk of malformation 1 , 2 . On the other hand, teratogenic risk with domperidone has been reported in only a few small‐scale, cohort studies. A report by JS Choi et al. investigated 120 pregnancies treated with domperidone in the first trimester and concluded that domperidone is unlikely to be a major human teratogen 3 . Also, in an abstract, J Cottin et al. compared 124 pregnancies exposed to domperidone during organogenesis with those exposed to other antiemetics or nonteratogenic drugs 4 . There was no significant difference between the three groups in the incidence of major congenital malformations, but the authors commented that the small sample size was a limitation. A report on drug use during pregnancy in the French population stated that about 13% of all pregnant women were using domperidone 5 . Although the teratogenic risk of domperidone was not analyzed in that survey, it suggests that the drug is widely used by pregnant women in some countries.
In the present study, we evaluated the teratogenic risk of domperidone exposure during the first trimester. This is based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy.
Methods
Subjects
This study included women who consulted the Counseling Clinic for “Pregnancy and Medicine” of Toranomon Hospital or the Japan Drug Information Institute in Pregnancy of National Center for Child Health and Development regarding the safety of drugs during pregnancy. Pregnancy outcome data were extracted from the clinical databases of these facilities.
The inclusion criteria were pregnant women who consented to the study and with known pregnancy outcomes who took domperidone (domperidone group), or control drugs (control group) in the first trimester. Among these, women who used domperidone in combination with metoclopramide were excluded from the study. First trimester exposure was defined as drug use between the 28th and 97th days (4th week to 13th week of pregnancy) after the last menstrual period. Experts discussed and selected control drugs considered to be nonteratogenic, referring the report by F. Habermann et al. 6 Control drugs included acetaminophen, antihistamines that were reported in previous studies to have no increased risk of teratogenicity, anti‐infectives like penicillins and cephalosporins, histamine H2‐receptor (H2) blockers, digestive enzyme preparations, and topical drugs (e.g., eye drops, ointment, or cream). Metoclopramide is a similar drug and is expected to be used for the same diseases. In addition, it has been commonly used as an antiemetic drug in pregnant women. Therefore, although statistical comparison with the domperidone group was not performed, patients who took metoclopramide were defined as the reference group.
Data collection
For Toranomon Hospital, women who consulted the Counseling Clinic for “Pregnancy and Medicine” during pregnancy between April 1988 and December 2016 were included in the study. People who wished to make a counseling appointment were first required by the clinic to complete a pre‐appointment questionnaire regarding information such as the names and dosages of drugs taken during pregnancy and expected delivery date, and to return it by mail. At the time of counseling, subjects were interviewed to confirm their expected delivery dates and to obtain other information, including previous medical history, pregnancy and reproductive history, alcohol use, smoking, and family history. We asked patients who provided informed consent for study participation to complete a study questionnaire regarding pregnancy outcomes and any abnormalities during delivery, as well as sex, length, and weight at birth, and any abnormalities of the neonate, and to submit it by mail. If patients provided unclear answers about pregnancy outcomes, an obstetrician contacted their attending physician to obtain clarification. Information on pregnancy outcomes was collected about 1 month after delivery, and the survey was considered complete when this information was obtained.
At the National Center for Child Health and Development, women in pregnancy who sought consultation the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017 were included in the study. The Japan Drug Information Institute in Pregnancy was established under a program of the Ministry of Health Labour and Welfare in October 2005. People who wished to make a counseling appointment were required to complete a pre‐appointment questionnaire and to return it by mail. The pre‐appointment questions were on age, use of drugs during pregnancy, history of present illness, previous medical history, experience of pregnancy, reproductive history, alcohol use, smoking, and intake of folic acid. Approximately a month after their expected delivery date, patients who provided informed consent for participation in the study were sent a postcard‐type questionnaire on pregnancy outcomes and the 1‐month checkup results of their infants. In cases where pregnancy outcomes were unclear, research assistants, doctors or pharmacists contacted the women's attending obstetricians to confirm their pregnancy outcome by telephone. The survey was concluded when information on pregnancy outcomes had been obtained.
Primary endpoint and statistical analysis
The primary endpoint of this study was the incidence of major malformation. To assess the teratogenic risk of domperidone, we compared the incidence of major malformation in the domperidone group with the control group. Major malformations were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) 7 . In cases of congenital abnormalities not included in EUROCAT, a specialist in congenital abnormalities provided diagnoses. Two of the authors concluded that congenital abnormalities could be defined either as surficial malformations or as those requiring surgical treatment. Finally, two independent specialists confirmed the diagnoses.
The incidence of major malformation was analyzed in liveborn, single‐birth infants, and was calculated by dividing the number of liveborn singletons with congenital malformation by the number of all liveborn singletons analyzed in each group. This incidence was compared between the domperidone and control groups. Using the control group as the reference of odds ratio (ORs), the crude ORs of the incidence of major malformations in the domperidone group were calculated using univariable logistic regression analysis. In addition, adjusted ORs were calculated using multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling. Similarly, the crude and adjusted ORs of the incidence of major malformations in the metoclopramide group were calculated. In a subgroup analysis, adjusted ORs were calculated for each facility. The significance level of the test was 5%.
Ethics statement
This study was approved by the Ethics Committee of National Center for Child Health and Development and that of Toranomon Hospital. It was conducted according to the Declaration of Helsinki, and informed consent was obtained from all participants. Information collected from questionnaires was entered into the database and de‐identified by an information administrator. Therefore, the investigators were unable to identify individuals based on the analysis data.
Results
Patient characteristics
At Toranomon Hospital, 12 074 women consulted the Counseling Clinic for “Pregnancy and Medicine” between April 1988 and December 2016. Of these, 1422 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. At National Center for Child Health and Development, 12 971 women consulted the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017. Of these, 1011 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. In total, the number of participants was 519 in the domperidone group, 1673 in the control group, and 241 in the metoclopramide group (Figure 1).
Figure 1 Flowchart
The median age of the subjects at the time of counseling was 30 years in all groups and the groups showed no difference in age distribution. There were no notable differences between groups in either alcohol use or smoking habits, as shown in Table 1.
Table 1 Patient characteristics
Domperidone group Control group Metoclopramide group
n 519 1673 241
Age (year), n (%)
50% [25%, 75%] 30 [26, 33] 30 [27, 34] 30 [27, 34]
≦24 79 (15.2) 160 (9.6) 30 (12.4)
25–29 170 (32.8) 548 (32.8) 81 (33.6)
30–34 167 (32.2) 628 (37.5) 83 (34.4)
35–39 84 (16.2) 288 (17.2) 40 (16.6)
40≦ 18 (3.5) 46 (2.7) 6 (2.5)
NA 1 (0.2) 3 (0.2) 1 (0.4)
Alcohol, n (%)
No use 292 (56.3) 861 (51.5) 125 (51.9)
Stop before pregnancy 7 (1.3) 45 (2.7) 13 (5.4)
Stop after pregnancy 84 (16.2) 305 (18.2) 48 (19.9)
Ongoing 3 (0.6) 16 (1.0) 5 (2.1)
Unknown stop time 75 (14.5) 250 (14.9) 28 (11.6)
NA 58 (11.2) 196 (11.7) 22 (9.1)
Smoking, n (%)
No habit 390 (75.1) 1244 (74.4) 176 (73.0)
Stop before pregnancy 9 (1.7) 36 (2.2) 10 (4.1)
Stop after pregnancy 25 (4.8) 56 (3.3) 16 (6.6)
Ongoing 16 (3.1) 59 (3.5) 10 (4.1)
Unknown stop time 32 (6.2) 122 (7.3) 13 (5.4)
NA 47 (9.1) 156 (9.3) 16 (6.6)
Abbreviation: NA, not available.
Delivery outcomes and incidence of major malformations
Delivery outcomes were aggregated for all subjects. The percentage of liveborn infants was 94.0% (488 cases) in the domperidone group, 93.8% (1570 cases) in the control group, and 94.2% (227 cases) in the metoclopramide group. There were no notable differences in the incidences of stillbirth, miscarriage or abortion between the three groups (Table 2).
Table 2 Pregnancy outcomes
Domperidone group Control group Metoclopramide group
n 519 1673 241
Outcome, n (%)
Live birth 488 (94.0) 1570 (93.8) 227 (94.2)
Stillbirth a 3 (0.6) 7 (0.4) 0 (0.0)
Miscarriage 18 (3.5) 80 (4.8) 8 (3.3)
Abortion 10 (1.9) 15 (0.9) 6 (2.5)
Other 0 (0.0) 1 b (0.1) 0 (0.0)
Number of infant, n (%)
1 506 (97.5) 1627 (97.3) 234 (97.1)
2≦ 1 (0.2) 9 (0.5) 3 (1.2)
NA 12 (2.3) 37 (2.2) 4 (1.7)
Abbreviation: NA, not available.
a Fetal death after 22 weeks gestation was defined as stillbirth.
b Ectopic pregnancy.
Major malformations in liveborn, single‐birth infants occurred in 14 cases in the domperidone group, 27 in the control group, and 8 in the metoclopramide group (Table 3). There was no pattern of malformation types between the three groups.
Table 3 Risk of major malformation
Major malformation 95%CI Crude OR (95%CI) p‐Value a Adjusted OR b (95%CI) p‐Value a
No Yes
Control group (n = 1554) 1527 27 c (1.7%) (1.1–2.5) 1 ‐ 1 ‐
Domperidone group (n = 485) 471 14 d (2.9%) (1.6–4.8) 1.68 (0.87–3.23) 0.119 1.86 (0.73–4.70) 0.191
Metoclopramide group (n = 224) 216 8 e (3.6%) (1.6–6.9) 2.09 (0.94–4.67) 0.071 2.20 (0.69–6.98) 0.183
Risk of major malformation was analyzed in liveborn, single‐birth infants.
Abbreviations: CI, confidence interval; OR, odds ratio.
a Significance level p < 0.05, *<0.05.
b Adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling.
c Ventricular septal defect (6); ventricular and atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); peripheral pulmonary stenosis (1); endocardial cushion defect (1); complete transposition of great arteries (1); double outlet right ventricle (1); esophageal atresia (1); cleft lip (1); diastasis recti (1); adhesion of scrotum and penis (1); hydronephrosis (2); imperforate anus (1); talipes varus (1); polydactyly (3); a combination of coarctation of the aorta and ventricular septal defect (1); a combination of single ventricle and pulmonary stenosis (1); a combination of ventricular septal defect, pulmonary stenosis and syndactyly (1).
d Ventricular septal defect (5); ventricular and atrial septal defect (1); atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); cleft lip and palate (1); double vagina (1); hydroureteropathy (1); hydronephrosis (1); a combination of duodenal obstruction, heart disease, upper aortic malposition and pulmonary artery occlusion (1).
e Ventricular septal defect (1); endocardial cushion defect (1); myelomeningocele (1); lissencephaly (1); hypospadias (1); talipes varus (1); polydactyly (1); scalp defect (1).
Risk of major malformation
The incidence of major malformation in liveborn, single‐birth infants (95% confidence interval [CI]) was 2.9% (14/485, 95%CI: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group.
Univariable logistic regression analysis showed no significant difference in the incidence of major malformation between the domperidone and control groups (OR: 1.68 [95% CI: 0.87–3.23], p = 0.119). Additionally, multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling also showed no significant difference in the incidence of major malformation between the domperidone and control groups (adjusted OR: 1.86 [95% CI: 0.73–4.70], p = 0.191) (Table 3). Similar results were obtained when comparing the metoclopramide and control groups (OR: 2.09 [95% CI: 0.94–4.67], p = 0.071; adjusted OR: 2.20 [95% CI: 0.69–6.98], p = 0.183).
Subgroup analysis
For the cases at Toranomon Hospital, the adjusted OR (95%CI) of the incidence of major malformation was 2.54 (95%CI: 0.68–9.46, p = 0.164) in the domperidone group and 2.54 (95%CI: 0.47–13.82, p = 0.282) in the metoclopramide group, indicating no significant difference for either group compared with the control group.
For the cases at National Center for Child Health and Development, the adjusted OR (95%CI) of the incidence of major malformation was 1.45 (95%CI: 0.38–5.54, p = 0.583) in the domperidone group and 2.06 (95%CI: 0.43–9.98, p = 0.370) in the metoclopramide group, again indicating no significant difference for either group compared with the control group (Supporting Information, Table SS1).
We also compared the adjusted OR of risk of major malformations by the year of counseling (Table SS2). To rule out the year of counseling as a possible confounding factor, we compared the first half of the data from Toranomon Hospital (1988–2004), to the second half (2005–2016) (adjusted OR: 0.79 [95%CI: 0.26–2.39], p = 0.680) and to the data from the National Center for Child Health and Development (2005–2017) (adjusted OR: 1.34 [95%CI: 0.69–2.60], p = 0.381), and found no significant differences in the adjusted OR.
Discussion
Although there are prior reports 3 , 4 of domperidone administered to pregnant women, those studies lacked sufficient detection power to ensure that domperidone exposure is not harmful to the fetus. Therefore, no information has been available to ensure the safety of using domperidone in pregnant women.
In this study, the 485 patients who received domperidone during the first trimester of pregnancy showed no increase in the incidence of major malformation compared with patients in the control group, who received drugs that are considered to have no teratogenicity. In addition, no difference was found in the results of a sensitivity analysis that assessed teratogenic risk by excluding patients who used teratogenic drugs defined by the clinical guidelines for gynecology and obstetrics 8 .
This study enrolled pregnant women who consulted at Toranomon Hospital or the National Center for Child Health and Development. We therefore performed a subgroup analysis to determine if there were any discrepancies in results between the facilities. There were no such differences, and the incidence of major malformation in the domperidone group did not higher than that in the control group at neither facility.
This study analyzed participants who received counseling at Toranomon Hospital after April 1988 and at National Center for Child Health and Development after October 2005. The use of imaging modalities to detect visceral malformations began in 1997. Therefore, it is presumed that since then it has been possible to detect even minor malformations, such as inconsequential heart defects. However, there was no significant difference in the incidence of major malformation at Toranomon Hospital between 1988 to 2004 and 2005 to 2016. Also, the data from National Center for Child Health and Development (2005–2017) yielded similar results as those from Toranomon Hospital (1988–2004). Thus, the timing of counseling is unlikely to be associated with the detection rate of malformation.
The package insert for domperidone states that it is contraindicated for use in pregnant women and in women suspected of being pregnant, due to teratogenicity observed in reproductive toxicity studies. This has led to the problem of pregnant women becoming anxious when they discover they have taken domperidone before finding out they were pregnant.
This observational cohort study was based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy. It showed that the risk of major malformation was not increased in women who received domperidone during pregnancy. However, it should be noted that a limitation of the study is that women could cancel their counseling if they had a miscarriage or abortion beforehand, resulting in underreported miscarriage or abortion cases.
In future counseling, this information is clinically very useful because it can reduce or eliminate the anxiety of patients who have taken domperidone during pregnancy. The Japanese clinical guidelines for obstetrics and gynecology (obstetrics portion) list domperidone as one of the “drugs that may be used by women in early pregnancy without having a clinically significant adverse effect on the fetus, even though the package inserts state that they are contraindicated in pregnant women.” 8 The results of this study support this statement in the guidelines.
Conflict of interest
Atsuko Murashima received lecture fees from Chugai Pharmaceutical Co.Ltd and Astellas Pharma Inc.
Supporting information
Table S1 Subgroup analysis by the facility
Click here for additional data file.
Table S2 Subgroup analysis by the year of counseling
Click here for additional data file.
Acknowledgments
This work was supported by a Research Program from the Japanese Agency for Medical Research and Development under Grant Number JP19mk0101086h0003, awarded to A.M. The authors would like to thank Dr. Kenjiro Kosaki and Dr. Rika Kosaki for their great advice in diagnosing congenital malformations and we would like to thank Mariko Takagai for her administrative assistance. They are also grateful to women who donated their clinical information and for colleagues worked as a member of Japan Teratology Information Services Network. | METOCLOPRAMIDE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33631840 | 19,020,052 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abortion'. | Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.
OBJECTIVE
To assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.
METHODS
Pregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.
RESULTS
The incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183).
CONCLUSIONS
This observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.
Introduction
Domperidone is an antidopaminergic benzimidazolone compound first synthesized by Janssen Pharmaceutica (Belgium) in 1974. Originally approved in Belgium in 1978, it has since been approved in over 100 countries, including in Japan in 1982. In Japan, domperidone has been widely used for the treatment of gastrointestinal symptoms such as nausea, vomiting, and anorexia.
In a study of domperidone administration during organogenesis in rats, skeletal and visceral malformations were observed in fetuses following an oral dose of 200 mg/kg or an intraperitoneal dose of ≥15 mg/kg. These observed malformations in rats occurred at approximately 300 times the daily oral dose for humans based on body weight. Due to these results, the package insert for domperidone in Japan states that it is contraindicated for use in pregnant women or women suspected of being pregnant.
In some cases, however, domperidone is prescribed for gastrointestinal symptoms such as nausea and vomiting to women who do not yet know they are pregnant due to the pregnancy being unplanned. In such cases, patients often become anxious when they find out they are pregnant and learn that domperidone is contraindicated.
Domperidone and metoclopramide are commonly used as antiemetic drugs in general clinical practice in Japan. Large‐scale epidemiological studies have shown that metoclopramide does not increase the risk of malformation 1 , 2 . On the other hand, teratogenic risk with domperidone has been reported in only a few small‐scale, cohort studies. A report by JS Choi et al. investigated 120 pregnancies treated with domperidone in the first trimester and concluded that domperidone is unlikely to be a major human teratogen 3 . Also, in an abstract, J Cottin et al. compared 124 pregnancies exposed to domperidone during organogenesis with those exposed to other antiemetics or nonteratogenic drugs 4 . There was no significant difference between the three groups in the incidence of major congenital malformations, but the authors commented that the small sample size was a limitation. A report on drug use during pregnancy in the French population stated that about 13% of all pregnant women were using domperidone 5 . Although the teratogenic risk of domperidone was not analyzed in that survey, it suggests that the drug is widely used by pregnant women in some countries.
In the present study, we evaluated the teratogenic risk of domperidone exposure during the first trimester. This is based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy.
Methods
Subjects
This study included women who consulted the Counseling Clinic for “Pregnancy and Medicine” of Toranomon Hospital or the Japan Drug Information Institute in Pregnancy of National Center for Child Health and Development regarding the safety of drugs during pregnancy. Pregnancy outcome data were extracted from the clinical databases of these facilities.
The inclusion criteria were pregnant women who consented to the study and with known pregnancy outcomes who took domperidone (domperidone group), or control drugs (control group) in the first trimester. Among these, women who used domperidone in combination with metoclopramide were excluded from the study. First trimester exposure was defined as drug use between the 28th and 97th days (4th week to 13th week of pregnancy) after the last menstrual period. Experts discussed and selected control drugs considered to be nonteratogenic, referring the report by F. Habermann et al. 6 Control drugs included acetaminophen, antihistamines that were reported in previous studies to have no increased risk of teratogenicity, anti‐infectives like penicillins and cephalosporins, histamine H2‐receptor (H2) blockers, digestive enzyme preparations, and topical drugs (e.g., eye drops, ointment, or cream). Metoclopramide is a similar drug and is expected to be used for the same diseases. In addition, it has been commonly used as an antiemetic drug in pregnant women. Therefore, although statistical comparison with the domperidone group was not performed, patients who took metoclopramide were defined as the reference group.
Data collection
For Toranomon Hospital, women who consulted the Counseling Clinic for “Pregnancy and Medicine” during pregnancy between April 1988 and December 2016 were included in the study. People who wished to make a counseling appointment were first required by the clinic to complete a pre‐appointment questionnaire regarding information such as the names and dosages of drugs taken during pregnancy and expected delivery date, and to return it by mail. At the time of counseling, subjects were interviewed to confirm their expected delivery dates and to obtain other information, including previous medical history, pregnancy and reproductive history, alcohol use, smoking, and family history. We asked patients who provided informed consent for study participation to complete a study questionnaire regarding pregnancy outcomes and any abnormalities during delivery, as well as sex, length, and weight at birth, and any abnormalities of the neonate, and to submit it by mail. If patients provided unclear answers about pregnancy outcomes, an obstetrician contacted their attending physician to obtain clarification. Information on pregnancy outcomes was collected about 1 month after delivery, and the survey was considered complete when this information was obtained.
At the National Center for Child Health and Development, women in pregnancy who sought consultation the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017 were included in the study. The Japan Drug Information Institute in Pregnancy was established under a program of the Ministry of Health Labour and Welfare in October 2005. People who wished to make a counseling appointment were required to complete a pre‐appointment questionnaire and to return it by mail. The pre‐appointment questions were on age, use of drugs during pregnancy, history of present illness, previous medical history, experience of pregnancy, reproductive history, alcohol use, smoking, and intake of folic acid. Approximately a month after their expected delivery date, patients who provided informed consent for participation in the study were sent a postcard‐type questionnaire on pregnancy outcomes and the 1‐month checkup results of their infants. In cases where pregnancy outcomes were unclear, research assistants, doctors or pharmacists contacted the women's attending obstetricians to confirm their pregnancy outcome by telephone. The survey was concluded when information on pregnancy outcomes had been obtained.
Primary endpoint and statistical analysis
The primary endpoint of this study was the incidence of major malformation. To assess the teratogenic risk of domperidone, we compared the incidence of major malformation in the domperidone group with the control group. Major malformations were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) 7 . In cases of congenital abnormalities not included in EUROCAT, a specialist in congenital abnormalities provided diagnoses. Two of the authors concluded that congenital abnormalities could be defined either as surficial malformations or as those requiring surgical treatment. Finally, two independent specialists confirmed the diagnoses.
The incidence of major malformation was analyzed in liveborn, single‐birth infants, and was calculated by dividing the number of liveborn singletons with congenital malformation by the number of all liveborn singletons analyzed in each group. This incidence was compared between the domperidone and control groups. Using the control group as the reference of odds ratio (ORs), the crude ORs of the incidence of major malformations in the domperidone group were calculated using univariable logistic regression analysis. In addition, adjusted ORs were calculated using multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling. Similarly, the crude and adjusted ORs of the incidence of major malformations in the metoclopramide group were calculated. In a subgroup analysis, adjusted ORs were calculated for each facility. The significance level of the test was 5%.
Ethics statement
This study was approved by the Ethics Committee of National Center for Child Health and Development and that of Toranomon Hospital. It was conducted according to the Declaration of Helsinki, and informed consent was obtained from all participants. Information collected from questionnaires was entered into the database and de‐identified by an information administrator. Therefore, the investigators were unable to identify individuals based on the analysis data.
Results
Patient characteristics
At Toranomon Hospital, 12 074 women consulted the Counseling Clinic for “Pregnancy and Medicine” between April 1988 and December 2016. Of these, 1422 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. At National Center for Child Health and Development, 12 971 women consulted the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017. Of these, 1011 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. In total, the number of participants was 519 in the domperidone group, 1673 in the control group, and 241 in the metoclopramide group (Figure 1).
Figure 1 Flowchart
The median age of the subjects at the time of counseling was 30 years in all groups and the groups showed no difference in age distribution. There were no notable differences between groups in either alcohol use or smoking habits, as shown in Table 1.
Table 1 Patient characteristics
Domperidone group Control group Metoclopramide group
n 519 1673 241
Age (year), n (%)
50% [25%, 75%] 30 [26, 33] 30 [27, 34] 30 [27, 34]
≦24 79 (15.2) 160 (9.6) 30 (12.4)
25–29 170 (32.8) 548 (32.8) 81 (33.6)
30–34 167 (32.2) 628 (37.5) 83 (34.4)
35–39 84 (16.2) 288 (17.2) 40 (16.6)
40≦ 18 (3.5) 46 (2.7) 6 (2.5)
NA 1 (0.2) 3 (0.2) 1 (0.4)
Alcohol, n (%)
No use 292 (56.3) 861 (51.5) 125 (51.9)
Stop before pregnancy 7 (1.3) 45 (2.7) 13 (5.4)
Stop after pregnancy 84 (16.2) 305 (18.2) 48 (19.9)
Ongoing 3 (0.6) 16 (1.0) 5 (2.1)
Unknown stop time 75 (14.5) 250 (14.9) 28 (11.6)
NA 58 (11.2) 196 (11.7) 22 (9.1)
Smoking, n (%)
No habit 390 (75.1) 1244 (74.4) 176 (73.0)
Stop before pregnancy 9 (1.7) 36 (2.2) 10 (4.1)
Stop after pregnancy 25 (4.8) 56 (3.3) 16 (6.6)
Ongoing 16 (3.1) 59 (3.5) 10 (4.1)
Unknown stop time 32 (6.2) 122 (7.3) 13 (5.4)
NA 47 (9.1) 156 (9.3) 16 (6.6)
Abbreviation: NA, not available.
Delivery outcomes and incidence of major malformations
Delivery outcomes were aggregated for all subjects. The percentage of liveborn infants was 94.0% (488 cases) in the domperidone group, 93.8% (1570 cases) in the control group, and 94.2% (227 cases) in the metoclopramide group. There were no notable differences in the incidences of stillbirth, miscarriage or abortion between the three groups (Table 2).
Table 2 Pregnancy outcomes
Domperidone group Control group Metoclopramide group
n 519 1673 241
Outcome, n (%)
Live birth 488 (94.0) 1570 (93.8) 227 (94.2)
Stillbirth a 3 (0.6) 7 (0.4) 0 (0.0)
Miscarriage 18 (3.5) 80 (4.8) 8 (3.3)
Abortion 10 (1.9) 15 (0.9) 6 (2.5)
Other 0 (0.0) 1 b (0.1) 0 (0.0)
Number of infant, n (%)
1 506 (97.5) 1627 (97.3) 234 (97.1)
2≦ 1 (0.2) 9 (0.5) 3 (1.2)
NA 12 (2.3) 37 (2.2) 4 (1.7)
Abbreviation: NA, not available.
a Fetal death after 22 weeks gestation was defined as stillbirth.
b Ectopic pregnancy.
Major malformations in liveborn, single‐birth infants occurred in 14 cases in the domperidone group, 27 in the control group, and 8 in the metoclopramide group (Table 3). There was no pattern of malformation types between the three groups.
Table 3 Risk of major malformation
Major malformation 95%CI Crude OR (95%CI) p‐Value a Adjusted OR b (95%CI) p‐Value a
No Yes
Control group (n = 1554) 1527 27 c (1.7%) (1.1–2.5) 1 ‐ 1 ‐
Domperidone group (n = 485) 471 14 d (2.9%) (1.6–4.8) 1.68 (0.87–3.23) 0.119 1.86 (0.73–4.70) 0.191
Metoclopramide group (n = 224) 216 8 e (3.6%) (1.6–6.9) 2.09 (0.94–4.67) 0.071 2.20 (0.69–6.98) 0.183
Risk of major malformation was analyzed in liveborn, single‐birth infants.
Abbreviations: CI, confidence interval; OR, odds ratio.
a Significance level p < 0.05, *<0.05.
b Adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling.
c Ventricular septal defect (6); ventricular and atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); peripheral pulmonary stenosis (1); endocardial cushion defect (1); complete transposition of great arteries (1); double outlet right ventricle (1); esophageal atresia (1); cleft lip (1); diastasis recti (1); adhesion of scrotum and penis (1); hydronephrosis (2); imperforate anus (1); talipes varus (1); polydactyly (3); a combination of coarctation of the aorta and ventricular septal defect (1); a combination of single ventricle and pulmonary stenosis (1); a combination of ventricular septal defect, pulmonary stenosis and syndactyly (1).
d Ventricular septal defect (5); ventricular and atrial septal defect (1); atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); cleft lip and palate (1); double vagina (1); hydroureteropathy (1); hydronephrosis (1); a combination of duodenal obstruction, heart disease, upper aortic malposition and pulmonary artery occlusion (1).
e Ventricular septal defect (1); endocardial cushion defect (1); myelomeningocele (1); lissencephaly (1); hypospadias (1); talipes varus (1); polydactyly (1); scalp defect (1).
Risk of major malformation
The incidence of major malformation in liveborn, single‐birth infants (95% confidence interval [CI]) was 2.9% (14/485, 95%CI: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group.
Univariable logistic regression analysis showed no significant difference in the incidence of major malformation between the domperidone and control groups (OR: 1.68 [95% CI: 0.87–3.23], p = 0.119). Additionally, multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling also showed no significant difference in the incidence of major malformation between the domperidone and control groups (adjusted OR: 1.86 [95% CI: 0.73–4.70], p = 0.191) (Table 3). Similar results were obtained when comparing the metoclopramide and control groups (OR: 2.09 [95% CI: 0.94–4.67], p = 0.071; adjusted OR: 2.20 [95% CI: 0.69–6.98], p = 0.183).
Subgroup analysis
For the cases at Toranomon Hospital, the adjusted OR (95%CI) of the incidence of major malformation was 2.54 (95%CI: 0.68–9.46, p = 0.164) in the domperidone group and 2.54 (95%CI: 0.47–13.82, p = 0.282) in the metoclopramide group, indicating no significant difference for either group compared with the control group.
For the cases at National Center for Child Health and Development, the adjusted OR (95%CI) of the incidence of major malformation was 1.45 (95%CI: 0.38–5.54, p = 0.583) in the domperidone group and 2.06 (95%CI: 0.43–9.98, p = 0.370) in the metoclopramide group, again indicating no significant difference for either group compared with the control group (Supporting Information, Table SS1).
We also compared the adjusted OR of risk of major malformations by the year of counseling (Table SS2). To rule out the year of counseling as a possible confounding factor, we compared the first half of the data from Toranomon Hospital (1988–2004), to the second half (2005–2016) (adjusted OR: 0.79 [95%CI: 0.26–2.39], p = 0.680) and to the data from the National Center for Child Health and Development (2005–2017) (adjusted OR: 1.34 [95%CI: 0.69–2.60], p = 0.381), and found no significant differences in the adjusted OR.
Discussion
Although there are prior reports 3 , 4 of domperidone administered to pregnant women, those studies lacked sufficient detection power to ensure that domperidone exposure is not harmful to the fetus. Therefore, no information has been available to ensure the safety of using domperidone in pregnant women.
In this study, the 485 patients who received domperidone during the first trimester of pregnancy showed no increase in the incidence of major malformation compared with patients in the control group, who received drugs that are considered to have no teratogenicity. In addition, no difference was found in the results of a sensitivity analysis that assessed teratogenic risk by excluding patients who used teratogenic drugs defined by the clinical guidelines for gynecology and obstetrics 8 .
This study enrolled pregnant women who consulted at Toranomon Hospital or the National Center for Child Health and Development. We therefore performed a subgroup analysis to determine if there were any discrepancies in results between the facilities. There were no such differences, and the incidence of major malformation in the domperidone group did not higher than that in the control group at neither facility.
This study analyzed participants who received counseling at Toranomon Hospital after April 1988 and at National Center for Child Health and Development after October 2005. The use of imaging modalities to detect visceral malformations began in 1997. Therefore, it is presumed that since then it has been possible to detect even minor malformations, such as inconsequential heart defects. However, there was no significant difference in the incidence of major malformation at Toranomon Hospital between 1988 to 2004 and 2005 to 2016. Also, the data from National Center for Child Health and Development (2005–2017) yielded similar results as those from Toranomon Hospital (1988–2004). Thus, the timing of counseling is unlikely to be associated with the detection rate of malformation.
The package insert for domperidone states that it is contraindicated for use in pregnant women and in women suspected of being pregnant, due to teratogenicity observed in reproductive toxicity studies. This has led to the problem of pregnant women becoming anxious when they discover they have taken domperidone before finding out they were pregnant.
This observational cohort study was based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy. It showed that the risk of major malformation was not increased in women who received domperidone during pregnancy. However, it should be noted that a limitation of the study is that women could cancel their counseling if they had a miscarriage or abortion beforehand, resulting in underreported miscarriage or abortion cases.
In future counseling, this information is clinically very useful because it can reduce or eliminate the anxiety of patients who have taken domperidone during pregnancy. The Japanese clinical guidelines for obstetrics and gynecology (obstetrics portion) list domperidone as one of the “drugs that may be used by women in early pregnancy without having a clinically significant adverse effect on the fetus, even though the package inserts state that they are contraindicated in pregnant women.” 8 The results of this study support this statement in the guidelines.
Conflict of interest
Atsuko Murashima received lecture fees from Chugai Pharmaceutical Co.Ltd and Astellas Pharma Inc.
Supporting information
Table S1 Subgroup analysis by the facility
Click here for additional data file.
Table S2 Subgroup analysis by the year of counseling
Click here for additional data file.
Acknowledgments
This work was supported by a Research Program from the Japanese Agency for Medical Research and Development under Grant Number JP19mk0101086h0003, awarded to A.M. The authors would like to thank Dr. Kenjiro Kosaki and Dr. Rika Kosaki for their great advice in diagnosing congenital malformations and we would like to thank Mariko Takagai for her administrative assistance. They are also grateful to women who donated their clinical information and for colleagues worked as a member of Japan Teratology Information Services Network. | METOCLOPRAMIDE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33631840 | 19,020,093 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Atrioventricular septal defect'. | Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.
OBJECTIVE
To assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.
METHODS
Pregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.
RESULTS
The incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183).
CONCLUSIONS
This observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.
Introduction
Domperidone is an antidopaminergic benzimidazolone compound first synthesized by Janssen Pharmaceutica (Belgium) in 1974. Originally approved in Belgium in 1978, it has since been approved in over 100 countries, including in Japan in 1982. In Japan, domperidone has been widely used for the treatment of gastrointestinal symptoms such as nausea, vomiting, and anorexia.
In a study of domperidone administration during organogenesis in rats, skeletal and visceral malformations were observed in fetuses following an oral dose of 200 mg/kg or an intraperitoneal dose of ≥15 mg/kg. These observed malformations in rats occurred at approximately 300 times the daily oral dose for humans based on body weight. Due to these results, the package insert for domperidone in Japan states that it is contraindicated for use in pregnant women or women suspected of being pregnant.
In some cases, however, domperidone is prescribed for gastrointestinal symptoms such as nausea and vomiting to women who do not yet know they are pregnant due to the pregnancy being unplanned. In such cases, patients often become anxious when they find out they are pregnant and learn that domperidone is contraindicated.
Domperidone and metoclopramide are commonly used as antiemetic drugs in general clinical practice in Japan. Large‐scale epidemiological studies have shown that metoclopramide does not increase the risk of malformation 1 , 2 . On the other hand, teratogenic risk with domperidone has been reported in only a few small‐scale, cohort studies. A report by JS Choi et al. investigated 120 pregnancies treated with domperidone in the first trimester and concluded that domperidone is unlikely to be a major human teratogen 3 . Also, in an abstract, J Cottin et al. compared 124 pregnancies exposed to domperidone during organogenesis with those exposed to other antiemetics or nonteratogenic drugs 4 . There was no significant difference between the three groups in the incidence of major congenital malformations, but the authors commented that the small sample size was a limitation. A report on drug use during pregnancy in the French population stated that about 13% of all pregnant women were using domperidone 5 . Although the teratogenic risk of domperidone was not analyzed in that survey, it suggests that the drug is widely used by pregnant women in some countries.
In the present study, we evaluated the teratogenic risk of domperidone exposure during the first trimester. This is based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy.
Methods
Subjects
This study included women who consulted the Counseling Clinic for “Pregnancy and Medicine” of Toranomon Hospital or the Japan Drug Information Institute in Pregnancy of National Center for Child Health and Development regarding the safety of drugs during pregnancy. Pregnancy outcome data were extracted from the clinical databases of these facilities.
The inclusion criteria were pregnant women who consented to the study and with known pregnancy outcomes who took domperidone (domperidone group), or control drugs (control group) in the first trimester. Among these, women who used domperidone in combination with metoclopramide were excluded from the study. First trimester exposure was defined as drug use between the 28th and 97th days (4th week to 13th week of pregnancy) after the last menstrual period. Experts discussed and selected control drugs considered to be nonteratogenic, referring the report by F. Habermann et al. 6 Control drugs included acetaminophen, antihistamines that were reported in previous studies to have no increased risk of teratogenicity, anti‐infectives like penicillins and cephalosporins, histamine H2‐receptor (H2) blockers, digestive enzyme preparations, and topical drugs (e.g., eye drops, ointment, or cream). Metoclopramide is a similar drug and is expected to be used for the same diseases. In addition, it has been commonly used as an antiemetic drug in pregnant women. Therefore, although statistical comparison with the domperidone group was not performed, patients who took metoclopramide were defined as the reference group.
Data collection
For Toranomon Hospital, women who consulted the Counseling Clinic for “Pregnancy and Medicine” during pregnancy between April 1988 and December 2016 were included in the study. People who wished to make a counseling appointment were first required by the clinic to complete a pre‐appointment questionnaire regarding information such as the names and dosages of drugs taken during pregnancy and expected delivery date, and to return it by mail. At the time of counseling, subjects were interviewed to confirm their expected delivery dates and to obtain other information, including previous medical history, pregnancy and reproductive history, alcohol use, smoking, and family history. We asked patients who provided informed consent for study participation to complete a study questionnaire regarding pregnancy outcomes and any abnormalities during delivery, as well as sex, length, and weight at birth, and any abnormalities of the neonate, and to submit it by mail. If patients provided unclear answers about pregnancy outcomes, an obstetrician contacted their attending physician to obtain clarification. Information on pregnancy outcomes was collected about 1 month after delivery, and the survey was considered complete when this information was obtained.
At the National Center for Child Health and Development, women in pregnancy who sought consultation the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017 were included in the study. The Japan Drug Information Institute in Pregnancy was established under a program of the Ministry of Health Labour and Welfare in October 2005. People who wished to make a counseling appointment were required to complete a pre‐appointment questionnaire and to return it by mail. The pre‐appointment questions were on age, use of drugs during pregnancy, history of present illness, previous medical history, experience of pregnancy, reproductive history, alcohol use, smoking, and intake of folic acid. Approximately a month after their expected delivery date, patients who provided informed consent for participation in the study were sent a postcard‐type questionnaire on pregnancy outcomes and the 1‐month checkup results of their infants. In cases where pregnancy outcomes were unclear, research assistants, doctors or pharmacists contacted the women's attending obstetricians to confirm their pregnancy outcome by telephone. The survey was concluded when information on pregnancy outcomes had been obtained.
Primary endpoint and statistical analysis
The primary endpoint of this study was the incidence of major malformation. To assess the teratogenic risk of domperidone, we compared the incidence of major malformation in the domperidone group with the control group. Major malformations were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) 7 . In cases of congenital abnormalities not included in EUROCAT, a specialist in congenital abnormalities provided diagnoses. Two of the authors concluded that congenital abnormalities could be defined either as surficial malformations or as those requiring surgical treatment. Finally, two independent specialists confirmed the diagnoses.
The incidence of major malformation was analyzed in liveborn, single‐birth infants, and was calculated by dividing the number of liveborn singletons with congenital malformation by the number of all liveborn singletons analyzed in each group. This incidence was compared between the domperidone and control groups. Using the control group as the reference of odds ratio (ORs), the crude ORs of the incidence of major malformations in the domperidone group were calculated using univariable logistic regression analysis. In addition, adjusted ORs were calculated using multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling. Similarly, the crude and adjusted ORs of the incidence of major malformations in the metoclopramide group were calculated. In a subgroup analysis, adjusted ORs were calculated for each facility. The significance level of the test was 5%.
Ethics statement
This study was approved by the Ethics Committee of National Center for Child Health and Development and that of Toranomon Hospital. It was conducted according to the Declaration of Helsinki, and informed consent was obtained from all participants. Information collected from questionnaires was entered into the database and de‐identified by an information administrator. Therefore, the investigators were unable to identify individuals based on the analysis data.
Results
Patient characteristics
At Toranomon Hospital, 12 074 women consulted the Counseling Clinic for “Pregnancy and Medicine” between April 1988 and December 2016. Of these, 1422 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. At National Center for Child Health and Development, 12 971 women consulted the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017. Of these, 1011 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. In total, the number of participants was 519 in the domperidone group, 1673 in the control group, and 241 in the metoclopramide group (Figure 1).
Figure 1 Flowchart
The median age of the subjects at the time of counseling was 30 years in all groups and the groups showed no difference in age distribution. There were no notable differences between groups in either alcohol use or smoking habits, as shown in Table 1.
Table 1 Patient characteristics
Domperidone group Control group Metoclopramide group
n 519 1673 241
Age (year), n (%)
50% [25%, 75%] 30 [26, 33] 30 [27, 34] 30 [27, 34]
≦24 79 (15.2) 160 (9.6) 30 (12.4)
25–29 170 (32.8) 548 (32.8) 81 (33.6)
30–34 167 (32.2) 628 (37.5) 83 (34.4)
35–39 84 (16.2) 288 (17.2) 40 (16.6)
40≦ 18 (3.5) 46 (2.7) 6 (2.5)
NA 1 (0.2) 3 (0.2) 1 (0.4)
Alcohol, n (%)
No use 292 (56.3) 861 (51.5) 125 (51.9)
Stop before pregnancy 7 (1.3) 45 (2.7) 13 (5.4)
Stop after pregnancy 84 (16.2) 305 (18.2) 48 (19.9)
Ongoing 3 (0.6) 16 (1.0) 5 (2.1)
Unknown stop time 75 (14.5) 250 (14.9) 28 (11.6)
NA 58 (11.2) 196 (11.7) 22 (9.1)
Smoking, n (%)
No habit 390 (75.1) 1244 (74.4) 176 (73.0)
Stop before pregnancy 9 (1.7) 36 (2.2) 10 (4.1)
Stop after pregnancy 25 (4.8) 56 (3.3) 16 (6.6)
Ongoing 16 (3.1) 59 (3.5) 10 (4.1)
Unknown stop time 32 (6.2) 122 (7.3) 13 (5.4)
NA 47 (9.1) 156 (9.3) 16 (6.6)
Abbreviation: NA, not available.
Delivery outcomes and incidence of major malformations
Delivery outcomes were aggregated for all subjects. The percentage of liveborn infants was 94.0% (488 cases) in the domperidone group, 93.8% (1570 cases) in the control group, and 94.2% (227 cases) in the metoclopramide group. There were no notable differences in the incidences of stillbirth, miscarriage or abortion between the three groups (Table 2).
Table 2 Pregnancy outcomes
Domperidone group Control group Metoclopramide group
n 519 1673 241
Outcome, n (%)
Live birth 488 (94.0) 1570 (93.8) 227 (94.2)
Stillbirth a 3 (0.6) 7 (0.4) 0 (0.0)
Miscarriage 18 (3.5) 80 (4.8) 8 (3.3)
Abortion 10 (1.9) 15 (0.9) 6 (2.5)
Other 0 (0.0) 1 b (0.1) 0 (0.0)
Number of infant, n (%)
1 506 (97.5) 1627 (97.3) 234 (97.1)
2≦ 1 (0.2) 9 (0.5) 3 (1.2)
NA 12 (2.3) 37 (2.2) 4 (1.7)
Abbreviation: NA, not available.
a Fetal death after 22 weeks gestation was defined as stillbirth.
b Ectopic pregnancy.
Major malformations in liveborn, single‐birth infants occurred in 14 cases in the domperidone group, 27 in the control group, and 8 in the metoclopramide group (Table 3). There was no pattern of malformation types between the three groups.
Table 3 Risk of major malformation
Major malformation 95%CI Crude OR (95%CI) p‐Value a Adjusted OR b (95%CI) p‐Value a
No Yes
Control group (n = 1554) 1527 27 c (1.7%) (1.1–2.5) 1 ‐ 1 ‐
Domperidone group (n = 485) 471 14 d (2.9%) (1.6–4.8) 1.68 (0.87–3.23) 0.119 1.86 (0.73–4.70) 0.191
Metoclopramide group (n = 224) 216 8 e (3.6%) (1.6–6.9) 2.09 (0.94–4.67) 0.071 2.20 (0.69–6.98) 0.183
Risk of major malformation was analyzed in liveborn, single‐birth infants.
Abbreviations: CI, confidence interval; OR, odds ratio.
a Significance level p < 0.05, *<0.05.
b Adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling.
c Ventricular septal defect (6); ventricular and atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); peripheral pulmonary stenosis (1); endocardial cushion defect (1); complete transposition of great arteries (1); double outlet right ventricle (1); esophageal atresia (1); cleft lip (1); diastasis recti (1); adhesion of scrotum and penis (1); hydronephrosis (2); imperforate anus (1); talipes varus (1); polydactyly (3); a combination of coarctation of the aorta and ventricular septal defect (1); a combination of single ventricle and pulmonary stenosis (1); a combination of ventricular septal defect, pulmonary stenosis and syndactyly (1).
d Ventricular septal defect (5); ventricular and atrial septal defect (1); atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); cleft lip and palate (1); double vagina (1); hydroureteropathy (1); hydronephrosis (1); a combination of duodenal obstruction, heart disease, upper aortic malposition and pulmonary artery occlusion (1).
e Ventricular septal defect (1); endocardial cushion defect (1); myelomeningocele (1); lissencephaly (1); hypospadias (1); talipes varus (1); polydactyly (1); scalp defect (1).
Risk of major malformation
The incidence of major malformation in liveborn, single‐birth infants (95% confidence interval [CI]) was 2.9% (14/485, 95%CI: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group.
Univariable logistic regression analysis showed no significant difference in the incidence of major malformation between the domperidone and control groups (OR: 1.68 [95% CI: 0.87–3.23], p = 0.119). Additionally, multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling also showed no significant difference in the incidence of major malformation between the domperidone and control groups (adjusted OR: 1.86 [95% CI: 0.73–4.70], p = 0.191) (Table 3). Similar results were obtained when comparing the metoclopramide and control groups (OR: 2.09 [95% CI: 0.94–4.67], p = 0.071; adjusted OR: 2.20 [95% CI: 0.69–6.98], p = 0.183).
Subgroup analysis
For the cases at Toranomon Hospital, the adjusted OR (95%CI) of the incidence of major malformation was 2.54 (95%CI: 0.68–9.46, p = 0.164) in the domperidone group and 2.54 (95%CI: 0.47–13.82, p = 0.282) in the metoclopramide group, indicating no significant difference for either group compared with the control group.
For the cases at National Center for Child Health and Development, the adjusted OR (95%CI) of the incidence of major malformation was 1.45 (95%CI: 0.38–5.54, p = 0.583) in the domperidone group and 2.06 (95%CI: 0.43–9.98, p = 0.370) in the metoclopramide group, again indicating no significant difference for either group compared with the control group (Supporting Information, Table SS1).
We also compared the adjusted OR of risk of major malformations by the year of counseling (Table SS2). To rule out the year of counseling as a possible confounding factor, we compared the first half of the data from Toranomon Hospital (1988–2004), to the second half (2005–2016) (adjusted OR: 0.79 [95%CI: 0.26–2.39], p = 0.680) and to the data from the National Center for Child Health and Development (2005–2017) (adjusted OR: 1.34 [95%CI: 0.69–2.60], p = 0.381), and found no significant differences in the adjusted OR.
Discussion
Although there are prior reports 3 , 4 of domperidone administered to pregnant women, those studies lacked sufficient detection power to ensure that domperidone exposure is not harmful to the fetus. Therefore, no information has been available to ensure the safety of using domperidone in pregnant women.
In this study, the 485 patients who received domperidone during the first trimester of pregnancy showed no increase in the incidence of major malformation compared with patients in the control group, who received drugs that are considered to have no teratogenicity. In addition, no difference was found in the results of a sensitivity analysis that assessed teratogenic risk by excluding patients who used teratogenic drugs defined by the clinical guidelines for gynecology and obstetrics 8 .
This study enrolled pregnant women who consulted at Toranomon Hospital or the National Center for Child Health and Development. We therefore performed a subgroup analysis to determine if there were any discrepancies in results between the facilities. There were no such differences, and the incidence of major malformation in the domperidone group did not higher than that in the control group at neither facility.
This study analyzed participants who received counseling at Toranomon Hospital after April 1988 and at National Center for Child Health and Development after October 2005. The use of imaging modalities to detect visceral malformations began in 1997. Therefore, it is presumed that since then it has been possible to detect even minor malformations, such as inconsequential heart defects. However, there was no significant difference in the incidence of major malformation at Toranomon Hospital between 1988 to 2004 and 2005 to 2016. Also, the data from National Center for Child Health and Development (2005–2017) yielded similar results as those from Toranomon Hospital (1988–2004). Thus, the timing of counseling is unlikely to be associated with the detection rate of malformation.
The package insert for domperidone states that it is contraindicated for use in pregnant women and in women suspected of being pregnant, due to teratogenicity observed in reproductive toxicity studies. This has led to the problem of pregnant women becoming anxious when they discover they have taken domperidone before finding out they were pregnant.
This observational cohort study was based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy. It showed that the risk of major malformation was not increased in women who received domperidone during pregnancy. However, it should be noted that a limitation of the study is that women could cancel their counseling if they had a miscarriage or abortion beforehand, resulting in underreported miscarriage or abortion cases.
In future counseling, this information is clinically very useful because it can reduce or eliminate the anxiety of patients who have taken domperidone during pregnancy. The Japanese clinical guidelines for obstetrics and gynecology (obstetrics portion) list domperidone as one of the “drugs that may be used by women in early pregnancy without having a clinically significant adverse effect on the fetus, even though the package inserts state that they are contraindicated in pregnant women.” 8 The results of this study support this statement in the guidelines.
Conflict of interest
Atsuko Murashima received lecture fees from Chugai Pharmaceutical Co.Ltd and Astellas Pharma Inc.
Supporting information
Table S1 Subgroup analysis by the facility
Click here for additional data file.
Table S2 Subgroup analysis by the year of counseling
Click here for additional data file.
Acknowledgments
This work was supported by a Research Program from the Japanese Agency for Medical Research and Development under Grant Number JP19mk0101086h0003, awarded to A.M. The authors would like to thank Dr. Kenjiro Kosaki and Dr. Rika Kosaki for their great advice in diagnosing congenital malformations and we would like to thank Mariko Takagai for her administrative assistance. They are also grateful to women who donated their clinical information and for colleagues worked as a member of Japan Teratology Information Services Network. | METOCLOPRAMIDE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33631840 | 19,020,387 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Craniofacial deformity'. | Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.
OBJECTIVE
To assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.
METHODS
Pregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.
RESULTS
The incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183).
CONCLUSIONS
This observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.
Introduction
Domperidone is an antidopaminergic benzimidazolone compound first synthesized by Janssen Pharmaceutica (Belgium) in 1974. Originally approved in Belgium in 1978, it has since been approved in over 100 countries, including in Japan in 1982. In Japan, domperidone has been widely used for the treatment of gastrointestinal symptoms such as nausea, vomiting, and anorexia.
In a study of domperidone administration during organogenesis in rats, skeletal and visceral malformations were observed in fetuses following an oral dose of 200 mg/kg or an intraperitoneal dose of ≥15 mg/kg. These observed malformations in rats occurred at approximately 300 times the daily oral dose for humans based on body weight. Due to these results, the package insert for domperidone in Japan states that it is contraindicated for use in pregnant women or women suspected of being pregnant.
In some cases, however, domperidone is prescribed for gastrointestinal symptoms such as nausea and vomiting to women who do not yet know they are pregnant due to the pregnancy being unplanned. In such cases, patients often become anxious when they find out they are pregnant and learn that domperidone is contraindicated.
Domperidone and metoclopramide are commonly used as antiemetic drugs in general clinical practice in Japan. Large‐scale epidemiological studies have shown that metoclopramide does not increase the risk of malformation 1 , 2 . On the other hand, teratogenic risk with domperidone has been reported in only a few small‐scale, cohort studies. A report by JS Choi et al. investigated 120 pregnancies treated with domperidone in the first trimester and concluded that domperidone is unlikely to be a major human teratogen 3 . Also, in an abstract, J Cottin et al. compared 124 pregnancies exposed to domperidone during organogenesis with those exposed to other antiemetics or nonteratogenic drugs 4 . There was no significant difference between the three groups in the incidence of major congenital malformations, but the authors commented that the small sample size was a limitation. A report on drug use during pregnancy in the French population stated that about 13% of all pregnant women were using domperidone 5 . Although the teratogenic risk of domperidone was not analyzed in that survey, it suggests that the drug is widely used by pregnant women in some countries.
In the present study, we evaluated the teratogenic risk of domperidone exposure during the first trimester. This is based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy.
Methods
Subjects
This study included women who consulted the Counseling Clinic for “Pregnancy and Medicine” of Toranomon Hospital or the Japan Drug Information Institute in Pregnancy of National Center for Child Health and Development regarding the safety of drugs during pregnancy. Pregnancy outcome data were extracted from the clinical databases of these facilities.
The inclusion criteria were pregnant women who consented to the study and with known pregnancy outcomes who took domperidone (domperidone group), or control drugs (control group) in the first trimester. Among these, women who used domperidone in combination with metoclopramide were excluded from the study. First trimester exposure was defined as drug use between the 28th and 97th days (4th week to 13th week of pregnancy) after the last menstrual period. Experts discussed and selected control drugs considered to be nonteratogenic, referring the report by F. Habermann et al. 6 Control drugs included acetaminophen, antihistamines that were reported in previous studies to have no increased risk of teratogenicity, anti‐infectives like penicillins and cephalosporins, histamine H2‐receptor (H2) blockers, digestive enzyme preparations, and topical drugs (e.g., eye drops, ointment, or cream). Metoclopramide is a similar drug and is expected to be used for the same diseases. In addition, it has been commonly used as an antiemetic drug in pregnant women. Therefore, although statistical comparison with the domperidone group was not performed, patients who took metoclopramide were defined as the reference group.
Data collection
For Toranomon Hospital, women who consulted the Counseling Clinic for “Pregnancy and Medicine” during pregnancy between April 1988 and December 2016 were included in the study. People who wished to make a counseling appointment were first required by the clinic to complete a pre‐appointment questionnaire regarding information such as the names and dosages of drugs taken during pregnancy and expected delivery date, and to return it by mail. At the time of counseling, subjects were interviewed to confirm their expected delivery dates and to obtain other information, including previous medical history, pregnancy and reproductive history, alcohol use, smoking, and family history. We asked patients who provided informed consent for study participation to complete a study questionnaire regarding pregnancy outcomes and any abnormalities during delivery, as well as sex, length, and weight at birth, and any abnormalities of the neonate, and to submit it by mail. If patients provided unclear answers about pregnancy outcomes, an obstetrician contacted their attending physician to obtain clarification. Information on pregnancy outcomes was collected about 1 month after delivery, and the survey was considered complete when this information was obtained.
At the National Center for Child Health and Development, women in pregnancy who sought consultation the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017 were included in the study. The Japan Drug Information Institute in Pregnancy was established under a program of the Ministry of Health Labour and Welfare in October 2005. People who wished to make a counseling appointment were required to complete a pre‐appointment questionnaire and to return it by mail. The pre‐appointment questions were on age, use of drugs during pregnancy, history of present illness, previous medical history, experience of pregnancy, reproductive history, alcohol use, smoking, and intake of folic acid. Approximately a month after their expected delivery date, patients who provided informed consent for participation in the study were sent a postcard‐type questionnaire on pregnancy outcomes and the 1‐month checkup results of their infants. In cases where pregnancy outcomes were unclear, research assistants, doctors or pharmacists contacted the women's attending obstetricians to confirm their pregnancy outcome by telephone. The survey was concluded when information on pregnancy outcomes had been obtained.
Primary endpoint and statistical analysis
The primary endpoint of this study was the incidence of major malformation. To assess the teratogenic risk of domperidone, we compared the incidence of major malformation in the domperidone group with the control group. Major malformations were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) 7 . In cases of congenital abnormalities not included in EUROCAT, a specialist in congenital abnormalities provided diagnoses. Two of the authors concluded that congenital abnormalities could be defined either as surficial malformations or as those requiring surgical treatment. Finally, two independent specialists confirmed the diagnoses.
The incidence of major malformation was analyzed in liveborn, single‐birth infants, and was calculated by dividing the number of liveborn singletons with congenital malformation by the number of all liveborn singletons analyzed in each group. This incidence was compared between the domperidone and control groups. Using the control group as the reference of odds ratio (ORs), the crude ORs of the incidence of major malformations in the domperidone group were calculated using univariable logistic regression analysis. In addition, adjusted ORs were calculated using multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling. Similarly, the crude and adjusted ORs of the incidence of major malformations in the metoclopramide group were calculated. In a subgroup analysis, adjusted ORs were calculated for each facility. The significance level of the test was 5%.
Ethics statement
This study was approved by the Ethics Committee of National Center for Child Health and Development and that of Toranomon Hospital. It was conducted according to the Declaration of Helsinki, and informed consent was obtained from all participants. Information collected from questionnaires was entered into the database and de‐identified by an information administrator. Therefore, the investigators were unable to identify individuals based on the analysis data.
Results
Patient characteristics
At Toranomon Hospital, 12 074 women consulted the Counseling Clinic for “Pregnancy and Medicine” between April 1988 and December 2016. Of these, 1422 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. At National Center for Child Health and Development, 12 971 women consulted the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017. Of these, 1011 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. In total, the number of participants was 519 in the domperidone group, 1673 in the control group, and 241 in the metoclopramide group (Figure 1).
Figure 1 Flowchart
The median age of the subjects at the time of counseling was 30 years in all groups and the groups showed no difference in age distribution. There were no notable differences between groups in either alcohol use or smoking habits, as shown in Table 1.
Table 1 Patient characteristics
Domperidone group Control group Metoclopramide group
n 519 1673 241
Age (year), n (%)
50% [25%, 75%] 30 [26, 33] 30 [27, 34] 30 [27, 34]
≦24 79 (15.2) 160 (9.6) 30 (12.4)
25–29 170 (32.8) 548 (32.8) 81 (33.6)
30–34 167 (32.2) 628 (37.5) 83 (34.4)
35–39 84 (16.2) 288 (17.2) 40 (16.6)
40≦ 18 (3.5) 46 (2.7) 6 (2.5)
NA 1 (0.2) 3 (0.2) 1 (0.4)
Alcohol, n (%)
No use 292 (56.3) 861 (51.5) 125 (51.9)
Stop before pregnancy 7 (1.3) 45 (2.7) 13 (5.4)
Stop after pregnancy 84 (16.2) 305 (18.2) 48 (19.9)
Ongoing 3 (0.6) 16 (1.0) 5 (2.1)
Unknown stop time 75 (14.5) 250 (14.9) 28 (11.6)
NA 58 (11.2) 196 (11.7) 22 (9.1)
Smoking, n (%)
No habit 390 (75.1) 1244 (74.4) 176 (73.0)
Stop before pregnancy 9 (1.7) 36 (2.2) 10 (4.1)
Stop after pregnancy 25 (4.8) 56 (3.3) 16 (6.6)
Ongoing 16 (3.1) 59 (3.5) 10 (4.1)
Unknown stop time 32 (6.2) 122 (7.3) 13 (5.4)
NA 47 (9.1) 156 (9.3) 16 (6.6)
Abbreviation: NA, not available.
Delivery outcomes and incidence of major malformations
Delivery outcomes were aggregated for all subjects. The percentage of liveborn infants was 94.0% (488 cases) in the domperidone group, 93.8% (1570 cases) in the control group, and 94.2% (227 cases) in the metoclopramide group. There were no notable differences in the incidences of stillbirth, miscarriage or abortion between the three groups (Table 2).
Table 2 Pregnancy outcomes
Domperidone group Control group Metoclopramide group
n 519 1673 241
Outcome, n (%)
Live birth 488 (94.0) 1570 (93.8) 227 (94.2)
Stillbirth a 3 (0.6) 7 (0.4) 0 (0.0)
Miscarriage 18 (3.5) 80 (4.8) 8 (3.3)
Abortion 10 (1.9) 15 (0.9) 6 (2.5)
Other 0 (0.0) 1 b (0.1) 0 (0.0)
Number of infant, n (%)
1 506 (97.5) 1627 (97.3) 234 (97.1)
2≦ 1 (0.2) 9 (0.5) 3 (1.2)
NA 12 (2.3) 37 (2.2) 4 (1.7)
Abbreviation: NA, not available.
a Fetal death after 22 weeks gestation was defined as stillbirth.
b Ectopic pregnancy.
Major malformations in liveborn, single‐birth infants occurred in 14 cases in the domperidone group, 27 in the control group, and 8 in the metoclopramide group (Table 3). There was no pattern of malformation types between the three groups.
Table 3 Risk of major malformation
Major malformation 95%CI Crude OR (95%CI) p‐Value a Adjusted OR b (95%CI) p‐Value a
No Yes
Control group (n = 1554) 1527 27 c (1.7%) (1.1–2.5) 1 ‐ 1 ‐
Domperidone group (n = 485) 471 14 d (2.9%) (1.6–4.8) 1.68 (0.87–3.23) 0.119 1.86 (0.73–4.70) 0.191
Metoclopramide group (n = 224) 216 8 e (3.6%) (1.6–6.9) 2.09 (0.94–4.67) 0.071 2.20 (0.69–6.98) 0.183
Risk of major malformation was analyzed in liveborn, single‐birth infants.
Abbreviations: CI, confidence interval; OR, odds ratio.
a Significance level p < 0.05, *<0.05.
b Adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling.
c Ventricular septal defect (6); ventricular and atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); peripheral pulmonary stenosis (1); endocardial cushion defect (1); complete transposition of great arteries (1); double outlet right ventricle (1); esophageal atresia (1); cleft lip (1); diastasis recti (1); adhesion of scrotum and penis (1); hydronephrosis (2); imperforate anus (1); talipes varus (1); polydactyly (3); a combination of coarctation of the aorta and ventricular septal defect (1); a combination of single ventricle and pulmonary stenosis (1); a combination of ventricular septal defect, pulmonary stenosis and syndactyly (1).
d Ventricular septal defect (5); ventricular and atrial septal defect (1); atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); cleft lip and palate (1); double vagina (1); hydroureteropathy (1); hydronephrosis (1); a combination of duodenal obstruction, heart disease, upper aortic malposition and pulmonary artery occlusion (1).
e Ventricular septal defect (1); endocardial cushion defect (1); myelomeningocele (1); lissencephaly (1); hypospadias (1); talipes varus (1); polydactyly (1); scalp defect (1).
Risk of major malformation
The incidence of major malformation in liveborn, single‐birth infants (95% confidence interval [CI]) was 2.9% (14/485, 95%CI: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group.
Univariable logistic regression analysis showed no significant difference in the incidence of major malformation between the domperidone and control groups (OR: 1.68 [95% CI: 0.87–3.23], p = 0.119). Additionally, multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling also showed no significant difference in the incidence of major malformation between the domperidone and control groups (adjusted OR: 1.86 [95% CI: 0.73–4.70], p = 0.191) (Table 3). Similar results were obtained when comparing the metoclopramide and control groups (OR: 2.09 [95% CI: 0.94–4.67], p = 0.071; adjusted OR: 2.20 [95% CI: 0.69–6.98], p = 0.183).
Subgroup analysis
For the cases at Toranomon Hospital, the adjusted OR (95%CI) of the incidence of major malformation was 2.54 (95%CI: 0.68–9.46, p = 0.164) in the domperidone group and 2.54 (95%CI: 0.47–13.82, p = 0.282) in the metoclopramide group, indicating no significant difference for either group compared with the control group.
For the cases at National Center for Child Health and Development, the adjusted OR (95%CI) of the incidence of major malformation was 1.45 (95%CI: 0.38–5.54, p = 0.583) in the domperidone group and 2.06 (95%CI: 0.43–9.98, p = 0.370) in the metoclopramide group, again indicating no significant difference for either group compared with the control group (Supporting Information, Table SS1).
We also compared the adjusted OR of risk of major malformations by the year of counseling (Table SS2). To rule out the year of counseling as a possible confounding factor, we compared the first half of the data from Toranomon Hospital (1988–2004), to the second half (2005–2016) (adjusted OR: 0.79 [95%CI: 0.26–2.39], p = 0.680) and to the data from the National Center for Child Health and Development (2005–2017) (adjusted OR: 1.34 [95%CI: 0.69–2.60], p = 0.381), and found no significant differences in the adjusted OR.
Discussion
Although there are prior reports 3 , 4 of domperidone administered to pregnant women, those studies lacked sufficient detection power to ensure that domperidone exposure is not harmful to the fetus. Therefore, no information has been available to ensure the safety of using domperidone in pregnant women.
In this study, the 485 patients who received domperidone during the first trimester of pregnancy showed no increase in the incidence of major malformation compared with patients in the control group, who received drugs that are considered to have no teratogenicity. In addition, no difference was found in the results of a sensitivity analysis that assessed teratogenic risk by excluding patients who used teratogenic drugs defined by the clinical guidelines for gynecology and obstetrics 8 .
This study enrolled pregnant women who consulted at Toranomon Hospital or the National Center for Child Health and Development. We therefore performed a subgroup analysis to determine if there were any discrepancies in results between the facilities. There were no such differences, and the incidence of major malformation in the domperidone group did not higher than that in the control group at neither facility.
This study analyzed participants who received counseling at Toranomon Hospital after April 1988 and at National Center for Child Health and Development after October 2005. The use of imaging modalities to detect visceral malformations began in 1997. Therefore, it is presumed that since then it has been possible to detect even minor malformations, such as inconsequential heart defects. However, there was no significant difference in the incidence of major malformation at Toranomon Hospital between 1988 to 2004 and 2005 to 2016. Also, the data from National Center for Child Health and Development (2005–2017) yielded similar results as those from Toranomon Hospital (1988–2004). Thus, the timing of counseling is unlikely to be associated with the detection rate of malformation.
The package insert for domperidone states that it is contraindicated for use in pregnant women and in women suspected of being pregnant, due to teratogenicity observed in reproductive toxicity studies. This has led to the problem of pregnant women becoming anxious when they discover they have taken domperidone before finding out they were pregnant.
This observational cohort study was based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy. It showed that the risk of major malformation was not increased in women who received domperidone during pregnancy. However, it should be noted that a limitation of the study is that women could cancel their counseling if they had a miscarriage or abortion beforehand, resulting in underreported miscarriage or abortion cases.
In future counseling, this information is clinically very useful because it can reduce or eliminate the anxiety of patients who have taken domperidone during pregnancy. The Japanese clinical guidelines for obstetrics and gynecology (obstetrics portion) list domperidone as one of the “drugs that may be used by women in early pregnancy without having a clinically significant adverse effect on the fetus, even though the package inserts state that they are contraindicated in pregnant women.” 8 The results of this study support this statement in the guidelines.
Conflict of interest
Atsuko Murashima received lecture fees from Chugai Pharmaceutical Co.Ltd and Astellas Pharma Inc.
Supporting information
Table S1 Subgroup analysis by the facility
Click here for additional data file.
Table S2 Subgroup analysis by the year of counseling
Click here for additional data file.
Acknowledgments
This work was supported by a Research Program from the Japanese Agency for Medical Research and Development under Grant Number JP19mk0101086h0003, awarded to A.M. The authors would like to thank Dr. Kenjiro Kosaki and Dr. Rika Kosaki for their great advice in diagnosing congenital malformations and we would like to thank Mariko Takagai for her administrative assistance. They are also grateful to women who donated their clinical information and for colleagues worked as a member of Japan Teratology Information Services Network. | METOCLOPRAMIDE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33631840 | 19,022,419 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'. | Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.
OBJECTIVE
To assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.
METHODS
Pregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.
RESULTS
The incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183).
CONCLUSIONS
This observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.
Introduction
Domperidone is an antidopaminergic benzimidazolone compound first synthesized by Janssen Pharmaceutica (Belgium) in 1974. Originally approved in Belgium in 1978, it has since been approved in over 100 countries, including in Japan in 1982. In Japan, domperidone has been widely used for the treatment of gastrointestinal symptoms such as nausea, vomiting, and anorexia.
In a study of domperidone administration during organogenesis in rats, skeletal and visceral malformations were observed in fetuses following an oral dose of 200 mg/kg or an intraperitoneal dose of ≥15 mg/kg. These observed malformations in rats occurred at approximately 300 times the daily oral dose for humans based on body weight. Due to these results, the package insert for domperidone in Japan states that it is contraindicated for use in pregnant women or women suspected of being pregnant.
In some cases, however, domperidone is prescribed for gastrointestinal symptoms such as nausea and vomiting to women who do not yet know they are pregnant due to the pregnancy being unplanned. In such cases, patients often become anxious when they find out they are pregnant and learn that domperidone is contraindicated.
Domperidone and metoclopramide are commonly used as antiemetic drugs in general clinical practice in Japan. Large‐scale epidemiological studies have shown that metoclopramide does not increase the risk of malformation 1 , 2 . On the other hand, teratogenic risk with domperidone has been reported in only a few small‐scale, cohort studies. A report by JS Choi et al. investigated 120 pregnancies treated with domperidone in the first trimester and concluded that domperidone is unlikely to be a major human teratogen 3 . Also, in an abstract, J Cottin et al. compared 124 pregnancies exposed to domperidone during organogenesis with those exposed to other antiemetics or nonteratogenic drugs 4 . There was no significant difference between the three groups in the incidence of major congenital malformations, but the authors commented that the small sample size was a limitation. A report on drug use during pregnancy in the French population stated that about 13% of all pregnant women were using domperidone 5 . Although the teratogenic risk of domperidone was not analyzed in that survey, it suggests that the drug is widely used by pregnant women in some countries.
In the present study, we evaluated the teratogenic risk of domperidone exposure during the first trimester. This is based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy.
Methods
Subjects
This study included women who consulted the Counseling Clinic for “Pregnancy and Medicine” of Toranomon Hospital or the Japan Drug Information Institute in Pregnancy of National Center for Child Health and Development regarding the safety of drugs during pregnancy. Pregnancy outcome data were extracted from the clinical databases of these facilities.
The inclusion criteria were pregnant women who consented to the study and with known pregnancy outcomes who took domperidone (domperidone group), or control drugs (control group) in the first trimester. Among these, women who used domperidone in combination with metoclopramide were excluded from the study. First trimester exposure was defined as drug use between the 28th and 97th days (4th week to 13th week of pregnancy) after the last menstrual period. Experts discussed and selected control drugs considered to be nonteratogenic, referring the report by F. Habermann et al. 6 Control drugs included acetaminophen, antihistamines that were reported in previous studies to have no increased risk of teratogenicity, anti‐infectives like penicillins and cephalosporins, histamine H2‐receptor (H2) blockers, digestive enzyme preparations, and topical drugs (e.g., eye drops, ointment, or cream). Metoclopramide is a similar drug and is expected to be used for the same diseases. In addition, it has been commonly used as an antiemetic drug in pregnant women. Therefore, although statistical comparison with the domperidone group was not performed, patients who took metoclopramide were defined as the reference group.
Data collection
For Toranomon Hospital, women who consulted the Counseling Clinic for “Pregnancy and Medicine” during pregnancy between April 1988 and December 2016 were included in the study. People who wished to make a counseling appointment were first required by the clinic to complete a pre‐appointment questionnaire regarding information such as the names and dosages of drugs taken during pregnancy and expected delivery date, and to return it by mail. At the time of counseling, subjects were interviewed to confirm their expected delivery dates and to obtain other information, including previous medical history, pregnancy and reproductive history, alcohol use, smoking, and family history. We asked patients who provided informed consent for study participation to complete a study questionnaire regarding pregnancy outcomes and any abnormalities during delivery, as well as sex, length, and weight at birth, and any abnormalities of the neonate, and to submit it by mail. If patients provided unclear answers about pregnancy outcomes, an obstetrician contacted their attending physician to obtain clarification. Information on pregnancy outcomes was collected about 1 month after delivery, and the survey was considered complete when this information was obtained.
At the National Center for Child Health and Development, women in pregnancy who sought consultation the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017 were included in the study. The Japan Drug Information Institute in Pregnancy was established under a program of the Ministry of Health Labour and Welfare in October 2005. People who wished to make a counseling appointment were required to complete a pre‐appointment questionnaire and to return it by mail. The pre‐appointment questions were on age, use of drugs during pregnancy, history of present illness, previous medical history, experience of pregnancy, reproductive history, alcohol use, smoking, and intake of folic acid. Approximately a month after their expected delivery date, patients who provided informed consent for participation in the study were sent a postcard‐type questionnaire on pregnancy outcomes and the 1‐month checkup results of their infants. In cases where pregnancy outcomes were unclear, research assistants, doctors or pharmacists contacted the women's attending obstetricians to confirm their pregnancy outcome by telephone. The survey was concluded when information on pregnancy outcomes had been obtained.
Primary endpoint and statistical analysis
The primary endpoint of this study was the incidence of major malformation. To assess the teratogenic risk of domperidone, we compared the incidence of major malformation in the domperidone group with the control group. Major malformations were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) 7 . In cases of congenital abnormalities not included in EUROCAT, a specialist in congenital abnormalities provided diagnoses. Two of the authors concluded that congenital abnormalities could be defined either as surficial malformations or as those requiring surgical treatment. Finally, two independent specialists confirmed the diagnoses.
The incidence of major malformation was analyzed in liveborn, single‐birth infants, and was calculated by dividing the number of liveborn singletons with congenital malformation by the number of all liveborn singletons analyzed in each group. This incidence was compared between the domperidone and control groups. Using the control group as the reference of odds ratio (ORs), the crude ORs of the incidence of major malformations in the domperidone group were calculated using univariable logistic regression analysis. In addition, adjusted ORs were calculated using multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling. Similarly, the crude and adjusted ORs of the incidence of major malformations in the metoclopramide group were calculated. In a subgroup analysis, adjusted ORs were calculated for each facility. The significance level of the test was 5%.
Ethics statement
This study was approved by the Ethics Committee of National Center for Child Health and Development and that of Toranomon Hospital. It was conducted according to the Declaration of Helsinki, and informed consent was obtained from all participants. Information collected from questionnaires was entered into the database and de‐identified by an information administrator. Therefore, the investigators were unable to identify individuals based on the analysis data.
Results
Patient characteristics
At Toranomon Hospital, 12 074 women consulted the Counseling Clinic for “Pregnancy and Medicine” between April 1988 and December 2016. Of these, 1422 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. At National Center for Child Health and Development, 12 971 women consulted the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017. Of these, 1011 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. In total, the number of participants was 519 in the domperidone group, 1673 in the control group, and 241 in the metoclopramide group (Figure 1).
Figure 1 Flowchart
The median age of the subjects at the time of counseling was 30 years in all groups and the groups showed no difference in age distribution. There were no notable differences between groups in either alcohol use or smoking habits, as shown in Table 1.
Table 1 Patient characteristics
Domperidone group Control group Metoclopramide group
n 519 1673 241
Age (year), n (%)
50% [25%, 75%] 30 [26, 33] 30 [27, 34] 30 [27, 34]
≦24 79 (15.2) 160 (9.6) 30 (12.4)
25–29 170 (32.8) 548 (32.8) 81 (33.6)
30–34 167 (32.2) 628 (37.5) 83 (34.4)
35–39 84 (16.2) 288 (17.2) 40 (16.6)
40≦ 18 (3.5) 46 (2.7) 6 (2.5)
NA 1 (0.2) 3 (0.2) 1 (0.4)
Alcohol, n (%)
No use 292 (56.3) 861 (51.5) 125 (51.9)
Stop before pregnancy 7 (1.3) 45 (2.7) 13 (5.4)
Stop after pregnancy 84 (16.2) 305 (18.2) 48 (19.9)
Ongoing 3 (0.6) 16 (1.0) 5 (2.1)
Unknown stop time 75 (14.5) 250 (14.9) 28 (11.6)
NA 58 (11.2) 196 (11.7) 22 (9.1)
Smoking, n (%)
No habit 390 (75.1) 1244 (74.4) 176 (73.0)
Stop before pregnancy 9 (1.7) 36 (2.2) 10 (4.1)
Stop after pregnancy 25 (4.8) 56 (3.3) 16 (6.6)
Ongoing 16 (3.1) 59 (3.5) 10 (4.1)
Unknown stop time 32 (6.2) 122 (7.3) 13 (5.4)
NA 47 (9.1) 156 (9.3) 16 (6.6)
Abbreviation: NA, not available.
Delivery outcomes and incidence of major malformations
Delivery outcomes were aggregated for all subjects. The percentage of liveborn infants was 94.0% (488 cases) in the domperidone group, 93.8% (1570 cases) in the control group, and 94.2% (227 cases) in the metoclopramide group. There were no notable differences in the incidences of stillbirth, miscarriage or abortion between the three groups (Table 2).
Table 2 Pregnancy outcomes
Domperidone group Control group Metoclopramide group
n 519 1673 241
Outcome, n (%)
Live birth 488 (94.0) 1570 (93.8) 227 (94.2)
Stillbirth a 3 (0.6) 7 (0.4) 0 (0.0)
Miscarriage 18 (3.5) 80 (4.8) 8 (3.3)
Abortion 10 (1.9) 15 (0.9) 6 (2.5)
Other 0 (0.0) 1 b (0.1) 0 (0.0)
Number of infant, n (%)
1 506 (97.5) 1627 (97.3) 234 (97.1)
2≦ 1 (0.2) 9 (0.5) 3 (1.2)
NA 12 (2.3) 37 (2.2) 4 (1.7)
Abbreviation: NA, not available.
a Fetal death after 22 weeks gestation was defined as stillbirth.
b Ectopic pregnancy.
Major malformations in liveborn, single‐birth infants occurred in 14 cases in the domperidone group, 27 in the control group, and 8 in the metoclopramide group (Table 3). There was no pattern of malformation types between the three groups.
Table 3 Risk of major malformation
Major malformation 95%CI Crude OR (95%CI) p‐Value a Adjusted OR b (95%CI) p‐Value a
No Yes
Control group (n = 1554) 1527 27 c (1.7%) (1.1–2.5) 1 ‐ 1 ‐
Domperidone group (n = 485) 471 14 d (2.9%) (1.6–4.8) 1.68 (0.87–3.23) 0.119 1.86 (0.73–4.70) 0.191
Metoclopramide group (n = 224) 216 8 e (3.6%) (1.6–6.9) 2.09 (0.94–4.67) 0.071 2.20 (0.69–6.98) 0.183
Risk of major malformation was analyzed in liveborn, single‐birth infants.
Abbreviations: CI, confidence interval; OR, odds ratio.
a Significance level p < 0.05, *<0.05.
b Adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling.
c Ventricular septal defect (6); ventricular and atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); peripheral pulmonary stenosis (1); endocardial cushion defect (1); complete transposition of great arteries (1); double outlet right ventricle (1); esophageal atresia (1); cleft lip (1); diastasis recti (1); adhesion of scrotum and penis (1); hydronephrosis (2); imperforate anus (1); talipes varus (1); polydactyly (3); a combination of coarctation of the aorta and ventricular septal defect (1); a combination of single ventricle and pulmonary stenosis (1); a combination of ventricular septal defect, pulmonary stenosis and syndactyly (1).
d Ventricular septal defect (5); ventricular and atrial septal defect (1); atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); cleft lip and palate (1); double vagina (1); hydroureteropathy (1); hydronephrosis (1); a combination of duodenal obstruction, heart disease, upper aortic malposition and pulmonary artery occlusion (1).
e Ventricular septal defect (1); endocardial cushion defect (1); myelomeningocele (1); lissencephaly (1); hypospadias (1); talipes varus (1); polydactyly (1); scalp defect (1).
Risk of major malformation
The incidence of major malformation in liveborn, single‐birth infants (95% confidence interval [CI]) was 2.9% (14/485, 95%CI: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group.
Univariable logistic regression analysis showed no significant difference in the incidence of major malformation between the domperidone and control groups (OR: 1.68 [95% CI: 0.87–3.23], p = 0.119). Additionally, multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling also showed no significant difference in the incidence of major malformation between the domperidone and control groups (adjusted OR: 1.86 [95% CI: 0.73–4.70], p = 0.191) (Table 3). Similar results were obtained when comparing the metoclopramide and control groups (OR: 2.09 [95% CI: 0.94–4.67], p = 0.071; adjusted OR: 2.20 [95% CI: 0.69–6.98], p = 0.183).
Subgroup analysis
For the cases at Toranomon Hospital, the adjusted OR (95%CI) of the incidence of major malformation was 2.54 (95%CI: 0.68–9.46, p = 0.164) in the domperidone group and 2.54 (95%CI: 0.47–13.82, p = 0.282) in the metoclopramide group, indicating no significant difference for either group compared with the control group.
For the cases at National Center for Child Health and Development, the adjusted OR (95%CI) of the incidence of major malformation was 1.45 (95%CI: 0.38–5.54, p = 0.583) in the domperidone group and 2.06 (95%CI: 0.43–9.98, p = 0.370) in the metoclopramide group, again indicating no significant difference for either group compared with the control group (Supporting Information, Table SS1).
We also compared the adjusted OR of risk of major malformations by the year of counseling (Table SS2). To rule out the year of counseling as a possible confounding factor, we compared the first half of the data from Toranomon Hospital (1988–2004), to the second half (2005–2016) (adjusted OR: 0.79 [95%CI: 0.26–2.39], p = 0.680) and to the data from the National Center for Child Health and Development (2005–2017) (adjusted OR: 1.34 [95%CI: 0.69–2.60], p = 0.381), and found no significant differences in the adjusted OR.
Discussion
Although there are prior reports 3 , 4 of domperidone administered to pregnant women, those studies lacked sufficient detection power to ensure that domperidone exposure is not harmful to the fetus. Therefore, no information has been available to ensure the safety of using domperidone in pregnant women.
In this study, the 485 patients who received domperidone during the first trimester of pregnancy showed no increase in the incidence of major malformation compared with patients in the control group, who received drugs that are considered to have no teratogenicity. In addition, no difference was found in the results of a sensitivity analysis that assessed teratogenic risk by excluding patients who used teratogenic drugs defined by the clinical guidelines for gynecology and obstetrics 8 .
This study enrolled pregnant women who consulted at Toranomon Hospital or the National Center for Child Health and Development. We therefore performed a subgroup analysis to determine if there were any discrepancies in results between the facilities. There were no such differences, and the incidence of major malformation in the domperidone group did not higher than that in the control group at neither facility.
This study analyzed participants who received counseling at Toranomon Hospital after April 1988 and at National Center for Child Health and Development after October 2005. The use of imaging modalities to detect visceral malformations began in 1997. Therefore, it is presumed that since then it has been possible to detect even minor malformations, such as inconsequential heart defects. However, there was no significant difference in the incidence of major malformation at Toranomon Hospital between 1988 to 2004 and 2005 to 2016. Also, the data from National Center for Child Health and Development (2005–2017) yielded similar results as those from Toranomon Hospital (1988–2004). Thus, the timing of counseling is unlikely to be associated with the detection rate of malformation.
The package insert for domperidone states that it is contraindicated for use in pregnant women and in women suspected of being pregnant, due to teratogenicity observed in reproductive toxicity studies. This has led to the problem of pregnant women becoming anxious when they discover they have taken domperidone before finding out they were pregnant.
This observational cohort study was based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy. It showed that the risk of major malformation was not increased in women who received domperidone during pregnancy. However, it should be noted that a limitation of the study is that women could cancel their counseling if they had a miscarriage or abortion beforehand, resulting in underreported miscarriage or abortion cases.
In future counseling, this information is clinically very useful because it can reduce or eliminate the anxiety of patients who have taken domperidone during pregnancy. The Japanese clinical guidelines for obstetrics and gynecology (obstetrics portion) list domperidone as one of the “drugs that may be used by women in early pregnancy without having a clinically significant adverse effect on the fetus, even though the package inserts state that they are contraindicated in pregnant women.” 8 The results of this study support this statement in the guidelines.
Conflict of interest
Atsuko Murashima received lecture fees from Chugai Pharmaceutical Co.Ltd and Astellas Pharma Inc.
Supporting information
Table S1 Subgroup analysis by the facility
Click here for additional data file.
Table S2 Subgroup analysis by the year of counseling
Click here for additional data file.
Acknowledgments
This work was supported by a Research Program from the Japanese Agency for Medical Research and Development under Grant Number JP19mk0101086h0003, awarded to A.M. The authors would like to thank Dr. Kenjiro Kosaki and Dr. Rika Kosaki for their great advice in diagnosing congenital malformations and we would like to thank Mariko Takagai for her administrative assistance. They are also grateful to women who donated their clinical information and for colleagues worked as a member of Japan Teratology Information Services Network. | METOCLOPRAMIDE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33631840 | 19,020,052 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal exposure during pregnancy'. | Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.
OBJECTIVE
To assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.
METHODS
Pregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.
RESULTS
The incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183).
CONCLUSIONS
This observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.
Introduction
Domperidone is an antidopaminergic benzimidazolone compound first synthesized by Janssen Pharmaceutica (Belgium) in 1974. Originally approved in Belgium in 1978, it has since been approved in over 100 countries, including in Japan in 1982. In Japan, domperidone has been widely used for the treatment of gastrointestinal symptoms such as nausea, vomiting, and anorexia.
In a study of domperidone administration during organogenesis in rats, skeletal and visceral malformations were observed in fetuses following an oral dose of 200 mg/kg or an intraperitoneal dose of ≥15 mg/kg. These observed malformations in rats occurred at approximately 300 times the daily oral dose for humans based on body weight. Due to these results, the package insert for domperidone in Japan states that it is contraindicated for use in pregnant women or women suspected of being pregnant.
In some cases, however, domperidone is prescribed for gastrointestinal symptoms such as nausea and vomiting to women who do not yet know they are pregnant due to the pregnancy being unplanned. In such cases, patients often become anxious when they find out they are pregnant and learn that domperidone is contraindicated.
Domperidone and metoclopramide are commonly used as antiemetic drugs in general clinical practice in Japan. Large‐scale epidemiological studies have shown that metoclopramide does not increase the risk of malformation 1 , 2 . On the other hand, teratogenic risk with domperidone has been reported in only a few small‐scale, cohort studies. A report by JS Choi et al. investigated 120 pregnancies treated with domperidone in the first trimester and concluded that domperidone is unlikely to be a major human teratogen 3 . Also, in an abstract, J Cottin et al. compared 124 pregnancies exposed to domperidone during organogenesis with those exposed to other antiemetics or nonteratogenic drugs 4 . There was no significant difference between the three groups in the incidence of major congenital malformations, but the authors commented that the small sample size was a limitation. A report on drug use during pregnancy in the French population stated that about 13% of all pregnant women were using domperidone 5 . Although the teratogenic risk of domperidone was not analyzed in that survey, it suggests that the drug is widely used by pregnant women in some countries.
In the present study, we evaluated the teratogenic risk of domperidone exposure during the first trimester. This is based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy.
Methods
Subjects
This study included women who consulted the Counseling Clinic for “Pregnancy and Medicine” of Toranomon Hospital or the Japan Drug Information Institute in Pregnancy of National Center for Child Health and Development regarding the safety of drugs during pregnancy. Pregnancy outcome data were extracted from the clinical databases of these facilities.
The inclusion criteria were pregnant women who consented to the study and with known pregnancy outcomes who took domperidone (domperidone group), or control drugs (control group) in the first trimester. Among these, women who used domperidone in combination with metoclopramide were excluded from the study. First trimester exposure was defined as drug use between the 28th and 97th days (4th week to 13th week of pregnancy) after the last menstrual period. Experts discussed and selected control drugs considered to be nonteratogenic, referring the report by F. Habermann et al. 6 Control drugs included acetaminophen, antihistamines that were reported in previous studies to have no increased risk of teratogenicity, anti‐infectives like penicillins and cephalosporins, histamine H2‐receptor (H2) blockers, digestive enzyme preparations, and topical drugs (e.g., eye drops, ointment, or cream). Metoclopramide is a similar drug and is expected to be used for the same diseases. In addition, it has been commonly used as an antiemetic drug in pregnant women. Therefore, although statistical comparison with the domperidone group was not performed, patients who took metoclopramide were defined as the reference group.
Data collection
For Toranomon Hospital, women who consulted the Counseling Clinic for “Pregnancy and Medicine” during pregnancy between April 1988 and December 2016 were included in the study. People who wished to make a counseling appointment were first required by the clinic to complete a pre‐appointment questionnaire regarding information such as the names and dosages of drugs taken during pregnancy and expected delivery date, and to return it by mail. At the time of counseling, subjects were interviewed to confirm their expected delivery dates and to obtain other information, including previous medical history, pregnancy and reproductive history, alcohol use, smoking, and family history. We asked patients who provided informed consent for study participation to complete a study questionnaire regarding pregnancy outcomes and any abnormalities during delivery, as well as sex, length, and weight at birth, and any abnormalities of the neonate, and to submit it by mail. If patients provided unclear answers about pregnancy outcomes, an obstetrician contacted their attending physician to obtain clarification. Information on pregnancy outcomes was collected about 1 month after delivery, and the survey was considered complete when this information was obtained.
At the National Center for Child Health and Development, women in pregnancy who sought consultation the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017 were included in the study. The Japan Drug Information Institute in Pregnancy was established under a program of the Ministry of Health Labour and Welfare in October 2005. People who wished to make a counseling appointment were required to complete a pre‐appointment questionnaire and to return it by mail. The pre‐appointment questions were on age, use of drugs during pregnancy, history of present illness, previous medical history, experience of pregnancy, reproductive history, alcohol use, smoking, and intake of folic acid. Approximately a month after their expected delivery date, patients who provided informed consent for participation in the study were sent a postcard‐type questionnaire on pregnancy outcomes and the 1‐month checkup results of their infants. In cases where pregnancy outcomes were unclear, research assistants, doctors or pharmacists contacted the women's attending obstetricians to confirm their pregnancy outcome by telephone. The survey was concluded when information on pregnancy outcomes had been obtained.
Primary endpoint and statistical analysis
The primary endpoint of this study was the incidence of major malformation. To assess the teratogenic risk of domperidone, we compared the incidence of major malformation in the domperidone group with the control group. Major malformations were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) 7 . In cases of congenital abnormalities not included in EUROCAT, a specialist in congenital abnormalities provided diagnoses. Two of the authors concluded that congenital abnormalities could be defined either as surficial malformations or as those requiring surgical treatment. Finally, two independent specialists confirmed the diagnoses.
The incidence of major malformation was analyzed in liveborn, single‐birth infants, and was calculated by dividing the number of liveborn singletons with congenital malformation by the number of all liveborn singletons analyzed in each group. This incidence was compared between the domperidone and control groups. Using the control group as the reference of odds ratio (ORs), the crude ORs of the incidence of major malformations in the domperidone group were calculated using univariable logistic regression analysis. In addition, adjusted ORs were calculated using multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling. Similarly, the crude and adjusted ORs of the incidence of major malformations in the metoclopramide group were calculated. In a subgroup analysis, adjusted ORs were calculated for each facility. The significance level of the test was 5%.
Ethics statement
This study was approved by the Ethics Committee of National Center for Child Health and Development and that of Toranomon Hospital. It was conducted according to the Declaration of Helsinki, and informed consent was obtained from all participants. Information collected from questionnaires was entered into the database and de‐identified by an information administrator. Therefore, the investigators were unable to identify individuals based on the analysis data.
Results
Patient characteristics
At Toranomon Hospital, 12 074 women consulted the Counseling Clinic for “Pregnancy and Medicine” between April 1988 and December 2016. Of these, 1422 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. At National Center for Child Health and Development, 12 971 women consulted the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017. Of these, 1011 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. In total, the number of participants was 519 in the domperidone group, 1673 in the control group, and 241 in the metoclopramide group (Figure 1).
Figure 1 Flowchart
The median age of the subjects at the time of counseling was 30 years in all groups and the groups showed no difference in age distribution. There were no notable differences between groups in either alcohol use or smoking habits, as shown in Table 1.
Table 1 Patient characteristics
Domperidone group Control group Metoclopramide group
n 519 1673 241
Age (year), n (%)
50% [25%, 75%] 30 [26, 33] 30 [27, 34] 30 [27, 34]
≦24 79 (15.2) 160 (9.6) 30 (12.4)
25–29 170 (32.8) 548 (32.8) 81 (33.6)
30–34 167 (32.2) 628 (37.5) 83 (34.4)
35–39 84 (16.2) 288 (17.2) 40 (16.6)
40≦ 18 (3.5) 46 (2.7) 6 (2.5)
NA 1 (0.2) 3 (0.2) 1 (0.4)
Alcohol, n (%)
No use 292 (56.3) 861 (51.5) 125 (51.9)
Stop before pregnancy 7 (1.3) 45 (2.7) 13 (5.4)
Stop after pregnancy 84 (16.2) 305 (18.2) 48 (19.9)
Ongoing 3 (0.6) 16 (1.0) 5 (2.1)
Unknown stop time 75 (14.5) 250 (14.9) 28 (11.6)
NA 58 (11.2) 196 (11.7) 22 (9.1)
Smoking, n (%)
No habit 390 (75.1) 1244 (74.4) 176 (73.0)
Stop before pregnancy 9 (1.7) 36 (2.2) 10 (4.1)
Stop after pregnancy 25 (4.8) 56 (3.3) 16 (6.6)
Ongoing 16 (3.1) 59 (3.5) 10 (4.1)
Unknown stop time 32 (6.2) 122 (7.3) 13 (5.4)
NA 47 (9.1) 156 (9.3) 16 (6.6)
Abbreviation: NA, not available.
Delivery outcomes and incidence of major malformations
Delivery outcomes were aggregated for all subjects. The percentage of liveborn infants was 94.0% (488 cases) in the domperidone group, 93.8% (1570 cases) in the control group, and 94.2% (227 cases) in the metoclopramide group. There were no notable differences in the incidences of stillbirth, miscarriage or abortion between the three groups (Table 2).
Table 2 Pregnancy outcomes
Domperidone group Control group Metoclopramide group
n 519 1673 241
Outcome, n (%)
Live birth 488 (94.0) 1570 (93.8) 227 (94.2)
Stillbirth a 3 (0.6) 7 (0.4) 0 (0.0)
Miscarriage 18 (3.5) 80 (4.8) 8 (3.3)
Abortion 10 (1.9) 15 (0.9) 6 (2.5)
Other 0 (0.0) 1 b (0.1) 0 (0.0)
Number of infant, n (%)
1 506 (97.5) 1627 (97.3) 234 (97.1)
2≦ 1 (0.2) 9 (0.5) 3 (1.2)
NA 12 (2.3) 37 (2.2) 4 (1.7)
Abbreviation: NA, not available.
a Fetal death after 22 weeks gestation was defined as stillbirth.
b Ectopic pregnancy.
Major malformations in liveborn, single‐birth infants occurred in 14 cases in the domperidone group, 27 in the control group, and 8 in the metoclopramide group (Table 3). There was no pattern of malformation types between the three groups.
Table 3 Risk of major malformation
Major malformation 95%CI Crude OR (95%CI) p‐Value a Adjusted OR b (95%CI) p‐Value a
No Yes
Control group (n = 1554) 1527 27 c (1.7%) (1.1–2.5) 1 ‐ 1 ‐
Domperidone group (n = 485) 471 14 d (2.9%) (1.6–4.8) 1.68 (0.87–3.23) 0.119 1.86 (0.73–4.70) 0.191
Metoclopramide group (n = 224) 216 8 e (3.6%) (1.6–6.9) 2.09 (0.94–4.67) 0.071 2.20 (0.69–6.98) 0.183
Risk of major malformation was analyzed in liveborn, single‐birth infants.
Abbreviations: CI, confidence interval; OR, odds ratio.
a Significance level p < 0.05, *<0.05.
b Adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling.
c Ventricular septal defect (6); ventricular and atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); peripheral pulmonary stenosis (1); endocardial cushion defect (1); complete transposition of great arteries (1); double outlet right ventricle (1); esophageal atresia (1); cleft lip (1); diastasis recti (1); adhesion of scrotum and penis (1); hydronephrosis (2); imperforate anus (1); talipes varus (1); polydactyly (3); a combination of coarctation of the aorta and ventricular septal defect (1); a combination of single ventricle and pulmonary stenosis (1); a combination of ventricular septal defect, pulmonary stenosis and syndactyly (1).
d Ventricular septal defect (5); ventricular and atrial septal defect (1); atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); cleft lip and palate (1); double vagina (1); hydroureteropathy (1); hydronephrosis (1); a combination of duodenal obstruction, heart disease, upper aortic malposition and pulmonary artery occlusion (1).
e Ventricular septal defect (1); endocardial cushion defect (1); myelomeningocele (1); lissencephaly (1); hypospadias (1); talipes varus (1); polydactyly (1); scalp defect (1).
Risk of major malformation
The incidence of major malformation in liveborn, single‐birth infants (95% confidence interval [CI]) was 2.9% (14/485, 95%CI: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group.
Univariable logistic regression analysis showed no significant difference in the incidence of major malformation between the domperidone and control groups (OR: 1.68 [95% CI: 0.87–3.23], p = 0.119). Additionally, multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling also showed no significant difference in the incidence of major malformation between the domperidone and control groups (adjusted OR: 1.86 [95% CI: 0.73–4.70], p = 0.191) (Table 3). Similar results were obtained when comparing the metoclopramide and control groups (OR: 2.09 [95% CI: 0.94–4.67], p = 0.071; adjusted OR: 2.20 [95% CI: 0.69–6.98], p = 0.183).
Subgroup analysis
For the cases at Toranomon Hospital, the adjusted OR (95%CI) of the incidence of major malformation was 2.54 (95%CI: 0.68–9.46, p = 0.164) in the domperidone group and 2.54 (95%CI: 0.47–13.82, p = 0.282) in the metoclopramide group, indicating no significant difference for either group compared with the control group.
For the cases at National Center for Child Health and Development, the adjusted OR (95%CI) of the incidence of major malformation was 1.45 (95%CI: 0.38–5.54, p = 0.583) in the domperidone group and 2.06 (95%CI: 0.43–9.98, p = 0.370) in the metoclopramide group, again indicating no significant difference for either group compared with the control group (Supporting Information, Table SS1).
We also compared the adjusted OR of risk of major malformations by the year of counseling (Table SS2). To rule out the year of counseling as a possible confounding factor, we compared the first half of the data from Toranomon Hospital (1988–2004), to the second half (2005–2016) (adjusted OR: 0.79 [95%CI: 0.26–2.39], p = 0.680) and to the data from the National Center for Child Health and Development (2005–2017) (adjusted OR: 1.34 [95%CI: 0.69–2.60], p = 0.381), and found no significant differences in the adjusted OR.
Discussion
Although there are prior reports 3 , 4 of domperidone administered to pregnant women, those studies lacked sufficient detection power to ensure that domperidone exposure is not harmful to the fetus. Therefore, no information has been available to ensure the safety of using domperidone in pregnant women.
In this study, the 485 patients who received domperidone during the first trimester of pregnancy showed no increase in the incidence of major malformation compared with patients in the control group, who received drugs that are considered to have no teratogenicity. In addition, no difference was found in the results of a sensitivity analysis that assessed teratogenic risk by excluding patients who used teratogenic drugs defined by the clinical guidelines for gynecology and obstetrics 8 .
This study enrolled pregnant women who consulted at Toranomon Hospital or the National Center for Child Health and Development. We therefore performed a subgroup analysis to determine if there were any discrepancies in results between the facilities. There were no such differences, and the incidence of major malformation in the domperidone group did not higher than that in the control group at neither facility.
This study analyzed participants who received counseling at Toranomon Hospital after April 1988 and at National Center for Child Health and Development after October 2005. The use of imaging modalities to detect visceral malformations began in 1997. Therefore, it is presumed that since then it has been possible to detect even minor malformations, such as inconsequential heart defects. However, there was no significant difference in the incidence of major malformation at Toranomon Hospital between 1988 to 2004 and 2005 to 2016. Also, the data from National Center for Child Health and Development (2005–2017) yielded similar results as those from Toranomon Hospital (1988–2004). Thus, the timing of counseling is unlikely to be associated with the detection rate of malformation.
The package insert for domperidone states that it is contraindicated for use in pregnant women and in women suspected of being pregnant, due to teratogenicity observed in reproductive toxicity studies. This has led to the problem of pregnant women becoming anxious when they discover they have taken domperidone before finding out they were pregnant.
This observational cohort study was based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy. It showed that the risk of major malformation was not increased in women who received domperidone during pregnancy. However, it should be noted that a limitation of the study is that women could cancel their counseling if they had a miscarriage or abortion beforehand, resulting in underreported miscarriage or abortion cases.
In future counseling, this information is clinically very useful because it can reduce or eliminate the anxiety of patients who have taken domperidone during pregnancy. The Japanese clinical guidelines for obstetrics and gynecology (obstetrics portion) list domperidone as one of the “drugs that may be used by women in early pregnancy without having a clinically significant adverse effect on the fetus, even though the package inserts state that they are contraindicated in pregnant women.” 8 The results of this study support this statement in the guidelines.
Conflict of interest
Atsuko Murashima received lecture fees from Chugai Pharmaceutical Co.Ltd and Astellas Pharma Inc.
Supporting information
Table S1 Subgroup analysis by the facility
Click here for additional data file.
Table S2 Subgroup analysis by the year of counseling
Click here for additional data file.
Acknowledgments
This work was supported by a Research Program from the Japanese Agency for Medical Research and Development under Grant Number JP19mk0101086h0003, awarded to A.M. The authors would like to thank Dr. Kenjiro Kosaki and Dr. Rika Kosaki for their great advice in diagnosing congenital malformations and we would like to thank Mariko Takagai for her administrative assistance. They are also grateful to women who donated their clinical information and for colleagues worked as a member of Japan Teratology Information Services Network. | METOCLOPRAMIDE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33631840 | 19,020,387 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypospadias'. | Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.
OBJECTIVE
To assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.
METHODS
Pregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.
RESULTS
The incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183).
CONCLUSIONS
This observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.
Introduction
Domperidone is an antidopaminergic benzimidazolone compound first synthesized by Janssen Pharmaceutica (Belgium) in 1974. Originally approved in Belgium in 1978, it has since been approved in over 100 countries, including in Japan in 1982. In Japan, domperidone has been widely used for the treatment of gastrointestinal symptoms such as nausea, vomiting, and anorexia.
In a study of domperidone administration during organogenesis in rats, skeletal and visceral malformations were observed in fetuses following an oral dose of 200 mg/kg or an intraperitoneal dose of ≥15 mg/kg. These observed malformations in rats occurred at approximately 300 times the daily oral dose for humans based on body weight. Due to these results, the package insert for domperidone in Japan states that it is contraindicated for use in pregnant women or women suspected of being pregnant.
In some cases, however, domperidone is prescribed for gastrointestinal symptoms such as nausea and vomiting to women who do not yet know they are pregnant due to the pregnancy being unplanned. In such cases, patients often become anxious when they find out they are pregnant and learn that domperidone is contraindicated.
Domperidone and metoclopramide are commonly used as antiemetic drugs in general clinical practice in Japan. Large‐scale epidemiological studies have shown that metoclopramide does not increase the risk of malformation 1 , 2 . On the other hand, teratogenic risk with domperidone has been reported in only a few small‐scale, cohort studies. A report by JS Choi et al. investigated 120 pregnancies treated with domperidone in the first trimester and concluded that domperidone is unlikely to be a major human teratogen 3 . Also, in an abstract, J Cottin et al. compared 124 pregnancies exposed to domperidone during organogenesis with those exposed to other antiemetics or nonteratogenic drugs 4 . There was no significant difference between the three groups in the incidence of major congenital malformations, but the authors commented that the small sample size was a limitation. A report on drug use during pregnancy in the French population stated that about 13% of all pregnant women were using domperidone 5 . Although the teratogenic risk of domperidone was not analyzed in that survey, it suggests that the drug is widely used by pregnant women in some countries.
In the present study, we evaluated the teratogenic risk of domperidone exposure during the first trimester. This is based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy.
Methods
Subjects
This study included women who consulted the Counseling Clinic for “Pregnancy and Medicine” of Toranomon Hospital or the Japan Drug Information Institute in Pregnancy of National Center for Child Health and Development regarding the safety of drugs during pregnancy. Pregnancy outcome data were extracted from the clinical databases of these facilities.
The inclusion criteria were pregnant women who consented to the study and with known pregnancy outcomes who took domperidone (domperidone group), or control drugs (control group) in the first trimester. Among these, women who used domperidone in combination with metoclopramide were excluded from the study. First trimester exposure was defined as drug use between the 28th and 97th days (4th week to 13th week of pregnancy) after the last menstrual period. Experts discussed and selected control drugs considered to be nonteratogenic, referring the report by F. Habermann et al. 6 Control drugs included acetaminophen, antihistamines that were reported in previous studies to have no increased risk of teratogenicity, anti‐infectives like penicillins and cephalosporins, histamine H2‐receptor (H2) blockers, digestive enzyme preparations, and topical drugs (e.g., eye drops, ointment, or cream). Metoclopramide is a similar drug and is expected to be used for the same diseases. In addition, it has been commonly used as an antiemetic drug in pregnant women. Therefore, although statistical comparison with the domperidone group was not performed, patients who took metoclopramide were defined as the reference group.
Data collection
For Toranomon Hospital, women who consulted the Counseling Clinic for “Pregnancy and Medicine” during pregnancy between April 1988 and December 2016 were included in the study. People who wished to make a counseling appointment were first required by the clinic to complete a pre‐appointment questionnaire regarding information such as the names and dosages of drugs taken during pregnancy and expected delivery date, and to return it by mail. At the time of counseling, subjects were interviewed to confirm their expected delivery dates and to obtain other information, including previous medical history, pregnancy and reproductive history, alcohol use, smoking, and family history. We asked patients who provided informed consent for study participation to complete a study questionnaire regarding pregnancy outcomes and any abnormalities during delivery, as well as sex, length, and weight at birth, and any abnormalities of the neonate, and to submit it by mail. If patients provided unclear answers about pregnancy outcomes, an obstetrician contacted their attending physician to obtain clarification. Information on pregnancy outcomes was collected about 1 month after delivery, and the survey was considered complete when this information was obtained.
At the National Center for Child Health and Development, women in pregnancy who sought consultation the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017 were included in the study. The Japan Drug Information Institute in Pregnancy was established under a program of the Ministry of Health Labour and Welfare in October 2005. People who wished to make a counseling appointment were required to complete a pre‐appointment questionnaire and to return it by mail. The pre‐appointment questions were on age, use of drugs during pregnancy, history of present illness, previous medical history, experience of pregnancy, reproductive history, alcohol use, smoking, and intake of folic acid. Approximately a month after their expected delivery date, patients who provided informed consent for participation in the study were sent a postcard‐type questionnaire on pregnancy outcomes and the 1‐month checkup results of their infants. In cases where pregnancy outcomes were unclear, research assistants, doctors or pharmacists contacted the women's attending obstetricians to confirm their pregnancy outcome by telephone. The survey was concluded when information on pregnancy outcomes had been obtained.
Primary endpoint and statistical analysis
The primary endpoint of this study was the incidence of major malformation. To assess the teratogenic risk of domperidone, we compared the incidence of major malformation in the domperidone group with the control group. Major malformations were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) 7 . In cases of congenital abnormalities not included in EUROCAT, a specialist in congenital abnormalities provided diagnoses. Two of the authors concluded that congenital abnormalities could be defined either as surficial malformations or as those requiring surgical treatment. Finally, two independent specialists confirmed the diagnoses.
The incidence of major malformation was analyzed in liveborn, single‐birth infants, and was calculated by dividing the number of liveborn singletons with congenital malformation by the number of all liveborn singletons analyzed in each group. This incidence was compared between the domperidone and control groups. Using the control group as the reference of odds ratio (ORs), the crude ORs of the incidence of major malformations in the domperidone group were calculated using univariable logistic regression analysis. In addition, adjusted ORs were calculated using multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling. Similarly, the crude and adjusted ORs of the incidence of major malformations in the metoclopramide group were calculated. In a subgroup analysis, adjusted ORs were calculated for each facility. The significance level of the test was 5%.
Ethics statement
This study was approved by the Ethics Committee of National Center for Child Health and Development and that of Toranomon Hospital. It was conducted according to the Declaration of Helsinki, and informed consent was obtained from all participants. Information collected from questionnaires was entered into the database and de‐identified by an information administrator. Therefore, the investigators were unable to identify individuals based on the analysis data.
Results
Patient characteristics
At Toranomon Hospital, 12 074 women consulted the Counseling Clinic for “Pregnancy and Medicine” between April 1988 and December 2016. Of these, 1422 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. At National Center for Child Health and Development, 12 971 women consulted the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017. Of these, 1011 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. In total, the number of participants was 519 in the domperidone group, 1673 in the control group, and 241 in the metoclopramide group (Figure 1).
Figure 1 Flowchart
The median age of the subjects at the time of counseling was 30 years in all groups and the groups showed no difference in age distribution. There were no notable differences between groups in either alcohol use or smoking habits, as shown in Table 1.
Table 1 Patient characteristics
Domperidone group Control group Metoclopramide group
n 519 1673 241
Age (year), n (%)
50% [25%, 75%] 30 [26, 33] 30 [27, 34] 30 [27, 34]
≦24 79 (15.2) 160 (9.6) 30 (12.4)
25–29 170 (32.8) 548 (32.8) 81 (33.6)
30–34 167 (32.2) 628 (37.5) 83 (34.4)
35–39 84 (16.2) 288 (17.2) 40 (16.6)
40≦ 18 (3.5) 46 (2.7) 6 (2.5)
NA 1 (0.2) 3 (0.2) 1 (0.4)
Alcohol, n (%)
No use 292 (56.3) 861 (51.5) 125 (51.9)
Stop before pregnancy 7 (1.3) 45 (2.7) 13 (5.4)
Stop after pregnancy 84 (16.2) 305 (18.2) 48 (19.9)
Ongoing 3 (0.6) 16 (1.0) 5 (2.1)
Unknown stop time 75 (14.5) 250 (14.9) 28 (11.6)
NA 58 (11.2) 196 (11.7) 22 (9.1)
Smoking, n (%)
No habit 390 (75.1) 1244 (74.4) 176 (73.0)
Stop before pregnancy 9 (1.7) 36 (2.2) 10 (4.1)
Stop after pregnancy 25 (4.8) 56 (3.3) 16 (6.6)
Ongoing 16 (3.1) 59 (3.5) 10 (4.1)
Unknown stop time 32 (6.2) 122 (7.3) 13 (5.4)
NA 47 (9.1) 156 (9.3) 16 (6.6)
Abbreviation: NA, not available.
Delivery outcomes and incidence of major malformations
Delivery outcomes were aggregated for all subjects. The percentage of liveborn infants was 94.0% (488 cases) in the domperidone group, 93.8% (1570 cases) in the control group, and 94.2% (227 cases) in the metoclopramide group. There were no notable differences in the incidences of stillbirth, miscarriage or abortion between the three groups (Table 2).
Table 2 Pregnancy outcomes
Domperidone group Control group Metoclopramide group
n 519 1673 241
Outcome, n (%)
Live birth 488 (94.0) 1570 (93.8) 227 (94.2)
Stillbirth a 3 (0.6) 7 (0.4) 0 (0.0)
Miscarriage 18 (3.5) 80 (4.8) 8 (3.3)
Abortion 10 (1.9) 15 (0.9) 6 (2.5)
Other 0 (0.0) 1 b (0.1) 0 (0.0)
Number of infant, n (%)
1 506 (97.5) 1627 (97.3) 234 (97.1)
2≦ 1 (0.2) 9 (0.5) 3 (1.2)
NA 12 (2.3) 37 (2.2) 4 (1.7)
Abbreviation: NA, not available.
a Fetal death after 22 weeks gestation was defined as stillbirth.
b Ectopic pregnancy.
Major malformations in liveborn, single‐birth infants occurred in 14 cases in the domperidone group, 27 in the control group, and 8 in the metoclopramide group (Table 3). There was no pattern of malformation types between the three groups.
Table 3 Risk of major malformation
Major malformation 95%CI Crude OR (95%CI) p‐Value a Adjusted OR b (95%CI) p‐Value a
No Yes
Control group (n = 1554) 1527 27 c (1.7%) (1.1–2.5) 1 ‐ 1 ‐
Domperidone group (n = 485) 471 14 d (2.9%) (1.6–4.8) 1.68 (0.87–3.23) 0.119 1.86 (0.73–4.70) 0.191
Metoclopramide group (n = 224) 216 8 e (3.6%) (1.6–6.9) 2.09 (0.94–4.67) 0.071 2.20 (0.69–6.98) 0.183
Risk of major malformation was analyzed in liveborn, single‐birth infants.
Abbreviations: CI, confidence interval; OR, odds ratio.
a Significance level p < 0.05, *<0.05.
b Adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling.
c Ventricular septal defect (6); ventricular and atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); peripheral pulmonary stenosis (1); endocardial cushion defect (1); complete transposition of great arteries (1); double outlet right ventricle (1); esophageal atresia (1); cleft lip (1); diastasis recti (1); adhesion of scrotum and penis (1); hydronephrosis (2); imperforate anus (1); talipes varus (1); polydactyly (3); a combination of coarctation of the aorta and ventricular septal defect (1); a combination of single ventricle and pulmonary stenosis (1); a combination of ventricular septal defect, pulmonary stenosis and syndactyly (1).
d Ventricular septal defect (5); ventricular and atrial septal defect (1); atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); cleft lip and palate (1); double vagina (1); hydroureteropathy (1); hydronephrosis (1); a combination of duodenal obstruction, heart disease, upper aortic malposition and pulmonary artery occlusion (1).
e Ventricular septal defect (1); endocardial cushion defect (1); myelomeningocele (1); lissencephaly (1); hypospadias (1); talipes varus (1); polydactyly (1); scalp defect (1).
Risk of major malformation
The incidence of major malformation in liveborn, single‐birth infants (95% confidence interval [CI]) was 2.9% (14/485, 95%CI: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group.
Univariable logistic regression analysis showed no significant difference in the incidence of major malformation between the domperidone and control groups (OR: 1.68 [95% CI: 0.87–3.23], p = 0.119). Additionally, multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling also showed no significant difference in the incidence of major malformation between the domperidone and control groups (adjusted OR: 1.86 [95% CI: 0.73–4.70], p = 0.191) (Table 3). Similar results were obtained when comparing the metoclopramide and control groups (OR: 2.09 [95% CI: 0.94–4.67], p = 0.071; adjusted OR: 2.20 [95% CI: 0.69–6.98], p = 0.183).
Subgroup analysis
For the cases at Toranomon Hospital, the adjusted OR (95%CI) of the incidence of major malformation was 2.54 (95%CI: 0.68–9.46, p = 0.164) in the domperidone group and 2.54 (95%CI: 0.47–13.82, p = 0.282) in the metoclopramide group, indicating no significant difference for either group compared with the control group.
For the cases at National Center for Child Health and Development, the adjusted OR (95%CI) of the incidence of major malformation was 1.45 (95%CI: 0.38–5.54, p = 0.583) in the domperidone group and 2.06 (95%CI: 0.43–9.98, p = 0.370) in the metoclopramide group, again indicating no significant difference for either group compared with the control group (Supporting Information, Table SS1).
We also compared the adjusted OR of risk of major malformations by the year of counseling (Table SS2). To rule out the year of counseling as a possible confounding factor, we compared the first half of the data from Toranomon Hospital (1988–2004), to the second half (2005–2016) (adjusted OR: 0.79 [95%CI: 0.26–2.39], p = 0.680) and to the data from the National Center for Child Health and Development (2005–2017) (adjusted OR: 1.34 [95%CI: 0.69–2.60], p = 0.381), and found no significant differences in the adjusted OR.
Discussion
Although there are prior reports 3 , 4 of domperidone administered to pregnant women, those studies lacked sufficient detection power to ensure that domperidone exposure is not harmful to the fetus. Therefore, no information has been available to ensure the safety of using domperidone in pregnant women.
In this study, the 485 patients who received domperidone during the first trimester of pregnancy showed no increase in the incidence of major malformation compared with patients in the control group, who received drugs that are considered to have no teratogenicity. In addition, no difference was found in the results of a sensitivity analysis that assessed teratogenic risk by excluding patients who used teratogenic drugs defined by the clinical guidelines for gynecology and obstetrics 8 .
This study enrolled pregnant women who consulted at Toranomon Hospital or the National Center for Child Health and Development. We therefore performed a subgroup analysis to determine if there were any discrepancies in results between the facilities. There were no such differences, and the incidence of major malformation in the domperidone group did not higher than that in the control group at neither facility.
This study analyzed participants who received counseling at Toranomon Hospital after April 1988 and at National Center for Child Health and Development after October 2005. The use of imaging modalities to detect visceral malformations began in 1997. Therefore, it is presumed that since then it has been possible to detect even minor malformations, such as inconsequential heart defects. However, there was no significant difference in the incidence of major malformation at Toranomon Hospital between 1988 to 2004 and 2005 to 2016. Also, the data from National Center for Child Health and Development (2005–2017) yielded similar results as those from Toranomon Hospital (1988–2004). Thus, the timing of counseling is unlikely to be associated with the detection rate of malformation.
The package insert for domperidone states that it is contraindicated for use in pregnant women and in women suspected of being pregnant, due to teratogenicity observed in reproductive toxicity studies. This has led to the problem of pregnant women becoming anxious when they discover they have taken domperidone before finding out they were pregnant.
This observational cohort study was based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy. It showed that the risk of major malformation was not increased in women who received domperidone during pregnancy. However, it should be noted that a limitation of the study is that women could cancel their counseling if they had a miscarriage or abortion beforehand, resulting in underreported miscarriage or abortion cases.
In future counseling, this information is clinically very useful because it can reduce or eliminate the anxiety of patients who have taken domperidone during pregnancy. The Japanese clinical guidelines for obstetrics and gynecology (obstetrics portion) list domperidone as one of the “drugs that may be used by women in early pregnancy without having a clinically significant adverse effect on the fetus, even though the package inserts state that they are contraindicated in pregnant women.” 8 The results of this study support this statement in the guidelines.
Conflict of interest
Atsuko Murashima received lecture fees from Chugai Pharmaceutical Co.Ltd and Astellas Pharma Inc.
Supporting information
Table S1 Subgroup analysis by the facility
Click here for additional data file.
Table S2 Subgroup analysis by the year of counseling
Click here for additional data file.
Acknowledgments
This work was supported by a Research Program from the Japanese Agency for Medical Research and Development under Grant Number JP19mk0101086h0003, awarded to A.M. The authors would like to thank Dr. Kenjiro Kosaki and Dr. Rika Kosaki for their great advice in diagnosing congenital malformations and we would like to thank Mariko Takagai for her administrative assistance. They are also grateful to women who donated their clinical information and for colleagues worked as a member of Japan Teratology Information Services Network. | METOCLOPRAMIDE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33631840 | 19,020,243 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lissencephaly'. | Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.
OBJECTIVE
To assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.
METHODS
Pregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.
RESULTS
The incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183).
CONCLUSIONS
This observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.
Introduction
Domperidone is an antidopaminergic benzimidazolone compound first synthesized by Janssen Pharmaceutica (Belgium) in 1974. Originally approved in Belgium in 1978, it has since been approved in over 100 countries, including in Japan in 1982. In Japan, domperidone has been widely used for the treatment of gastrointestinal symptoms such as nausea, vomiting, and anorexia.
In a study of domperidone administration during organogenesis in rats, skeletal and visceral malformations were observed in fetuses following an oral dose of 200 mg/kg or an intraperitoneal dose of ≥15 mg/kg. These observed malformations in rats occurred at approximately 300 times the daily oral dose for humans based on body weight. Due to these results, the package insert for domperidone in Japan states that it is contraindicated for use in pregnant women or women suspected of being pregnant.
In some cases, however, domperidone is prescribed for gastrointestinal symptoms such as nausea and vomiting to women who do not yet know they are pregnant due to the pregnancy being unplanned. In such cases, patients often become anxious when they find out they are pregnant and learn that domperidone is contraindicated.
Domperidone and metoclopramide are commonly used as antiemetic drugs in general clinical practice in Japan. Large‐scale epidemiological studies have shown that metoclopramide does not increase the risk of malformation 1 , 2 . On the other hand, teratogenic risk with domperidone has been reported in only a few small‐scale, cohort studies. A report by JS Choi et al. investigated 120 pregnancies treated with domperidone in the first trimester and concluded that domperidone is unlikely to be a major human teratogen 3 . Also, in an abstract, J Cottin et al. compared 124 pregnancies exposed to domperidone during organogenesis with those exposed to other antiemetics or nonteratogenic drugs 4 . There was no significant difference between the three groups in the incidence of major congenital malformations, but the authors commented that the small sample size was a limitation. A report on drug use during pregnancy in the French population stated that about 13% of all pregnant women were using domperidone 5 . Although the teratogenic risk of domperidone was not analyzed in that survey, it suggests that the drug is widely used by pregnant women in some countries.
In the present study, we evaluated the teratogenic risk of domperidone exposure during the first trimester. This is based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy.
Methods
Subjects
This study included women who consulted the Counseling Clinic for “Pregnancy and Medicine” of Toranomon Hospital or the Japan Drug Information Institute in Pregnancy of National Center for Child Health and Development regarding the safety of drugs during pregnancy. Pregnancy outcome data were extracted from the clinical databases of these facilities.
The inclusion criteria were pregnant women who consented to the study and with known pregnancy outcomes who took domperidone (domperidone group), or control drugs (control group) in the first trimester. Among these, women who used domperidone in combination with metoclopramide were excluded from the study. First trimester exposure was defined as drug use between the 28th and 97th days (4th week to 13th week of pregnancy) after the last menstrual period. Experts discussed and selected control drugs considered to be nonteratogenic, referring the report by F. Habermann et al. 6 Control drugs included acetaminophen, antihistamines that were reported in previous studies to have no increased risk of teratogenicity, anti‐infectives like penicillins and cephalosporins, histamine H2‐receptor (H2) blockers, digestive enzyme preparations, and topical drugs (e.g., eye drops, ointment, or cream). Metoclopramide is a similar drug and is expected to be used for the same diseases. In addition, it has been commonly used as an antiemetic drug in pregnant women. Therefore, although statistical comparison with the domperidone group was not performed, patients who took metoclopramide were defined as the reference group.
Data collection
For Toranomon Hospital, women who consulted the Counseling Clinic for “Pregnancy and Medicine” during pregnancy between April 1988 and December 2016 were included in the study. People who wished to make a counseling appointment were first required by the clinic to complete a pre‐appointment questionnaire regarding information such as the names and dosages of drugs taken during pregnancy and expected delivery date, and to return it by mail. At the time of counseling, subjects were interviewed to confirm their expected delivery dates and to obtain other information, including previous medical history, pregnancy and reproductive history, alcohol use, smoking, and family history. We asked patients who provided informed consent for study participation to complete a study questionnaire regarding pregnancy outcomes and any abnormalities during delivery, as well as sex, length, and weight at birth, and any abnormalities of the neonate, and to submit it by mail. If patients provided unclear answers about pregnancy outcomes, an obstetrician contacted their attending physician to obtain clarification. Information on pregnancy outcomes was collected about 1 month after delivery, and the survey was considered complete when this information was obtained.
At the National Center for Child Health and Development, women in pregnancy who sought consultation the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017 were included in the study. The Japan Drug Information Institute in Pregnancy was established under a program of the Ministry of Health Labour and Welfare in October 2005. People who wished to make a counseling appointment were required to complete a pre‐appointment questionnaire and to return it by mail. The pre‐appointment questions were on age, use of drugs during pregnancy, history of present illness, previous medical history, experience of pregnancy, reproductive history, alcohol use, smoking, and intake of folic acid. Approximately a month after their expected delivery date, patients who provided informed consent for participation in the study were sent a postcard‐type questionnaire on pregnancy outcomes and the 1‐month checkup results of their infants. In cases where pregnancy outcomes were unclear, research assistants, doctors or pharmacists contacted the women's attending obstetricians to confirm their pregnancy outcome by telephone. The survey was concluded when information on pregnancy outcomes had been obtained.
Primary endpoint and statistical analysis
The primary endpoint of this study was the incidence of major malformation. To assess the teratogenic risk of domperidone, we compared the incidence of major malformation in the domperidone group with the control group. Major malformations were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) 7 . In cases of congenital abnormalities not included in EUROCAT, a specialist in congenital abnormalities provided diagnoses. Two of the authors concluded that congenital abnormalities could be defined either as surficial malformations or as those requiring surgical treatment. Finally, two independent specialists confirmed the diagnoses.
The incidence of major malformation was analyzed in liveborn, single‐birth infants, and was calculated by dividing the number of liveborn singletons with congenital malformation by the number of all liveborn singletons analyzed in each group. This incidence was compared between the domperidone and control groups. Using the control group as the reference of odds ratio (ORs), the crude ORs of the incidence of major malformations in the domperidone group were calculated using univariable logistic regression analysis. In addition, adjusted ORs were calculated using multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling. Similarly, the crude and adjusted ORs of the incidence of major malformations in the metoclopramide group were calculated. In a subgroup analysis, adjusted ORs were calculated for each facility. The significance level of the test was 5%.
Ethics statement
This study was approved by the Ethics Committee of National Center for Child Health and Development and that of Toranomon Hospital. It was conducted according to the Declaration of Helsinki, and informed consent was obtained from all participants. Information collected from questionnaires was entered into the database and de‐identified by an information administrator. Therefore, the investigators were unable to identify individuals based on the analysis data.
Results
Patient characteristics
At Toranomon Hospital, 12 074 women consulted the Counseling Clinic for “Pregnancy and Medicine” between April 1988 and December 2016. Of these, 1422 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. At National Center for Child Health and Development, 12 971 women consulted the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017. Of these, 1011 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. In total, the number of participants was 519 in the domperidone group, 1673 in the control group, and 241 in the metoclopramide group (Figure 1).
Figure 1 Flowchart
The median age of the subjects at the time of counseling was 30 years in all groups and the groups showed no difference in age distribution. There were no notable differences between groups in either alcohol use or smoking habits, as shown in Table 1.
Table 1 Patient characteristics
Domperidone group Control group Metoclopramide group
n 519 1673 241
Age (year), n (%)
50% [25%, 75%] 30 [26, 33] 30 [27, 34] 30 [27, 34]
≦24 79 (15.2) 160 (9.6) 30 (12.4)
25–29 170 (32.8) 548 (32.8) 81 (33.6)
30–34 167 (32.2) 628 (37.5) 83 (34.4)
35–39 84 (16.2) 288 (17.2) 40 (16.6)
40≦ 18 (3.5) 46 (2.7) 6 (2.5)
NA 1 (0.2) 3 (0.2) 1 (0.4)
Alcohol, n (%)
No use 292 (56.3) 861 (51.5) 125 (51.9)
Stop before pregnancy 7 (1.3) 45 (2.7) 13 (5.4)
Stop after pregnancy 84 (16.2) 305 (18.2) 48 (19.9)
Ongoing 3 (0.6) 16 (1.0) 5 (2.1)
Unknown stop time 75 (14.5) 250 (14.9) 28 (11.6)
NA 58 (11.2) 196 (11.7) 22 (9.1)
Smoking, n (%)
No habit 390 (75.1) 1244 (74.4) 176 (73.0)
Stop before pregnancy 9 (1.7) 36 (2.2) 10 (4.1)
Stop after pregnancy 25 (4.8) 56 (3.3) 16 (6.6)
Ongoing 16 (3.1) 59 (3.5) 10 (4.1)
Unknown stop time 32 (6.2) 122 (7.3) 13 (5.4)
NA 47 (9.1) 156 (9.3) 16 (6.6)
Abbreviation: NA, not available.
Delivery outcomes and incidence of major malformations
Delivery outcomes were aggregated for all subjects. The percentage of liveborn infants was 94.0% (488 cases) in the domperidone group, 93.8% (1570 cases) in the control group, and 94.2% (227 cases) in the metoclopramide group. There were no notable differences in the incidences of stillbirth, miscarriage or abortion between the three groups (Table 2).
Table 2 Pregnancy outcomes
Domperidone group Control group Metoclopramide group
n 519 1673 241
Outcome, n (%)
Live birth 488 (94.0) 1570 (93.8) 227 (94.2)
Stillbirth a 3 (0.6) 7 (0.4) 0 (0.0)
Miscarriage 18 (3.5) 80 (4.8) 8 (3.3)
Abortion 10 (1.9) 15 (0.9) 6 (2.5)
Other 0 (0.0) 1 b (0.1) 0 (0.0)
Number of infant, n (%)
1 506 (97.5) 1627 (97.3) 234 (97.1)
2≦ 1 (0.2) 9 (0.5) 3 (1.2)
NA 12 (2.3) 37 (2.2) 4 (1.7)
Abbreviation: NA, not available.
a Fetal death after 22 weeks gestation was defined as stillbirth.
b Ectopic pregnancy.
Major malformations in liveborn, single‐birth infants occurred in 14 cases in the domperidone group, 27 in the control group, and 8 in the metoclopramide group (Table 3). There was no pattern of malformation types between the three groups.
Table 3 Risk of major malformation
Major malformation 95%CI Crude OR (95%CI) p‐Value a Adjusted OR b (95%CI) p‐Value a
No Yes
Control group (n = 1554) 1527 27 c (1.7%) (1.1–2.5) 1 ‐ 1 ‐
Domperidone group (n = 485) 471 14 d (2.9%) (1.6–4.8) 1.68 (0.87–3.23) 0.119 1.86 (0.73–4.70) 0.191
Metoclopramide group (n = 224) 216 8 e (3.6%) (1.6–6.9) 2.09 (0.94–4.67) 0.071 2.20 (0.69–6.98) 0.183
Risk of major malformation was analyzed in liveborn, single‐birth infants.
Abbreviations: CI, confidence interval; OR, odds ratio.
a Significance level p < 0.05, *<0.05.
b Adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling.
c Ventricular septal defect (6); ventricular and atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); peripheral pulmonary stenosis (1); endocardial cushion defect (1); complete transposition of great arteries (1); double outlet right ventricle (1); esophageal atresia (1); cleft lip (1); diastasis recti (1); adhesion of scrotum and penis (1); hydronephrosis (2); imperforate anus (1); talipes varus (1); polydactyly (3); a combination of coarctation of the aorta and ventricular septal defect (1); a combination of single ventricle and pulmonary stenosis (1); a combination of ventricular septal defect, pulmonary stenosis and syndactyly (1).
d Ventricular septal defect (5); ventricular and atrial septal defect (1); atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); cleft lip and palate (1); double vagina (1); hydroureteropathy (1); hydronephrosis (1); a combination of duodenal obstruction, heart disease, upper aortic malposition and pulmonary artery occlusion (1).
e Ventricular septal defect (1); endocardial cushion defect (1); myelomeningocele (1); lissencephaly (1); hypospadias (1); talipes varus (1); polydactyly (1); scalp defect (1).
Risk of major malformation
The incidence of major malformation in liveborn, single‐birth infants (95% confidence interval [CI]) was 2.9% (14/485, 95%CI: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group.
Univariable logistic regression analysis showed no significant difference in the incidence of major malformation between the domperidone and control groups (OR: 1.68 [95% CI: 0.87–3.23], p = 0.119). Additionally, multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling also showed no significant difference in the incidence of major malformation between the domperidone and control groups (adjusted OR: 1.86 [95% CI: 0.73–4.70], p = 0.191) (Table 3). Similar results were obtained when comparing the metoclopramide and control groups (OR: 2.09 [95% CI: 0.94–4.67], p = 0.071; adjusted OR: 2.20 [95% CI: 0.69–6.98], p = 0.183).
Subgroup analysis
For the cases at Toranomon Hospital, the adjusted OR (95%CI) of the incidence of major malformation was 2.54 (95%CI: 0.68–9.46, p = 0.164) in the domperidone group and 2.54 (95%CI: 0.47–13.82, p = 0.282) in the metoclopramide group, indicating no significant difference for either group compared with the control group.
For the cases at National Center for Child Health and Development, the adjusted OR (95%CI) of the incidence of major malformation was 1.45 (95%CI: 0.38–5.54, p = 0.583) in the domperidone group and 2.06 (95%CI: 0.43–9.98, p = 0.370) in the metoclopramide group, again indicating no significant difference for either group compared with the control group (Supporting Information, Table SS1).
We also compared the adjusted OR of risk of major malformations by the year of counseling (Table SS2). To rule out the year of counseling as a possible confounding factor, we compared the first half of the data from Toranomon Hospital (1988–2004), to the second half (2005–2016) (adjusted OR: 0.79 [95%CI: 0.26–2.39], p = 0.680) and to the data from the National Center for Child Health and Development (2005–2017) (adjusted OR: 1.34 [95%CI: 0.69–2.60], p = 0.381), and found no significant differences in the adjusted OR.
Discussion
Although there are prior reports 3 , 4 of domperidone administered to pregnant women, those studies lacked sufficient detection power to ensure that domperidone exposure is not harmful to the fetus. Therefore, no information has been available to ensure the safety of using domperidone in pregnant women.
In this study, the 485 patients who received domperidone during the first trimester of pregnancy showed no increase in the incidence of major malformation compared with patients in the control group, who received drugs that are considered to have no teratogenicity. In addition, no difference was found in the results of a sensitivity analysis that assessed teratogenic risk by excluding patients who used teratogenic drugs defined by the clinical guidelines for gynecology and obstetrics 8 .
This study enrolled pregnant women who consulted at Toranomon Hospital or the National Center for Child Health and Development. We therefore performed a subgroup analysis to determine if there were any discrepancies in results between the facilities. There were no such differences, and the incidence of major malformation in the domperidone group did not higher than that in the control group at neither facility.
This study analyzed participants who received counseling at Toranomon Hospital after April 1988 and at National Center for Child Health and Development after October 2005. The use of imaging modalities to detect visceral malformations began in 1997. Therefore, it is presumed that since then it has been possible to detect even minor malformations, such as inconsequential heart defects. However, there was no significant difference in the incidence of major malformation at Toranomon Hospital between 1988 to 2004 and 2005 to 2016. Also, the data from National Center for Child Health and Development (2005–2017) yielded similar results as those from Toranomon Hospital (1988–2004). Thus, the timing of counseling is unlikely to be associated with the detection rate of malformation.
The package insert for domperidone states that it is contraindicated for use in pregnant women and in women suspected of being pregnant, due to teratogenicity observed in reproductive toxicity studies. This has led to the problem of pregnant women becoming anxious when they discover they have taken domperidone before finding out they were pregnant.
This observational cohort study was based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy. It showed that the risk of major malformation was not increased in women who received domperidone during pregnancy. However, it should be noted that a limitation of the study is that women could cancel their counseling if they had a miscarriage or abortion beforehand, resulting in underreported miscarriage or abortion cases.
In future counseling, this information is clinically very useful because it can reduce or eliminate the anxiety of patients who have taken domperidone during pregnancy. The Japanese clinical guidelines for obstetrics and gynecology (obstetrics portion) list domperidone as one of the “drugs that may be used by women in early pregnancy without having a clinically significant adverse effect on the fetus, even though the package inserts state that they are contraindicated in pregnant women.” 8 The results of this study support this statement in the guidelines.
Conflict of interest
Atsuko Murashima received lecture fees from Chugai Pharmaceutical Co.Ltd and Astellas Pharma Inc.
Supporting information
Table S1 Subgroup analysis by the facility
Click here for additional data file.
Table S2 Subgroup analysis by the year of counseling
Click here for additional data file.
Acknowledgments
This work was supported by a Research Program from the Japanese Agency for Medical Research and Development under Grant Number JP19mk0101086h0003, awarded to A.M. The authors would like to thank Dr. Kenjiro Kosaki and Dr. Rika Kosaki for their great advice in diagnosing congenital malformations and we would like to thank Mariko Takagai for her administrative assistance. They are also grateful to women who donated their clinical information and for colleagues worked as a member of Japan Teratology Information Services Network. | METOCLOPRAMIDE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33631840 | 19,020,185 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Meningomyelocele'. | Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.
OBJECTIVE
To assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.
METHODS
Pregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.
RESULTS
The incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183).
CONCLUSIONS
This observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.
Introduction
Domperidone is an antidopaminergic benzimidazolone compound first synthesized by Janssen Pharmaceutica (Belgium) in 1974. Originally approved in Belgium in 1978, it has since been approved in over 100 countries, including in Japan in 1982. In Japan, domperidone has been widely used for the treatment of gastrointestinal symptoms such as nausea, vomiting, and anorexia.
In a study of domperidone administration during organogenesis in rats, skeletal and visceral malformations were observed in fetuses following an oral dose of 200 mg/kg or an intraperitoneal dose of ≥15 mg/kg. These observed malformations in rats occurred at approximately 300 times the daily oral dose for humans based on body weight. Due to these results, the package insert for domperidone in Japan states that it is contraindicated for use in pregnant women or women suspected of being pregnant.
In some cases, however, domperidone is prescribed for gastrointestinal symptoms such as nausea and vomiting to women who do not yet know they are pregnant due to the pregnancy being unplanned. In such cases, patients often become anxious when they find out they are pregnant and learn that domperidone is contraindicated.
Domperidone and metoclopramide are commonly used as antiemetic drugs in general clinical practice in Japan. Large‐scale epidemiological studies have shown that metoclopramide does not increase the risk of malformation 1 , 2 . On the other hand, teratogenic risk with domperidone has been reported in only a few small‐scale, cohort studies. A report by JS Choi et al. investigated 120 pregnancies treated with domperidone in the first trimester and concluded that domperidone is unlikely to be a major human teratogen 3 . Also, in an abstract, J Cottin et al. compared 124 pregnancies exposed to domperidone during organogenesis with those exposed to other antiemetics or nonteratogenic drugs 4 . There was no significant difference between the three groups in the incidence of major congenital malformations, but the authors commented that the small sample size was a limitation. A report on drug use during pregnancy in the French population stated that about 13% of all pregnant women were using domperidone 5 . Although the teratogenic risk of domperidone was not analyzed in that survey, it suggests that the drug is widely used by pregnant women in some countries.
In the present study, we evaluated the teratogenic risk of domperidone exposure during the first trimester. This is based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy.
Methods
Subjects
This study included women who consulted the Counseling Clinic for “Pregnancy and Medicine” of Toranomon Hospital or the Japan Drug Information Institute in Pregnancy of National Center for Child Health and Development regarding the safety of drugs during pregnancy. Pregnancy outcome data were extracted from the clinical databases of these facilities.
The inclusion criteria were pregnant women who consented to the study and with known pregnancy outcomes who took domperidone (domperidone group), or control drugs (control group) in the first trimester. Among these, women who used domperidone in combination with metoclopramide were excluded from the study. First trimester exposure was defined as drug use between the 28th and 97th days (4th week to 13th week of pregnancy) after the last menstrual period. Experts discussed and selected control drugs considered to be nonteratogenic, referring the report by F. Habermann et al. 6 Control drugs included acetaminophen, antihistamines that were reported in previous studies to have no increased risk of teratogenicity, anti‐infectives like penicillins and cephalosporins, histamine H2‐receptor (H2) blockers, digestive enzyme preparations, and topical drugs (e.g., eye drops, ointment, or cream). Metoclopramide is a similar drug and is expected to be used for the same diseases. In addition, it has been commonly used as an antiemetic drug in pregnant women. Therefore, although statistical comparison with the domperidone group was not performed, patients who took metoclopramide were defined as the reference group.
Data collection
For Toranomon Hospital, women who consulted the Counseling Clinic for “Pregnancy and Medicine” during pregnancy between April 1988 and December 2016 were included in the study. People who wished to make a counseling appointment were first required by the clinic to complete a pre‐appointment questionnaire regarding information such as the names and dosages of drugs taken during pregnancy and expected delivery date, and to return it by mail. At the time of counseling, subjects were interviewed to confirm their expected delivery dates and to obtain other information, including previous medical history, pregnancy and reproductive history, alcohol use, smoking, and family history. We asked patients who provided informed consent for study participation to complete a study questionnaire regarding pregnancy outcomes and any abnormalities during delivery, as well as sex, length, and weight at birth, and any abnormalities of the neonate, and to submit it by mail. If patients provided unclear answers about pregnancy outcomes, an obstetrician contacted their attending physician to obtain clarification. Information on pregnancy outcomes was collected about 1 month after delivery, and the survey was considered complete when this information was obtained.
At the National Center for Child Health and Development, women in pregnancy who sought consultation the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017 were included in the study. The Japan Drug Information Institute in Pregnancy was established under a program of the Ministry of Health Labour and Welfare in October 2005. People who wished to make a counseling appointment were required to complete a pre‐appointment questionnaire and to return it by mail. The pre‐appointment questions were on age, use of drugs during pregnancy, history of present illness, previous medical history, experience of pregnancy, reproductive history, alcohol use, smoking, and intake of folic acid. Approximately a month after their expected delivery date, patients who provided informed consent for participation in the study were sent a postcard‐type questionnaire on pregnancy outcomes and the 1‐month checkup results of their infants. In cases where pregnancy outcomes were unclear, research assistants, doctors or pharmacists contacted the women's attending obstetricians to confirm their pregnancy outcome by telephone. The survey was concluded when information on pregnancy outcomes had been obtained.
Primary endpoint and statistical analysis
The primary endpoint of this study was the incidence of major malformation. To assess the teratogenic risk of domperidone, we compared the incidence of major malformation in the domperidone group with the control group. Major malformations were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) 7 . In cases of congenital abnormalities not included in EUROCAT, a specialist in congenital abnormalities provided diagnoses. Two of the authors concluded that congenital abnormalities could be defined either as surficial malformations or as those requiring surgical treatment. Finally, two independent specialists confirmed the diagnoses.
The incidence of major malformation was analyzed in liveborn, single‐birth infants, and was calculated by dividing the number of liveborn singletons with congenital malformation by the number of all liveborn singletons analyzed in each group. This incidence was compared between the domperidone and control groups. Using the control group as the reference of odds ratio (ORs), the crude ORs of the incidence of major malformations in the domperidone group were calculated using univariable logistic regression analysis. In addition, adjusted ORs were calculated using multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling. Similarly, the crude and adjusted ORs of the incidence of major malformations in the metoclopramide group were calculated. In a subgroup analysis, adjusted ORs were calculated for each facility. The significance level of the test was 5%.
Ethics statement
This study was approved by the Ethics Committee of National Center for Child Health and Development and that of Toranomon Hospital. It was conducted according to the Declaration of Helsinki, and informed consent was obtained from all participants. Information collected from questionnaires was entered into the database and de‐identified by an information administrator. Therefore, the investigators were unable to identify individuals based on the analysis data.
Results
Patient characteristics
At Toranomon Hospital, 12 074 women consulted the Counseling Clinic for “Pregnancy and Medicine” between April 1988 and December 2016. Of these, 1422 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. At National Center for Child Health and Development, 12 971 women consulted the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017. Of these, 1011 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. In total, the number of participants was 519 in the domperidone group, 1673 in the control group, and 241 in the metoclopramide group (Figure 1).
Figure 1 Flowchart
The median age of the subjects at the time of counseling was 30 years in all groups and the groups showed no difference in age distribution. There were no notable differences between groups in either alcohol use or smoking habits, as shown in Table 1.
Table 1 Patient characteristics
Domperidone group Control group Metoclopramide group
n 519 1673 241
Age (year), n (%)
50% [25%, 75%] 30 [26, 33] 30 [27, 34] 30 [27, 34]
≦24 79 (15.2) 160 (9.6) 30 (12.4)
25–29 170 (32.8) 548 (32.8) 81 (33.6)
30–34 167 (32.2) 628 (37.5) 83 (34.4)
35–39 84 (16.2) 288 (17.2) 40 (16.6)
40≦ 18 (3.5) 46 (2.7) 6 (2.5)
NA 1 (0.2) 3 (0.2) 1 (0.4)
Alcohol, n (%)
No use 292 (56.3) 861 (51.5) 125 (51.9)
Stop before pregnancy 7 (1.3) 45 (2.7) 13 (5.4)
Stop after pregnancy 84 (16.2) 305 (18.2) 48 (19.9)
Ongoing 3 (0.6) 16 (1.0) 5 (2.1)
Unknown stop time 75 (14.5) 250 (14.9) 28 (11.6)
NA 58 (11.2) 196 (11.7) 22 (9.1)
Smoking, n (%)
No habit 390 (75.1) 1244 (74.4) 176 (73.0)
Stop before pregnancy 9 (1.7) 36 (2.2) 10 (4.1)
Stop after pregnancy 25 (4.8) 56 (3.3) 16 (6.6)
Ongoing 16 (3.1) 59 (3.5) 10 (4.1)
Unknown stop time 32 (6.2) 122 (7.3) 13 (5.4)
NA 47 (9.1) 156 (9.3) 16 (6.6)
Abbreviation: NA, not available.
Delivery outcomes and incidence of major malformations
Delivery outcomes were aggregated for all subjects. The percentage of liveborn infants was 94.0% (488 cases) in the domperidone group, 93.8% (1570 cases) in the control group, and 94.2% (227 cases) in the metoclopramide group. There were no notable differences in the incidences of stillbirth, miscarriage or abortion between the three groups (Table 2).
Table 2 Pregnancy outcomes
Domperidone group Control group Metoclopramide group
n 519 1673 241
Outcome, n (%)
Live birth 488 (94.0) 1570 (93.8) 227 (94.2)
Stillbirth a 3 (0.6) 7 (0.4) 0 (0.0)
Miscarriage 18 (3.5) 80 (4.8) 8 (3.3)
Abortion 10 (1.9) 15 (0.9) 6 (2.5)
Other 0 (0.0) 1 b (0.1) 0 (0.0)
Number of infant, n (%)
1 506 (97.5) 1627 (97.3) 234 (97.1)
2≦ 1 (0.2) 9 (0.5) 3 (1.2)
NA 12 (2.3) 37 (2.2) 4 (1.7)
Abbreviation: NA, not available.
a Fetal death after 22 weeks gestation was defined as stillbirth.
b Ectopic pregnancy.
Major malformations in liveborn, single‐birth infants occurred in 14 cases in the domperidone group, 27 in the control group, and 8 in the metoclopramide group (Table 3). There was no pattern of malformation types between the three groups.
Table 3 Risk of major malformation
Major malformation 95%CI Crude OR (95%CI) p‐Value a Adjusted OR b (95%CI) p‐Value a
No Yes
Control group (n = 1554) 1527 27 c (1.7%) (1.1–2.5) 1 ‐ 1 ‐
Domperidone group (n = 485) 471 14 d (2.9%) (1.6–4.8) 1.68 (0.87–3.23) 0.119 1.86 (0.73–4.70) 0.191
Metoclopramide group (n = 224) 216 8 e (3.6%) (1.6–6.9) 2.09 (0.94–4.67) 0.071 2.20 (0.69–6.98) 0.183
Risk of major malformation was analyzed in liveborn, single‐birth infants.
Abbreviations: CI, confidence interval; OR, odds ratio.
a Significance level p < 0.05, *<0.05.
b Adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling.
c Ventricular septal defect (6); ventricular and atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); peripheral pulmonary stenosis (1); endocardial cushion defect (1); complete transposition of great arteries (1); double outlet right ventricle (1); esophageal atresia (1); cleft lip (1); diastasis recti (1); adhesion of scrotum and penis (1); hydronephrosis (2); imperforate anus (1); talipes varus (1); polydactyly (3); a combination of coarctation of the aorta and ventricular septal defect (1); a combination of single ventricle and pulmonary stenosis (1); a combination of ventricular septal defect, pulmonary stenosis and syndactyly (1).
d Ventricular septal defect (5); ventricular and atrial septal defect (1); atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); cleft lip and palate (1); double vagina (1); hydroureteropathy (1); hydronephrosis (1); a combination of duodenal obstruction, heart disease, upper aortic malposition and pulmonary artery occlusion (1).
e Ventricular septal defect (1); endocardial cushion defect (1); myelomeningocele (1); lissencephaly (1); hypospadias (1); talipes varus (1); polydactyly (1); scalp defect (1).
Risk of major malformation
The incidence of major malformation in liveborn, single‐birth infants (95% confidence interval [CI]) was 2.9% (14/485, 95%CI: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group.
Univariable logistic regression analysis showed no significant difference in the incidence of major malformation between the domperidone and control groups (OR: 1.68 [95% CI: 0.87–3.23], p = 0.119). Additionally, multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling also showed no significant difference in the incidence of major malformation between the domperidone and control groups (adjusted OR: 1.86 [95% CI: 0.73–4.70], p = 0.191) (Table 3). Similar results were obtained when comparing the metoclopramide and control groups (OR: 2.09 [95% CI: 0.94–4.67], p = 0.071; adjusted OR: 2.20 [95% CI: 0.69–6.98], p = 0.183).
Subgroup analysis
For the cases at Toranomon Hospital, the adjusted OR (95%CI) of the incidence of major malformation was 2.54 (95%CI: 0.68–9.46, p = 0.164) in the domperidone group and 2.54 (95%CI: 0.47–13.82, p = 0.282) in the metoclopramide group, indicating no significant difference for either group compared with the control group.
For the cases at National Center for Child Health and Development, the adjusted OR (95%CI) of the incidence of major malformation was 1.45 (95%CI: 0.38–5.54, p = 0.583) in the domperidone group and 2.06 (95%CI: 0.43–9.98, p = 0.370) in the metoclopramide group, again indicating no significant difference for either group compared with the control group (Supporting Information, Table SS1).
We also compared the adjusted OR of risk of major malformations by the year of counseling (Table SS2). To rule out the year of counseling as a possible confounding factor, we compared the first half of the data from Toranomon Hospital (1988–2004), to the second half (2005–2016) (adjusted OR: 0.79 [95%CI: 0.26–2.39], p = 0.680) and to the data from the National Center for Child Health and Development (2005–2017) (adjusted OR: 1.34 [95%CI: 0.69–2.60], p = 0.381), and found no significant differences in the adjusted OR.
Discussion
Although there are prior reports 3 , 4 of domperidone administered to pregnant women, those studies lacked sufficient detection power to ensure that domperidone exposure is not harmful to the fetus. Therefore, no information has been available to ensure the safety of using domperidone in pregnant women.
In this study, the 485 patients who received domperidone during the first trimester of pregnancy showed no increase in the incidence of major malformation compared with patients in the control group, who received drugs that are considered to have no teratogenicity. In addition, no difference was found in the results of a sensitivity analysis that assessed teratogenic risk by excluding patients who used teratogenic drugs defined by the clinical guidelines for gynecology and obstetrics 8 .
This study enrolled pregnant women who consulted at Toranomon Hospital or the National Center for Child Health and Development. We therefore performed a subgroup analysis to determine if there were any discrepancies in results between the facilities. There were no such differences, and the incidence of major malformation in the domperidone group did not higher than that in the control group at neither facility.
This study analyzed participants who received counseling at Toranomon Hospital after April 1988 and at National Center for Child Health and Development after October 2005. The use of imaging modalities to detect visceral malformations began in 1997. Therefore, it is presumed that since then it has been possible to detect even minor malformations, such as inconsequential heart defects. However, there was no significant difference in the incidence of major malformation at Toranomon Hospital between 1988 to 2004 and 2005 to 2016. Also, the data from National Center for Child Health and Development (2005–2017) yielded similar results as those from Toranomon Hospital (1988–2004). Thus, the timing of counseling is unlikely to be associated with the detection rate of malformation.
The package insert for domperidone states that it is contraindicated for use in pregnant women and in women suspected of being pregnant, due to teratogenicity observed in reproductive toxicity studies. This has led to the problem of pregnant women becoming anxious when they discover they have taken domperidone before finding out they were pregnant.
This observational cohort study was based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy. It showed that the risk of major malformation was not increased in women who received domperidone during pregnancy. However, it should be noted that a limitation of the study is that women could cancel their counseling if they had a miscarriage or abortion beforehand, resulting in underreported miscarriage or abortion cases.
In future counseling, this information is clinically very useful because it can reduce or eliminate the anxiety of patients who have taken domperidone during pregnancy. The Japanese clinical guidelines for obstetrics and gynecology (obstetrics portion) list domperidone as one of the “drugs that may be used by women in early pregnancy without having a clinically significant adverse effect on the fetus, even though the package inserts state that they are contraindicated in pregnant women.” 8 The results of this study support this statement in the guidelines.
Conflict of interest
Atsuko Murashima received lecture fees from Chugai Pharmaceutical Co.Ltd and Astellas Pharma Inc.
Supporting information
Table S1 Subgroup analysis by the facility
Click here for additional data file.
Table S2 Subgroup analysis by the year of counseling
Click here for additional data file.
Acknowledgments
This work was supported by a Research Program from the Japanese Agency for Medical Research and Development under Grant Number JP19mk0101086h0003, awarded to A.M. The authors would like to thank Dr. Kenjiro Kosaki and Dr. Rika Kosaki for their great advice in diagnosing congenital malformations and we would like to thank Mariko Takagai for her administrative assistance. They are also grateful to women who donated their clinical information and for colleagues worked as a member of Japan Teratology Information Services Network. | METOCLOPRAMIDE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33631840 | 19,020,181 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Polydactyly'. | Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.
OBJECTIVE
To assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.
METHODS
Pregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.
RESULTS
The incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183).
CONCLUSIONS
This observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.
Introduction
Domperidone is an antidopaminergic benzimidazolone compound first synthesized by Janssen Pharmaceutica (Belgium) in 1974. Originally approved in Belgium in 1978, it has since been approved in over 100 countries, including in Japan in 1982. In Japan, domperidone has been widely used for the treatment of gastrointestinal symptoms such as nausea, vomiting, and anorexia.
In a study of domperidone administration during organogenesis in rats, skeletal and visceral malformations were observed in fetuses following an oral dose of 200 mg/kg or an intraperitoneal dose of ≥15 mg/kg. These observed malformations in rats occurred at approximately 300 times the daily oral dose for humans based on body weight. Due to these results, the package insert for domperidone in Japan states that it is contraindicated for use in pregnant women or women suspected of being pregnant.
In some cases, however, domperidone is prescribed for gastrointestinal symptoms such as nausea and vomiting to women who do not yet know they are pregnant due to the pregnancy being unplanned. In such cases, patients often become anxious when they find out they are pregnant and learn that domperidone is contraindicated.
Domperidone and metoclopramide are commonly used as antiemetic drugs in general clinical practice in Japan. Large‐scale epidemiological studies have shown that metoclopramide does not increase the risk of malformation 1 , 2 . On the other hand, teratogenic risk with domperidone has been reported in only a few small‐scale, cohort studies. A report by JS Choi et al. investigated 120 pregnancies treated with domperidone in the first trimester and concluded that domperidone is unlikely to be a major human teratogen 3 . Also, in an abstract, J Cottin et al. compared 124 pregnancies exposed to domperidone during organogenesis with those exposed to other antiemetics or nonteratogenic drugs 4 . There was no significant difference between the three groups in the incidence of major congenital malformations, but the authors commented that the small sample size was a limitation. A report on drug use during pregnancy in the French population stated that about 13% of all pregnant women were using domperidone 5 . Although the teratogenic risk of domperidone was not analyzed in that survey, it suggests that the drug is widely used by pregnant women in some countries.
In the present study, we evaluated the teratogenic risk of domperidone exposure during the first trimester. This is based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy.
Methods
Subjects
This study included women who consulted the Counseling Clinic for “Pregnancy and Medicine” of Toranomon Hospital or the Japan Drug Information Institute in Pregnancy of National Center for Child Health and Development regarding the safety of drugs during pregnancy. Pregnancy outcome data were extracted from the clinical databases of these facilities.
The inclusion criteria were pregnant women who consented to the study and with known pregnancy outcomes who took domperidone (domperidone group), or control drugs (control group) in the first trimester. Among these, women who used domperidone in combination with metoclopramide were excluded from the study. First trimester exposure was defined as drug use between the 28th and 97th days (4th week to 13th week of pregnancy) after the last menstrual period. Experts discussed and selected control drugs considered to be nonteratogenic, referring the report by F. Habermann et al. 6 Control drugs included acetaminophen, antihistamines that were reported in previous studies to have no increased risk of teratogenicity, anti‐infectives like penicillins and cephalosporins, histamine H2‐receptor (H2) blockers, digestive enzyme preparations, and topical drugs (e.g., eye drops, ointment, or cream). Metoclopramide is a similar drug and is expected to be used for the same diseases. In addition, it has been commonly used as an antiemetic drug in pregnant women. Therefore, although statistical comparison with the domperidone group was not performed, patients who took metoclopramide were defined as the reference group.
Data collection
For Toranomon Hospital, women who consulted the Counseling Clinic for “Pregnancy and Medicine” during pregnancy between April 1988 and December 2016 were included in the study. People who wished to make a counseling appointment were first required by the clinic to complete a pre‐appointment questionnaire regarding information such as the names and dosages of drugs taken during pregnancy and expected delivery date, and to return it by mail. At the time of counseling, subjects were interviewed to confirm their expected delivery dates and to obtain other information, including previous medical history, pregnancy and reproductive history, alcohol use, smoking, and family history. We asked patients who provided informed consent for study participation to complete a study questionnaire regarding pregnancy outcomes and any abnormalities during delivery, as well as sex, length, and weight at birth, and any abnormalities of the neonate, and to submit it by mail. If patients provided unclear answers about pregnancy outcomes, an obstetrician contacted their attending physician to obtain clarification. Information on pregnancy outcomes was collected about 1 month after delivery, and the survey was considered complete when this information was obtained.
At the National Center for Child Health and Development, women in pregnancy who sought consultation the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017 were included in the study. The Japan Drug Information Institute in Pregnancy was established under a program of the Ministry of Health Labour and Welfare in October 2005. People who wished to make a counseling appointment were required to complete a pre‐appointment questionnaire and to return it by mail. The pre‐appointment questions were on age, use of drugs during pregnancy, history of present illness, previous medical history, experience of pregnancy, reproductive history, alcohol use, smoking, and intake of folic acid. Approximately a month after their expected delivery date, patients who provided informed consent for participation in the study were sent a postcard‐type questionnaire on pregnancy outcomes and the 1‐month checkup results of their infants. In cases where pregnancy outcomes were unclear, research assistants, doctors or pharmacists contacted the women's attending obstetricians to confirm their pregnancy outcome by telephone. The survey was concluded when information on pregnancy outcomes had been obtained.
Primary endpoint and statistical analysis
The primary endpoint of this study was the incidence of major malformation. To assess the teratogenic risk of domperidone, we compared the incidence of major malformation in the domperidone group with the control group. Major malformations were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) 7 . In cases of congenital abnormalities not included in EUROCAT, a specialist in congenital abnormalities provided diagnoses. Two of the authors concluded that congenital abnormalities could be defined either as surficial malformations or as those requiring surgical treatment. Finally, two independent specialists confirmed the diagnoses.
The incidence of major malformation was analyzed in liveborn, single‐birth infants, and was calculated by dividing the number of liveborn singletons with congenital malformation by the number of all liveborn singletons analyzed in each group. This incidence was compared between the domperidone and control groups. Using the control group as the reference of odds ratio (ORs), the crude ORs of the incidence of major malformations in the domperidone group were calculated using univariable logistic regression analysis. In addition, adjusted ORs were calculated using multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling. Similarly, the crude and adjusted ORs of the incidence of major malformations in the metoclopramide group were calculated. In a subgroup analysis, adjusted ORs were calculated for each facility. The significance level of the test was 5%.
Ethics statement
This study was approved by the Ethics Committee of National Center for Child Health and Development and that of Toranomon Hospital. It was conducted according to the Declaration of Helsinki, and informed consent was obtained from all participants. Information collected from questionnaires was entered into the database and de‐identified by an information administrator. Therefore, the investigators were unable to identify individuals based on the analysis data.
Results
Patient characteristics
At Toranomon Hospital, 12 074 women consulted the Counseling Clinic for “Pregnancy and Medicine” between April 1988 and December 2016. Of these, 1422 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. At National Center for Child Health and Development, 12 971 women consulted the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017. Of these, 1011 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. In total, the number of participants was 519 in the domperidone group, 1673 in the control group, and 241 in the metoclopramide group (Figure 1).
Figure 1 Flowchart
The median age of the subjects at the time of counseling was 30 years in all groups and the groups showed no difference in age distribution. There were no notable differences between groups in either alcohol use or smoking habits, as shown in Table 1.
Table 1 Patient characteristics
Domperidone group Control group Metoclopramide group
n 519 1673 241
Age (year), n (%)
50% [25%, 75%] 30 [26, 33] 30 [27, 34] 30 [27, 34]
≦24 79 (15.2) 160 (9.6) 30 (12.4)
25–29 170 (32.8) 548 (32.8) 81 (33.6)
30–34 167 (32.2) 628 (37.5) 83 (34.4)
35–39 84 (16.2) 288 (17.2) 40 (16.6)
40≦ 18 (3.5) 46 (2.7) 6 (2.5)
NA 1 (0.2) 3 (0.2) 1 (0.4)
Alcohol, n (%)
No use 292 (56.3) 861 (51.5) 125 (51.9)
Stop before pregnancy 7 (1.3) 45 (2.7) 13 (5.4)
Stop after pregnancy 84 (16.2) 305 (18.2) 48 (19.9)
Ongoing 3 (0.6) 16 (1.0) 5 (2.1)
Unknown stop time 75 (14.5) 250 (14.9) 28 (11.6)
NA 58 (11.2) 196 (11.7) 22 (9.1)
Smoking, n (%)
No habit 390 (75.1) 1244 (74.4) 176 (73.0)
Stop before pregnancy 9 (1.7) 36 (2.2) 10 (4.1)
Stop after pregnancy 25 (4.8) 56 (3.3) 16 (6.6)
Ongoing 16 (3.1) 59 (3.5) 10 (4.1)
Unknown stop time 32 (6.2) 122 (7.3) 13 (5.4)
NA 47 (9.1) 156 (9.3) 16 (6.6)
Abbreviation: NA, not available.
Delivery outcomes and incidence of major malformations
Delivery outcomes were aggregated for all subjects. The percentage of liveborn infants was 94.0% (488 cases) in the domperidone group, 93.8% (1570 cases) in the control group, and 94.2% (227 cases) in the metoclopramide group. There were no notable differences in the incidences of stillbirth, miscarriage or abortion between the three groups (Table 2).
Table 2 Pregnancy outcomes
Domperidone group Control group Metoclopramide group
n 519 1673 241
Outcome, n (%)
Live birth 488 (94.0) 1570 (93.8) 227 (94.2)
Stillbirth a 3 (0.6) 7 (0.4) 0 (0.0)
Miscarriage 18 (3.5) 80 (4.8) 8 (3.3)
Abortion 10 (1.9) 15 (0.9) 6 (2.5)
Other 0 (0.0) 1 b (0.1) 0 (0.0)
Number of infant, n (%)
1 506 (97.5) 1627 (97.3) 234 (97.1)
2≦ 1 (0.2) 9 (0.5) 3 (1.2)
NA 12 (2.3) 37 (2.2) 4 (1.7)
Abbreviation: NA, not available.
a Fetal death after 22 weeks gestation was defined as stillbirth.
b Ectopic pregnancy.
Major malformations in liveborn, single‐birth infants occurred in 14 cases in the domperidone group, 27 in the control group, and 8 in the metoclopramide group (Table 3). There was no pattern of malformation types between the three groups.
Table 3 Risk of major malformation
Major malformation 95%CI Crude OR (95%CI) p‐Value a Adjusted OR b (95%CI) p‐Value a
No Yes
Control group (n = 1554) 1527 27 c (1.7%) (1.1–2.5) 1 ‐ 1 ‐
Domperidone group (n = 485) 471 14 d (2.9%) (1.6–4.8) 1.68 (0.87–3.23) 0.119 1.86 (0.73–4.70) 0.191
Metoclopramide group (n = 224) 216 8 e (3.6%) (1.6–6.9) 2.09 (0.94–4.67) 0.071 2.20 (0.69–6.98) 0.183
Risk of major malformation was analyzed in liveborn, single‐birth infants.
Abbreviations: CI, confidence interval; OR, odds ratio.
a Significance level p < 0.05, *<0.05.
b Adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling.
c Ventricular septal defect (6); ventricular and atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); peripheral pulmonary stenosis (1); endocardial cushion defect (1); complete transposition of great arteries (1); double outlet right ventricle (1); esophageal atresia (1); cleft lip (1); diastasis recti (1); adhesion of scrotum and penis (1); hydronephrosis (2); imperforate anus (1); talipes varus (1); polydactyly (3); a combination of coarctation of the aorta and ventricular septal defect (1); a combination of single ventricle and pulmonary stenosis (1); a combination of ventricular septal defect, pulmonary stenosis and syndactyly (1).
d Ventricular septal defect (5); ventricular and atrial septal defect (1); atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); cleft lip and palate (1); double vagina (1); hydroureteropathy (1); hydronephrosis (1); a combination of duodenal obstruction, heart disease, upper aortic malposition and pulmonary artery occlusion (1).
e Ventricular septal defect (1); endocardial cushion defect (1); myelomeningocele (1); lissencephaly (1); hypospadias (1); talipes varus (1); polydactyly (1); scalp defect (1).
Risk of major malformation
The incidence of major malformation in liveborn, single‐birth infants (95% confidence interval [CI]) was 2.9% (14/485, 95%CI: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group.
Univariable logistic regression analysis showed no significant difference in the incidence of major malformation between the domperidone and control groups (OR: 1.68 [95% CI: 0.87–3.23], p = 0.119). Additionally, multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling also showed no significant difference in the incidence of major malformation between the domperidone and control groups (adjusted OR: 1.86 [95% CI: 0.73–4.70], p = 0.191) (Table 3). Similar results were obtained when comparing the metoclopramide and control groups (OR: 2.09 [95% CI: 0.94–4.67], p = 0.071; adjusted OR: 2.20 [95% CI: 0.69–6.98], p = 0.183).
Subgroup analysis
For the cases at Toranomon Hospital, the adjusted OR (95%CI) of the incidence of major malformation was 2.54 (95%CI: 0.68–9.46, p = 0.164) in the domperidone group and 2.54 (95%CI: 0.47–13.82, p = 0.282) in the metoclopramide group, indicating no significant difference for either group compared with the control group.
For the cases at National Center for Child Health and Development, the adjusted OR (95%CI) of the incidence of major malformation was 1.45 (95%CI: 0.38–5.54, p = 0.583) in the domperidone group and 2.06 (95%CI: 0.43–9.98, p = 0.370) in the metoclopramide group, again indicating no significant difference for either group compared with the control group (Supporting Information, Table SS1).
We also compared the adjusted OR of risk of major malformations by the year of counseling (Table SS2). To rule out the year of counseling as a possible confounding factor, we compared the first half of the data from Toranomon Hospital (1988–2004), to the second half (2005–2016) (adjusted OR: 0.79 [95%CI: 0.26–2.39], p = 0.680) and to the data from the National Center for Child Health and Development (2005–2017) (adjusted OR: 1.34 [95%CI: 0.69–2.60], p = 0.381), and found no significant differences in the adjusted OR.
Discussion
Although there are prior reports 3 , 4 of domperidone administered to pregnant women, those studies lacked sufficient detection power to ensure that domperidone exposure is not harmful to the fetus. Therefore, no information has been available to ensure the safety of using domperidone in pregnant women.
In this study, the 485 patients who received domperidone during the first trimester of pregnancy showed no increase in the incidence of major malformation compared with patients in the control group, who received drugs that are considered to have no teratogenicity. In addition, no difference was found in the results of a sensitivity analysis that assessed teratogenic risk by excluding patients who used teratogenic drugs defined by the clinical guidelines for gynecology and obstetrics 8 .
This study enrolled pregnant women who consulted at Toranomon Hospital or the National Center for Child Health and Development. We therefore performed a subgroup analysis to determine if there were any discrepancies in results between the facilities. There were no such differences, and the incidence of major malformation in the domperidone group did not higher than that in the control group at neither facility.
This study analyzed participants who received counseling at Toranomon Hospital after April 1988 and at National Center for Child Health and Development after October 2005. The use of imaging modalities to detect visceral malformations began in 1997. Therefore, it is presumed that since then it has been possible to detect even minor malformations, such as inconsequential heart defects. However, there was no significant difference in the incidence of major malformation at Toranomon Hospital between 1988 to 2004 and 2005 to 2016. Also, the data from National Center for Child Health and Development (2005–2017) yielded similar results as those from Toranomon Hospital (1988–2004). Thus, the timing of counseling is unlikely to be associated with the detection rate of malformation.
The package insert for domperidone states that it is contraindicated for use in pregnant women and in women suspected of being pregnant, due to teratogenicity observed in reproductive toxicity studies. This has led to the problem of pregnant women becoming anxious when they discover they have taken domperidone before finding out they were pregnant.
This observational cohort study was based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy. It showed that the risk of major malformation was not increased in women who received domperidone during pregnancy. However, it should be noted that a limitation of the study is that women could cancel their counseling if they had a miscarriage or abortion beforehand, resulting in underreported miscarriage or abortion cases.
In future counseling, this information is clinically very useful because it can reduce or eliminate the anxiety of patients who have taken domperidone during pregnancy. The Japanese clinical guidelines for obstetrics and gynecology (obstetrics portion) list domperidone as one of the “drugs that may be used by women in early pregnancy without having a clinically significant adverse effect on the fetus, even though the package inserts state that they are contraindicated in pregnant women.” 8 The results of this study support this statement in the guidelines.
Conflict of interest
Atsuko Murashima received lecture fees from Chugai Pharmaceutical Co.Ltd and Astellas Pharma Inc.
Supporting information
Table S1 Subgroup analysis by the facility
Click here for additional data file.
Table S2 Subgroup analysis by the year of counseling
Click here for additional data file.
Acknowledgments
This work was supported by a Research Program from the Japanese Agency for Medical Research and Development under Grant Number JP19mk0101086h0003, awarded to A.M. The authors would like to thank Dr. Kenjiro Kosaki and Dr. Rika Kosaki for their great advice in diagnosing congenital malformations and we would like to thank Mariko Takagai for her administrative assistance. They are also grateful to women who donated their clinical information and for colleagues worked as a member of Japan Teratology Information Services Network. | METOCLOPRAMIDE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33631840 | 19,020,263 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Talipes'. | Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.
OBJECTIVE
To assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.
METHODS
Pregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.
RESULTS
The incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183).
CONCLUSIONS
This observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.
Introduction
Domperidone is an antidopaminergic benzimidazolone compound first synthesized by Janssen Pharmaceutica (Belgium) in 1974. Originally approved in Belgium in 1978, it has since been approved in over 100 countries, including in Japan in 1982. In Japan, domperidone has been widely used for the treatment of gastrointestinal symptoms such as nausea, vomiting, and anorexia.
In a study of domperidone administration during organogenesis in rats, skeletal and visceral malformations were observed in fetuses following an oral dose of 200 mg/kg or an intraperitoneal dose of ≥15 mg/kg. These observed malformations in rats occurred at approximately 300 times the daily oral dose for humans based on body weight. Due to these results, the package insert for domperidone in Japan states that it is contraindicated for use in pregnant women or women suspected of being pregnant.
In some cases, however, domperidone is prescribed for gastrointestinal symptoms such as nausea and vomiting to women who do not yet know they are pregnant due to the pregnancy being unplanned. In such cases, patients often become anxious when they find out they are pregnant and learn that domperidone is contraindicated.
Domperidone and metoclopramide are commonly used as antiemetic drugs in general clinical practice in Japan. Large‐scale epidemiological studies have shown that metoclopramide does not increase the risk of malformation 1 , 2 . On the other hand, teratogenic risk with domperidone has been reported in only a few small‐scale, cohort studies. A report by JS Choi et al. investigated 120 pregnancies treated with domperidone in the first trimester and concluded that domperidone is unlikely to be a major human teratogen 3 . Also, in an abstract, J Cottin et al. compared 124 pregnancies exposed to domperidone during organogenesis with those exposed to other antiemetics or nonteratogenic drugs 4 . There was no significant difference between the three groups in the incidence of major congenital malformations, but the authors commented that the small sample size was a limitation. A report on drug use during pregnancy in the French population stated that about 13% of all pregnant women were using domperidone 5 . Although the teratogenic risk of domperidone was not analyzed in that survey, it suggests that the drug is widely used by pregnant women in some countries.
In the present study, we evaluated the teratogenic risk of domperidone exposure during the first trimester. This is based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy.
Methods
Subjects
This study included women who consulted the Counseling Clinic for “Pregnancy and Medicine” of Toranomon Hospital or the Japan Drug Information Institute in Pregnancy of National Center for Child Health and Development regarding the safety of drugs during pregnancy. Pregnancy outcome data were extracted from the clinical databases of these facilities.
The inclusion criteria were pregnant women who consented to the study and with known pregnancy outcomes who took domperidone (domperidone group), or control drugs (control group) in the first trimester. Among these, women who used domperidone in combination with metoclopramide were excluded from the study. First trimester exposure was defined as drug use between the 28th and 97th days (4th week to 13th week of pregnancy) after the last menstrual period. Experts discussed and selected control drugs considered to be nonteratogenic, referring the report by F. Habermann et al. 6 Control drugs included acetaminophen, antihistamines that were reported in previous studies to have no increased risk of teratogenicity, anti‐infectives like penicillins and cephalosporins, histamine H2‐receptor (H2) blockers, digestive enzyme preparations, and topical drugs (e.g., eye drops, ointment, or cream). Metoclopramide is a similar drug and is expected to be used for the same diseases. In addition, it has been commonly used as an antiemetic drug in pregnant women. Therefore, although statistical comparison with the domperidone group was not performed, patients who took metoclopramide were defined as the reference group.
Data collection
For Toranomon Hospital, women who consulted the Counseling Clinic for “Pregnancy and Medicine” during pregnancy between April 1988 and December 2016 were included in the study. People who wished to make a counseling appointment were first required by the clinic to complete a pre‐appointment questionnaire regarding information such as the names and dosages of drugs taken during pregnancy and expected delivery date, and to return it by mail. At the time of counseling, subjects were interviewed to confirm their expected delivery dates and to obtain other information, including previous medical history, pregnancy and reproductive history, alcohol use, smoking, and family history. We asked patients who provided informed consent for study participation to complete a study questionnaire regarding pregnancy outcomes and any abnormalities during delivery, as well as sex, length, and weight at birth, and any abnormalities of the neonate, and to submit it by mail. If patients provided unclear answers about pregnancy outcomes, an obstetrician contacted their attending physician to obtain clarification. Information on pregnancy outcomes was collected about 1 month after delivery, and the survey was considered complete when this information was obtained.
At the National Center for Child Health and Development, women in pregnancy who sought consultation the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017 were included in the study. The Japan Drug Information Institute in Pregnancy was established under a program of the Ministry of Health Labour and Welfare in October 2005. People who wished to make a counseling appointment were required to complete a pre‐appointment questionnaire and to return it by mail. The pre‐appointment questions were on age, use of drugs during pregnancy, history of present illness, previous medical history, experience of pregnancy, reproductive history, alcohol use, smoking, and intake of folic acid. Approximately a month after their expected delivery date, patients who provided informed consent for participation in the study were sent a postcard‐type questionnaire on pregnancy outcomes and the 1‐month checkup results of their infants. In cases where pregnancy outcomes were unclear, research assistants, doctors or pharmacists contacted the women's attending obstetricians to confirm their pregnancy outcome by telephone. The survey was concluded when information on pregnancy outcomes had been obtained.
Primary endpoint and statistical analysis
The primary endpoint of this study was the incidence of major malformation. To assess the teratogenic risk of domperidone, we compared the incidence of major malformation in the domperidone group with the control group. Major malformations were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) 7 . In cases of congenital abnormalities not included in EUROCAT, a specialist in congenital abnormalities provided diagnoses. Two of the authors concluded that congenital abnormalities could be defined either as surficial malformations or as those requiring surgical treatment. Finally, two independent specialists confirmed the diagnoses.
The incidence of major malformation was analyzed in liveborn, single‐birth infants, and was calculated by dividing the number of liveborn singletons with congenital malformation by the number of all liveborn singletons analyzed in each group. This incidence was compared between the domperidone and control groups. Using the control group as the reference of odds ratio (ORs), the crude ORs of the incidence of major malformations in the domperidone group were calculated using univariable logistic regression analysis. In addition, adjusted ORs were calculated using multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling. Similarly, the crude and adjusted ORs of the incidence of major malformations in the metoclopramide group were calculated. In a subgroup analysis, adjusted ORs were calculated for each facility. The significance level of the test was 5%.
Ethics statement
This study was approved by the Ethics Committee of National Center for Child Health and Development and that of Toranomon Hospital. It was conducted according to the Declaration of Helsinki, and informed consent was obtained from all participants. Information collected from questionnaires was entered into the database and de‐identified by an information administrator. Therefore, the investigators were unable to identify individuals based on the analysis data.
Results
Patient characteristics
At Toranomon Hospital, 12 074 women consulted the Counseling Clinic for “Pregnancy and Medicine” between April 1988 and December 2016. Of these, 1422 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. At National Center for Child Health and Development, 12 971 women consulted the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017. Of these, 1011 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. In total, the number of participants was 519 in the domperidone group, 1673 in the control group, and 241 in the metoclopramide group (Figure 1).
Figure 1 Flowchart
The median age of the subjects at the time of counseling was 30 years in all groups and the groups showed no difference in age distribution. There were no notable differences between groups in either alcohol use or smoking habits, as shown in Table 1.
Table 1 Patient characteristics
Domperidone group Control group Metoclopramide group
n 519 1673 241
Age (year), n (%)
50% [25%, 75%] 30 [26, 33] 30 [27, 34] 30 [27, 34]
≦24 79 (15.2) 160 (9.6) 30 (12.4)
25–29 170 (32.8) 548 (32.8) 81 (33.6)
30–34 167 (32.2) 628 (37.5) 83 (34.4)
35–39 84 (16.2) 288 (17.2) 40 (16.6)
40≦ 18 (3.5) 46 (2.7) 6 (2.5)
NA 1 (0.2) 3 (0.2) 1 (0.4)
Alcohol, n (%)
No use 292 (56.3) 861 (51.5) 125 (51.9)
Stop before pregnancy 7 (1.3) 45 (2.7) 13 (5.4)
Stop after pregnancy 84 (16.2) 305 (18.2) 48 (19.9)
Ongoing 3 (0.6) 16 (1.0) 5 (2.1)
Unknown stop time 75 (14.5) 250 (14.9) 28 (11.6)
NA 58 (11.2) 196 (11.7) 22 (9.1)
Smoking, n (%)
No habit 390 (75.1) 1244 (74.4) 176 (73.0)
Stop before pregnancy 9 (1.7) 36 (2.2) 10 (4.1)
Stop after pregnancy 25 (4.8) 56 (3.3) 16 (6.6)
Ongoing 16 (3.1) 59 (3.5) 10 (4.1)
Unknown stop time 32 (6.2) 122 (7.3) 13 (5.4)
NA 47 (9.1) 156 (9.3) 16 (6.6)
Abbreviation: NA, not available.
Delivery outcomes and incidence of major malformations
Delivery outcomes were aggregated for all subjects. The percentage of liveborn infants was 94.0% (488 cases) in the domperidone group, 93.8% (1570 cases) in the control group, and 94.2% (227 cases) in the metoclopramide group. There were no notable differences in the incidences of stillbirth, miscarriage or abortion between the three groups (Table 2).
Table 2 Pregnancy outcomes
Domperidone group Control group Metoclopramide group
n 519 1673 241
Outcome, n (%)
Live birth 488 (94.0) 1570 (93.8) 227 (94.2)
Stillbirth a 3 (0.6) 7 (0.4) 0 (0.0)
Miscarriage 18 (3.5) 80 (4.8) 8 (3.3)
Abortion 10 (1.9) 15 (0.9) 6 (2.5)
Other 0 (0.0) 1 b (0.1) 0 (0.0)
Number of infant, n (%)
1 506 (97.5) 1627 (97.3) 234 (97.1)
2≦ 1 (0.2) 9 (0.5) 3 (1.2)
NA 12 (2.3) 37 (2.2) 4 (1.7)
Abbreviation: NA, not available.
a Fetal death after 22 weeks gestation was defined as stillbirth.
b Ectopic pregnancy.
Major malformations in liveborn, single‐birth infants occurred in 14 cases in the domperidone group, 27 in the control group, and 8 in the metoclopramide group (Table 3). There was no pattern of malformation types between the three groups.
Table 3 Risk of major malformation
Major malformation 95%CI Crude OR (95%CI) p‐Value a Adjusted OR b (95%CI) p‐Value a
No Yes
Control group (n = 1554) 1527 27 c (1.7%) (1.1–2.5) 1 ‐ 1 ‐
Domperidone group (n = 485) 471 14 d (2.9%) (1.6–4.8) 1.68 (0.87–3.23) 0.119 1.86 (0.73–4.70) 0.191
Metoclopramide group (n = 224) 216 8 e (3.6%) (1.6–6.9) 2.09 (0.94–4.67) 0.071 2.20 (0.69–6.98) 0.183
Risk of major malformation was analyzed in liveborn, single‐birth infants.
Abbreviations: CI, confidence interval; OR, odds ratio.
a Significance level p < 0.05, *<0.05.
b Adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling.
c Ventricular septal defect (6); ventricular and atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); peripheral pulmonary stenosis (1); endocardial cushion defect (1); complete transposition of great arteries (1); double outlet right ventricle (1); esophageal atresia (1); cleft lip (1); diastasis recti (1); adhesion of scrotum and penis (1); hydronephrosis (2); imperforate anus (1); talipes varus (1); polydactyly (3); a combination of coarctation of the aorta and ventricular septal defect (1); a combination of single ventricle and pulmonary stenosis (1); a combination of ventricular septal defect, pulmonary stenosis and syndactyly (1).
d Ventricular septal defect (5); ventricular and atrial septal defect (1); atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); cleft lip and palate (1); double vagina (1); hydroureteropathy (1); hydronephrosis (1); a combination of duodenal obstruction, heart disease, upper aortic malposition and pulmonary artery occlusion (1).
e Ventricular septal defect (1); endocardial cushion defect (1); myelomeningocele (1); lissencephaly (1); hypospadias (1); talipes varus (1); polydactyly (1); scalp defect (1).
Risk of major malformation
The incidence of major malformation in liveborn, single‐birth infants (95% confidence interval [CI]) was 2.9% (14/485, 95%CI: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group.
Univariable logistic regression analysis showed no significant difference in the incidence of major malformation between the domperidone and control groups (OR: 1.68 [95% CI: 0.87–3.23], p = 0.119). Additionally, multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling also showed no significant difference in the incidence of major malformation between the domperidone and control groups (adjusted OR: 1.86 [95% CI: 0.73–4.70], p = 0.191) (Table 3). Similar results were obtained when comparing the metoclopramide and control groups (OR: 2.09 [95% CI: 0.94–4.67], p = 0.071; adjusted OR: 2.20 [95% CI: 0.69–6.98], p = 0.183).
Subgroup analysis
For the cases at Toranomon Hospital, the adjusted OR (95%CI) of the incidence of major malformation was 2.54 (95%CI: 0.68–9.46, p = 0.164) in the domperidone group and 2.54 (95%CI: 0.47–13.82, p = 0.282) in the metoclopramide group, indicating no significant difference for either group compared with the control group.
For the cases at National Center for Child Health and Development, the adjusted OR (95%CI) of the incidence of major malformation was 1.45 (95%CI: 0.38–5.54, p = 0.583) in the domperidone group and 2.06 (95%CI: 0.43–9.98, p = 0.370) in the metoclopramide group, again indicating no significant difference for either group compared with the control group (Supporting Information, Table SS1).
We also compared the adjusted OR of risk of major malformations by the year of counseling (Table SS2). To rule out the year of counseling as a possible confounding factor, we compared the first half of the data from Toranomon Hospital (1988–2004), to the second half (2005–2016) (adjusted OR: 0.79 [95%CI: 0.26–2.39], p = 0.680) and to the data from the National Center for Child Health and Development (2005–2017) (adjusted OR: 1.34 [95%CI: 0.69–2.60], p = 0.381), and found no significant differences in the adjusted OR.
Discussion
Although there are prior reports 3 , 4 of domperidone administered to pregnant women, those studies lacked sufficient detection power to ensure that domperidone exposure is not harmful to the fetus. Therefore, no information has been available to ensure the safety of using domperidone in pregnant women.
In this study, the 485 patients who received domperidone during the first trimester of pregnancy showed no increase in the incidence of major malformation compared with patients in the control group, who received drugs that are considered to have no teratogenicity. In addition, no difference was found in the results of a sensitivity analysis that assessed teratogenic risk by excluding patients who used teratogenic drugs defined by the clinical guidelines for gynecology and obstetrics 8 .
This study enrolled pregnant women who consulted at Toranomon Hospital or the National Center for Child Health and Development. We therefore performed a subgroup analysis to determine if there were any discrepancies in results between the facilities. There were no such differences, and the incidence of major malformation in the domperidone group did not higher than that in the control group at neither facility.
This study analyzed participants who received counseling at Toranomon Hospital after April 1988 and at National Center for Child Health and Development after October 2005. The use of imaging modalities to detect visceral malformations began in 1997. Therefore, it is presumed that since then it has been possible to detect even minor malformations, such as inconsequential heart defects. However, there was no significant difference in the incidence of major malformation at Toranomon Hospital between 1988 to 2004 and 2005 to 2016. Also, the data from National Center for Child Health and Development (2005–2017) yielded similar results as those from Toranomon Hospital (1988–2004). Thus, the timing of counseling is unlikely to be associated with the detection rate of malformation.
The package insert for domperidone states that it is contraindicated for use in pregnant women and in women suspected of being pregnant, due to teratogenicity observed in reproductive toxicity studies. This has led to the problem of pregnant women becoming anxious when they discover they have taken domperidone before finding out they were pregnant.
This observational cohort study was based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy. It showed that the risk of major malformation was not increased in women who received domperidone during pregnancy. However, it should be noted that a limitation of the study is that women could cancel their counseling if they had a miscarriage or abortion beforehand, resulting in underreported miscarriage or abortion cases.
In future counseling, this information is clinically very useful because it can reduce or eliminate the anxiety of patients who have taken domperidone during pregnancy. The Japanese clinical guidelines for obstetrics and gynecology (obstetrics portion) list domperidone as one of the “drugs that may be used by women in early pregnancy without having a clinically significant adverse effect on the fetus, even though the package inserts state that they are contraindicated in pregnant women.” 8 The results of this study support this statement in the guidelines.
Conflict of interest
Atsuko Murashima received lecture fees from Chugai Pharmaceutical Co.Ltd and Astellas Pharma Inc.
Supporting information
Table S1 Subgroup analysis by the facility
Click here for additional data file.
Table S2 Subgroup analysis by the year of counseling
Click here for additional data file.
Acknowledgments
This work was supported by a Research Program from the Japanese Agency for Medical Research and Development under Grant Number JP19mk0101086h0003, awarded to A.M. The authors would like to thank Dr. Kenjiro Kosaki and Dr. Rika Kosaki for their great advice in diagnosing congenital malformations and we would like to thank Mariko Takagai for her administrative assistance. They are also grateful to women who donated their clinical information and for colleagues worked as a member of Japan Teratology Information Services Network. | METOCLOPRAMIDE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33631840 | 19,020,260 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ventricular septal defect'. | Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.
OBJECTIVE
To assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.
METHODS
Pregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.
RESULTS
The incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183).
CONCLUSIONS
This observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.
Introduction
Domperidone is an antidopaminergic benzimidazolone compound first synthesized by Janssen Pharmaceutica (Belgium) in 1974. Originally approved in Belgium in 1978, it has since been approved in over 100 countries, including in Japan in 1982. In Japan, domperidone has been widely used for the treatment of gastrointestinal symptoms such as nausea, vomiting, and anorexia.
In a study of domperidone administration during organogenesis in rats, skeletal and visceral malformations were observed in fetuses following an oral dose of 200 mg/kg or an intraperitoneal dose of ≥15 mg/kg. These observed malformations in rats occurred at approximately 300 times the daily oral dose for humans based on body weight. Due to these results, the package insert for domperidone in Japan states that it is contraindicated for use in pregnant women or women suspected of being pregnant.
In some cases, however, domperidone is prescribed for gastrointestinal symptoms such as nausea and vomiting to women who do not yet know they are pregnant due to the pregnancy being unplanned. In such cases, patients often become anxious when they find out they are pregnant and learn that domperidone is contraindicated.
Domperidone and metoclopramide are commonly used as antiemetic drugs in general clinical practice in Japan. Large‐scale epidemiological studies have shown that metoclopramide does not increase the risk of malformation 1 , 2 . On the other hand, teratogenic risk with domperidone has been reported in only a few small‐scale, cohort studies. A report by JS Choi et al. investigated 120 pregnancies treated with domperidone in the first trimester and concluded that domperidone is unlikely to be a major human teratogen 3 . Also, in an abstract, J Cottin et al. compared 124 pregnancies exposed to domperidone during organogenesis with those exposed to other antiemetics or nonteratogenic drugs 4 . There was no significant difference between the three groups in the incidence of major congenital malformations, but the authors commented that the small sample size was a limitation. A report on drug use during pregnancy in the French population stated that about 13% of all pregnant women were using domperidone 5 . Although the teratogenic risk of domperidone was not analyzed in that survey, it suggests that the drug is widely used by pregnant women in some countries.
In the present study, we evaluated the teratogenic risk of domperidone exposure during the first trimester. This is based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy.
Methods
Subjects
This study included women who consulted the Counseling Clinic for “Pregnancy and Medicine” of Toranomon Hospital or the Japan Drug Information Institute in Pregnancy of National Center for Child Health and Development regarding the safety of drugs during pregnancy. Pregnancy outcome data were extracted from the clinical databases of these facilities.
The inclusion criteria were pregnant women who consented to the study and with known pregnancy outcomes who took domperidone (domperidone group), or control drugs (control group) in the first trimester. Among these, women who used domperidone in combination with metoclopramide were excluded from the study. First trimester exposure was defined as drug use between the 28th and 97th days (4th week to 13th week of pregnancy) after the last menstrual period. Experts discussed and selected control drugs considered to be nonteratogenic, referring the report by F. Habermann et al. 6 Control drugs included acetaminophen, antihistamines that were reported in previous studies to have no increased risk of teratogenicity, anti‐infectives like penicillins and cephalosporins, histamine H2‐receptor (H2) blockers, digestive enzyme preparations, and topical drugs (e.g., eye drops, ointment, or cream). Metoclopramide is a similar drug and is expected to be used for the same diseases. In addition, it has been commonly used as an antiemetic drug in pregnant women. Therefore, although statistical comparison with the domperidone group was not performed, patients who took metoclopramide were defined as the reference group.
Data collection
For Toranomon Hospital, women who consulted the Counseling Clinic for “Pregnancy and Medicine” during pregnancy between April 1988 and December 2016 were included in the study. People who wished to make a counseling appointment were first required by the clinic to complete a pre‐appointment questionnaire regarding information such as the names and dosages of drugs taken during pregnancy and expected delivery date, and to return it by mail. At the time of counseling, subjects were interviewed to confirm their expected delivery dates and to obtain other information, including previous medical history, pregnancy and reproductive history, alcohol use, smoking, and family history. We asked patients who provided informed consent for study participation to complete a study questionnaire regarding pregnancy outcomes and any abnormalities during delivery, as well as sex, length, and weight at birth, and any abnormalities of the neonate, and to submit it by mail. If patients provided unclear answers about pregnancy outcomes, an obstetrician contacted their attending physician to obtain clarification. Information on pregnancy outcomes was collected about 1 month after delivery, and the survey was considered complete when this information was obtained.
At the National Center for Child Health and Development, women in pregnancy who sought consultation the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017 were included in the study. The Japan Drug Information Institute in Pregnancy was established under a program of the Ministry of Health Labour and Welfare in October 2005. People who wished to make a counseling appointment were required to complete a pre‐appointment questionnaire and to return it by mail. The pre‐appointment questions were on age, use of drugs during pregnancy, history of present illness, previous medical history, experience of pregnancy, reproductive history, alcohol use, smoking, and intake of folic acid. Approximately a month after their expected delivery date, patients who provided informed consent for participation in the study were sent a postcard‐type questionnaire on pregnancy outcomes and the 1‐month checkup results of their infants. In cases where pregnancy outcomes were unclear, research assistants, doctors or pharmacists contacted the women's attending obstetricians to confirm their pregnancy outcome by telephone. The survey was concluded when information on pregnancy outcomes had been obtained.
Primary endpoint and statistical analysis
The primary endpoint of this study was the incidence of major malformation. To assess the teratogenic risk of domperidone, we compared the incidence of major malformation in the domperidone group with the control group. Major malformations were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) 7 . In cases of congenital abnormalities not included in EUROCAT, a specialist in congenital abnormalities provided diagnoses. Two of the authors concluded that congenital abnormalities could be defined either as surficial malformations or as those requiring surgical treatment. Finally, two independent specialists confirmed the diagnoses.
The incidence of major malformation was analyzed in liveborn, single‐birth infants, and was calculated by dividing the number of liveborn singletons with congenital malformation by the number of all liveborn singletons analyzed in each group. This incidence was compared between the domperidone and control groups. Using the control group as the reference of odds ratio (ORs), the crude ORs of the incidence of major malformations in the domperidone group were calculated using univariable logistic regression analysis. In addition, adjusted ORs were calculated using multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling. Similarly, the crude and adjusted ORs of the incidence of major malformations in the metoclopramide group were calculated. In a subgroup analysis, adjusted ORs were calculated for each facility. The significance level of the test was 5%.
Ethics statement
This study was approved by the Ethics Committee of National Center for Child Health and Development and that of Toranomon Hospital. It was conducted according to the Declaration of Helsinki, and informed consent was obtained from all participants. Information collected from questionnaires was entered into the database and de‐identified by an information administrator. Therefore, the investigators were unable to identify individuals based on the analysis data.
Results
Patient characteristics
At Toranomon Hospital, 12 074 women consulted the Counseling Clinic for “Pregnancy and Medicine” between April 1988 and December 2016. Of these, 1422 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. At National Center for Child Health and Development, 12 971 women consulted the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017. Of these, 1011 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. In total, the number of participants was 519 in the domperidone group, 1673 in the control group, and 241 in the metoclopramide group (Figure 1).
Figure 1 Flowchart
The median age of the subjects at the time of counseling was 30 years in all groups and the groups showed no difference in age distribution. There were no notable differences between groups in either alcohol use or smoking habits, as shown in Table 1.
Table 1 Patient characteristics
Domperidone group Control group Metoclopramide group
n 519 1673 241
Age (year), n (%)
50% [25%, 75%] 30 [26, 33] 30 [27, 34] 30 [27, 34]
≦24 79 (15.2) 160 (9.6) 30 (12.4)
25–29 170 (32.8) 548 (32.8) 81 (33.6)
30–34 167 (32.2) 628 (37.5) 83 (34.4)
35–39 84 (16.2) 288 (17.2) 40 (16.6)
40≦ 18 (3.5) 46 (2.7) 6 (2.5)
NA 1 (0.2) 3 (0.2) 1 (0.4)
Alcohol, n (%)
No use 292 (56.3) 861 (51.5) 125 (51.9)
Stop before pregnancy 7 (1.3) 45 (2.7) 13 (5.4)
Stop after pregnancy 84 (16.2) 305 (18.2) 48 (19.9)
Ongoing 3 (0.6) 16 (1.0) 5 (2.1)
Unknown stop time 75 (14.5) 250 (14.9) 28 (11.6)
NA 58 (11.2) 196 (11.7) 22 (9.1)
Smoking, n (%)
No habit 390 (75.1) 1244 (74.4) 176 (73.0)
Stop before pregnancy 9 (1.7) 36 (2.2) 10 (4.1)
Stop after pregnancy 25 (4.8) 56 (3.3) 16 (6.6)
Ongoing 16 (3.1) 59 (3.5) 10 (4.1)
Unknown stop time 32 (6.2) 122 (7.3) 13 (5.4)
NA 47 (9.1) 156 (9.3) 16 (6.6)
Abbreviation: NA, not available.
Delivery outcomes and incidence of major malformations
Delivery outcomes were aggregated for all subjects. The percentage of liveborn infants was 94.0% (488 cases) in the domperidone group, 93.8% (1570 cases) in the control group, and 94.2% (227 cases) in the metoclopramide group. There were no notable differences in the incidences of stillbirth, miscarriage or abortion between the three groups (Table 2).
Table 2 Pregnancy outcomes
Domperidone group Control group Metoclopramide group
n 519 1673 241
Outcome, n (%)
Live birth 488 (94.0) 1570 (93.8) 227 (94.2)
Stillbirth a 3 (0.6) 7 (0.4) 0 (0.0)
Miscarriage 18 (3.5) 80 (4.8) 8 (3.3)
Abortion 10 (1.9) 15 (0.9) 6 (2.5)
Other 0 (0.0) 1 b (0.1) 0 (0.0)
Number of infant, n (%)
1 506 (97.5) 1627 (97.3) 234 (97.1)
2≦ 1 (0.2) 9 (0.5) 3 (1.2)
NA 12 (2.3) 37 (2.2) 4 (1.7)
Abbreviation: NA, not available.
a Fetal death after 22 weeks gestation was defined as stillbirth.
b Ectopic pregnancy.
Major malformations in liveborn, single‐birth infants occurred in 14 cases in the domperidone group, 27 in the control group, and 8 in the metoclopramide group (Table 3). There was no pattern of malformation types between the three groups.
Table 3 Risk of major malformation
Major malformation 95%CI Crude OR (95%CI) p‐Value a Adjusted OR b (95%CI) p‐Value a
No Yes
Control group (n = 1554) 1527 27 c (1.7%) (1.1–2.5) 1 ‐ 1 ‐
Domperidone group (n = 485) 471 14 d (2.9%) (1.6–4.8) 1.68 (0.87–3.23) 0.119 1.86 (0.73–4.70) 0.191
Metoclopramide group (n = 224) 216 8 e (3.6%) (1.6–6.9) 2.09 (0.94–4.67) 0.071 2.20 (0.69–6.98) 0.183
Risk of major malformation was analyzed in liveborn, single‐birth infants.
Abbreviations: CI, confidence interval; OR, odds ratio.
a Significance level p < 0.05, *<0.05.
b Adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling.
c Ventricular septal defect (6); ventricular and atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); peripheral pulmonary stenosis (1); endocardial cushion defect (1); complete transposition of great arteries (1); double outlet right ventricle (1); esophageal atresia (1); cleft lip (1); diastasis recti (1); adhesion of scrotum and penis (1); hydronephrosis (2); imperforate anus (1); talipes varus (1); polydactyly (3); a combination of coarctation of the aorta and ventricular septal defect (1); a combination of single ventricle and pulmonary stenosis (1); a combination of ventricular septal defect, pulmonary stenosis and syndactyly (1).
d Ventricular septal defect (5); ventricular and atrial septal defect (1); atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); cleft lip and palate (1); double vagina (1); hydroureteropathy (1); hydronephrosis (1); a combination of duodenal obstruction, heart disease, upper aortic malposition and pulmonary artery occlusion (1).
e Ventricular septal defect (1); endocardial cushion defect (1); myelomeningocele (1); lissencephaly (1); hypospadias (1); talipes varus (1); polydactyly (1); scalp defect (1).
Risk of major malformation
The incidence of major malformation in liveborn, single‐birth infants (95% confidence interval [CI]) was 2.9% (14/485, 95%CI: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group.
Univariable logistic regression analysis showed no significant difference in the incidence of major malformation between the domperidone and control groups (OR: 1.68 [95% CI: 0.87–3.23], p = 0.119). Additionally, multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling also showed no significant difference in the incidence of major malformation between the domperidone and control groups (adjusted OR: 1.86 [95% CI: 0.73–4.70], p = 0.191) (Table 3). Similar results were obtained when comparing the metoclopramide and control groups (OR: 2.09 [95% CI: 0.94–4.67], p = 0.071; adjusted OR: 2.20 [95% CI: 0.69–6.98], p = 0.183).
Subgroup analysis
For the cases at Toranomon Hospital, the adjusted OR (95%CI) of the incidence of major malformation was 2.54 (95%CI: 0.68–9.46, p = 0.164) in the domperidone group and 2.54 (95%CI: 0.47–13.82, p = 0.282) in the metoclopramide group, indicating no significant difference for either group compared with the control group.
For the cases at National Center for Child Health and Development, the adjusted OR (95%CI) of the incidence of major malformation was 1.45 (95%CI: 0.38–5.54, p = 0.583) in the domperidone group and 2.06 (95%CI: 0.43–9.98, p = 0.370) in the metoclopramide group, again indicating no significant difference for either group compared with the control group (Supporting Information, Table SS1).
We also compared the adjusted OR of risk of major malformations by the year of counseling (Table SS2). To rule out the year of counseling as a possible confounding factor, we compared the first half of the data from Toranomon Hospital (1988–2004), to the second half (2005–2016) (adjusted OR: 0.79 [95%CI: 0.26–2.39], p = 0.680) and to the data from the National Center for Child Health and Development (2005–2017) (adjusted OR: 1.34 [95%CI: 0.69–2.60], p = 0.381), and found no significant differences in the adjusted OR.
Discussion
Although there are prior reports 3 , 4 of domperidone administered to pregnant women, those studies lacked sufficient detection power to ensure that domperidone exposure is not harmful to the fetus. Therefore, no information has been available to ensure the safety of using domperidone in pregnant women.
In this study, the 485 patients who received domperidone during the first trimester of pregnancy showed no increase in the incidence of major malformation compared with patients in the control group, who received drugs that are considered to have no teratogenicity. In addition, no difference was found in the results of a sensitivity analysis that assessed teratogenic risk by excluding patients who used teratogenic drugs defined by the clinical guidelines for gynecology and obstetrics 8 .
This study enrolled pregnant women who consulted at Toranomon Hospital or the National Center for Child Health and Development. We therefore performed a subgroup analysis to determine if there were any discrepancies in results between the facilities. There were no such differences, and the incidence of major malformation in the domperidone group did not higher than that in the control group at neither facility.
This study analyzed participants who received counseling at Toranomon Hospital after April 1988 and at National Center for Child Health and Development after October 2005. The use of imaging modalities to detect visceral malformations began in 1997. Therefore, it is presumed that since then it has been possible to detect even minor malformations, such as inconsequential heart defects. However, there was no significant difference in the incidence of major malformation at Toranomon Hospital between 1988 to 2004 and 2005 to 2016. Also, the data from National Center for Child Health and Development (2005–2017) yielded similar results as those from Toranomon Hospital (1988–2004). Thus, the timing of counseling is unlikely to be associated with the detection rate of malformation.
The package insert for domperidone states that it is contraindicated for use in pregnant women and in women suspected of being pregnant, due to teratogenicity observed in reproductive toxicity studies. This has led to the problem of pregnant women becoming anxious when they discover they have taken domperidone before finding out they were pregnant.
This observational cohort study was based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy. It showed that the risk of major malformation was not increased in women who received domperidone during pregnancy. However, it should be noted that a limitation of the study is that women could cancel their counseling if they had a miscarriage or abortion beforehand, resulting in underreported miscarriage or abortion cases.
In future counseling, this information is clinically very useful because it can reduce or eliminate the anxiety of patients who have taken domperidone during pregnancy. The Japanese clinical guidelines for obstetrics and gynecology (obstetrics portion) list domperidone as one of the “drugs that may be used by women in early pregnancy without having a clinically significant adverse effect on the fetus, even though the package inserts state that they are contraindicated in pregnant women.” 8 The results of this study support this statement in the guidelines.
Conflict of interest
Atsuko Murashima received lecture fees from Chugai Pharmaceutical Co.Ltd and Astellas Pharma Inc.
Supporting information
Table S1 Subgroup analysis by the facility
Click here for additional data file.
Table S2 Subgroup analysis by the year of counseling
Click here for additional data file.
Acknowledgments
This work was supported by a Research Program from the Japanese Agency for Medical Research and Development under Grant Number JP19mk0101086h0003, awarded to A.M. The authors would like to thank Dr. Kenjiro Kosaki and Dr. Rika Kosaki for their great advice in diagnosing congenital malformations and we would like to thank Mariko Takagai for her administrative assistance. They are also grateful to women who donated their clinical information and for colleagues worked as a member of Japan Teratology Information Services Network. | METOCLOPRAMIDE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33631840 | 19,020,175 | 2021-05 |
What was the administration route of drug 'METOCLOPRAMIDE HYDROCHLORIDE'? | Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.
OBJECTIVE
To assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.
METHODS
Pregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.
RESULTS
The incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183).
CONCLUSIONS
This observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.
Introduction
Domperidone is an antidopaminergic benzimidazolone compound first synthesized by Janssen Pharmaceutica (Belgium) in 1974. Originally approved in Belgium in 1978, it has since been approved in over 100 countries, including in Japan in 1982. In Japan, domperidone has been widely used for the treatment of gastrointestinal symptoms such as nausea, vomiting, and anorexia.
In a study of domperidone administration during organogenesis in rats, skeletal and visceral malformations were observed in fetuses following an oral dose of 200 mg/kg or an intraperitoneal dose of ≥15 mg/kg. These observed malformations in rats occurred at approximately 300 times the daily oral dose for humans based on body weight. Due to these results, the package insert for domperidone in Japan states that it is contraindicated for use in pregnant women or women suspected of being pregnant.
In some cases, however, domperidone is prescribed for gastrointestinal symptoms such as nausea and vomiting to women who do not yet know they are pregnant due to the pregnancy being unplanned. In such cases, patients often become anxious when they find out they are pregnant and learn that domperidone is contraindicated.
Domperidone and metoclopramide are commonly used as antiemetic drugs in general clinical practice in Japan. Large‐scale epidemiological studies have shown that metoclopramide does not increase the risk of malformation 1 , 2 . On the other hand, teratogenic risk with domperidone has been reported in only a few small‐scale, cohort studies. A report by JS Choi et al. investigated 120 pregnancies treated with domperidone in the first trimester and concluded that domperidone is unlikely to be a major human teratogen 3 . Also, in an abstract, J Cottin et al. compared 124 pregnancies exposed to domperidone during organogenesis with those exposed to other antiemetics or nonteratogenic drugs 4 . There was no significant difference between the three groups in the incidence of major congenital malformations, but the authors commented that the small sample size was a limitation. A report on drug use during pregnancy in the French population stated that about 13% of all pregnant women were using domperidone 5 . Although the teratogenic risk of domperidone was not analyzed in that survey, it suggests that the drug is widely used by pregnant women in some countries.
In the present study, we evaluated the teratogenic risk of domperidone exposure during the first trimester. This is based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy.
Methods
Subjects
This study included women who consulted the Counseling Clinic for “Pregnancy and Medicine” of Toranomon Hospital or the Japan Drug Information Institute in Pregnancy of National Center for Child Health and Development regarding the safety of drugs during pregnancy. Pregnancy outcome data were extracted from the clinical databases of these facilities.
The inclusion criteria were pregnant women who consented to the study and with known pregnancy outcomes who took domperidone (domperidone group), or control drugs (control group) in the first trimester. Among these, women who used domperidone in combination with metoclopramide were excluded from the study. First trimester exposure was defined as drug use between the 28th and 97th days (4th week to 13th week of pregnancy) after the last menstrual period. Experts discussed and selected control drugs considered to be nonteratogenic, referring the report by F. Habermann et al. 6 Control drugs included acetaminophen, antihistamines that were reported in previous studies to have no increased risk of teratogenicity, anti‐infectives like penicillins and cephalosporins, histamine H2‐receptor (H2) blockers, digestive enzyme preparations, and topical drugs (e.g., eye drops, ointment, or cream). Metoclopramide is a similar drug and is expected to be used for the same diseases. In addition, it has been commonly used as an antiemetic drug in pregnant women. Therefore, although statistical comparison with the domperidone group was not performed, patients who took metoclopramide were defined as the reference group.
Data collection
For Toranomon Hospital, women who consulted the Counseling Clinic for “Pregnancy and Medicine” during pregnancy between April 1988 and December 2016 were included in the study. People who wished to make a counseling appointment were first required by the clinic to complete a pre‐appointment questionnaire regarding information such as the names and dosages of drugs taken during pregnancy and expected delivery date, and to return it by mail. At the time of counseling, subjects were interviewed to confirm their expected delivery dates and to obtain other information, including previous medical history, pregnancy and reproductive history, alcohol use, smoking, and family history. We asked patients who provided informed consent for study participation to complete a study questionnaire regarding pregnancy outcomes and any abnormalities during delivery, as well as sex, length, and weight at birth, and any abnormalities of the neonate, and to submit it by mail. If patients provided unclear answers about pregnancy outcomes, an obstetrician contacted their attending physician to obtain clarification. Information on pregnancy outcomes was collected about 1 month after delivery, and the survey was considered complete when this information was obtained.
At the National Center for Child Health and Development, women in pregnancy who sought consultation the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017 were included in the study. The Japan Drug Information Institute in Pregnancy was established under a program of the Ministry of Health Labour and Welfare in October 2005. People who wished to make a counseling appointment were required to complete a pre‐appointment questionnaire and to return it by mail. The pre‐appointment questions were on age, use of drugs during pregnancy, history of present illness, previous medical history, experience of pregnancy, reproductive history, alcohol use, smoking, and intake of folic acid. Approximately a month after their expected delivery date, patients who provided informed consent for participation in the study were sent a postcard‐type questionnaire on pregnancy outcomes and the 1‐month checkup results of their infants. In cases where pregnancy outcomes were unclear, research assistants, doctors or pharmacists contacted the women's attending obstetricians to confirm their pregnancy outcome by telephone. The survey was concluded when information on pregnancy outcomes had been obtained.
Primary endpoint and statistical analysis
The primary endpoint of this study was the incidence of major malformation. To assess the teratogenic risk of domperidone, we compared the incidence of major malformation in the domperidone group with the control group. Major malformations were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) 7 . In cases of congenital abnormalities not included in EUROCAT, a specialist in congenital abnormalities provided diagnoses. Two of the authors concluded that congenital abnormalities could be defined either as surficial malformations or as those requiring surgical treatment. Finally, two independent specialists confirmed the diagnoses.
The incidence of major malformation was analyzed in liveborn, single‐birth infants, and was calculated by dividing the number of liveborn singletons with congenital malformation by the number of all liveborn singletons analyzed in each group. This incidence was compared between the domperidone and control groups. Using the control group as the reference of odds ratio (ORs), the crude ORs of the incidence of major malformations in the domperidone group were calculated using univariable logistic regression analysis. In addition, adjusted ORs were calculated using multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling. Similarly, the crude and adjusted ORs of the incidence of major malformations in the metoclopramide group were calculated. In a subgroup analysis, adjusted ORs were calculated for each facility. The significance level of the test was 5%.
Ethics statement
This study was approved by the Ethics Committee of National Center for Child Health and Development and that of Toranomon Hospital. It was conducted according to the Declaration of Helsinki, and informed consent was obtained from all participants. Information collected from questionnaires was entered into the database and de‐identified by an information administrator. Therefore, the investigators were unable to identify individuals based on the analysis data.
Results
Patient characteristics
At Toranomon Hospital, 12 074 women consulted the Counseling Clinic for “Pregnancy and Medicine” between April 1988 and December 2016. Of these, 1422 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. At National Center for Child Health and Development, 12 971 women consulted the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017. Of these, 1011 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. In total, the number of participants was 519 in the domperidone group, 1673 in the control group, and 241 in the metoclopramide group (Figure 1).
Figure 1 Flowchart
The median age of the subjects at the time of counseling was 30 years in all groups and the groups showed no difference in age distribution. There were no notable differences between groups in either alcohol use or smoking habits, as shown in Table 1.
Table 1 Patient characteristics
Domperidone group Control group Metoclopramide group
n 519 1673 241
Age (year), n (%)
50% [25%, 75%] 30 [26, 33] 30 [27, 34] 30 [27, 34]
≦24 79 (15.2) 160 (9.6) 30 (12.4)
25–29 170 (32.8) 548 (32.8) 81 (33.6)
30–34 167 (32.2) 628 (37.5) 83 (34.4)
35–39 84 (16.2) 288 (17.2) 40 (16.6)
40≦ 18 (3.5) 46 (2.7) 6 (2.5)
NA 1 (0.2) 3 (0.2) 1 (0.4)
Alcohol, n (%)
No use 292 (56.3) 861 (51.5) 125 (51.9)
Stop before pregnancy 7 (1.3) 45 (2.7) 13 (5.4)
Stop after pregnancy 84 (16.2) 305 (18.2) 48 (19.9)
Ongoing 3 (0.6) 16 (1.0) 5 (2.1)
Unknown stop time 75 (14.5) 250 (14.9) 28 (11.6)
NA 58 (11.2) 196 (11.7) 22 (9.1)
Smoking, n (%)
No habit 390 (75.1) 1244 (74.4) 176 (73.0)
Stop before pregnancy 9 (1.7) 36 (2.2) 10 (4.1)
Stop after pregnancy 25 (4.8) 56 (3.3) 16 (6.6)
Ongoing 16 (3.1) 59 (3.5) 10 (4.1)
Unknown stop time 32 (6.2) 122 (7.3) 13 (5.4)
NA 47 (9.1) 156 (9.3) 16 (6.6)
Abbreviation: NA, not available.
Delivery outcomes and incidence of major malformations
Delivery outcomes were aggregated for all subjects. The percentage of liveborn infants was 94.0% (488 cases) in the domperidone group, 93.8% (1570 cases) in the control group, and 94.2% (227 cases) in the metoclopramide group. There were no notable differences in the incidences of stillbirth, miscarriage or abortion between the three groups (Table 2).
Table 2 Pregnancy outcomes
Domperidone group Control group Metoclopramide group
n 519 1673 241
Outcome, n (%)
Live birth 488 (94.0) 1570 (93.8) 227 (94.2)
Stillbirth a 3 (0.6) 7 (0.4) 0 (0.0)
Miscarriage 18 (3.5) 80 (4.8) 8 (3.3)
Abortion 10 (1.9) 15 (0.9) 6 (2.5)
Other 0 (0.0) 1 b (0.1) 0 (0.0)
Number of infant, n (%)
1 506 (97.5) 1627 (97.3) 234 (97.1)
2≦ 1 (0.2) 9 (0.5) 3 (1.2)
NA 12 (2.3) 37 (2.2) 4 (1.7)
Abbreviation: NA, not available.
a Fetal death after 22 weeks gestation was defined as stillbirth.
b Ectopic pregnancy.
Major malformations in liveborn, single‐birth infants occurred in 14 cases in the domperidone group, 27 in the control group, and 8 in the metoclopramide group (Table 3). There was no pattern of malformation types between the three groups.
Table 3 Risk of major malformation
Major malformation 95%CI Crude OR (95%CI) p‐Value a Adjusted OR b (95%CI) p‐Value a
No Yes
Control group (n = 1554) 1527 27 c (1.7%) (1.1–2.5) 1 ‐ 1 ‐
Domperidone group (n = 485) 471 14 d (2.9%) (1.6–4.8) 1.68 (0.87–3.23) 0.119 1.86 (0.73–4.70) 0.191
Metoclopramide group (n = 224) 216 8 e (3.6%) (1.6–6.9) 2.09 (0.94–4.67) 0.071 2.20 (0.69–6.98) 0.183
Risk of major malformation was analyzed in liveborn, single‐birth infants.
Abbreviations: CI, confidence interval; OR, odds ratio.
a Significance level p < 0.05, *<0.05.
b Adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling.
c Ventricular septal defect (6); ventricular and atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); peripheral pulmonary stenosis (1); endocardial cushion defect (1); complete transposition of great arteries (1); double outlet right ventricle (1); esophageal atresia (1); cleft lip (1); diastasis recti (1); adhesion of scrotum and penis (1); hydronephrosis (2); imperforate anus (1); talipes varus (1); polydactyly (3); a combination of coarctation of the aorta and ventricular septal defect (1); a combination of single ventricle and pulmonary stenosis (1); a combination of ventricular septal defect, pulmonary stenosis and syndactyly (1).
d Ventricular septal defect (5); ventricular and atrial septal defect (1); atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); cleft lip and palate (1); double vagina (1); hydroureteropathy (1); hydronephrosis (1); a combination of duodenal obstruction, heart disease, upper aortic malposition and pulmonary artery occlusion (1).
e Ventricular septal defect (1); endocardial cushion defect (1); myelomeningocele (1); lissencephaly (1); hypospadias (1); talipes varus (1); polydactyly (1); scalp defect (1).
Risk of major malformation
The incidence of major malformation in liveborn, single‐birth infants (95% confidence interval [CI]) was 2.9% (14/485, 95%CI: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group.
Univariable logistic regression analysis showed no significant difference in the incidence of major malformation between the domperidone and control groups (OR: 1.68 [95% CI: 0.87–3.23], p = 0.119). Additionally, multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling also showed no significant difference in the incidence of major malformation between the domperidone and control groups (adjusted OR: 1.86 [95% CI: 0.73–4.70], p = 0.191) (Table 3). Similar results were obtained when comparing the metoclopramide and control groups (OR: 2.09 [95% CI: 0.94–4.67], p = 0.071; adjusted OR: 2.20 [95% CI: 0.69–6.98], p = 0.183).
Subgroup analysis
For the cases at Toranomon Hospital, the adjusted OR (95%CI) of the incidence of major malformation was 2.54 (95%CI: 0.68–9.46, p = 0.164) in the domperidone group and 2.54 (95%CI: 0.47–13.82, p = 0.282) in the metoclopramide group, indicating no significant difference for either group compared with the control group.
For the cases at National Center for Child Health and Development, the adjusted OR (95%CI) of the incidence of major malformation was 1.45 (95%CI: 0.38–5.54, p = 0.583) in the domperidone group and 2.06 (95%CI: 0.43–9.98, p = 0.370) in the metoclopramide group, again indicating no significant difference for either group compared with the control group (Supporting Information, Table SS1).
We also compared the adjusted OR of risk of major malformations by the year of counseling (Table SS2). To rule out the year of counseling as a possible confounding factor, we compared the first half of the data from Toranomon Hospital (1988–2004), to the second half (2005–2016) (adjusted OR: 0.79 [95%CI: 0.26–2.39], p = 0.680) and to the data from the National Center for Child Health and Development (2005–2017) (adjusted OR: 1.34 [95%CI: 0.69–2.60], p = 0.381), and found no significant differences in the adjusted OR.
Discussion
Although there are prior reports 3 , 4 of domperidone administered to pregnant women, those studies lacked sufficient detection power to ensure that domperidone exposure is not harmful to the fetus. Therefore, no information has been available to ensure the safety of using domperidone in pregnant women.
In this study, the 485 patients who received domperidone during the first trimester of pregnancy showed no increase in the incidence of major malformation compared with patients in the control group, who received drugs that are considered to have no teratogenicity. In addition, no difference was found in the results of a sensitivity analysis that assessed teratogenic risk by excluding patients who used teratogenic drugs defined by the clinical guidelines for gynecology and obstetrics 8 .
This study enrolled pregnant women who consulted at Toranomon Hospital or the National Center for Child Health and Development. We therefore performed a subgroup analysis to determine if there were any discrepancies in results between the facilities. There were no such differences, and the incidence of major malformation in the domperidone group did not higher than that in the control group at neither facility.
This study analyzed participants who received counseling at Toranomon Hospital after April 1988 and at National Center for Child Health and Development after October 2005. The use of imaging modalities to detect visceral malformations began in 1997. Therefore, it is presumed that since then it has been possible to detect even minor malformations, such as inconsequential heart defects. However, there was no significant difference in the incidence of major malformation at Toranomon Hospital between 1988 to 2004 and 2005 to 2016. Also, the data from National Center for Child Health and Development (2005–2017) yielded similar results as those from Toranomon Hospital (1988–2004). Thus, the timing of counseling is unlikely to be associated with the detection rate of malformation.
The package insert for domperidone states that it is contraindicated for use in pregnant women and in women suspected of being pregnant, due to teratogenicity observed in reproductive toxicity studies. This has led to the problem of pregnant women becoming anxious when they discover they have taken domperidone before finding out they were pregnant.
This observational cohort study was based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy. It showed that the risk of major malformation was not increased in women who received domperidone during pregnancy. However, it should be noted that a limitation of the study is that women could cancel their counseling if they had a miscarriage or abortion beforehand, resulting in underreported miscarriage or abortion cases.
In future counseling, this information is clinically very useful because it can reduce or eliminate the anxiety of patients who have taken domperidone during pregnancy. The Japanese clinical guidelines for obstetrics and gynecology (obstetrics portion) list domperidone as one of the “drugs that may be used by women in early pregnancy without having a clinically significant adverse effect on the fetus, even though the package inserts state that they are contraindicated in pregnant women.” 8 The results of this study support this statement in the guidelines.
Conflict of interest
Atsuko Murashima received lecture fees from Chugai Pharmaceutical Co.Ltd and Astellas Pharma Inc.
Supporting information
Table S1 Subgroup analysis by the facility
Click here for additional data file.
Table S2 Subgroup analysis by the year of counseling
Click here for additional data file.
Acknowledgments
This work was supported by a Research Program from the Japanese Agency for Medical Research and Development under Grant Number JP19mk0101086h0003, awarded to A.M. The authors would like to thank Dr. Kenjiro Kosaki and Dr. Rika Kosaki for their great advice in diagnosing congenital malformations and we would like to thank Mariko Takagai for her administrative assistance. They are also grateful to women who donated their clinical information and for colleagues worked as a member of Japan Teratology Information Services Network. | Transplacental | DrugAdministrationRoute | CC BY-NC-ND | 33631840 | 19,020,387 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anterior chamber flare'. | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | AFLIBERCEPT | DrugsGivenReaction | CC BY | 33631912 | 19,243,928 | 2021-02-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blindness'. | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | AFLIBERCEPT | DrugsGivenReaction | CC BY | 33631912 | 19,085,908 | 2021-02-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Eye inflammation'. | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | AFLIBERCEPT | DrugsGivenReaction | CC BY | 33631912 | 19,243,928 | 2021-02-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vision blurred'. | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | AFLIBERCEPT | DrugsGivenReaction | CC BY | 33631912 | 19,243,928 | 2021-02-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Visual acuity reduced'. | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | AFLIBERCEPT | DrugsGivenReaction | CC BY | 33631912 | 19,243,928 | 2021-02-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vitreous opacities'. | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | AFLIBERCEPT | DrugsGivenReaction | CC BY | 33631912 | 19,247,775 | 2021-02-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vitritis'. | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | AFLIBERCEPT | DrugsGivenReaction | CC BY | 33631912 | 19,243,928 | 2021-02-25 |
What was the administration route of drug 'AFLIBERCEPT'? | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | Intraocular | DrugAdministrationRoute | CC BY | 33631912 | 19,243,928 | 2021-02-25 |
What was the outcome of reaction 'Anterior chamber flare'? | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | Recovered | ReactionOutcome | CC BY | 33631912 | 19,243,928 | 2021-02-25 |
What was the outcome of reaction 'Blindness'? | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | Recovered | ReactionOutcome | CC BY | 33631912 | 19,085,908 | 2021-02-25 |
What was the outcome of reaction 'Eye inflammation'? | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | Recovered | ReactionOutcome | CC BY | 33631912 | 19,243,928 | 2021-02-25 |
What was the outcome of reaction 'Vision blurred'? | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | Recovered | ReactionOutcome | CC BY | 33631912 | 19,243,928 | 2021-02-25 |
What was the outcome of reaction 'Visual acuity reduced'? | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | Recovered | ReactionOutcome | CC BY | 33631912 | 19,243,928 | 2021-02-25 |
What was the outcome of reaction 'Vitreous opacities'? | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | Recovered | ReactionOutcome | CC BY | 33631912 | 19,247,775 | 2021-02-25 |
What was the outcome of reaction 'Vitritis'? | Non-infectious Intraocular Inflammation Following Intravitreal Anti-Vascular Endothelial Growth Factor Injection.
To evaluate the functional and anatomical results of patients with non-infectious intraocular inflammation (IOI) following intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of neovascular age-related macular degeneration (nAMD).
The medical records of patients receiving anti-VEGF treatment for nAMD between January 2015 and March 2019 were retrospectively analyzed. Preoperative and postoperative routine ophthalmological examinations, central macular thickness, duration of inflammation, and follow-up time of the patients with non-infectious IOI following anti-VEGF injection were recorded.
Non-infectious IOI was determined in 13 eyes (11 eyes with aflibercept, 2 eyes with ranibizumab) of 1,966 patients who received a total of 12,652 anti-VEGF (4,796 aflibercept and 7,856 ranibizumab) injections. IOI was detected after a mean of 7 injections (2-12 injections). All eyes had both anterior chamber reaction (Tyndall +1/+3) and vitritis (grade 1-3). None of the patients had pain, hypopyon, or fibrin reaction. Visual acuity progressed to baseline levels within 28.3 days. Vitritis continued with a mean of 40 days. All patients recovered with topical steroid therapy. In 11 eyes, injection of the same anti-VEGF agent was continued. No recurrence of IOI was observed in any patients.
Non-infectious IOI following intravitreal anti-VEGF injection typically occurs without pain, conjunctival injection, hypopyon, or fibrin and responds well to topical steroid therapy. Visual acuity returns to baseline levels within weeks according to the severity of inflammation.
Introduction
Non-infectious intraocular inflammation (IOI) is an acute, sterile inflammation that is not associated with an infectious agent and resolves without intravitreal antibiotic therapy. It occurs as a rare complication of intravitreal pharmacological agents.1 As more intravitreal injections are performed, the number of such side effects is also increasing.1,2 Non-infectious IOI has been reported in response to all anti-vascular endothelial growth factor (anti-VEGF) drugs 1,3,4,5,6,7,8,9,10,11, triamcinolone 12,13, and ocriplasmin.14 It typically occurs within a few days after injection, manifesting with visual impairment and vitritis without conjunctival injection and substantial pain.3 The reported incidence ranges from 0.09% to 0.55%.1,8,9,10,11
The aim of this study was to evaluate the frequency, characteristics, treatment, and functional and anatomical outcomes of non-infectious IOI after intravitreal anti-VEGF injection in patients with wet age-related macular degeneration (AMD).
Materials and Methods
The medical records of 1966 patients who received intravitreal anti-VEGF (ranibizumab or aflibercept) injection for wet AMD in the retina unit of Dokuz Eylül University Department of Ophthalmology between January 2015 and March 2019 were retrospectively reviewed. The patients received a total of 12652 doses of anti-VEGF, and non-infectious IOI was detected in 13 eyes.
The study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki after obtaining approval from the Dokuz Eylül University Ethics Committee. Patients aged 50 years and older who had wet AMD, were under ongoing anti-VEGF therapy and follow-up in our clinic, and were followed for at least 6 months were included in the study. Patients who did not receive the full anti-VEGF loading dose and those who had diabetes mellitus, uveitis, or history of ocular surgery in the last 6 months (cataract, glaucoma surgery) were excluded.
All anti-VEGF injections were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine®, Alcon Laboratories Inc, Fort Worth, TX, USA) in the operating room under sterile conditions. Before the procedure, mydriasis was induced using 2.5% phenylephrine hydrochloride (Mydfrin®, Alcon Laboratories Inc, Fort Worth, TX, USA), 0.5% tropicamide (Tropamid®, Bilim Pharmaceuticals, Istanbul, Turkey), and 1% cyclopentolate hydrochloride (Sikloplejin®, Abdi İbrahim Pharmaceuticals, İstanbul, Turkey). Before injection, 5% povidone iodine was instilled in the lower fornix and left for at least 5 minutes. After cleaning the periocular skin and eyelids with 10% povidone iodine solution, a sterile eye drape was placed over the area and the eyelids were retracted using a blepharostat. Using a 30-gauge (G) needle, 0.05 ml of 0.5 mg ranibizumab or 2 mg aflibercept was administered in the superotemporal quadrant at a distance of 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes. After administering the intravitreal injection, pressure was applied to the injection site with a sterile cotton-tip applicator while withdrawing the needle to prevent drug reflux and vitreous prolapse. Following injection, 5% povidone iodine was applied to the ocular surface. Patients were prescribed 0.3% ofloxacin (Exocin®, Allergan Pharmaceuticals Inc, Dublin, Ireland) eye drops and 1% fusidic acid (Fucithalmic®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) viscous eye drops 6 times a day for 5 days. They were advised to present to our clinic immediately if they experienced vision loss, hyperemia, light sensitivity, or severe pain after the injection. Evaluations were performed at post-injection day 1, day 15, and day 30.
From the records of patients who developed non-infectious IOI after intravitreal anti-VEGF injection, the following data were recorded in detail: best corrected visual acuity (BCVA) measured during the inflammation; presence of conjunctival hyperemia and cells, lens status, and presence of cells in the anterior vitreous on slit-lamp examination; and the presence of vitritis, optic disc and macula findings, peripheral retinal findings, and vascular changes observed in fundus examination. In addition, colored fundus photographs (Visucam 500®, Zeiss, Germany) and macular thicknesses measured from spectral domain-optical coherence tomography ([SD-OCT]; Spectralis OCT®, Heidelberg Engineering, Heidelberg, Germany) obtained during routine examination were recorded from the SD-OCT archive for all patients. After intravitreal anti-VEGF injection, color fundus photographs were obtained only for patients who developed choroidal neovascularization activation or complications/adverse effects. Non-infectious IOI was diagnosed according to the definition on the American Society of Retina Specialists website (https://www.asrs.org/) in the presence of blurred vision and only anterior chamber cells, vitreous cells, or mild fibrous opacity in the vitreous, in the absence of pain, hyperemia, severe vision loss, hypopyon, fibrin reaction, or retinitis focus. These eyes were treated with topical 1% prednisolone acetate (Pred Forte®, Allergan Inc, Dublin, Ireland) and follow-up was continued until complete clinical resolution was observed. Based on clinical severity, follow-up examinations were performed every other day for the first week. After the first week, follow-up intervals were extended according to the patient’s clinical presentation.
Statistical Analysis
All patient data were recorded in the IBM SPSS Statistics (version 24.0, IBM Corp, Armonk, NY, USA) software package and statistical analyses were performed using paired t-test. The results are presented as mean ± standard deviation, and a p-value <0.05 was considered statistically significant.
Results
Of the 12652 anti-VEGF injections administered for wet AMD, 4796 were aflibercept and 7856 were ranibizumab. Non-infectious IOI was detected in a total of 13 eyes of 13 patients. Therefore, the incidence of non-infectious IOI per injection was 0.1% (13/12,652) and the incidence per patient was 0.66% (13/1,966). Nine (69.2%) of the 13 patients with IOI were male and 4 (30.8%) were female. The patients’ characteristics are summarized in Table 1. The median age was 73 (51-86) years. Nine eyes (69.2%) were pseudophakic. Non-infectious IOI occurred after ranibizumab in 2/7856 eyes (0.02%) and after aflibercept in 11/4796 eyes (0.2%). Median time to presentation to our clinic was 11 (4-21) days. None of the patients had IOI on postoperative day 1. Six patients (46.2%) presented to our clinic with complaints of blurred vision in the first 10 days after the procedure, while in the other 7 patients (53.8%) IOI was detected during routine follow-up examination at 2 weeks. When the patients’ symptoms were examined, we found that 13 patients (100%) had blurred vision, 5 patients (38.5%) had floaters, and 3 patients (23.1%) had photophobia. In wet AMD patients on ongoing anti-VEGF therapy, non-infectious IOI was detected after a median of 7 (2-12) injections.
According to the patients’ medical records, it was determined that all patients had anterior chamber reaction (Tyndall +1 to +3) and vitritis (grade 1-3) (Figure 1A, B). Hypopyon and fibrin reactions were not observed in any of the eyes (Table 2). The median pre-injection visual acuity of the patients was 0.4 (0.1-0.7; ≤0.1 in 23.1% [3/13]; Snellen chart) and the median visual acuity with IOI was 0.2 (0.05-0.5; ≤0.1 in 30.8% [4/13]). After inflammation resolved, the median visual acuity was 0.5 (0.1-0.7; ≤0.1 in 7.7% [1/13]). We observed that BCVA was significantly reduced during IOI, then increased significantly compared to the inflammation period (p<0.0001). According to the patients’ SD-OCT archives, the median central macular thickness (CMT) before injection was 322 (226-398) µm. The median CMT was 276 (203-370) µm during inflammation and 235 (181-306) µm after the regression of inflammatory findings (Figure 1C, D). Changes in mean CMT due to IOI were not statistically significant compared to pre-injection (p=0.120).
In one patient, a vitreous sample had been obtained during follow-up due to grade 2 vitritis and a white opacity in the vitreous (Patient 2, Figure 2A, B, C). Upon detailed review of the patient’s records, we determined that the eye had been treated with intravitreal 1 mg/0.1 mL vancomycin, 2.25 mg/0.1 mL ceftazidime, and 0.4 mg/0.1 mL dexamethasone injections for presumed infectious endophthalmitis. However, no etiological agent was detected in vitreous culture or direct microscopic examination. For all other eyes, topical 1% prednisolone acetate (PredForte®) was given every hour for the first 2 days, every 2 hours for the next 3 days, then continued with tapering doses until IOI fully resolved (Figure 2D, E, F).
Patient records indicated that both visual acuity and vitritis improved over time in all patients during follow-up after IOI. The median time to visual acuity recovery was 28 (17-42) days and the median time to vitritis resolution was 32 (20-75) days.
Following functional and anatomical recovery after non-infectious IOI, treatment for wet AMD was continued with the same intravitreal agent in 11 eyes, with a median of 3 (1-12) additional injections. In the other 2 eyes, additional injections were not considered due to scar development. IOI did not recur in any of the eyes and no systemic adverse effects associated with anti-VEGF injection were reported.
Discussion
Non-infectious IOI can develop after intravitreal injections of ocriplasmin, bevacizumab, ranibizumab, triamcinolone acetonide, and aflibercept.1,3,4,5,6,7,8,9,10,11,12,13,14 Its incidence after anti-VEGF injection varies between 0.09% and 0.37% in the literature.3,4,5 In the present study, it occurred after intravitreal anti-VEGF injection for wet AMD at a rate of 0.1% of all injections and 0.66% of all patients. The relationship between the indication for anti-VEGF administration and the incidence of IOI is not yet fully understood. In a series of 66 patients who developed IOI after aflibercept injections, Greenberg et al.1 reported that the indication for treatment was wet AMD in 74%, macular edema secondary to retinal vein occlusion in 13%, and diabetic macular edema in 10% of the patients.
In our study, the most common symptom at presentation was blurred vision and this symptom was present in all of the patients. The second most common symptom was floaters. The case series reported by Greenberg et al.1 is the largest on this subject and the most common symptoms were blurred vision and floaters, consistent with our case series. In our study, the mean time from anti-VEGF administration to presentation due to complaints of blurred vision and floaters was 11.7 days (4-21 days). This is a longer interval compared to previous studies in the literature, in which the mean time to admission was 2.6 to 5 days.7,8,9,10,11 We believe the longer time to admission in our patients may be due to the fact that most patients’ inflammation was mild to moderate in severity and therefore they waited for their scheduled follow-up on day 15. One of the patients presented on day 21, which was attributed to low initial visual acuity. However, there were also patients who developed severe inflammation and one-eyed patients who noticed blurred vision early and presented within the first 5 days. In patients with wet AMD who continue anti-VEGF therapy, slit-lamp examinations in addition to follow-up OCT are particularly important for the detection of such inflammation.
Studies have reported the coexistence of anterior chamber reaction and vitritis in 60% to 74% of cases and the presence of severe inflammation (fibrin reaction, presence of hypopyon) in approximately 20%.1,8,9,10,11 In our study, all patients who developed non-infectious IOI had anterior chamber reaction and vitritis. Only 23% of our patients had +3 Tyndall and/or grade 3 vitritis, while the majority had mild to moderate IOI. None of our patients developed fibrin reaction and/or hypopyon.
In the present study, IOI was associated with a statistically significant decrease in visual acuity. Upon resolution of the inflammation, all patients showed a statistically significant increase in visual acuity. It was reported that patients with IOI may have functional loss in eyes with rapid symptom onset and severe initial inflammation.8,9,10 In this case series, as IOI was not severe in any of the eyes, inflammation resolved in 3 to 4 weeks of follow-up and visual acuity returned to the pre-inflammation level.
There are not many studies demonstrating a relationship between non-infectious IOI and activation of wet AMD.15 In our study, despite IOI there was a decrease in CMT compared to pre-injection values. However, only SD-OCT findings (subretinal and intraretinal fluid) were evaluated in terms of AMD activation in our case series. Prospective studies with large case series investigating the relationship between IOI development and activation of wet AMD lesions are needed.
Non-infectious IOI can occur regardless of injection number.5 Some studies have reported that administration of aflibercept can induce sensitivity and increase the risk of immune reactions with subsequent injections.10 Other studies reported that a history of IOI associated with aflibercept injection did not increase the risk or severity of ocular inflammation with subsequent injections.3,11 In wet AMD patients who require ongoing treatment, even if IOI occurs it was reported to be unlikely to recur if treatment with the same anti-VEGF agent is continued after the inflammation resolves.1,7,8,9,10 Recurrence was not observed in any of the patients in our case series, despite receiving at least 3 anti-VEGF injections during a mean follow-up period of 1 year after IOI.
The mechanism by which non-infectious IOI develops after anti-VEGF injection is not fully understood. Many hypotheses have been proposed regarding the development of inflammation. The most likely hypothesis is that inflammation occurs as a result of an immune reaction caused by the molecular structure of the drug and patient-specific factors. The reported incidence of inflammation is higher after aflibercept than other anti-VEGF agents.1,3,8,9,10,11,16 This has been attributed to a proinflammatory interaction between the Fc component in the molecular structure of aflibercept and retinal Fc receptors and/or the fact that aflibercept is a fusion protein with a more viscous structure. We believe that the white opacity seen in the vitreous in one of our patients may be an immune complex formed via a similar mechanism. Other factors that increase the risk of inflammation include contamination of anti-VEGF agents with bacterial endotoxin,3,4,6 contamination of the syringes in injection kits with silicon particles,4 and inappropriate storage conditions of anti-VEGF agents (cold chain conditions).3,8
The most important consideration in cases with non-infectious IOI is the differential diagnosis from infectious endophthalmitis. Several important clinical findings in infectious endophthalmitis facilitate its differential diagnosis. According to the Endophthalmic Vitrectomy Study 17, the most important symptoms and findings in infectious endophthalmitis are intense pain, severe vision loss, conjunctival hyperemia, chemosis, fibrin reaction, hypotension, and dense vitreous opacities. The lack of severe visual loss, conjunctival hyperemia, fibrin reaction, hypotension, and dense vitreous opacities in our patients at admission were the main findings for the differential diagnosis of endophthalmitis. In only one of our patients, detection of a whitish opacity in the vitreous (Figure 1) raised suspicion of endophthalmitis and led to collection of a vitreous sample and intravitreal treatment. Examination of the sample revealed no infectious pathogens. During follow-up, the patient’s opacity disappeared within 10 days. The patient was followed up with topical 1% prednisolone acetate until the inflammation resolved.
In patients with non-infectious IOI, systemic and/or topical steroid therapy is recommended depending on the severity of the disease. In most cases, topical steroid therapy is sufficient. All patients in our series were treated with topical steroid therapy and their inflammation resolved. Systemic steroid therapy was not needed in any of our cases. The median time to functional recovery was 28 days and the median time to inflammation resolution was 32 days. No local or systemic adverse effects of topical steroid therapy were observed.
Study Limitations
The most important limitations of our study are that it was retrospective and included only wet AMD patients. Another limiting factor was the small number of cases.
Conclusion
Non-infectious IOI following anti-VEGF therapy is a rare complication. The clinical course is mild in many patients. However, it is important to carefully differentiate the condition from infectious endophthalmitis. Patients should be followed very closely and those showing clinical deterioration should be presumed to have infectious endophthalmitis and treated accordingly. Non-infectious IOI responds well to topical steroid therapy. Functional recovery is usually seen in 3 to 4 weeks. After inflammation has completely resolved, treatment with the same anti-VEGF agent can be continued in patients with AMD reactivation.
Table 1 Demographic characteristics and clinical findings of the patients
Table 2 Features and recovery times of the patients’ intraocular inflammation
Figure 1 Color fundus and Spectralis optical coherence tomography (OCT) imaging of Patient 1 during intraocular inflammation (A-D). Color fundus image at admission (A) and colored fundus image 1 month after admission (B). Spectralis OCT images before intraocular inflammation (C) and on day 7 of inflammation (D)
Figure 2 Color fundus and Spectralis optical coherence tomography (OCT) imaging of intraocular inflammation in Patient 2 (A-F). Color fundus photographs at initial presentation (at onset of intraocular inflammation) (A) and at 1 month (B), 2 months (C), and 3 months (D) after presentation. Spectralis OCT images before development of intraocular inflammation (E) and on day 7 of inflammation (F)
Ethics
Ethics Committee Approval: Approval was obtained from the Non-interventional Research Ethics Committee of Dokuz Eylül University.
Informed Consent: Consent was obtained from the patients.
Author Contributions:
Surgical and Medical Procedures: M.K., F.H.Ö., T.Ö., Concept: F.H.Ö., M.K., T.Ö., Design: M.K., F.H.Ö., T.Ö., Data Collection and Processing: M.K., F.H.Ö., B.A.Y., F.A., Analysis or Interpretation: M.K., F.H.Ö., Literature Search: M.K., F.H.Ö., B.A.Y., F.A., Writing: M.K., F.H.O., B.A.Y., F.A., T.O.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Disclosure: The authors report receiving no financial support. | Recovered | ReactionOutcome | CC BY | 33631912 | 19,243,928 | 2021-02-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adverse event'. | Survival analysis of elderly patients over 65 years old with stage II/III gastric cancer treated with adjuvant chemotherapy after laparoscopic D2 gastrectomy: a retrospective cohort study.
BACKGROUND
The benefits of adjuvant chemotherapy for elderly patients with gastric cancer (GC) remain unknown because elderly patients are underrepresented in most clinical trials. This study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy in patients > 65 years of age after laparoscopic D2 gastrectomy.
METHODS
This was a single-center retrospective cohort study of elderly patients (> 65 years) with stage II/III GC who underwent curative laparoscopic D2 gastrectomy with R0 resection between 2004 and 2018. The adjuvant chemotherapy regimens included monotherapy (oral capecitabine) and doublet chemotherapy (oral capecitabine plus intravenous oxaliplatin [XELOX] or intravenous oxaliplatin, leucovorin, and 5-fluorouracil [FOLFOX]). The data were retrieved from a prospectively registered database maintained at the Department of General Surgery in Nanfang Hospital, China. The patients were divided as surgery alone and surgery plus adjuvant chemotherapy (chemo group). The overall survival (OS), disease-free survival (DFS), chemotherapy duration, and toxicity were examined.
RESULTS
There were 270 patients included: 169 and 101 in the surgery and chemo groups, respectively. There were 10 (10/101) and six (6/101) patients with grade 3+ non-hematological and hematological adverse events. The 1-/3-/5-year OS rates of the surgery group were 72.9%/51.8%/48.3%, compared with 90.1%/66.4%/48.6% for the chemo group (log-rank test: P = 0.018). For stage III patients, the 1-/3-/5-year OS rates of the surgery group were 83.7%/40.7%/28.7%, compared with 89.9%/61.2%/43.6% for the chemo group (log-rank test: P = 0.015). Adjuvant chemotherapy was significantly associated with higher OS (HR = 0.568, 95%CI: 0.357-0.903, P = 0.017) and DFS (HR = 0.511, 95%CI: 0.322-0.811, P = 0.004) in stage III patients.
CONCLUSIONS
This study suggested that adjuvant chemotherapy significantly improves OS and DFS compared with surgery alone in elderly patients with stage III GC after D2 laparoscopic gastrectomy, with a tolerable adverse event profile.
Background
Gastric cancer (GC), as the fifth most frequently diagnosed cancer and the third leading cause of cancer death worldwide, was responsible for over 1,000,000 new cases and an estimated 783,000 deaths in 2018 [1]. The markedly elevated incidence rates of GC in Eastern Asia (China, Japan, and Korea) indicate that GC is a significant public health threat, especially to the elderly, since over 60% of the GC diagnoses and 70% of GC-related mortality occur in elderly patients (aged 65 years or older) [2, 3]. As the population continues to age, the proportion of the population aged 60 years and over will increase from 12.4% in 2010 to 28% in 2040 [4]. Longer life expectancy also results in an increasing number of the elderly (aged 65 years or older) undergoing cancer operation and chemotherapy.
The survival benefits from gastrectomy plus chemotherapy have been confirmed in patients with advanced GC [5–7]. In the United States of America, chemoradiotherapy after gastrectomy has been confirmed to improve overall survival (OS) by the INT-0116 trial [8], while the progression-free survival (PFS) and OS benefits of perioperative chemotherapy have been shown by the MAGIC and FLOT4 trials [9, 10]. The adjuvant chemotherapy following D2 gastrectomy is a standard treatment for stage II/III GC in East Asia [11–13]. Although prior randomized controlled studies (RCTs) indicated that postoperative adjuvant treatment in patients who underwent D2 gastrectomy could improve the 5-year disease-free survival (DFS) and OS, the subgroup analyses showed that the survival benefits decreased with increasing age. Furthermore, the ACTS-GC study showed no statistically significant effects of postoperative chemotherapy on DFS and OS for patients older than 70 years (DFS: hazard ratios (HR) = 0.779, 95% confidence interval (CI): 0.527–1.151; OS: HR = 0.706, 95% CI: 0.490–1.017) [11]. Similar results for OS were observed in the CLASSIC study for patients older than 65 (HR = 0.70, 95% CI: 0.4–1.12) [12]. These results might be due to the considerably higher incidence of comorbidities, higher risk of complications, and shorter life expectancy of elderly patients [14]. Nevertheless, when considering those conflicting results, whether to give or not adjuvant chemotherapy to elderly patients with GC after D2 gastrectomy remains a dilemma for physicians. Therefore, the International Society of Geriatric Oncology suggested that specific trials for older patients with cancer should be conducted [15].
Laparoscopic gastrectomy has gained popularity worldwide for its safety and effectiveness [16, 17]. The Chinese Laparoscopic Gastrointestinal Surgery (CLASS) group recently reported the primary endpoints of the CLASS-01 trial, which suggested that laparoscopic distal gastrectomy for advanced gastric cancer was non-inferior to open surgery in terms of 3-year DFS and safety, with significant minimally invasive benefits [18, 19]. A previous study by our group indicated the potential benefits of laparoscopic gastrectomy for elderly patients with resectable GC [20]. Ushimaru et al. [21] reported that laparoscopic gastrectomy might improve the OS by reducing mortality from respiratory diseases. Still, the benefit of adjuvant chemotherapy after laparoscopic D2 gastrectomy in elderly patients is unknown.
As the elderly patients (over 65 years of age) are underrepresented in most RCTs, the present study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy retrospectively in elderly patients (over 65 years of age) after laparoscopic D2 gastrectomy, based on a prospectively registered database in China. Those results could help shed some light on this controversy.
Methods
Study design and patients
This was a retrospective cohort study conducted in the Department of General Surgery of Nanfang Hospital in patients treated between June 2004 and June 2018. This study was approved by the Ethics Committee of Nanfang Hospital. The need for written informed consent was waived due to the retrospective nature of this study.
The inclusion criteria were: 1) over 65 years of age; 2) histologically confirmed stage II or III gastric adenocarcinoma, according to American Joint Committee on Cancer (AJCC, 7th Edition); 3) received curative laparoscopic gastrectomy with D2 nodal dissection at Nanfang Hospital; and 4) at least 15 lymph nodes were available to ensure adequate disease classification. The exclusion criteria were: 1) residual tumors (R1/R2 resections or palliative surgery; 2) death within 1 month after surgery; 3) a previous history of primary or secondary tumor beside the current GC; 4) neoadjuvant chemotherapy or adjuvant radiotherapy; or 5) incomplete medical record .
The enrolled patients were divided into surgery alone group (surgery group) and the surgery plus adjuvant chemotherapy group (chemo group).
Adjuvant chemotherapy protocols
The adjuvant chemotherapy regimens administered during the study period included monotherapy and doublet chemotherapy. The initial dose of each regimen was reduced to 75% of the original value to minimize toxic effects in elderly patients. For monotherapy, the patients received 3-week cycles of oral capecitabine (750 mg/m2 twice daily on days 1 to 14 of each cycle) for 6 months if tolerated. For doublet chemotherapy, the patients received oral capecitabine plus intravenous oxaliplatin (XELOX) or 2-week cycles of intravenous oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX). For the XELOX regimen, patients received 3-week cycles of oral capecitabine (750 mg/m2 twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m2 on day 1 of each cycle) for 6 months if tolerated. The FOLFOX regimen was administered as follows: intravenous (IV) treatment with 63.75 mg/m2 of oxaliplatin, 300 mg/m2 of leucovorin and IV push administration of 300 mg/m2 of fluorouracil on day 1, and 900 mg/m2 of fluorouracil IV by continuous infusion for 24 h on days 1 and 2. This regimen was repeated every 14 days and lasted for 6 months if tolerated. In all regimens, the dose of each drug was reduced to the next lower dose increment in case of grade 4 neutropenia or thrombocytopenia, or grade 3 or above febrile neutropenia.
Data collection
The data were retrieved from a prospectively registered database maintained at the Department of General Surgery in Nanfang Hospital, China. The database includes patient characteristics (age at diagnosis, sex, etc.), clinical variables (postoperative stay, circulating tumor cells [CTCs] collected at postoperative two weeks, etc.), pathological features (tumor size, histological grade, etc.), chemotherapy (regimen, duration, cycles of chemotherapy, and grade 3 or above toxicity events), and follow-up. All data are routinely updated after each routine follow-up visit, either at the outpatient clinic or by phone. For the present study, the last follow-up data were collected on May 30th, 2018.
Outcomes
The observation outcomes of this study were OS and DFS. The OS was calculated from the date of operation to either the date of death or the date of the last follow-up visit. The DFS was calculated from the date of resection to the date of the first recurrence detected, or the last follow-up visit. Recurrence was determined as the appearance of any new lesion either locally, regionally, or distant. All grade 3 or above hematological and non-hematological toxicity events were recorded. Toxicities were graded according to the National Cancer Institute common toxicity criteria version 3.0 [22].
Statistical analysis
All statistical analyses were performed using SPSS 24.0 (IBM Corp., Armonk, NY, USA). Continuous variables were tested for normal distribution using the Kolmogorov-Smirnov test. Those with a normal distribution were expressed as means ± standard deviations (SD) and were analyzed using Student’s t-test; otherwise, they were presented as medians (ranges) and analyzed using the Mann-Whitney U-test. Categorical variables were reported as numbers with percentages and analyzed using the chi-square test with the Yates correction or Fisher’s exact test, as appropriate. The OS and DFS rates were compared between the surgery and chemo groups using unadjusted Kaplan-Meier curves and the log-rank test. The OS and DFS rates of different clinicopathological characteristics and different chemotherapy regimen were compared. HR and 95% CI were used to estimate the role of each independent predictor of survival. The Cox regression model was used for univariable and multivariable analyses. We adjusted for the following variables: treatment regimens (with adjuvant chemotherapy or not), age of diagnosis, time of surgery, sex, ECOG score, Charlson score, tumor location, retrieved lymph node, hospital stays, AJCC stage, histologic grade, lymphatic, blood vessel or perineural invasion, tumor size, and CTC counts. Variables with P < 0.1 in the univariable analysis were included in the multivariable analysis. The level of significance was set at a two-tailed P-value of 0.05.
Results
Patient characteristics
At first, 298 patients were eligible, but 28 were excluded because of the presence of residual tumors (R1/R2 resections and palliative surgery), death within 1 month of surgery, primary or secondary tumor history, neoadjuvant chemotherapy, adjuvant radiotherapy, or incomplete medical record. The remaining 270 patients were included in the analysis; 169 and 101 were classified in the surgery and chemo groups, respectively (Fig. 1).
Fig. 1 Patient flowchart
Table 1 presents the characteristics of the patients. The median age in the surgery and chemo groups was 70 years (69–75 years) and 69 years (66–72 years), respectively (P = 0.001). The male-to-female ratio was 2.1:1 in the surgery group and 3.2:1 in the chemo group (P = 0.152). Most patients in the two groups had an ECOG score and a Charlson comorbidity score of < 1 (ECOG: 88.2 and 89.1%; Charlson score: 94.7 and 96.0%; all P > 0.05). The number of CTCs in the surgery group was 5 (2–16), while 4 (1–7) in the chemo group (P = 0.328). In the surgery group, there were 56 patients with AJCC stage II and 113 with AJCC stage III, while in the chemo group, there were 25 patients with AJCC stage II and 76 with AJCC stage III (P = 0.147). In the chemo group, six patients received monotherapy, and 95 patients received platinum-based doublet chemotherapy therapy; 57 patients received adjuvant chemotherapy for less than 3 months, while 44 patients received 3–6 months of adjuvant chemotherapy. The median follow-up in the surgery and chemo groups was 25 (IQR 13–44) months, and 22 (IQR 11–54.5) months, respectively (P = 0.452).
Table 1 Baseline information of patients
Characteristics Surgery N = 169 Chemotherapy N = 101 p
Clinical characteristics
Age at diagnosis (years), median (IQR) 70 (67–75) 69 (66–72) 0.001
65–70, n (%) 92 (54.4) 64 (63.4) 0.152
> 70, n (%) 77 (45.6) 40 (39.6)
Time of surgery, n (%) 0.684
2005–2014 81 (47.9) 51 (50.5)
2015–2018 88 (52.1) 50 (49.5)
Sex, n (%) 0.152
Male 115 (68.0) 77 (76.2)
Female 54 (32.0) 24 (23.8)
ECOG score 0.281
0 78 (46.2) 54 (63.5)
1 71 (42.0) 36 (35.6)
2 14 (8.3) 9 (8.9)
2+ 6 (3.5) 2 (2.0)
Charlson score 0.711
0 128 (75.7) 74 (73.3)
1 32 (18.9) 23 (22.8)
2 8 (4.8) 3 (2.9)
2+ 1 (0.6) 1 (1.0)
Tumour location 0.524
Gastroesophageal junction 58 (34.3) 39 (38.6)
Antrum 88 (52.1) 49 (48.5)
Other 23 (13.6) 13 (12.9)
Hospital stays (days), median (IQR) 11 (8–16) 10.0 (8–15) 0.328
CTC (number), median (IQR) 5 (2–16) 4 (1–7) 0.270
Pathological characteristics
TMN stage, n (%) 0.147
II 56 (33.1) 25 (24.8)
III 113 (66.9) 76 (75.2)
T stage, n (%) 0.286
T1–2 13 (7.7) 5 (5.0)
T3 35 (20.7) 18 (17.8)
T4 121 (71.6) 78 (77.2)
N stage, n (%) 0.285
N0 45 (26.6) 17 (16.8)
N1 18 (10.7) 17 (16.8)
N2 44 (26.0) 26 (25.8)
N3 62 (36.7) 41 (40.6)
Retrieved lymph nodes (number), median (IQR) 40 (25–55.5) 38 (24–54) 0.516
Grade, n (%) 0.051
Well or moderately differentiated 123 (72.8) 84 (83.2)
Poorly differentiated or undifferentiated 46 (27.2) 17 (16.8)
Lymphatic, blood vessel or perineural invasion, n (%) 100 (59.2) 62 (61.4) 0.720
Tumour size (cm), mean ± SD 4.0 (3.0–5.5) 4.5 (3.2–6.0) 0.121
≤ 5 cm 104 (61.5) 51 (50.5) 0.076
> 5 cm 65 (38.5) 50 (49.5)
Drug delivery and toxicities
Adjuvant chemotherapy regimen
Mono chemotherapy 6 (5.9)
Doublet chemotherapy 95 (94.1)
Length of adjuvant chemotherapy
< 3 months 57 (56.4)
3–6 months 44 (43.6)
Toxicities (grade 3 or more)
Monotherapy 1 (1.0)
Non-hematological adverse events 1 (1.0)
Hematological adverse events 0
Double therapy 15 (14.9)
Non-hematological adverse events 9 (8.9)
Hematological adverse events 6 (5.9)
IQR interquartile range, ECOG Eastern Cooperative Oncology Group, CTC circulating tumor cells
Factors associated with OS and DFS in all patients
The univariable and multivariable Cox proportional hazards models for all patients are shown in Table 2. In the multivariable analysis, age > 70 years (HR = 1.640, 95% CI: 1.119–2.403, P = 0.011) and stage III GC (HR = 2.738, 95% CI: 1.677–4.471, P < 0.001) were independently associated with OS. Surgery plus adjuvant chemotherapy (HR = 0.511, 95% CI: 0.322–0.811, P = 0.004), surgery performed in 2015–2018 (HR = 0.586, 95% CI: 0.376–0.912, P = 0.018), and stage III GC (HR = 2.345, 95% CI: 1.466–3.751, P < 0.001) were independently associated with DFS. Therefore, stage III GC was independently associated with both OS and DFS.
Table 2 Association factors of OS and DFS in the total patients
Overall survival Disease-free survival
Univariable analysis Multivariable analysis Univariable analysis Multivariable analysis
Factors HR (95% CI) p HR (95% CI) p HR (95% CI) p HR (95% CI) p
Treatment
Surgery alone 1 (Reference) – 1 (Reference) – 1 (Reference) –
Surgery/adjuvant chemotherapy 0.733 (0.486–1.106) 0.139 0.673 (0.447–1.012) 0.057 0.511 (0.322–0.811) 0.004
Age of diagnosis
65–70 years 1 (Reference) – 1 (Reference) – 1 (Reference) –
> 70 years 1.560 (1.021–2.385) 0.028 1.640 (1.119–2.403) 0.011 1.422 (0.978–2.067) 0.065
Time of surgery
2004–2014 1 (Reference) – 1 (Reference) – 1 (Reference) –
2015–2018 0.967 (0.632–1.478) 0.876 0.713 (0.475–1.069) 0.102 0.586 (0.376–0.912) 0.018
Sex
Male 1 (Reference) – 1 (Reference) –
Female 0.903 (0.589–1.383) 0.638 0.895 (0.588–1.361) 0.603
ECOG score
0 1 (Reference) – 1 (Reference) –
1 1.325 (0.879–1.996) 0.179 1.468 (0.982–2.194) 0.062
2 1.006 (0.504–2.008) 0.987 1.105 (0.554–2.202) 0.777
2+ 2.016 (0.797–5.100) 0.139 2.017 (0.798–5.097) 0.138
Charlson score
0 1 (Reference) – 1 (Reference) –
1 1.029 (0.631–1.679) 0.909 1.068 (0.661–1.724) 0.788
2 0.992 (0.363–2.710) 0.988 1.182 (0.479–2.961) 0.716
2+ 1.135 (0.158–8.174) 0.900 1.368 (0.190–9.852) 0.756
Tumor location
Gastroesophageal junction 1 (Reference) – 1 (Reference) –
Antrum 1.304 (0.841–2.023) 0.236 1.321 (0.861–2.027) 0.203
Other 1.511 (0.832–2.724) 0.175 1.497 (0.840–2.670) 0.171
Retrieved lymph node 1.002 (0.9931.011) 0.656 0.999 (0.990–1.008) 0.841
Hospital stays 1.003 (0.983–1.023) 0.793 1.006 (0.987–1.025) 0.550
AJCC stage
II 1 (Reference) – 1 (Reference) – 1 (Reference) – 1 (Reference) –
III 2.626 (1.610–4.284) < 0.001 2.738 (1.677–4.471) < 0.001 2.345 (1.466–3.751) < 0.001 2.345 (1.466–3.751) < 0.001
Histologic Grade
Well or moderately differentiated 1 (Reference) – 1 (Reference) –
Poorly differentiated or undifferentiated 1.293 (0.809–2.068) 0.283 1.247 (0.788–1.975) 0.346
Lymphatic, blood vessel or perineural invasion
Yes 1 (Reference) – 1 (Reference) –
No 0.857 (0.581–1.7266 0.439 0.740 (0.505–1.083) 0.121
Tumor size
≤ 5 cm 1 (Reference) – 1 (Reference) 1 (Reference) –
> 5 cm 1.610 (1.099–2.356) 0.014 1.356 (0.921–1.996) 0.123 1.440 (0.991–2.091) 0.560
CTC 0.937 (0.802–1.096) 0.416 1.007 (0.924–1.088) 0.866
HR hazards ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, AJCC American Joint Cancer Committee, CTC circulating tumor cells
We adjusted for the following variables: treatment regimens (with adjuvant chemotherapy or not), age of diagnosis, time of surgery, sex, ECOG score, Charlson score, tumor location, retrieved lymph node, hospital stays, AJCC stage, histologic grade, lymphatic, blood vessel or perineural invasion, tumor size, and CTC counts
Overall survival
Unadjusted Kaplan-Meier survival curves were constructed for all patients in the two groups. The 1-, 3-, and 5-year OS rates of the surgery group were 72.9, 51.8, and 48.3%, compared with 90.1, 66.4, and 48.6% for the chemo group, respectively (HR = 0.61, 95% CI: 0.42–0.92, P = 0.135) (Fig. 2a). In the stage II cohort, the 1-, 3-, and 5-year OS rates of the surgery group were 96.3, 80.4, and 72.7%, compared with 90.5, 73.8, and 50.9% for the chemo group, respectively (HR = 1.26, 95% CI: 0.483–3.29, P = 0.637) (Fig. 2b). For stage III patients, the 1-, 3-, and 5-year OS rates of the surgery group were 83.7, 40.7, and 28.7%, compared with 89.9, 61.2, and 43.6% for the chemo group, respectively (HR = 0.58, 95% CI: 0.38–0.90, P = 0.016) (Fig. 2c).
Fig. 2 Survival curves for overall survival (OS) and disease-free survival (DFS) in all the patients a, d, stage II patients b, e, and stage III patients c, f
Disease-free survival
The 1-, 3-, and 5-year DFS rates of the surgery group were 72.9, 51.8, and 48.4%, compared with 81.3, 65.1, and 53.6% for the chemo group, respectively (HR = 0.682, 95% CI: 0.463–1.005, P = 0.053) (Fig. 2d). In the stage II cohort, the 1-, 3-, and 5-year DFS rates of the surgery group were 85.3, 78.5, and 74.2%, compared with 91.8, 64.4, and 64.4% for the chemo group, respectively (HR = 1.02, 95% CI: 0.416–2.54, P = 0.950 (Fig. 2e). In stage III patients, the 1-, 3-, and 5-year DFS rates of the surgery group were 66.5, 37.7, and 34.8%, compared with 77.9, 60.0, and 49.0% for the chemo group, respectively (HR = 0.55, 95% CI: 0.36–0.83, P = 0.007) (Fig. 2f). The OS and DFS in the stage III subgroup were significantly different between the surgery and Chemo groups.
Subgroup survival analysis in stage III patients
The univariable and multivariable Cox proportional hazards models in stage III patients are shown in Table 3. Surgery plus adjuvant chemotherapy (HR = 0.568, 95% CI: 0.357–0.903, P = 0.017) and age > 70 years (HR = 1.573, 95% CI: 1.029–2.405, P = 0.036) were independently associated with OS. Surgery plus adjuvant chemotherapy (HR = 0.511, 95% CI: 0.322–0.811, P = 0.004) and surgery performed in 2015–2018, HR = 0.586, 95% CI: 0.376–0.912, P = 0.018) were independently associated with DFS.
Table 3 Association factors of OS and DFS in stage III patients
Overall survival Disease-free survival
Univariable analysis Multivariable analysis Univariable analysis Multivariable analysis
Factors HR (95% CI) p HR (95% CI) p HR (95% CI) p HR (95% CI) p
Treatment
Surgery alone 1 (Reference) – 1 (Reference) – 1 (Reference) – 1 (Reference) –
Surgery/adjuvant chemotherapy 0.572 (0.360–0.910) 0.018 0.568 (0.357–0.903) 0.017 0.542 (0.342–0.859) 0.009 0.511 (0.322–0.811) 0.004
Age of diagnosis
65–70 years 1 (Reference) – 1 (Reference) – 1 (Reference) –
> 70 years 1.560 (1.021–2.385) 0.040 1.573 (1.029–2.405) 0.036 1.409 (0.926–1.943) 0.109
Time of surgery
2004–2014 1 (Reference) – 1 (Reference) – 1 (Reference) –
2015–2018 0.895 (0.565–1.417) 0.636 0.630 (0.405–0.980) 0.041 0.586 (0.376–0.912) 0.018
Sex
Male 1 (Reference) – 1 (Reference) –
Female 0.987 (0.609–1.602) 0.959 0.957 (0.591–1.55) 0.860
ECOG score
0 1 (Reference) – 1 (Reference) –
1 1.345 (0.848–2.132) 0.207 – – 1.493 (0.948–2.351) 0.083
2 1.201 (0.576–2.507) 0.625 1.335 (0.643–2.773) 0.438
2+ 2.810 (1.098–7.188) 0.031 2.715 (1.061–6.950) 0.037
Charlson score
0 1 (Reference) – 1 (Reference) –
1 1.038 (0.609–1.771) 0.890 1.119 (0.664–1.885) 0.674
2 1.000 (0.364–2.749) 0.999 1.186 (0.477–2.946) 0.713
2+ – –
Tumor location
Gastroesophageal junction 1 (Reference) – 1 (Reference) –
Antrum 1.347 (0.838–2.166) 0.219 1.368 (0.858–2.183) 0.188
Other 1.862 (0.917–3.780) 0.086 1.521 (0.753–3.073) 0.242
Retrieved lymph node 1.001 (0.991–1.010) 0.853 0.999 (0.989–1.009) 0.782
Hospital stays 1.001 (0.980–1.023) 0.905 1.005 (0.986–1.025) 0.600
T stage
T1–2 1 (Reference) – 1 (Reference) –
T3 0.596 (0.130–2.729) 0.505 0.464 (0.103–2.098) 0.318
T4 0.722 (0.176–2.958) 0.651 0.576 (0.141–2.358) 0.443
N stage
N0 1 (Reference) – 1 (Reference) –
N1 0.223 (0.040–1.231) 0.085 0.234 (0.042–1.288) 0.095
N2 0.517 (0.121–2.207) 0.373 0.555 (0.131–2.357) 0.425
N3 1.071 (0.261–4.398) 0.924 1.065 (0.259–4.375) 0.930
Histologic Grade
Well or moderately differentiated 1 (Reference) – 1 (Reference) –
Poorly differentiated or undifferentiated 1.035 (0.609–1.759) 0.899 1.043 (0.615–1.769) 0.877
Lymphatic, blood vessel or perineural invasion
Yes 1 (Reference) – 1 (Reference) –
No 0.899 (0.581–1.389) 0.631 0.741 (0.484–1.134) 0.167
Tumor size
≤ 5 cm 1 (Reference) – 1 (Reference) –
> 5 cm 1.209 (0.793–1.843) 0.377 1.147 (0.756–1.738) 0.519
HR hazards ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, AJCC American Joint Cancer Committee
We adjusted for the following variables: treatment regimens (with adjuvant chemotherapy or not), age of diagnosis, time of surgery, sex, ECOG score, Charlson score, tumor location, retrieved lymph node, hospital stays, T stage, N stage, histologic grade, lymphatic, blood vessel or perineural invasion, and tumor size
Chemotherapy regimens, duration, and toxicity
In stage III patients, the platinum-based doublet chemotherapy led to better OS and DFS compared with monotherapy (OS: P = 0.037; DFS: P = 0.013) (Supplementary Fig. S2 A, C), but the differences were not statistically significant in stage II patients (P = 0.473 and P = 0.499) (Supplementary Fig. S1A, C). No significant differences in OS and DFS were observed in relation to chemotherapy duration (all P > 0.05) (Supplementary Fig. S1 B,D; Supplementary Fig. S2 B, D). There were 10 patients with grade 3 or above non-hematological toxicity adverse events, and six with grade 3 hematological toxicity adverse events (neutropenia) (Table 1).
Analysis in patients with available CTC data
Forty-three patients had a CTC count before surgery, and 40 of them were positive. There were no significant differences in OS and DFS between the surgery and chemo groups among CTC-tested patients (Supplementary Fig. S3 A, C) and CTC-positive patients (all P > 0.05) (Supplementary Fig. S3 B,D).
Discussion
The benefits of adjuvant chemotherapy for elderly patients (age over 65) with GC remain unknown because the elderly patients are underrepresented in most clinical trials [15]. Therefore this study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy in elderly patients (over 65 years of age) after laparoscopic D2 gastrectomy. The results strongly suggest that adjuvant chemotherapy improves the OS and DFS of elderly patients with stage III GC operated using D2 laparoscopic gastrectomy compared with surgery alone.
Previously, there were a few single-center retrospective studies that focused on adjuvant chemotherapy for elderly patients after gastrectomy [23, 24]. Still, those previous studies might not represent the current status of advanced GC treatment since laparoscopic D2 gastrectomy became popular relatively recently [18]. In the present study, only elderly gastric patients who underwent laparoscopic D2 gastrectomy were included. Among them, 41% received adjuvant chemotherapy in the 65–70 age group and only 33% in the > 70 age group. This finding is similar to other cancers [25, 26]. This may be due to two reasons. First, there is no solid evidence to prove the efficacy of adjuvant chemotherapy in elderly patients with GC. Second, with a high comorbidity rate, older patients may prefer not to undergo chemotherapy treatment in their relatively limited lifetime [27].
Chemotherapy toxicity is another concern of the elderly who just underwent surgery. In the CLASSIC study, 56% of the patients who received the fluoropyrimidine-platinum chemotherapy regimen experienced grade 3–4 adverse events [12]. In the ACTS-GC study, 22.8% of patients with mono-chemotherapy experienced grade 3–4 adverse events [11]. In the present study, 95 (94.0%) patients in the chemo group received platinum-based doublet chemotherapy, including XELOX and FOLFOX, and 15 (15.6%) patients suffered from grade 3–4 adverse events. In the monotherapy group, one patient suffered from grade 3–4 non-hematological adverse events. The adverse event rate in our cohort is similar to a retrospective study from Korea [24]. Low rates of grade 3–4 adverse events may be due to the low Charlson comorbidity score in the present study since the patients were required to be able to tolerate laparoscopic D2 gastrectomy. The result indicates that adjuvant chemotherapy is tolerable in elderly patients who were suitable for gastrectomy. Still, it is possible that the adverse events were underestimated or not measured strictly in this retrospective study.
In the present study, adjuvant chemotherapy could significantly improve the OS in stage III elderly patients. Jin et al. [23] revealed an OS benefit (P = 0.003) of adjuvant chemotherapy in elderly patients in a single-center retrospective study. A single-center retrospective study of elderly patients with GC (over 70 years) in Korea reported a DFS benefit (P = 0.03) after adjuvant chemotherapy, but without an OS benefit (P = 0.242, 24]. Nevertheless, by analyzing elderly patients with resected GC in the SEER-Medicare database, Hoffman et al. [28] reported that elderly patients might not gain a survival benefit from adjuvant chemotherapy, but most cases in this database underwent D0 or D1 gastrectomy. Up to now, no standard adjuvant chemotherapy regimens were established for the elderly. Some reports suggest that patients might benefit from adjuvant chemotherapy, no matter which chemotherapy regimen is used [29]. The CLASSIC study indicated that the fluoropyrimidine and oxaliplatin combination reduced both locoregional and distant recurrences, but had a smaller effect on peritoneal recurrences [12]. Kim et al. [30] reported that there were no significant improvements in OS and RFS when using longer treatments of fluoropyrimidine-based adjuvant chemotherapy in patients with stage II or III GC. Similar results were also observed in stage III colon cancer with 3 vs. 6 months of XELOX [31]. On the other hand, Feng et al. [32] reported that additional oral capecitabine for 6 months after eight cycles of XELOX improved the DFS and OS for stage IIIA GC. Still, those previous studies were not focused on elderly patients with GC. Elderly patients may prefer to undergo fewer treatments or treatments with fewer adverse effects in their relatively limited lifetime [27].
There are several limitations to this study. First, this study was based on retrospective data, with inherent shortcomings. For example, immortal time bias in the adjuvant group could not be completely avoided in a retrospective study. Secondly, it was a single center study, and it is unknown whether the results are valid externally. In addition, this was a strictly selected group of patients, excluding those with previous cancers, R1/2 resections and post-operative death. Consequently, the survival rates in both groups might not reflect real-world data. Finally, differences between the < 65 and ≥ 65 year-old groups were not assessed. Further prospective studies are needed to address those issues.
Conclusions
In this retrospective, single-institution study, the OS and DFS benefited from adjuvant chemotherapy in elderly patients with stage III GC after D2 laparoscopic gastrectomy. Well-designed prospective studies are needed to confirm these findings. Elderly patients are highly variable in their functional status and comorbidities. Thus, cofactors regarding the functional, social, and mental status should also be considered. Further studies are needed to identify the elderly who can tolerate and benefit from adjuvant chemotherapy.
Contribution to the field statement
The benefits of adjuvant chemotherapy for elderly patients (age > 65) with gastric cancer (GC) remain unknown because elderly patients are underrepresented in most clinical trials. A total of 270 patients included for analysis. There were ten (10/101) and six (6/101) patients with grade 3+ non-hematological and hematological adverse events. The 1−/3−/5-year OS rates of the surgery group were 72.9%/51.8%/48.3%, compared with 90.1%/66.4%/48.6% for the chemo group (log-rank test: P = 0.018). For stage III patients, the 1−/3−/5-year OS rates of the surgery group were 83.7%/40.7%/28.7%, compared with 89.9%/61.2%/43.6% for the chemo group (log-rank test: P = 0.015). Adjuvant chemotherapy was significantly associated with higher OS (HR = 0.568, 95%CI: 0.357–0.903, P = 0.017) and DFS (HR = 0.511, 95%CI: 0.322–0.811, P = 0.004) in stage III patients. CTC > 0 had no significant impact on the benefits of adjuvant chemotherapy on OS and DFS. These findings suggested that adjuvant chemotherapy significantly improves OS and DFS for elderly patients with stage III GC after D2 laparoscopic gastrectomy, with a tolerable adverse event profile.
Supplementary Information
Additional file 1: Supplementary Figure S1. Subgroup survival analysis for stage II patients in the chemotherapy group.
Additional file 2; Supplementary Figure S2. Subgroup survival analysis for stage III patients in the chemotherapy group.
Additional file 3: Supplementary Figure S3. Subgroup survival analysis in patients who had been tested for circulating tumor cells (CTCs) (A, C), and for those with positive CTCs (B, D).
Abbreviations
GCGastric cancer
OSOverall survival
DFSDisease-free survival
CTCsCirculating tumor cells
PFSProgression-free survival
RCTsRandomized controlled studies
HRHazard ratios
CIConfidence interval
CLASSThe chinese laparoscopic gastrointestinal surgery
AJCCAmerican Joint Committee on Cancer
SDStandard deviations
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yanrui Liang, Liying Zhao and Hao Chen contributed equally to this work.
The authors would like to thank all study participants who were enrolled in this study.
Authors’ contributions
YR L, LY Z and HC carried out the studies, participated in collecting data, and drafted the manuscript. TL, TC, ML Z, YF H and JY performed the statistical analysis and participated in its design. HL and GX L participated in acquisition, analysis, or interpretation of data and draft the manuscript. All authors read and approved the final manuscript.
Funding
The project was supported by grants from the State’s Key Project of Research and Development Plan (2017YFC0108300), the National Natural Science Foundation of China (81672446), the Southern Medical University Clinical Research Start-Up Project (LC2016ZD003), and the Key Clinical Specialty Discipline Construction Program ([2012]121). The funding bodies had no rule in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Availability of data and materials
The datasets used and analysed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Nanfang Hospital. The need for written informed consent was waived due to the retrospective nature of this study.
Consent for publication
Not applicable.
Competing interests
All authors declare no conflict of interest associated with this manuscript. | CAPECITABINE | DrugsGivenReaction | CC BY | 33632161 | 18,987,167 | 2021-02-25 |
What was the administration route of drug 'CAPECITABINE'? | Survival analysis of elderly patients over 65 years old with stage II/III gastric cancer treated with adjuvant chemotherapy after laparoscopic D2 gastrectomy: a retrospective cohort study.
BACKGROUND
The benefits of adjuvant chemotherapy for elderly patients with gastric cancer (GC) remain unknown because elderly patients are underrepresented in most clinical trials. This study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy in patients > 65 years of age after laparoscopic D2 gastrectomy.
METHODS
This was a single-center retrospective cohort study of elderly patients (> 65 years) with stage II/III GC who underwent curative laparoscopic D2 gastrectomy with R0 resection between 2004 and 2018. The adjuvant chemotherapy regimens included monotherapy (oral capecitabine) and doublet chemotherapy (oral capecitabine plus intravenous oxaliplatin [XELOX] or intravenous oxaliplatin, leucovorin, and 5-fluorouracil [FOLFOX]). The data were retrieved from a prospectively registered database maintained at the Department of General Surgery in Nanfang Hospital, China. The patients were divided as surgery alone and surgery plus adjuvant chemotherapy (chemo group). The overall survival (OS), disease-free survival (DFS), chemotherapy duration, and toxicity were examined.
RESULTS
There were 270 patients included: 169 and 101 in the surgery and chemo groups, respectively. There were 10 (10/101) and six (6/101) patients with grade 3+ non-hematological and hematological adverse events. The 1-/3-/5-year OS rates of the surgery group were 72.9%/51.8%/48.3%, compared with 90.1%/66.4%/48.6% for the chemo group (log-rank test: P = 0.018). For stage III patients, the 1-/3-/5-year OS rates of the surgery group were 83.7%/40.7%/28.7%, compared with 89.9%/61.2%/43.6% for the chemo group (log-rank test: P = 0.015). Adjuvant chemotherapy was significantly associated with higher OS (HR = 0.568, 95%CI: 0.357-0.903, P = 0.017) and DFS (HR = 0.511, 95%CI: 0.322-0.811, P = 0.004) in stage III patients.
CONCLUSIONS
This study suggested that adjuvant chemotherapy significantly improves OS and DFS compared with surgery alone in elderly patients with stage III GC after D2 laparoscopic gastrectomy, with a tolerable adverse event profile.
Background
Gastric cancer (GC), as the fifth most frequently diagnosed cancer and the third leading cause of cancer death worldwide, was responsible for over 1,000,000 new cases and an estimated 783,000 deaths in 2018 [1]. The markedly elevated incidence rates of GC in Eastern Asia (China, Japan, and Korea) indicate that GC is a significant public health threat, especially to the elderly, since over 60% of the GC diagnoses and 70% of GC-related mortality occur in elderly patients (aged 65 years or older) [2, 3]. As the population continues to age, the proportion of the population aged 60 years and over will increase from 12.4% in 2010 to 28% in 2040 [4]. Longer life expectancy also results in an increasing number of the elderly (aged 65 years or older) undergoing cancer operation and chemotherapy.
The survival benefits from gastrectomy plus chemotherapy have been confirmed in patients with advanced GC [5–7]. In the United States of America, chemoradiotherapy after gastrectomy has been confirmed to improve overall survival (OS) by the INT-0116 trial [8], while the progression-free survival (PFS) and OS benefits of perioperative chemotherapy have been shown by the MAGIC and FLOT4 trials [9, 10]. The adjuvant chemotherapy following D2 gastrectomy is a standard treatment for stage II/III GC in East Asia [11–13]. Although prior randomized controlled studies (RCTs) indicated that postoperative adjuvant treatment in patients who underwent D2 gastrectomy could improve the 5-year disease-free survival (DFS) and OS, the subgroup analyses showed that the survival benefits decreased with increasing age. Furthermore, the ACTS-GC study showed no statistically significant effects of postoperative chemotherapy on DFS and OS for patients older than 70 years (DFS: hazard ratios (HR) = 0.779, 95% confidence interval (CI): 0.527–1.151; OS: HR = 0.706, 95% CI: 0.490–1.017) [11]. Similar results for OS were observed in the CLASSIC study for patients older than 65 (HR = 0.70, 95% CI: 0.4–1.12) [12]. These results might be due to the considerably higher incidence of comorbidities, higher risk of complications, and shorter life expectancy of elderly patients [14]. Nevertheless, when considering those conflicting results, whether to give or not adjuvant chemotherapy to elderly patients with GC after D2 gastrectomy remains a dilemma for physicians. Therefore, the International Society of Geriatric Oncology suggested that specific trials for older patients with cancer should be conducted [15].
Laparoscopic gastrectomy has gained popularity worldwide for its safety and effectiveness [16, 17]. The Chinese Laparoscopic Gastrointestinal Surgery (CLASS) group recently reported the primary endpoints of the CLASS-01 trial, which suggested that laparoscopic distal gastrectomy for advanced gastric cancer was non-inferior to open surgery in terms of 3-year DFS and safety, with significant minimally invasive benefits [18, 19]. A previous study by our group indicated the potential benefits of laparoscopic gastrectomy for elderly patients with resectable GC [20]. Ushimaru et al. [21] reported that laparoscopic gastrectomy might improve the OS by reducing mortality from respiratory diseases. Still, the benefit of adjuvant chemotherapy after laparoscopic D2 gastrectomy in elderly patients is unknown.
As the elderly patients (over 65 years of age) are underrepresented in most RCTs, the present study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy retrospectively in elderly patients (over 65 years of age) after laparoscopic D2 gastrectomy, based on a prospectively registered database in China. Those results could help shed some light on this controversy.
Methods
Study design and patients
This was a retrospective cohort study conducted in the Department of General Surgery of Nanfang Hospital in patients treated between June 2004 and June 2018. This study was approved by the Ethics Committee of Nanfang Hospital. The need for written informed consent was waived due to the retrospective nature of this study.
The inclusion criteria were: 1) over 65 years of age; 2) histologically confirmed stage II or III gastric adenocarcinoma, according to American Joint Committee on Cancer (AJCC, 7th Edition); 3) received curative laparoscopic gastrectomy with D2 nodal dissection at Nanfang Hospital; and 4) at least 15 lymph nodes were available to ensure adequate disease classification. The exclusion criteria were: 1) residual tumors (R1/R2 resections or palliative surgery; 2) death within 1 month after surgery; 3) a previous history of primary or secondary tumor beside the current GC; 4) neoadjuvant chemotherapy or adjuvant radiotherapy; or 5) incomplete medical record .
The enrolled patients were divided into surgery alone group (surgery group) and the surgery plus adjuvant chemotherapy group (chemo group).
Adjuvant chemotherapy protocols
The adjuvant chemotherapy regimens administered during the study period included monotherapy and doublet chemotherapy. The initial dose of each regimen was reduced to 75% of the original value to minimize toxic effects in elderly patients. For monotherapy, the patients received 3-week cycles of oral capecitabine (750 mg/m2 twice daily on days 1 to 14 of each cycle) for 6 months if tolerated. For doublet chemotherapy, the patients received oral capecitabine plus intravenous oxaliplatin (XELOX) or 2-week cycles of intravenous oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX). For the XELOX regimen, patients received 3-week cycles of oral capecitabine (750 mg/m2 twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m2 on day 1 of each cycle) for 6 months if tolerated. The FOLFOX regimen was administered as follows: intravenous (IV) treatment with 63.75 mg/m2 of oxaliplatin, 300 mg/m2 of leucovorin and IV push administration of 300 mg/m2 of fluorouracil on day 1, and 900 mg/m2 of fluorouracil IV by continuous infusion for 24 h on days 1 and 2. This regimen was repeated every 14 days and lasted for 6 months if tolerated. In all regimens, the dose of each drug was reduced to the next lower dose increment in case of grade 4 neutropenia or thrombocytopenia, or grade 3 or above febrile neutropenia.
Data collection
The data were retrieved from a prospectively registered database maintained at the Department of General Surgery in Nanfang Hospital, China. The database includes patient characteristics (age at diagnosis, sex, etc.), clinical variables (postoperative stay, circulating tumor cells [CTCs] collected at postoperative two weeks, etc.), pathological features (tumor size, histological grade, etc.), chemotherapy (regimen, duration, cycles of chemotherapy, and grade 3 or above toxicity events), and follow-up. All data are routinely updated after each routine follow-up visit, either at the outpatient clinic or by phone. For the present study, the last follow-up data were collected on May 30th, 2018.
Outcomes
The observation outcomes of this study were OS and DFS. The OS was calculated from the date of operation to either the date of death or the date of the last follow-up visit. The DFS was calculated from the date of resection to the date of the first recurrence detected, or the last follow-up visit. Recurrence was determined as the appearance of any new lesion either locally, regionally, or distant. All grade 3 or above hematological and non-hematological toxicity events were recorded. Toxicities were graded according to the National Cancer Institute common toxicity criteria version 3.0 [22].
Statistical analysis
All statistical analyses were performed using SPSS 24.0 (IBM Corp., Armonk, NY, USA). Continuous variables were tested for normal distribution using the Kolmogorov-Smirnov test. Those with a normal distribution were expressed as means ± standard deviations (SD) and were analyzed using Student’s t-test; otherwise, they were presented as medians (ranges) and analyzed using the Mann-Whitney U-test. Categorical variables were reported as numbers with percentages and analyzed using the chi-square test with the Yates correction or Fisher’s exact test, as appropriate. The OS and DFS rates were compared between the surgery and chemo groups using unadjusted Kaplan-Meier curves and the log-rank test. The OS and DFS rates of different clinicopathological characteristics and different chemotherapy regimen were compared. HR and 95% CI were used to estimate the role of each independent predictor of survival. The Cox regression model was used for univariable and multivariable analyses. We adjusted for the following variables: treatment regimens (with adjuvant chemotherapy or not), age of diagnosis, time of surgery, sex, ECOG score, Charlson score, tumor location, retrieved lymph node, hospital stays, AJCC stage, histologic grade, lymphatic, blood vessel or perineural invasion, tumor size, and CTC counts. Variables with P < 0.1 in the univariable analysis were included in the multivariable analysis. The level of significance was set at a two-tailed P-value of 0.05.
Results
Patient characteristics
At first, 298 patients were eligible, but 28 were excluded because of the presence of residual tumors (R1/R2 resections and palliative surgery), death within 1 month of surgery, primary or secondary tumor history, neoadjuvant chemotherapy, adjuvant radiotherapy, or incomplete medical record. The remaining 270 patients were included in the analysis; 169 and 101 were classified in the surgery and chemo groups, respectively (Fig. 1).
Fig. 1 Patient flowchart
Table 1 presents the characteristics of the patients. The median age in the surgery and chemo groups was 70 years (69–75 years) and 69 years (66–72 years), respectively (P = 0.001). The male-to-female ratio was 2.1:1 in the surgery group and 3.2:1 in the chemo group (P = 0.152). Most patients in the two groups had an ECOG score and a Charlson comorbidity score of < 1 (ECOG: 88.2 and 89.1%; Charlson score: 94.7 and 96.0%; all P > 0.05). The number of CTCs in the surgery group was 5 (2–16), while 4 (1–7) in the chemo group (P = 0.328). In the surgery group, there were 56 patients with AJCC stage II and 113 with AJCC stage III, while in the chemo group, there were 25 patients with AJCC stage II and 76 with AJCC stage III (P = 0.147). In the chemo group, six patients received monotherapy, and 95 patients received platinum-based doublet chemotherapy therapy; 57 patients received adjuvant chemotherapy for less than 3 months, while 44 patients received 3–6 months of adjuvant chemotherapy. The median follow-up in the surgery and chemo groups was 25 (IQR 13–44) months, and 22 (IQR 11–54.5) months, respectively (P = 0.452).
Table 1 Baseline information of patients
Characteristics Surgery N = 169 Chemotherapy N = 101 p
Clinical characteristics
Age at diagnosis (years), median (IQR) 70 (67–75) 69 (66–72) 0.001
65–70, n (%) 92 (54.4) 64 (63.4) 0.152
> 70, n (%) 77 (45.6) 40 (39.6)
Time of surgery, n (%) 0.684
2005–2014 81 (47.9) 51 (50.5)
2015–2018 88 (52.1) 50 (49.5)
Sex, n (%) 0.152
Male 115 (68.0) 77 (76.2)
Female 54 (32.0) 24 (23.8)
ECOG score 0.281
0 78 (46.2) 54 (63.5)
1 71 (42.0) 36 (35.6)
2 14 (8.3) 9 (8.9)
2+ 6 (3.5) 2 (2.0)
Charlson score 0.711
0 128 (75.7) 74 (73.3)
1 32 (18.9) 23 (22.8)
2 8 (4.8) 3 (2.9)
2+ 1 (0.6) 1 (1.0)
Tumour location 0.524
Gastroesophageal junction 58 (34.3) 39 (38.6)
Antrum 88 (52.1) 49 (48.5)
Other 23 (13.6) 13 (12.9)
Hospital stays (days), median (IQR) 11 (8–16) 10.0 (8–15) 0.328
CTC (number), median (IQR) 5 (2–16) 4 (1–7) 0.270
Pathological characteristics
TMN stage, n (%) 0.147
II 56 (33.1) 25 (24.8)
III 113 (66.9) 76 (75.2)
T stage, n (%) 0.286
T1–2 13 (7.7) 5 (5.0)
T3 35 (20.7) 18 (17.8)
T4 121 (71.6) 78 (77.2)
N stage, n (%) 0.285
N0 45 (26.6) 17 (16.8)
N1 18 (10.7) 17 (16.8)
N2 44 (26.0) 26 (25.8)
N3 62 (36.7) 41 (40.6)
Retrieved lymph nodes (number), median (IQR) 40 (25–55.5) 38 (24–54) 0.516
Grade, n (%) 0.051
Well or moderately differentiated 123 (72.8) 84 (83.2)
Poorly differentiated or undifferentiated 46 (27.2) 17 (16.8)
Lymphatic, blood vessel or perineural invasion, n (%) 100 (59.2) 62 (61.4) 0.720
Tumour size (cm), mean ± SD 4.0 (3.0–5.5) 4.5 (3.2–6.0) 0.121
≤ 5 cm 104 (61.5) 51 (50.5) 0.076
> 5 cm 65 (38.5) 50 (49.5)
Drug delivery and toxicities
Adjuvant chemotherapy regimen
Mono chemotherapy 6 (5.9)
Doublet chemotherapy 95 (94.1)
Length of adjuvant chemotherapy
< 3 months 57 (56.4)
3–6 months 44 (43.6)
Toxicities (grade 3 or more)
Monotherapy 1 (1.0)
Non-hematological adverse events 1 (1.0)
Hematological adverse events 0
Double therapy 15 (14.9)
Non-hematological adverse events 9 (8.9)
Hematological adverse events 6 (5.9)
IQR interquartile range, ECOG Eastern Cooperative Oncology Group, CTC circulating tumor cells
Factors associated with OS and DFS in all patients
The univariable and multivariable Cox proportional hazards models for all patients are shown in Table 2. In the multivariable analysis, age > 70 years (HR = 1.640, 95% CI: 1.119–2.403, P = 0.011) and stage III GC (HR = 2.738, 95% CI: 1.677–4.471, P < 0.001) were independently associated with OS. Surgery plus adjuvant chemotherapy (HR = 0.511, 95% CI: 0.322–0.811, P = 0.004), surgery performed in 2015–2018 (HR = 0.586, 95% CI: 0.376–0.912, P = 0.018), and stage III GC (HR = 2.345, 95% CI: 1.466–3.751, P < 0.001) were independently associated with DFS. Therefore, stage III GC was independently associated with both OS and DFS.
Table 2 Association factors of OS and DFS in the total patients
Overall survival Disease-free survival
Univariable analysis Multivariable analysis Univariable analysis Multivariable analysis
Factors HR (95% CI) p HR (95% CI) p HR (95% CI) p HR (95% CI) p
Treatment
Surgery alone 1 (Reference) – 1 (Reference) – 1 (Reference) –
Surgery/adjuvant chemotherapy 0.733 (0.486–1.106) 0.139 0.673 (0.447–1.012) 0.057 0.511 (0.322–0.811) 0.004
Age of diagnosis
65–70 years 1 (Reference) – 1 (Reference) – 1 (Reference) –
> 70 years 1.560 (1.021–2.385) 0.028 1.640 (1.119–2.403) 0.011 1.422 (0.978–2.067) 0.065
Time of surgery
2004–2014 1 (Reference) – 1 (Reference) – 1 (Reference) –
2015–2018 0.967 (0.632–1.478) 0.876 0.713 (0.475–1.069) 0.102 0.586 (0.376–0.912) 0.018
Sex
Male 1 (Reference) – 1 (Reference) –
Female 0.903 (0.589–1.383) 0.638 0.895 (0.588–1.361) 0.603
ECOG score
0 1 (Reference) – 1 (Reference) –
1 1.325 (0.879–1.996) 0.179 1.468 (0.982–2.194) 0.062
2 1.006 (0.504–2.008) 0.987 1.105 (0.554–2.202) 0.777
2+ 2.016 (0.797–5.100) 0.139 2.017 (0.798–5.097) 0.138
Charlson score
0 1 (Reference) – 1 (Reference) –
1 1.029 (0.631–1.679) 0.909 1.068 (0.661–1.724) 0.788
2 0.992 (0.363–2.710) 0.988 1.182 (0.479–2.961) 0.716
2+ 1.135 (0.158–8.174) 0.900 1.368 (0.190–9.852) 0.756
Tumor location
Gastroesophageal junction 1 (Reference) – 1 (Reference) –
Antrum 1.304 (0.841–2.023) 0.236 1.321 (0.861–2.027) 0.203
Other 1.511 (0.832–2.724) 0.175 1.497 (0.840–2.670) 0.171
Retrieved lymph node 1.002 (0.9931.011) 0.656 0.999 (0.990–1.008) 0.841
Hospital stays 1.003 (0.983–1.023) 0.793 1.006 (0.987–1.025) 0.550
AJCC stage
II 1 (Reference) – 1 (Reference) – 1 (Reference) – 1 (Reference) –
III 2.626 (1.610–4.284) < 0.001 2.738 (1.677–4.471) < 0.001 2.345 (1.466–3.751) < 0.001 2.345 (1.466–3.751) < 0.001
Histologic Grade
Well or moderately differentiated 1 (Reference) – 1 (Reference) –
Poorly differentiated or undifferentiated 1.293 (0.809–2.068) 0.283 1.247 (0.788–1.975) 0.346
Lymphatic, blood vessel or perineural invasion
Yes 1 (Reference) – 1 (Reference) –
No 0.857 (0.581–1.7266 0.439 0.740 (0.505–1.083) 0.121
Tumor size
≤ 5 cm 1 (Reference) – 1 (Reference) 1 (Reference) –
> 5 cm 1.610 (1.099–2.356) 0.014 1.356 (0.921–1.996) 0.123 1.440 (0.991–2.091) 0.560
CTC 0.937 (0.802–1.096) 0.416 1.007 (0.924–1.088) 0.866
HR hazards ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, AJCC American Joint Cancer Committee, CTC circulating tumor cells
We adjusted for the following variables: treatment regimens (with adjuvant chemotherapy or not), age of diagnosis, time of surgery, sex, ECOG score, Charlson score, tumor location, retrieved lymph node, hospital stays, AJCC stage, histologic grade, lymphatic, blood vessel or perineural invasion, tumor size, and CTC counts
Overall survival
Unadjusted Kaplan-Meier survival curves were constructed for all patients in the two groups. The 1-, 3-, and 5-year OS rates of the surgery group were 72.9, 51.8, and 48.3%, compared with 90.1, 66.4, and 48.6% for the chemo group, respectively (HR = 0.61, 95% CI: 0.42–0.92, P = 0.135) (Fig. 2a). In the stage II cohort, the 1-, 3-, and 5-year OS rates of the surgery group were 96.3, 80.4, and 72.7%, compared with 90.5, 73.8, and 50.9% for the chemo group, respectively (HR = 1.26, 95% CI: 0.483–3.29, P = 0.637) (Fig. 2b). For stage III patients, the 1-, 3-, and 5-year OS rates of the surgery group were 83.7, 40.7, and 28.7%, compared with 89.9, 61.2, and 43.6% for the chemo group, respectively (HR = 0.58, 95% CI: 0.38–0.90, P = 0.016) (Fig. 2c).
Fig. 2 Survival curves for overall survival (OS) and disease-free survival (DFS) in all the patients a, d, stage II patients b, e, and stage III patients c, f
Disease-free survival
The 1-, 3-, and 5-year DFS rates of the surgery group were 72.9, 51.8, and 48.4%, compared with 81.3, 65.1, and 53.6% for the chemo group, respectively (HR = 0.682, 95% CI: 0.463–1.005, P = 0.053) (Fig. 2d). In the stage II cohort, the 1-, 3-, and 5-year DFS rates of the surgery group were 85.3, 78.5, and 74.2%, compared with 91.8, 64.4, and 64.4% for the chemo group, respectively (HR = 1.02, 95% CI: 0.416–2.54, P = 0.950 (Fig. 2e). In stage III patients, the 1-, 3-, and 5-year DFS rates of the surgery group were 66.5, 37.7, and 34.8%, compared with 77.9, 60.0, and 49.0% for the chemo group, respectively (HR = 0.55, 95% CI: 0.36–0.83, P = 0.007) (Fig. 2f). The OS and DFS in the stage III subgroup were significantly different between the surgery and Chemo groups.
Subgroup survival analysis in stage III patients
The univariable and multivariable Cox proportional hazards models in stage III patients are shown in Table 3. Surgery plus adjuvant chemotherapy (HR = 0.568, 95% CI: 0.357–0.903, P = 0.017) and age > 70 years (HR = 1.573, 95% CI: 1.029–2.405, P = 0.036) were independently associated with OS. Surgery plus adjuvant chemotherapy (HR = 0.511, 95% CI: 0.322–0.811, P = 0.004) and surgery performed in 2015–2018, HR = 0.586, 95% CI: 0.376–0.912, P = 0.018) were independently associated with DFS.
Table 3 Association factors of OS and DFS in stage III patients
Overall survival Disease-free survival
Univariable analysis Multivariable analysis Univariable analysis Multivariable analysis
Factors HR (95% CI) p HR (95% CI) p HR (95% CI) p HR (95% CI) p
Treatment
Surgery alone 1 (Reference) – 1 (Reference) – 1 (Reference) – 1 (Reference) –
Surgery/adjuvant chemotherapy 0.572 (0.360–0.910) 0.018 0.568 (0.357–0.903) 0.017 0.542 (0.342–0.859) 0.009 0.511 (0.322–0.811) 0.004
Age of diagnosis
65–70 years 1 (Reference) – 1 (Reference) – 1 (Reference) –
> 70 years 1.560 (1.021–2.385) 0.040 1.573 (1.029–2.405) 0.036 1.409 (0.926–1.943) 0.109
Time of surgery
2004–2014 1 (Reference) – 1 (Reference) – 1 (Reference) –
2015–2018 0.895 (0.565–1.417) 0.636 0.630 (0.405–0.980) 0.041 0.586 (0.376–0.912) 0.018
Sex
Male 1 (Reference) – 1 (Reference) –
Female 0.987 (0.609–1.602) 0.959 0.957 (0.591–1.55) 0.860
ECOG score
0 1 (Reference) – 1 (Reference) –
1 1.345 (0.848–2.132) 0.207 – – 1.493 (0.948–2.351) 0.083
2 1.201 (0.576–2.507) 0.625 1.335 (0.643–2.773) 0.438
2+ 2.810 (1.098–7.188) 0.031 2.715 (1.061–6.950) 0.037
Charlson score
0 1 (Reference) – 1 (Reference) –
1 1.038 (0.609–1.771) 0.890 1.119 (0.664–1.885) 0.674
2 1.000 (0.364–2.749) 0.999 1.186 (0.477–2.946) 0.713
2+ – –
Tumor location
Gastroesophageal junction 1 (Reference) – 1 (Reference) –
Antrum 1.347 (0.838–2.166) 0.219 1.368 (0.858–2.183) 0.188
Other 1.862 (0.917–3.780) 0.086 1.521 (0.753–3.073) 0.242
Retrieved lymph node 1.001 (0.991–1.010) 0.853 0.999 (0.989–1.009) 0.782
Hospital stays 1.001 (0.980–1.023) 0.905 1.005 (0.986–1.025) 0.600
T stage
T1–2 1 (Reference) – 1 (Reference) –
T3 0.596 (0.130–2.729) 0.505 0.464 (0.103–2.098) 0.318
T4 0.722 (0.176–2.958) 0.651 0.576 (0.141–2.358) 0.443
N stage
N0 1 (Reference) – 1 (Reference) –
N1 0.223 (0.040–1.231) 0.085 0.234 (0.042–1.288) 0.095
N2 0.517 (0.121–2.207) 0.373 0.555 (0.131–2.357) 0.425
N3 1.071 (0.261–4.398) 0.924 1.065 (0.259–4.375) 0.930
Histologic Grade
Well or moderately differentiated 1 (Reference) – 1 (Reference) –
Poorly differentiated or undifferentiated 1.035 (0.609–1.759) 0.899 1.043 (0.615–1.769) 0.877
Lymphatic, blood vessel or perineural invasion
Yes 1 (Reference) – 1 (Reference) –
No 0.899 (0.581–1.389) 0.631 0.741 (0.484–1.134) 0.167
Tumor size
≤ 5 cm 1 (Reference) – 1 (Reference) –
> 5 cm 1.209 (0.793–1.843) 0.377 1.147 (0.756–1.738) 0.519
HR hazards ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, AJCC American Joint Cancer Committee
We adjusted for the following variables: treatment regimens (with adjuvant chemotherapy or not), age of diagnosis, time of surgery, sex, ECOG score, Charlson score, tumor location, retrieved lymph node, hospital stays, T stage, N stage, histologic grade, lymphatic, blood vessel or perineural invasion, and tumor size
Chemotherapy regimens, duration, and toxicity
In stage III patients, the platinum-based doublet chemotherapy led to better OS and DFS compared with monotherapy (OS: P = 0.037; DFS: P = 0.013) (Supplementary Fig. S2 A, C), but the differences were not statistically significant in stage II patients (P = 0.473 and P = 0.499) (Supplementary Fig. S1A, C). No significant differences in OS and DFS were observed in relation to chemotherapy duration (all P > 0.05) (Supplementary Fig. S1 B,D; Supplementary Fig. S2 B, D). There were 10 patients with grade 3 or above non-hematological toxicity adverse events, and six with grade 3 hematological toxicity adverse events (neutropenia) (Table 1).
Analysis in patients with available CTC data
Forty-three patients had a CTC count before surgery, and 40 of them were positive. There were no significant differences in OS and DFS between the surgery and chemo groups among CTC-tested patients (Supplementary Fig. S3 A, C) and CTC-positive patients (all P > 0.05) (Supplementary Fig. S3 B,D).
Discussion
The benefits of adjuvant chemotherapy for elderly patients (age over 65) with GC remain unknown because the elderly patients are underrepresented in most clinical trials [15]. Therefore this study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy in elderly patients (over 65 years of age) after laparoscopic D2 gastrectomy. The results strongly suggest that adjuvant chemotherapy improves the OS and DFS of elderly patients with stage III GC operated using D2 laparoscopic gastrectomy compared with surgery alone.
Previously, there were a few single-center retrospective studies that focused on adjuvant chemotherapy for elderly patients after gastrectomy [23, 24]. Still, those previous studies might not represent the current status of advanced GC treatment since laparoscopic D2 gastrectomy became popular relatively recently [18]. In the present study, only elderly gastric patients who underwent laparoscopic D2 gastrectomy were included. Among them, 41% received adjuvant chemotherapy in the 65–70 age group and only 33% in the > 70 age group. This finding is similar to other cancers [25, 26]. This may be due to two reasons. First, there is no solid evidence to prove the efficacy of adjuvant chemotherapy in elderly patients with GC. Second, with a high comorbidity rate, older patients may prefer not to undergo chemotherapy treatment in their relatively limited lifetime [27].
Chemotherapy toxicity is another concern of the elderly who just underwent surgery. In the CLASSIC study, 56% of the patients who received the fluoropyrimidine-platinum chemotherapy regimen experienced grade 3–4 adverse events [12]. In the ACTS-GC study, 22.8% of patients with mono-chemotherapy experienced grade 3–4 adverse events [11]. In the present study, 95 (94.0%) patients in the chemo group received platinum-based doublet chemotherapy, including XELOX and FOLFOX, and 15 (15.6%) patients suffered from grade 3–4 adverse events. In the monotherapy group, one patient suffered from grade 3–4 non-hematological adverse events. The adverse event rate in our cohort is similar to a retrospective study from Korea [24]. Low rates of grade 3–4 adverse events may be due to the low Charlson comorbidity score in the present study since the patients were required to be able to tolerate laparoscopic D2 gastrectomy. The result indicates that adjuvant chemotherapy is tolerable in elderly patients who were suitable for gastrectomy. Still, it is possible that the adverse events were underestimated or not measured strictly in this retrospective study.
In the present study, adjuvant chemotherapy could significantly improve the OS in stage III elderly patients. Jin et al. [23] revealed an OS benefit (P = 0.003) of adjuvant chemotherapy in elderly patients in a single-center retrospective study. A single-center retrospective study of elderly patients with GC (over 70 years) in Korea reported a DFS benefit (P = 0.03) after adjuvant chemotherapy, but without an OS benefit (P = 0.242, 24]. Nevertheless, by analyzing elderly patients with resected GC in the SEER-Medicare database, Hoffman et al. [28] reported that elderly patients might not gain a survival benefit from adjuvant chemotherapy, but most cases in this database underwent D0 or D1 gastrectomy. Up to now, no standard adjuvant chemotherapy regimens were established for the elderly. Some reports suggest that patients might benefit from adjuvant chemotherapy, no matter which chemotherapy regimen is used [29]. The CLASSIC study indicated that the fluoropyrimidine and oxaliplatin combination reduced both locoregional and distant recurrences, but had a smaller effect on peritoneal recurrences [12]. Kim et al. [30] reported that there were no significant improvements in OS and RFS when using longer treatments of fluoropyrimidine-based adjuvant chemotherapy in patients with stage II or III GC. Similar results were also observed in stage III colon cancer with 3 vs. 6 months of XELOX [31]. On the other hand, Feng et al. [32] reported that additional oral capecitabine for 6 months after eight cycles of XELOX improved the DFS and OS for stage IIIA GC. Still, those previous studies were not focused on elderly patients with GC. Elderly patients may prefer to undergo fewer treatments or treatments with fewer adverse effects in their relatively limited lifetime [27].
There are several limitations to this study. First, this study was based on retrospective data, with inherent shortcomings. For example, immortal time bias in the adjuvant group could not be completely avoided in a retrospective study. Secondly, it was a single center study, and it is unknown whether the results are valid externally. In addition, this was a strictly selected group of patients, excluding those with previous cancers, R1/2 resections and post-operative death. Consequently, the survival rates in both groups might not reflect real-world data. Finally, differences between the < 65 and ≥ 65 year-old groups were not assessed. Further prospective studies are needed to address those issues.
Conclusions
In this retrospective, single-institution study, the OS and DFS benefited from adjuvant chemotherapy in elderly patients with stage III GC after D2 laparoscopic gastrectomy. Well-designed prospective studies are needed to confirm these findings. Elderly patients are highly variable in their functional status and comorbidities. Thus, cofactors regarding the functional, social, and mental status should also be considered. Further studies are needed to identify the elderly who can tolerate and benefit from adjuvant chemotherapy.
Contribution to the field statement
The benefits of adjuvant chemotherapy for elderly patients (age > 65) with gastric cancer (GC) remain unknown because elderly patients are underrepresented in most clinical trials. A total of 270 patients included for analysis. There were ten (10/101) and six (6/101) patients with grade 3+ non-hematological and hematological adverse events. The 1−/3−/5-year OS rates of the surgery group were 72.9%/51.8%/48.3%, compared with 90.1%/66.4%/48.6% for the chemo group (log-rank test: P = 0.018). For stage III patients, the 1−/3−/5-year OS rates of the surgery group were 83.7%/40.7%/28.7%, compared with 89.9%/61.2%/43.6% for the chemo group (log-rank test: P = 0.015). Adjuvant chemotherapy was significantly associated with higher OS (HR = 0.568, 95%CI: 0.357–0.903, P = 0.017) and DFS (HR = 0.511, 95%CI: 0.322–0.811, P = 0.004) in stage III patients. CTC > 0 had no significant impact on the benefits of adjuvant chemotherapy on OS and DFS. These findings suggested that adjuvant chemotherapy significantly improves OS and DFS for elderly patients with stage III GC after D2 laparoscopic gastrectomy, with a tolerable adverse event profile.
Supplementary Information
Additional file 1: Supplementary Figure S1. Subgroup survival analysis for stage II patients in the chemotherapy group.
Additional file 2; Supplementary Figure S2. Subgroup survival analysis for stage III patients in the chemotherapy group.
Additional file 3: Supplementary Figure S3. Subgroup survival analysis in patients who had been tested for circulating tumor cells (CTCs) (A, C), and for those with positive CTCs (B, D).
Abbreviations
GCGastric cancer
OSOverall survival
DFSDisease-free survival
CTCsCirculating tumor cells
PFSProgression-free survival
RCTsRandomized controlled studies
HRHazard ratios
CIConfidence interval
CLASSThe chinese laparoscopic gastrointestinal surgery
AJCCAmerican Joint Committee on Cancer
SDStandard deviations
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yanrui Liang, Liying Zhao and Hao Chen contributed equally to this work.
The authors would like to thank all study participants who were enrolled in this study.
Authors’ contributions
YR L, LY Z and HC carried out the studies, participated in collecting data, and drafted the manuscript. TL, TC, ML Z, YF H and JY performed the statistical analysis and participated in its design. HL and GX L participated in acquisition, analysis, or interpretation of data and draft the manuscript. All authors read and approved the final manuscript.
Funding
The project was supported by grants from the State’s Key Project of Research and Development Plan (2017YFC0108300), the National Natural Science Foundation of China (81672446), the Southern Medical University Clinical Research Start-Up Project (LC2016ZD003), and the Key Clinical Specialty Discipline Construction Program ([2012]121). The funding bodies had no rule in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Availability of data and materials
The datasets used and analysed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Nanfang Hospital. The need for written informed consent was waived due to the retrospective nature of this study.
Consent for publication
Not applicable.
Competing interests
All authors declare no conflict of interest associated with this manuscript. | Oral | DrugAdministrationRoute | CC BY | 33632161 | 18,987,167 | 2021-02-25 |
What was the dosage of drug 'CAPECITABINE'? | Survival analysis of elderly patients over 65 years old with stage II/III gastric cancer treated with adjuvant chemotherapy after laparoscopic D2 gastrectomy: a retrospective cohort study.
BACKGROUND
The benefits of adjuvant chemotherapy for elderly patients with gastric cancer (GC) remain unknown because elderly patients are underrepresented in most clinical trials. This study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy in patients > 65 years of age after laparoscopic D2 gastrectomy.
METHODS
This was a single-center retrospective cohort study of elderly patients (> 65 years) with stage II/III GC who underwent curative laparoscopic D2 gastrectomy with R0 resection between 2004 and 2018. The adjuvant chemotherapy regimens included monotherapy (oral capecitabine) and doublet chemotherapy (oral capecitabine plus intravenous oxaliplatin [XELOX] or intravenous oxaliplatin, leucovorin, and 5-fluorouracil [FOLFOX]). The data were retrieved from a prospectively registered database maintained at the Department of General Surgery in Nanfang Hospital, China. The patients were divided as surgery alone and surgery plus adjuvant chemotherapy (chemo group). The overall survival (OS), disease-free survival (DFS), chemotherapy duration, and toxicity were examined.
RESULTS
There were 270 patients included: 169 and 101 in the surgery and chemo groups, respectively. There were 10 (10/101) and six (6/101) patients with grade 3+ non-hematological and hematological adverse events. The 1-/3-/5-year OS rates of the surgery group were 72.9%/51.8%/48.3%, compared with 90.1%/66.4%/48.6% for the chemo group (log-rank test: P = 0.018). For stage III patients, the 1-/3-/5-year OS rates of the surgery group were 83.7%/40.7%/28.7%, compared with 89.9%/61.2%/43.6% for the chemo group (log-rank test: P = 0.015). Adjuvant chemotherapy was significantly associated with higher OS (HR = 0.568, 95%CI: 0.357-0.903, P = 0.017) and DFS (HR = 0.511, 95%CI: 0.322-0.811, P = 0.004) in stage III patients.
CONCLUSIONS
This study suggested that adjuvant chemotherapy significantly improves OS and DFS compared with surgery alone in elderly patients with stage III GC after D2 laparoscopic gastrectomy, with a tolerable adverse event profile.
Background
Gastric cancer (GC), as the fifth most frequently diagnosed cancer and the third leading cause of cancer death worldwide, was responsible for over 1,000,000 new cases and an estimated 783,000 deaths in 2018 [1]. The markedly elevated incidence rates of GC in Eastern Asia (China, Japan, and Korea) indicate that GC is a significant public health threat, especially to the elderly, since over 60% of the GC diagnoses and 70% of GC-related mortality occur in elderly patients (aged 65 years or older) [2, 3]. As the population continues to age, the proportion of the population aged 60 years and over will increase from 12.4% in 2010 to 28% in 2040 [4]. Longer life expectancy also results in an increasing number of the elderly (aged 65 years or older) undergoing cancer operation and chemotherapy.
The survival benefits from gastrectomy plus chemotherapy have been confirmed in patients with advanced GC [5–7]. In the United States of America, chemoradiotherapy after gastrectomy has been confirmed to improve overall survival (OS) by the INT-0116 trial [8], while the progression-free survival (PFS) and OS benefits of perioperative chemotherapy have been shown by the MAGIC and FLOT4 trials [9, 10]. The adjuvant chemotherapy following D2 gastrectomy is a standard treatment for stage II/III GC in East Asia [11–13]. Although prior randomized controlled studies (RCTs) indicated that postoperative adjuvant treatment in patients who underwent D2 gastrectomy could improve the 5-year disease-free survival (DFS) and OS, the subgroup analyses showed that the survival benefits decreased with increasing age. Furthermore, the ACTS-GC study showed no statistically significant effects of postoperative chemotherapy on DFS and OS for patients older than 70 years (DFS: hazard ratios (HR) = 0.779, 95% confidence interval (CI): 0.527–1.151; OS: HR = 0.706, 95% CI: 0.490–1.017) [11]. Similar results for OS were observed in the CLASSIC study for patients older than 65 (HR = 0.70, 95% CI: 0.4–1.12) [12]. These results might be due to the considerably higher incidence of comorbidities, higher risk of complications, and shorter life expectancy of elderly patients [14]. Nevertheless, when considering those conflicting results, whether to give or not adjuvant chemotherapy to elderly patients with GC after D2 gastrectomy remains a dilemma for physicians. Therefore, the International Society of Geriatric Oncology suggested that specific trials for older patients with cancer should be conducted [15].
Laparoscopic gastrectomy has gained popularity worldwide for its safety and effectiveness [16, 17]. The Chinese Laparoscopic Gastrointestinal Surgery (CLASS) group recently reported the primary endpoints of the CLASS-01 trial, which suggested that laparoscopic distal gastrectomy for advanced gastric cancer was non-inferior to open surgery in terms of 3-year DFS and safety, with significant minimally invasive benefits [18, 19]. A previous study by our group indicated the potential benefits of laparoscopic gastrectomy for elderly patients with resectable GC [20]. Ushimaru et al. [21] reported that laparoscopic gastrectomy might improve the OS by reducing mortality from respiratory diseases. Still, the benefit of adjuvant chemotherapy after laparoscopic D2 gastrectomy in elderly patients is unknown.
As the elderly patients (over 65 years of age) are underrepresented in most RCTs, the present study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy retrospectively in elderly patients (over 65 years of age) after laparoscopic D2 gastrectomy, based on a prospectively registered database in China. Those results could help shed some light on this controversy.
Methods
Study design and patients
This was a retrospective cohort study conducted in the Department of General Surgery of Nanfang Hospital in patients treated between June 2004 and June 2018. This study was approved by the Ethics Committee of Nanfang Hospital. The need for written informed consent was waived due to the retrospective nature of this study.
The inclusion criteria were: 1) over 65 years of age; 2) histologically confirmed stage II or III gastric adenocarcinoma, according to American Joint Committee on Cancer (AJCC, 7th Edition); 3) received curative laparoscopic gastrectomy with D2 nodal dissection at Nanfang Hospital; and 4) at least 15 lymph nodes were available to ensure adequate disease classification. The exclusion criteria were: 1) residual tumors (R1/R2 resections or palliative surgery; 2) death within 1 month after surgery; 3) a previous history of primary or secondary tumor beside the current GC; 4) neoadjuvant chemotherapy or adjuvant radiotherapy; or 5) incomplete medical record .
The enrolled patients were divided into surgery alone group (surgery group) and the surgery plus adjuvant chemotherapy group (chemo group).
Adjuvant chemotherapy protocols
The adjuvant chemotherapy regimens administered during the study period included monotherapy and doublet chemotherapy. The initial dose of each regimen was reduced to 75% of the original value to minimize toxic effects in elderly patients. For monotherapy, the patients received 3-week cycles of oral capecitabine (750 mg/m2 twice daily on days 1 to 14 of each cycle) for 6 months if tolerated. For doublet chemotherapy, the patients received oral capecitabine plus intravenous oxaliplatin (XELOX) or 2-week cycles of intravenous oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX). For the XELOX regimen, patients received 3-week cycles of oral capecitabine (750 mg/m2 twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m2 on day 1 of each cycle) for 6 months if tolerated. The FOLFOX regimen was administered as follows: intravenous (IV) treatment with 63.75 mg/m2 of oxaliplatin, 300 mg/m2 of leucovorin and IV push administration of 300 mg/m2 of fluorouracil on day 1, and 900 mg/m2 of fluorouracil IV by continuous infusion for 24 h on days 1 and 2. This regimen was repeated every 14 days and lasted for 6 months if tolerated. In all regimens, the dose of each drug was reduced to the next lower dose increment in case of grade 4 neutropenia or thrombocytopenia, or grade 3 or above febrile neutropenia.
Data collection
The data were retrieved from a prospectively registered database maintained at the Department of General Surgery in Nanfang Hospital, China. The database includes patient characteristics (age at diagnosis, sex, etc.), clinical variables (postoperative stay, circulating tumor cells [CTCs] collected at postoperative two weeks, etc.), pathological features (tumor size, histological grade, etc.), chemotherapy (regimen, duration, cycles of chemotherapy, and grade 3 or above toxicity events), and follow-up. All data are routinely updated after each routine follow-up visit, either at the outpatient clinic or by phone. For the present study, the last follow-up data were collected on May 30th, 2018.
Outcomes
The observation outcomes of this study were OS and DFS. The OS was calculated from the date of operation to either the date of death or the date of the last follow-up visit. The DFS was calculated from the date of resection to the date of the first recurrence detected, or the last follow-up visit. Recurrence was determined as the appearance of any new lesion either locally, regionally, or distant. All grade 3 or above hematological and non-hematological toxicity events were recorded. Toxicities were graded according to the National Cancer Institute common toxicity criteria version 3.0 [22].
Statistical analysis
All statistical analyses were performed using SPSS 24.0 (IBM Corp., Armonk, NY, USA). Continuous variables were tested for normal distribution using the Kolmogorov-Smirnov test. Those with a normal distribution were expressed as means ± standard deviations (SD) and were analyzed using Student’s t-test; otherwise, they were presented as medians (ranges) and analyzed using the Mann-Whitney U-test. Categorical variables were reported as numbers with percentages and analyzed using the chi-square test with the Yates correction or Fisher’s exact test, as appropriate. The OS and DFS rates were compared between the surgery and chemo groups using unadjusted Kaplan-Meier curves and the log-rank test. The OS and DFS rates of different clinicopathological characteristics and different chemotherapy regimen were compared. HR and 95% CI were used to estimate the role of each independent predictor of survival. The Cox regression model was used for univariable and multivariable analyses. We adjusted for the following variables: treatment regimens (with adjuvant chemotherapy or not), age of diagnosis, time of surgery, sex, ECOG score, Charlson score, tumor location, retrieved lymph node, hospital stays, AJCC stage, histologic grade, lymphatic, blood vessel or perineural invasion, tumor size, and CTC counts. Variables with P < 0.1 in the univariable analysis were included in the multivariable analysis. The level of significance was set at a two-tailed P-value of 0.05.
Results
Patient characteristics
At first, 298 patients were eligible, but 28 were excluded because of the presence of residual tumors (R1/R2 resections and palliative surgery), death within 1 month of surgery, primary or secondary tumor history, neoadjuvant chemotherapy, adjuvant radiotherapy, or incomplete medical record. The remaining 270 patients were included in the analysis; 169 and 101 were classified in the surgery and chemo groups, respectively (Fig. 1).
Fig. 1 Patient flowchart
Table 1 presents the characteristics of the patients. The median age in the surgery and chemo groups was 70 years (69–75 years) and 69 years (66–72 years), respectively (P = 0.001). The male-to-female ratio was 2.1:1 in the surgery group and 3.2:1 in the chemo group (P = 0.152). Most patients in the two groups had an ECOG score and a Charlson comorbidity score of < 1 (ECOG: 88.2 and 89.1%; Charlson score: 94.7 and 96.0%; all P > 0.05). The number of CTCs in the surgery group was 5 (2–16), while 4 (1–7) in the chemo group (P = 0.328). In the surgery group, there were 56 patients with AJCC stage II and 113 with AJCC stage III, while in the chemo group, there were 25 patients with AJCC stage II and 76 with AJCC stage III (P = 0.147). In the chemo group, six patients received monotherapy, and 95 patients received platinum-based doublet chemotherapy therapy; 57 patients received adjuvant chemotherapy for less than 3 months, while 44 patients received 3–6 months of adjuvant chemotherapy. The median follow-up in the surgery and chemo groups was 25 (IQR 13–44) months, and 22 (IQR 11–54.5) months, respectively (P = 0.452).
Table 1 Baseline information of patients
Characteristics Surgery N = 169 Chemotherapy N = 101 p
Clinical characteristics
Age at diagnosis (years), median (IQR) 70 (67–75) 69 (66–72) 0.001
65–70, n (%) 92 (54.4) 64 (63.4) 0.152
> 70, n (%) 77 (45.6) 40 (39.6)
Time of surgery, n (%) 0.684
2005–2014 81 (47.9) 51 (50.5)
2015–2018 88 (52.1) 50 (49.5)
Sex, n (%) 0.152
Male 115 (68.0) 77 (76.2)
Female 54 (32.0) 24 (23.8)
ECOG score 0.281
0 78 (46.2) 54 (63.5)
1 71 (42.0) 36 (35.6)
2 14 (8.3) 9 (8.9)
2+ 6 (3.5) 2 (2.0)
Charlson score 0.711
0 128 (75.7) 74 (73.3)
1 32 (18.9) 23 (22.8)
2 8 (4.8) 3 (2.9)
2+ 1 (0.6) 1 (1.0)
Tumour location 0.524
Gastroesophageal junction 58 (34.3) 39 (38.6)
Antrum 88 (52.1) 49 (48.5)
Other 23 (13.6) 13 (12.9)
Hospital stays (days), median (IQR) 11 (8–16) 10.0 (8–15) 0.328
CTC (number), median (IQR) 5 (2–16) 4 (1–7) 0.270
Pathological characteristics
TMN stage, n (%) 0.147
II 56 (33.1) 25 (24.8)
III 113 (66.9) 76 (75.2)
T stage, n (%) 0.286
T1–2 13 (7.7) 5 (5.0)
T3 35 (20.7) 18 (17.8)
T4 121 (71.6) 78 (77.2)
N stage, n (%) 0.285
N0 45 (26.6) 17 (16.8)
N1 18 (10.7) 17 (16.8)
N2 44 (26.0) 26 (25.8)
N3 62 (36.7) 41 (40.6)
Retrieved lymph nodes (number), median (IQR) 40 (25–55.5) 38 (24–54) 0.516
Grade, n (%) 0.051
Well or moderately differentiated 123 (72.8) 84 (83.2)
Poorly differentiated or undifferentiated 46 (27.2) 17 (16.8)
Lymphatic, blood vessel or perineural invasion, n (%) 100 (59.2) 62 (61.4) 0.720
Tumour size (cm), mean ± SD 4.0 (3.0–5.5) 4.5 (3.2–6.0) 0.121
≤ 5 cm 104 (61.5) 51 (50.5) 0.076
> 5 cm 65 (38.5) 50 (49.5)
Drug delivery and toxicities
Adjuvant chemotherapy regimen
Mono chemotherapy 6 (5.9)
Doublet chemotherapy 95 (94.1)
Length of adjuvant chemotherapy
< 3 months 57 (56.4)
3–6 months 44 (43.6)
Toxicities (grade 3 or more)
Monotherapy 1 (1.0)
Non-hematological adverse events 1 (1.0)
Hematological adverse events 0
Double therapy 15 (14.9)
Non-hematological adverse events 9 (8.9)
Hematological adverse events 6 (5.9)
IQR interquartile range, ECOG Eastern Cooperative Oncology Group, CTC circulating tumor cells
Factors associated with OS and DFS in all patients
The univariable and multivariable Cox proportional hazards models for all patients are shown in Table 2. In the multivariable analysis, age > 70 years (HR = 1.640, 95% CI: 1.119–2.403, P = 0.011) and stage III GC (HR = 2.738, 95% CI: 1.677–4.471, P < 0.001) were independently associated with OS. Surgery plus adjuvant chemotherapy (HR = 0.511, 95% CI: 0.322–0.811, P = 0.004), surgery performed in 2015–2018 (HR = 0.586, 95% CI: 0.376–0.912, P = 0.018), and stage III GC (HR = 2.345, 95% CI: 1.466–3.751, P < 0.001) were independently associated with DFS. Therefore, stage III GC was independently associated with both OS and DFS.
Table 2 Association factors of OS and DFS in the total patients
Overall survival Disease-free survival
Univariable analysis Multivariable analysis Univariable analysis Multivariable analysis
Factors HR (95% CI) p HR (95% CI) p HR (95% CI) p HR (95% CI) p
Treatment
Surgery alone 1 (Reference) – 1 (Reference) – 1 (Reference) –
Surgery/adjuvant chemotherapy 0.733 (0.486–1.106) 0.139 0.673 (0.447–1.012) 0.057 0.511 (0.322–0.811) 0.004
Age of diagnosis
65–70 years 1 (Reference) – 1 (Reference) – 1 (Reference) –
> 70 years 1.560 (1.021–2.385) 0.028 1.640 (1.119–2.403) 0.011 1.422 (0.978–2.067) 0.065
Time of surgery
2004–2014 1 (Reference) – 1 (Reference) – 1 (Reference) –
2015–2018 0.967 (0.632–1.478) 0.876 0.713 (0.475–1.069) 0.102 0.586 (0.376–0.912) 0.018
Sex
Male 1 (Reference) – 1 (Reference) –
Female 0.903 (0.589–1.383) 0.638 0.895 (0.588–1.361) 0.603
ECOG score
0 1 (Reference) – 1 (Reference) –
1 1.325 (0.879–1.996) 0.179 1.468 (0.982–2.194) 0.062
2 1.006 (0.504–2.008) 0.987 1.105 (0.554–2.202) 0.777
2+ 2.016 (0.797–5.100) 0.139 2.017 (0.798–5.097) 0.138
Charlson score
0 1 (Reference) – 1 (Reference) –
1 1.029 (0.631–1.679) 0.909 1.068 (0.661–1.724) 0.788
2 0.992 (0.363–2.710) 0.988 1.182 (0.479–2.961) 0.716
2+ 1.135 (0.158–8.174) 0.900 1.368 (0.190–9.852) 0.756
Tumor location
Gastroesophageal junction 1 (Reference) – 1 (Reference) –
Antrum 1.304 (0.841–2.023) 0.236 1.321 (0.861–2.027) 0.203
Other 1.511 (0.832–2.724) 0.175 1.497 (0.840–2.670) 0.171
Retrieved lymph node 1.002 (0.9931.011) 0.656 0.999 (0.990–1.008) 0.841
Hospital stays 1.003 (0.983–1.023) 0.793 1.006 (0.987–1.025) 0.550
AJCC stage
II 1 (Reference) – 1 (Reference) – 1 (Reference) – 1 (Reference) –
III 2.626 (1.610–4.284) < 0.001 2.738 (1.677–4.471) < 0.001 2.345 (1.466–3.751) < 0.001 2.345 (1.466–3.751) < 0.001
Histologic Grade
Well or moderately differentiated 1 (Reference) – 1 (Reference) –
Poorly differentiated or undifferentiated 1.293 (0.809–2.068) 0.283 1.247 (0.788–1.975) 0.346
Lymphatic, blood vessel or perineural invasion
Yes 1 (Reference) – 1 (Reference) –
No 0.857 (0.581–1.7266 0.439 0.740 (0.505–1.083) 0.121
Tumor size
≤ 5 cm 1 (Reference) – 1 (Reference) 1 (Reference) –
> 5 cm 1.610 (1.099–2.356) 0.014 1.356 (0.921–1.996) 0.123 1.440 (0.991–2.091) 0.560
CTC 0.937 (0.802–1.096) 0.416 1.007 (0.924–1.088) 0.866
HR hazards ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, AJCC American Joint Cancer Committee, CTC circulating tumor cells
We adjusted for the following variables: treatment regimens (with adjuvant chemotherapy or not), age of diagnosis, time of surgery, sex, ECOG score, Charlson score, tumor location, retrieved lymph node, hospital stays, AJCC stage, histologic grade, lymphatic, blood vessel or perineural invasion, tumor size, and CTC counts
Overall survival
Unadjusted Kaplan-Meier survival curves were constructed for all patients in the two groups. The 1-, 3-, and 5-year OS rates of the surgery group were 72.9, 51.8, and 48.3%, compared with 90.1, 66.4, and 48.6% for the chemo group, respectively (HR = 0.61, 95% CI: 0.42–0.92, P = 0.135) (Fig. 2a). In the stage II cohort, the 1-, 3-, and 5-year OS rates of the surgery group were 96.3, 80.4, and 72.7%, compared with 90.5, 73.8, and 50.9% for the chemo group, respectively (HR = 1.26, 95% CI: 0.483–3.29, P = 0.637) (Fig. 2b). For stage III patients, the 1-, 3-, and 5-year OS rates of the surgery group were 83.7, 40.7, and 28.7%, compared with 89.9, 61.2, and 43.6% for the chemo group, respectively (HR = 0.58, 95% CI: 0.38–0.90, P = 0.016) (Fig. 2c).
Fig. 2 Survival curves for overall survival (OS) and disease-free survival (DFS) in all the patients a, d, stage II patients b, e, and stage III patients c, f
Disease-free survival
The 1-, 3-, and 5-year DFS rates of the surgery group were 72.9, 51.8, and 48.4%, compared with 81.3, 65.1, and 53.6% for the chemo group, respectively (HR = 0.682, 95% CI: 0.463–1.005, P = 0.053) (Fig. 2d). In the stage II cohort, the 1-, 3-, and 5-year DFS rates of the surgery group were 85.3, 78.5, and 74.2%, compared with 91.8, 64.4, and 64.4% for the chemo group, respectively (HR = 1.02, 95% CI: 0.416–2.54, P = 0.950 (Fig. 2e). In stage III patients, the 1-, 3-, and 5-year DFS rates of the surgery group were 66.5, 37.7, and 34.8%, compared with 77.9, 60.0, and 49.0% for the chemo group, respectively (HR = 0.55, 95% CI: 0.36–0.83, P = 0.007) (Fig. 2f). The OS and DFS in the stage III subgroup were significantly different between the surgery and Chemo groups.
Subgroup survival analysis in stage III patients
The univariable and multivariable Cox proportional hazards models in stage III patients are shown in Table 3. Surgery plus adjuvant chemotherapy (HR = 0.568, 95% CI: 0.357–0.903, P = 0.017) and age > 70 years (HR = 1.573, 95% CI: 1.029–2.405, P = 0.036) were independently associated with OS. Surgery plus adjuvant chemotherapy (HR = 0.511, 95% CI: 0.322–0.811, P = 0.004) and surgery performed in 2015–2018, HR = 0.586, 95% CI: 0.376–0.912, P = 0.018) were independently associated with DFS.
Table 3 Association factors of OS and DFS in stage III patients
Overall survival Disease-free survival
Univariable analysis Multivariable analysis Univariable analysis Multivariable analysis
Factors HR (95% CI) p HR (95% CI) p HR (95% CI) p HR (95% CI) p
Treatment
Surgery alone 1 (Reference) – 1 (Reference) – 1 (Reference) – 1 (Reference) –
Surgery/adjuvant chemotherapy 0.572 (0.360–0.910) 0.018 0.568 (0.357–0.903) 0.017 0.542 (0.342–0.859) 0.009 0.511 (0.322–0.811) 0.004
Age of diagnosis
65–70 years 1 (Reference) – 1 (Reference) – 1 (Reference) –
> 70 years 1.560 (1.021–2.385) 0.040 1.573 (1.029–2.405) 0.036 1.409 (0.926–1.943) 0.109
Time of surgery
2004–2014 1 (Reference) – 1 (Reference) – 1 (Reference) –
2015–2018 0.895 (0.565–1.417) 0.636 0.630 (0.405–0.980) 0.041 0.586 (0.376–0.912) 0.018
Sex
Male 1 (Reference) – 1 (Reference) –
Female 0.987 (0.609–1.602) 0.959 0.957 (0.591–1.55) 0.860
ECOG score
0 1 (Reference) – 1 (Reference) –
1 1.345 (0.848–2.132) 0.207 – – 1.493 (0.948–2.351) 0.083
2 1.201 (0.576–2.507) 0.625 1.335 (0.643–2.773) 0.438
2+ 2.810 (1.098–7.188) 0.031 2.715 (1.061–6.950) 0.037
Charlson score
0 1 (Reference) – 1 (Reference) –
1 1.038 (0.609–1.771) 0.890 1.119 (0.664–1.885) 0.674
2 1.000 (0.364–2.749) 0.999 1.186 (0.477–2.946) 0.713
2+ – –
Tumor location
Gastroesophageal junction 1 (Reference) – 1 (Reference) –
Antrum 1.347 (0.838–2.166) 0.219 1.368 (0.858–2.183) 0.188
Other 1.862 (0.917–3.780) 0.086 1.521 (0.753–3.073) 0.242
Retrieved lymph node 1.001 (0.991–1.010) 0.853 0.999 (0.989–1.009) 0.782
Hospital stays 1.001 (0.980–1.023) 0.905 1.005 (0.986–1.025) 0.600
T stage
T1–2 1 (Reference) – 1 (Reference) –
T3 0.596 (0.130–2.729) 0.505 0.464 (0.103–2.098) 0.318
T4 0.722 (0.176–2.958) 0.651 0.576 (0.141–2.358) 0.443
N stage
N0 1 (Reference) – 1 (Reference) –
N1 0.223 (0.040–1.231) 0.085 0.234 (0.042–1.288) 0.095
N2 0.517 (0.121–2.207) 0.373 0.555 (0.131–2.357) 0.425
N3 1.071 (0.261–4.398) 0.924 1.065 (0.259–4.375) 0.930
Histologic Grade
Well or moderately differentiated 1 (Reference) – 1 (Reference) –
Poorly differentiated or undifferentiated 1.035 (0.609–1.759) 0.899 1.043 (0.615–1.769) 0.877
Lymphatic, blood vessel or perineural invasion
Yes 1 (Reference) – 1 (Reference) –
No 0.899 (0.581–1.389) 0.631 0.741 (0.484–1.134) 0.167
Tumor size
≤ 5 cm 1 (Reference) – 1 (Reference) –
> 5 cm 1.209 (0.793–1.843) 0.377 1.147 (0.756–1.738) 0.519
HR hazards ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, AJCC American Joint Cancer Committee
We adjusted for the following variables: treatment regimens (with adjuvant chemotherapy or not), age of diagnosis, time of surgery, sex, ECOG score, Charlson score, tumor location, retrieved lymph node, hospital stays, T stage, N stage, histologic grade, lymphatic, blood vessel or perineural invasion, and tumor size
Chemotherapy regimens, duration, and toxicity
In stage III patients, the platinum-based doublet chemotherapy led to better OS and DFS compared with monotherapy (OS: P = 0.037; DFS: P = 0.013) (Supplementary Fig. S2 A, C), but the differences were not statistically significant in stage II patients (P = 0.473 and P = 0.499) (Supplementary Fig. S1A, C). No significant differences in OS and DFS were observed in relation to chemotherapy duration (all P > 0.05) (Supplementary Fig. S1 B,D; Supplementary Fig. S2 B, D). There were 10 patients with grade 3 or above non-hematological toxicity adverse events, and six with grade 3 hematological toxicity adverse events (neutropenia) (Table 1).
Analysis in patients with available CTC data
Forty-three patients had a CTC count before surgery, and 40 of them were positive. There were no significant differences in OS and DFS between the surgery and chemo groups among CTC-tested patients (Supplementary Fig. S3 A, C) and CTC-positive patients (all P > 0.05) (Supplementary Fig. S3 B,D).
Discussion
The benefits of adjuvant chemotherapy for elderly patients (age over 65) with GC remain unknown because the elderly patients are underrepresented in most clinical trials [15]. Therefore this study aimed to evaluate the effectiveness and complications of adjuvant chemotherapy in elderly patients (over 65 years of age) after laparoscopic D2 gastrectomy. The results strongly suggest that adjuvant chemotherapy improves the OS and DFS of elderly patients with stage III GC operated using D2 laparoscopic gastrectomy compared with surgery alone.
Previously, there were a few single-center retrospective studies that focused on adjuvant chemotherapy for elderly patients after gastrectomy [23, 24]. Still, those previous studies might not represent the current status of advanced GC treatment since laparoscopic D2 gastrectomy became popular relatively recently [18]. In the present study, only elderly gastric patients who underwent laparoscopic D2 gastrectomy were included. Among them, 41% received adjuvant chemotherapy in the 65–70 age group and only 33% in the > 70 age group. This finding is similar to other cancers [25, 26]. This may be due to two reasons. First, there is no solid evidence to prove the efficacy of adjuvant chemotherapy in elderly patients with GC. Second, with a high comorbidity rate, older patients may prefer not to undergo chemotherapy treatment in their relatively limited lifetime [27].
Chemotherapy toxicity is another concern of the elderly who just underwent surgery. In the CLASSIC study, 56% of the patients who received the fluoropyrimidine-platinum chemotherapy regimen experienced grade 3–4 adverse events [12]. In the ACTS-GC study, 22.8% of patients with mono-chemotherapy experienced grade 3–4 adverse events [11]. In the present study, 95 (94.0%) patients in the chemo group received platinum-based doublet chemotherapy, including XELOX and FOLFOX, and 15 (15.6%) patients suffered from grade 3–4 adverse events. In the monotherapy group, one patient suffered from grade 3–4 non-hematological adverse events. The adverse event rate in our cohort is similar to a retrospective study from Korea [24]. Low rates of grade 3–4 adverse events may be due to the low Charlson comorbidity score in the present study since the patients were required to be able to tolerate laparoscopic D2 gastrectomy. The result indicates that adjuvant chemotherapy is tolerable in elderly patients who were suitable for gastrectomy. Still, it is possible that the adverse events were underestimated or not measured strictly in this retrospective study.
In the present study, adjuvant chemotherapy could significantly improve the OS in stage III elderly patients. Jin et al. [23] revealed an OS benefit (P = 0.003) of adjuvant chemotherapy in elderly patients in a single-center retrospective study. A single-center retrospective study of elderly patients with GC (over 70 years) in Korea reported a DFS benefit (P = 0.03) after adjuvant chemotherapy, but without an OS benefit (P = 0.242, 24]. Nevertheless, by analyzing elderly patients with resected GC in the SEER-Medicare database, Hoffman et al. [28] reported that elderly patients might not gain a survival benefit from adjuvant chemotherapy, but most cases in this database underwent D0 or D1 gastrectomy. Up to now, no standard adjuvant chemotherapy regimens were established for the elderly. Some reports suggest that patients might benefit from adjuvant chemotherapy, no matter which chemotherapy regimen is used [29]. The CLASSIC study indicated that the fluoropyrimidine and oxaliplatin combination reduced both locoregional and distant recurrences, but had a smaller effect on peritoneal recurrences [12]. Kim et al. [30] reported that there were no significant improvements in OS and RFS when using longer treatments of fluoropyrimidine-based adjuvant chemotherapy in patients with stage II or III GC. Similar results were also observed in stage III colon cancer with 3 vs. 6 months of XELOX [31]. On the other hand, Feng et al. [32] reported that additional oral capecitabine for 6 months after eight cycles of XELOX improved the DFS and OS for stage IIIA GC. Still, those previous studies were not focused on elderly patients with GC. Elderly patients may prefer to undergo fewer treatments or treatments with fewer adverse effects in their relatively limited lifetime [27].
There are several limitations to this study. First, this study was based on retrospective data, with inherent shortcomings. For example, immortal time bias in the adjuvant group could not be completely avoided in a retrospective study. Secondly, it was a single center study, and it is unknown whether the results are valid externally. In addition, this was a strictly selected group of patients, excluding those with previous cancers, R1/2 resections and post-operative death. Consequently, the survival rates in both groups might not reflect real-world data. Finally, differences between the < 65 and ≥ 65 year-old groups were not assessed. Further prospective studies are needed to address those issues.
Conclusions
In this retrospective, single-institution study, the OS and DFS benefited from adjuvant chemotherapy in elderly patients with stage III GC after D2 laparoscopic gastrectomy. Well-designed prospective studies are needed to confirm these findings. Elderly patients are highly variable in their functional status and comorbidities. Thus, cofactors regarding the functional, social, and mental status should also be considered. Further studies are needed to identify the elderly who can tolerate and benefit from adjuvant chemotherapy.
Contribution to the field statement
The benefits of adjuvant chemotherapy for elderly patients (age > 65) with gastric cancer (GC) remain unknown because elderly patients are underrepresented in most clinical trials. A total of 270 patients included for analysis. There were ten (10/101) and six (6/101) patients with grade 3+ non-hematological and hematological adverse events. The 1−/3−/5-year OS rates of the surgery group were 72.9%/51.8%/48.3%, compared with 90.1%/66.4%/48.6% for the chemo group (log-rank test: P = 0.018). For stage III patients, the 1−/3−/5-year OS rates of the surgery group were 83.7%/40.7%/28.7%, compared with 89.9%/61.2%/43.6% for the chemo group (log-rank test: P = 0.015). Adjuvant chemotherapy was significantly associated with higher OS (HR = 0.568, 95%CI: 0.357–0.903, P = 0.017) and DFS (HR = 0.511, 95%CI: 0.322–0.811, P = 0.004) in stage III patients. CTC > 0 had no significant impact on the benefits of adjuvant chemotherapy on OS and DFS. These findings suggested that adjuvant chemotherapy significantly improves OS and DFS for elderly patients with stage III GC after D2 laparoscopic gastrectomy, with a tolerable adverse event profile.
Supplementary Information
Additional file 1: Supplementary Figure S1. Subgroup survival analysis for stage II patients in the chemotherapy group.
Additional file 2; Supplementary Figure S2. Subgroup survival analysis for stage III patients in the chemotherapy group.
Additional file 3: Supplementary Figure S3. Subgroup survival analysis in patients who had been tested for circulating tumor cells (CTCs) (A, C), and for those with positive CTCs (B, D).
Abbreviations
GCGastric cancer
OSOverall survival
DFSDisease-free survival
CTCsCirculating tumor cells
PFSProgression-free survival
RCTsRandomized controlled studies
HRHazard ratios
CIConfidence interval
CLASSThe chinese laparoscopic gastrointestinal surgery
AJCCAmerican Joint Committee on Cancer
SDStandard deviations
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yanrui Liang, Liying Zhao and Hao Chen contributed equally to this work.
The authors would like to thank all study participants who were enrolled in this study.
Authors’ contributions
YR L, LY Z and HC carried out the studies, participated in collecting data, and drafted the manuscript. TL, TC, ML Z, YF H and JY performed the statistical analysis and participated in its design. HL and GX L participated in acquisition, analysis, or interpretation of data and draft the manuscript. All authors read and approved the final manuscript.
Funding
The project was supported by grants from the State’s Key Project of Research and Development Plan (2017YFC0108300), the National Natural Science Foundation of China (81672446), the Southern Medical University Clinical Research Start-Up Project (LC2016ZD003), and the Key Clinical Specialty Discipline Construction Program ([2012]121). The funding bodies had no rule in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Availability of data and materials
The datasets used and analysed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Nanfang Hospital. The need for written informed consent was waived due to the retrospective nature of this study.
Consent for publication
Not applicable.
Competing interests
All authors declare no conflict of interest associated with this manuscript. | TWICE DAILY ON DAYS 1 TO 14 OF EACH CYCLE | DrugDosageText | CC BY | 33632161 | 18,987,167 | 2021-02-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Keratitis fungal'. | Keratitis by Scopulariopsis brevicaulis Fungus After LASIK - A Case Report.
To describe a rare case of an interface filamentous fungal keratitis and its successful clinical approach and management.
Retrospective case report. Analysis of the patient's clinical records.
A healthy 30-year-old woman presenting with complaints of blurred vision, photophobia and intense pain, was previously diagnosed with a suspected unilateral diffuse lamellar keratitis after laser in situ keratomileusis surgery, and accordingly treated with a scheme of oral and subconjunctival corticosteroids. Due to worsening of symptoms, the patient was later referred to our ophthalmology department. Upon examination, a corneal infiltration was observed and a fungal infection was suspected. Treatment with fortified Voriconazole (1%) was initiated and both topical and oral corticosteroids were tapered. The infiltrate resolved after 6 weeks of antifungal topical treatment. Scopulariopsis brevicaulis was isolated on culture media. At the end of follow-up, the uncorrected distance visual acuity was 20/20 with mild scarring.
Scopulariopsis brevicaulis can be associated with post-laser in situ keratomileusis interface infection. A quick intervention may dictate a good outcome, when combining early suspicion and microbiological diagnosis, and an appropriate conservative management. Furthermore, Voriconazole seems to be effective and safe in the treatment of such cases.
Introduction
Laser in situ keratomileusis (LASIK) is an effective and safe procedure applied to correct low to moderate ametropia, commonly used worldwide. Despite being very rare, any infection after the procedure, mainly those related to flap interface, can be a sight-threatening complication in previously otherwise healthy eyes, in young individuals.1
Over time, the main cause of non-viral infectious keratitis after LASIK has changed from the atypical Mycobacterium to gram-positive organisms, particularly Methicillin-resistant Staphylococcus aureus (MRSA). Additionally, the postoperative intensive steroid use increases host susceptibility to opportunistic agents, including fungi.2 Only a few cases3–6 of Scopulariopsis spp. fungal keratitis have been reported in the literature, with only one case describing infection after laser refractive surgery.
In this report, we present a rare case of post-LASIK interface filamentous fungal keratitis and its successful clinical management.
Patients and Methods
Retrospective case-report. Data were collected from the patient’s clinical records.
Results
A healthy 30-year-old woman underwent uncomplicated bilateral LASIK surgery for myopia at a private medical center (day 1). In the postoperative period, she was medicated with topical ofloxacin 5id (Floxedol®), dexamethasone phosphate 5id (Ronic®) and artificial tears.
Two weeks after surgery (day 14), the patient presented complaints of blurred vision, photophobia and intense pain on her left eye (LE). As diffuse lamellar keratitis (DLK) diagnosis was postulated, in addition to the previously established medication, oral prednisolone (Lepicortinolo®) 60mg/day was initiated and two injections of subconjunctival triamcinolone (Kenalog A-40®) were applied in two consecutive days (day 15 and 16). Despite only mild clinical improvement, a third subconjunctival injection of triamcinolone was applied to the patient (day 18) and a flap lift was proposed.
Due to worsening of symptoms and clinical deterioration, seven days after the third subconjunctival corticosteroid injection, the patient came to our department, seeking second medical opinion (day 25). A complete medical history was then carried out, highlighting close contact to cereal seeds for a short period of time, when cooking, and jogging in a natural park, 4 and 10 days after surgery, respectively. Uncorrected distance visual acuity (UDVA) of the LE was 20/100. Slit-lamp examination revealed diffuse corneal edema, a central and irregular white nodular infiltrate with corneal ulceration and the presence of numerous inflammatory cells on the flap’s interface [Figure 1] [e-Figures 1–3]. As infectious etiology (namely fungal or acanthamoeba) was suspected, corneal scrapings were taken from the ulcer and the treatment scheme was altered to fortified voriconazole (1%) drops applied hourly and moxifloxacin (Vigamox®) drops 5id. Dexamethasone phosphate drops were tapered by one drop per day and oral prednisolone was tapered from 60mg/day, by steps of 20mg, every 3 days. The flap lift approach was postponed.Figure 1 Slit-lamp examination, day 25.
After three days (day 28), clinical improvement was perceived [e-Figures 4 and 5] and the treatment plan was maintained. Continued gradual progress was observed in the following days (day 33), with a visual recovery to 20/40 [e-Figure 6]. One week later (day 40), after oral and topical corticosteroid withdrawal, improvement was sustained, with a residual mild to moderate central double-ring shaped opacity with defined edges [e-Figures 7 and 8]. The morphologic analysis of the cultural media from the initial ulcer scraping by an experienced microbiologist revealed the presence of Scopulariopsis brevicaulis fungus. The fungus was sensible to Voriconazole. After confirmation of the suspected diagnosis, moxifloxacin was suspended, and only topical Voriconazole 1% 5id was maintained.
After 50 days of treatment (day 75), the corneal infiltrate had resolved with mild scarring and the topical fortified voriconazole was stopped. There were no side effects reported from medication. More than one year after the infection, the patient maintains a mild density leucoma, with 20/20 of UCVA [Figure 2].Figure 2 (A) Slit-lamp examination, one year and a half after the infection; (B) anterior segment OCT, one year and a half after the infection.
Discussion
The authors present a very rare case of unilateral fungal infection by Scopulariopsis brevicaulis. As these species are soil saprophytes,7 the authors hypothesize that the contact with cereal seeds and jogging activity in the park, 4 and 10 days after the surgery, respectively, might have played a role as risk factors; however, intraoperative contamination from adjacent structures like the conjunctiva, eyelids and eyelashes, or even from surgical gloves, operative drapes and room air during the procedure should not be neglected.8 Additionally, the risk can be increased by other factors, such as an epithelial break after LASIK, allowing the penetration of pathogens,9 or the long-term use of steroids, decreasing the host immune response. Moreover, these pathogens are usually associated to mild onychomycosis in humans,7 so a possible source of infection could be the hands of both healthcare professionals or the patient.
Only few cases3–6 of Scopulariopsis spp. keratitis have been reported, of which only one case described after laser refractive surgery. In the present case, hypopyon was never observed and the infection was initially misdiagnosed as a DLK, justified by the presence of a pattern of diffuse inflammatory infiltrates, rather than satellite lesions. Thus, the initial treatment with a large dose of local corticosteroids, could have allowed the fungus to spread, as reported in the literature.10
The rapid progression and the difficulties in the treatment of corneal fungal infections make a timely microbiological workup, including sensitivity tests, of utmost importance when post-LASIK infection is suspected; however, it is crucial to be aware of the time-consuming cultural exams and its high rate of false negative results, which may contribute to a challenging diagnosis and delayed directed treatment. A careful clinical biomicroscopic examination is helpful towards reaching a diagnosis and the subsequent decision of antifungal treatment. In this case, considering the initial suspicion of a possible fungal etiology, broad spectrum fortified topical antifungal agent was promptly initiated and corticotherapy was tapered, in order to decrease the risk of rebound inflammation due to complete withdrawal.
Flap lifting for culturing and irrigation with directed antimicrobial solution is recommended by the American Society of Cataract and Refractive Surgery.11 In this case, the central infiltrate almost occupying the complete flap thickness and its communication with the corneal ulcer raised the risk of flap break during surgical lift, with subsequent amputation and its severe visual function implications. Therefore, a conservative approach with close monitoring was preferred, and ulcer scraps were collected for culture.
In fact, usually, fungal keratitis requires long-term administration of antifungal treatment and the possibility of clinical relapse, even after complete clinical improvement, should not be neglected. In this case, we experienced a good and fast clinical response based on topical, fortified Voriconazole, which was maintained for fifty days. Plus, more than one year after antifungal discontinuation and without chemoprophylaxis, the patient did not present any sign of relapse and conserved a very good visual function after the keratorefractive procedure.
The strengths of the present case-report are the rarity of the etiological agent and the good clinical response and outcome to medical treatment, without the need for a more invasive intervention, such as flap lifting. The main limitation is the absence of photographic data from ophthalmological examination before the first evaluation in our department.
Conclusions
Despite being an extremely rare complication, post-LASIK fungal keratitis is a severe complication that can lead to poor visual outcomes. This report shows that despite the initial difficulty in the differential diagnosis with DLK, an early diagnostic suspicion, combined with early microbiological diagnosis and appropriate conservative management can result in good clinical outcomes. Furthermore, voriconazole seems to be effective and safe to treat such cases.
Acknowledgments
We want to express our gratitude to the chief of the Ophthalmology department from the Centro Hospitalar e Universitário do Porto, Prof. Dr. Pedro Menéres, for his vision and enthusiasm with new technologies and resources to improve the ophthalmic care of the population.
Data Sharing Statement
The data used in the current study are available from the corresponding author on reasonable request. The abstract of this paper was presented at the European Society of Cataract and Refractive Surgeons as a poster presentation with interim findings.
Ethics Approval and Consent to Participate
The ethics committee of the Centro Hospitalar e Universitário do Porto approved the study (nr. 2020.167 (130-DEFI/132-CE)). Consent to participate was signed by the patient.
Consent for Publication
Consent to publish the case report with anonymized data, including images, was signed by the patient.
Disclosure
The authors report no conflicts of interest in this work. | DEXAMETHASONE SODIUM PHOSPHATE, PREDNISOLONE, TRIAMCINOLONE | DrugsGivenReaction | CC BY-NC | 33633469 | 19,950,282 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Scopulariopsis infection'. | Keratitis by Scopulariopsis brevicaulis Fungus After LASIK - A Case Report.
To describe a rare case of an interface filamentous fungal keratitis and its successful clinical approach and management.
Retrospective case report. Analysis of the patient's clinical records.
A healthy 30-year-old woman presenting with complaints of blurred vision, photophobia and intense pain, was previously diagnosed with a suspected unilateral diffuse lamellar keratitis after laser in situ keratomileusis surgery, and accordingly treated with a scheme of oral and subconjunctival corticosteroids. Due to worsening of symptoms, the patient was later referred to our ophthalmology department. Upon examination, a corneal infiltration was observed and a fungal infection was suspected. Treatment with fortified Voriconazole (1%) was initiated and both topical and oral corticosteroids were tapered. The infiltrate resolved after 6 weeks of antifungal topical treatment. Scopulariopsis brevicaulis was isolated on culture media. At the end of follow-up, the uncorrected distance visual acuity was 20/20 with mild scarring.
Scopulariopsis brevicaulis can be associated with post-laser in situ keratomileusis interface infection. A quick intervention may dictate a good outcome, when combining early suspicion and microbiological diagnosis, and an appropriate conservative management. Furthermore, Voriconazole seems to be effective and safe in the treatment of such cases.
Introduction
Laser in situ keratomileusis (LASIK) is an effective and safe procedure applied to correct low to moderate ametropia, commonly used worldwide. Despite being very rare, any infection after the procedure, mainly those related to flap interface, can be a sight-threatening complication in previously otherwise healthy eyes, in young individuals.1
Over time, the main cause of non-viral infectious keratitis after LASIK has changed from the atypical Mycobacterium to gram-positive organisms, particularly Methicillin-resistant Staphylococcus aureus (MRSA). Additionally, the postoperative intensive steroid use increases host susceptibility to opportunistic agents, including fungi.2 Only a few cases3–6 of Scopulariopsis spp. fungal keratitis have been reported in the literature, with only one case describing infection after laser refractive surgery.
In this report, we present a rare case of post-LASIK interface filamentous fungal keratitis and its successful clinical management.
Patients and Methods
Retrospective case-report. Data were collected from the patient’s clinical records.
Results
A healthy 30-year-old woman underwent uncomplicated bilateral LASIK surgery for myopia at a private medical center (day 1). In the postoperative period, she was medicated with topical ofloxacin 5id (Floxedol®), dexamethasone phosphate 5id (Ronic®) and artificial tears.
Two weeks after surgery (day 14), the patient presented complaints of blurred vision, photophobia and intense pain on her left eye (LE). As diffuse lamellar keratitis (DLK) diagnosis was postulated, in addition to the previously established medication, oral prednisolone (Lepicortinolo®) 60mg/day was initiated and two injections of subconjunctival triamcinolone (Kenalog A-40®) were applied in two consecutive days (day 15 and 16). Despite only mild clinical improvement, a third subconjunctival injection of triamcinolone was applied to the patient (day 18) and a flap lift was proposed.
Due to worsening of symptoms and clinical deterioration, seven days after the third subconjunctival corticosteroid injection, the patient came to our department, seeking second medical opinion (day 25). A complete medical history was then carried out, highlighting close contact to cereal seeds for a short period of time, when cooking, and jogging in a natural park, 4 and 10 days after surgery, respectively. Uncorrected distance visual acuity (UDVA) of the LE was 20/100. Slit-lamp examination revealed diffuse corneal edema, a central and irregular white nodular infiltrate with corneal ulceration and the presence of numerous inflammatory cells on the flap’s interface [Figure 1] [e-Figures 1–3]. As infectious etiology (namely fungal or acanthamoeba) was suspected, corneal scrapings were taken from the ulcer and the treatment scheme was altered to fortified voriconazole (1%) drops applied hourly and moxifloxacin (Vigamox®) drops 5id. Dexamethasone phosphate drops were tapered by one drop per day and oral prednisolone was tapered from 60mg/day, by steps of 20mg, every 3 days. The flap lift approach was postponed.Figure 1 Slit-lamp examination, day 25.
After three days (day 28), clinical improvement was perceived [e-Figures 4 and 5] and the treatment plan was maintained. Continued gradual progress was observed in the following days (day 33), with a visual recovery to 20/40 [e-Figure 6]. One week later (day 40), after oral and topical corticosteroid withdrawal, improvement was sustained, with a residual mild to moderate central double-ring shaped opacity with defined edges [e-Figures 7 and 8]. The morphologic analysis of the cultural media from the initial ulcer scraping by an experienced microbiologist revealed the presence of Scopulariopsis brevicaulis fungus. The fungus was sensible to Voriconazole. After confirmation of the suspected diagnosis, moxifloxacin was suspended, and only topical Voriconazole 1% 5id was maintained.
After 50 days of treatment (day 75), the corneal infiltrate had resolved with mild scarring and the topical fortified voriconazole was stopped. There were no side effects reported from medication. More than one year after the infection, the patient maintains a mild density leucoma, with 20/20 of UCVA [Figure 2].Figure 2 (A) Slit-lamp examination, one year and a half after the infection; (B) anterior segment OCT, one year and a half after the infection.
Discussion
The authors present a very rare case of unilateral fungal infection by Scopulariopsis brevicaulis. As these species are soil saprophytes,7 the authors hypothesize that the contact with cereal seeds and jogging activity in the park, 4 and 10 days after the surgery, respectively, might have played a role as risk factors; however, intraoperative contamination from adjacent structures like the conjunctiva, eyelids and eyelashes, or even from surgical gloves, operative drapes and room air during the procedure should not be neglected.8 Additionally, the risk can be increased by other factors, such as an epithelial break after LASIK, allowing the penetration of pathogens,9 or the long-term use of steroids, decreasing the host immune response. Moreover, these pathogens are usually associated to mild onychomycosis in humans,7 so a possible source of infection could be the hands of both healthcare professionals or the patient.
Only few cases3–6 of Scopulariopsis spp. keratitis have been reported, of which only one case described after laser refractive surgery. In the present case, hypopyon was never observed and the infection was initially misdiagnosed as a DLK, justified by the presence of a pattern of diffuse inflammatory infiltrates, rather than satellite lesions. Thus, the initial treatment with a large dose of local corticosteroids, could have allowed the fungus to spread, as reported in the literature.10
The rapid progression and the difficulties in the treatment of corneal fungal infections make a timely microbiological workup, including sensitivity tests, of utmost importance when post-LASIK infection is suspected; however, it is crucial to be aware of the time-consuming cultural exams and its high rate of false negative results, which may contribute to a challenging diagnosis and delayed directed treatment. A careful clinical biomicroscopic examination is helpful towards reaching a diagnosis and the subsequent decision of antifungal treatment. In this case, considering the initial suspicion of a possible fungal etiology, broad spectrum fortified topical antifungal agent was promptly initiated and corticotherapy was tapered, in order to decrease the risk of rebound inflammation due to complete withdrawal.
Flap lifting for culturing and irrigation with directed antimicrobial solution is recommended by the American Society of Cataract and Refractive Surgery.11 In this case, the central infiltrate almost occupying the complete flap thickness and its communication with the corneal ulcer raised the risk of flap break during surgical lift, with subsequent amputation and its severe visual function implications. Therefore, a conservative approach with close monitoring was preferred, and ulcer scraps were collected for culture.
In fact, usually, fungal keratitis requires long-term administration of antifungal treatment and the possibility of clinical relapse, even after complete clinical improvement, should not be neglected. In this case, we experienced a good and fast clinical response based on topical, fortified Voriconazole, which was maintained for fifty days. Plus, more than one year after antifungal discontinuation and without chemoprophylaxis, the patient did not present any sign of relapse and conserved a very good visual function after the keratorefractive procedure.
The strengths of the present case-report are the rarity of the etiological agent and the good clinical response and outcome to medical treatment, without the need for a more invasive intervention, such as flap lifting. The main limitation is the absence of photographic data from ophthalmological examination before the first evaluation in our department.
Conclusions
Despite being an extremely rare complication, post-LASIK fungal keratitis is a severe complication that can lead to poor visual outcomes. This report shows that despite the initial difficulty in the differential diagnosis with DLK, an early diagnostic suspicion, combined with early microbiological diagnosis and appropriate conservative management can result in good clinical outcomes. Furthermore, voriconazole seems to be effective and safe to treat such cases.
Acknowledgments
We want to express our gratitude to the chief of the Ophthalmology department from the Centro Hospitalar e Universitário do Porto, Prof. Dr. Pedro Menéres, for his vision and enthusiasm with new technologies and resources to improve the ophthalmic care of the population.
Data Sharing Statement
The data used in the current study are available from the corresponding author on reasonable request. The abstract of this paper was presented at the European Society of Cataract and Refractive Surgeons as a poster presentation with interim findings.
Ethics Approval and Consent to Participate
The ethics committee of the Centro Hospitalar e Universitário do Porto approved the study (nr. 2020.167 (130-DEFI/132-CE)). Consent to participate was signed by the patient.
Consent for Publication
Consent to publish the case report with anonymized data, including images, was signed by the patient.
Disclosure
The authors report no conflicts of interest in this work. | DEXAMETHASONE SODIUM PHOSPHATE, PREDNISOLONE, TRIAMCINOLONE | DrugsGivenReaction | CC BY-NC | 33633469 | 19,950,282 | 2021 |
What was the administration route of drug 'PREDNISOLONE'? | Keratitis by Scopulariopsis brevicaulis Fungus After LASIK - A Case Report.
To describe a rare case of an interface filamentous fungal keratitis and its successful clinical approach and management.
Retrospective case report. Analysis of the patient's clinical records.
A healthy 30-year-old woman presenting with complaints of blurred vision, photophobia and intense pain, was previously diagnosed with a suspected unilateral diffuse lamellar keratitis after laser in situ keratomileusis surgery, and accordingly treated with a scheme of oral and subconjunctival corticosteroids. Due to worsening of symptoms, the patient was later referred to our ophthalmology department. Upon examination, a corneal infiltration was observed and a fungal infection was suspected. Treatment with fortified Voriconazole (1%) was initiated and both topical and oral corticosteroids were tapered. The infiltrate resolved after 6 weeks of antifungal topical treatment. Scopulariopsis brevicaulis was isolated on culture media. At the end of follow-up, the uncorrected distance visual acuity was 20/20 with mild scarring.
Scopulariopsis brevicaulis can be associated with post-laser in situ keratomileusis interface infection. A quick intervention may dictate a good outcome, when combining early suspicion and microbiological diagnosis, and an appropriate conservative management. Furthermore, Voriconazole seems to be effective and safe in the treatment of such cases.
Introduction
Laser in situ keratomileusis (LASIK) is an effective and safe procedure applied to correct low to moderate ametropia, commonly used worldwide. Despite being very rare, any infection after the procedure, mainly those related to flap interface, can be a sight-threatening complication in previously otherwise healthy eyes, in young individuals.1
Over time, the main cause of non-viral infectious keratitis after LASIK has changed from the atypical Mycobacterium to gram-positive organisms, particularly Methicillin-resistant Staphylococcus aureus (MRSA). Additionally, the postoperative intensive steroid use increases host susceptibility to opportunistic agents, including fungi.2 Only a few cases3–6 of Scopulariopsis spp. fungal keratitis have been reported in the literature, with only one case describing infection after laser refractive surgery.
In this report, we present a rare case of post-LASIK interface filamentous fungal keratitis and its successful clinical management.
Patients and Methods
Retrospective case-report. Data were collected from the patient’s clinical records.
Results
A healthy 30-year-old woman underwent uncomplicated bilateral LASIK surgery for myopia at a private medical center (day 1). In the postoperative period, she was medicated with topical ofloxacin 5id (Floxedol®), dexamethasone phosphate 5id (Ronic®) and artificial tears.
Two weeks after surgery (day 14), the patient presented complaints of blurred vision, photophobia and intense pain on her left eye (LE). As diffuse lamellar keratitis (DLK) diagnosis was postulated, in addition to the previously established medication, oral prednisolone (Lepicortinolo®) 60mg/day was initiated and two injections of subconjunctival triamcinolone (Kenalog A-40®) were applied in two consecutive days (day 15 and 16). Despite only mild clinical improvement, a third subconjunctival injection of triamcinolone was applied to the patient (day 18) and a flap lift was proposed.
Due to worsening of symptoms and clinical deterioration, seven days after the third subconjunctival corticosteroid injection, the patient came to our department, seeking second medical opinion (day 25). A complete medical history was then carried out, highlighting close contact to cereal seeds for a short period of time, when cooking, and jogging in a natural park, 4 and 10 days after surgery, respectively. Uncorrected distance visual acuity (UDVA) of the LE was 20/100. Slit-lamp examination revealed diffuse corneal edema, a central and irregular white nodular infiltrate with corneal ulceration and the presence of numerous inflammatory cells on the flap’s interface [Figure 1] [e-Figures 1–3]. As infectious etiology (namely fungal or acanthamoeba) was suspected, corneal scrapings were taken from the ulcer and the treatment scheme was altered to fortified voriconazole (1%) drops applied hourly and moxifloxacin (Vigamox®) drops 5id. Dexamethasone phosphate drops were tapered by one drop per day and oral prednisolone was tapered from 60mg/day, by steps of 20mg, every 3 days. The flap lift approach was postponed.Figure 1 Slit-lamp examination, day 25.
After three days (day 28), clinical improvement was perceived [e-Figures 4 and 5] and the treatment plan was maintained. Continued gradual progress was observed in the following days (day 33), with a visual recovery to 20/40 [e-Figure 6]. One week later (day 40), after oral and topical corticosteroid withdrawal, improvement was sustained, with a residual mild to moderate central double-ring shaped opacity with defined edges [e-Figures 7 and 8]. The morphologic analysis of the cultural media from the initial ulcer scraping by an experienced microbiologist revealed the presence of Scopulariopsis brevicaulis fungus. The fungus was sensible to Voriconazole. After confirmation of the suspected diagnosis, moxifloxacin was suspended, and only topical Voriconazole 1% 5id was maintained.
After 50 days of treatment (day 75), the corneal infiltrate had resolved with mild scarring and the topical fortified voriconazole was stopped. There were no side effects reported from medication. More than one year after the infection, the patient maintains a mild density leucoma, with 20/20 of UCVA [Figure 2].Figure 2 (A) Slit-lamp examination, one year and a half after the infection; (B) anterior segment OCT, one year and a half after the infection.
Discussion
The authors present a very rare case of unilateral fungal infection by Scopulariopsis brevicaulis. As these species are soil saprophytes,7 the authors hypothesize that the contact with cereal seeds and jogging activity in the park, 4 and 10 days after the surgery, respectively, might have played a role as risk factors; however, intraoperative contamination from adjacent structures like the conjunctiva, eyelids and eyelashes, or even from surgical gloves, operative drapes and room air during the procedure should not be neglected.8 Additionally, the risk can be increased by other factors, such as an epithelial break after LASIK, allowing the penetration of pathogens,9 or the long-term use of steroids, decreasing the host immune response. Moreover, these pathogens are usually associated to mild onychomycosis in humans,7 so a possible source of infection could be the hands of both healthcare professionals or the patient.
Only few cases3–6 of Scopulariopsis spp. keratitis have been reported, of which only one case described after laser refractive surgery. In the present case, hypopyon was never observed and the infection was initially misdiagnosed as a DLK, justified by the presence of a pattern of diffuse inflammatory infiltrates, rather than satellite lesions. Thus, the initial treatment with a large dose of local corticosteroids, could have allowed the fungus to spread, as reported in the literature.10
The rapid progression and the difficulties in the treatment of corneal fungal infections make a timely microbiological workup, including sensitivity tests, of utmost importance when post-LASIK infection is suspected; however, it is crucial to be aware of the time-consuming cultural exams and its high rate of false negative results, which may contribute to a challenging diagnosis and delayed directed treatment. A careful clinical biomicroscopic examination is helpful towards reaching a diagnosis and the subsequent decision of antifungal treatment. In this case, considering the initial suspicion of a possible fungal etiology, broad spectrum fortified topical antifungal agent was promptly initiated and corticotherapy was tapered, in order to decrease the risk of rebound inflammation due to complete withdrawal.
Flap lifting for culturing and irrigation with directed antimicrobial solution is recommended by the American Society of Cataract and Refractive Surgery.11 In this case, the central infiltrate almost occupying the complete flap thickness and its communication with the corneal ulcer raised the risk of flap break during surgical lift, with subsequent amputation and its severe visual function implications. Therefore, a conservative approach with close monitoring was preferred, and ulcer scraps were collected for culture.
In fact, usually, fungal keratitis requires long-term administration of antifungal treatment and the possibility of clinical relapse, even after complete clinical improvement, should not be neglected. In this case, we experienced a good and fast clinical response based on topical, fortified Voriconazole, which was maintained for fifty days. Plus, more than one year after antifungal discontinuation and without chemoprophylaxis, the patient did not present any sign of relapse and conserved a very good visual function after the keratorefractive procedure.
The strengths of the present case-report are the rarity of the etiological agent and the good clinical response and outcome to medical treatment, without the need for a more invasive intervention, such as flap lifting. The main limitation is the absence of photographic data from ophthalmological examination before the first evaluation in our department.
Conclusions
Despite being an extremely rare complication, post-LASIK fungal keratitis is a severe complication that can lead to poor visual outcomes. This report shows that despite the initial difficulty in the differential diagnosis with DLK, an early diagnostic suspicion, combined with early microbiological diagnosis and appropriate conservative management can result in good clinical outcomes. Furthermore, voriconazole seems to be effective and safe to treat such cases.
Acknowledgments
We want to express our gratitude to the chief of the Ophthalmology department from the Centro Hospitalar e Universitário do Porto, Prof. Dr. Pedro Menéres, for his vision and enthusiasm with new technologies and resources to improve the ophthalmic care of the population.
Data Sharing Statement
The data used in the current study are available from the corresponding author on reasonable request. The abstract of this paper was presented at the European Society of Cataract and Refractive Surgeons as a poster presentation with interim findings.
Ethics Approval and Consent to Participate
The ethics committee of the Centro Hospitalar e Universitário do Porto approved the study (nr. 2020.167 (130-DEFI/132-CE)). Consent to participate was signed by the patient.
Consent for Publication
Consent to publish the case report with anonymized data, including images, was signed by the patient.
Disclosure
The authors report no conflicts of interest in this work. | Oral | DrugAdministrationRoute | CC BY-NC | 33633469 | 19,950,282 | 2021 |
What was the administration route of drug 'TRIAMCINOLONE'? | Keratitis by Scopulariopsis brevicaulis Fungus After LASIK - A Case Report.
To describe a rare case of an interface filamentous fungal keratitis and its successful clinical approach and management.
Retrospective case report. Analysis of the patient's clinical records.
A healthy 30-year-old woman presenting with complaints of blurred vision, photophobia and intense pain, was previously diagnosed with a suspected unilateral diffuse lamellar keratitis after laser in situ keratomileusis surgery, and accordingly treated with a scheme of oral and subconjunctival corticosteroids. Due to worsening of symptoms, the patient was later referred to our ophthalmology department. Upon examination, a corneal infiltration was observed and a fungal infection was suspected. Treatment with fortified Voriconazole (1%) was initiated and both topical and oral corticosteroids were tapered. The infiltrate resolved after 6 weeks of antifungal topical treatment. Scopulariopsis brevicaulis was isolated on culture media. At the end of follow-up, the uncorrected distance visual acuity was 20/20 with mild scarring.
Scopulariopsis brevicaulis can be associated with post-laser in situ keratomileusis interface infection. A quick intervention may dictate a good outcome, when combining early suspicion and microbiological diagnosis, and an appropriate conservative management. Furthermore, Voriconazole seems to be effective and safe in the treatment of such cases.
Introduction
Laser in situ keratomileusis (LASIK) is an effective and safe procedure applied to correct low to moderate ametropia, commonly used worldwide. Despite being very rare, any infection after the procedure, mainly those related to flap interface, can be a sight-threatening complication in previously otherwise healthy eyes, in young individuals.1
Over time, the main cause of non-viral infectious keratitis after LASIK has changed from the atypical Mycobacterium to gram-positive organisms, particularly Methicillin-resistant Staphylococcus aureus (MRSA). Additionally, the postoperative intensive steroid use increases host susceptibility to opportunistic agents, including fungi.2 Only a few cases3–6 of Scopulariopsis spp. fungal keratitis have been reported in the literature, with only one case describing infection after laser refractive surgery.
In this report, we present a rare case of post-LASIK interface filamentous fungal keratitis and its successful clinical management.
Patients and Methods
Retrospective case-report. Data were collected from the patient’s clinical records.
Results
A healthy 30-year-old woman underwent uncomplicated bilateral LASIK surgery for myopia at a private medical center (day 1). In the postoperative period, she was medicated with topical ofloxacin 5id (Floxedol®), dexamethasone phosphate 5id (Ronic®) and artificial tears.
Two weeks after surgery (day 14), the patient presented complaints of blurred vision, photophobia and intense pain on her left eye (LE). As diffuse lamellar keratitis (DLK) diagnosis was postulated, in addition to the previously established medication, oral prednisolone (Lepicortinolo®) 60mg/day was initiated and two injections of subconjunctival triamcinolone (Kenalog A-40®) were applied in two consecutive days (day 15 and 16). Despite only mild clinical improvement, a third subconjunctival injection of triamcinolone was applied to the patient (day 18) and a flap lift was proposed.
Due to worsening of symptoms and clinical deterioration, seven days after the third subconjunctival corticosteroid injection, the patient came to our department, seeking second medical opinion (day 25). A complete medical history was then carried out, highlighting close contact to cereal seeds for a short period of time, when cooking, and jogging in a natural park, 4 and 10 days after surgery, respectively. Uncorrected distance visual acuity (UDVA) of the LE was 20/100. Slit-lamp examination revealed diffuse corneal edema, a central and irregular white nodular infiltrate with corneal ulceration and the presence of numerous inflammatory cells on the flap’s interface [Figure 1] [e-Figures 1–3]. As infectious etiology (namely fungal or acanthamoeba) was suspected, corneal scrapings were taken from the ulcer and the treatment scheme was altered to fortified voriconazole (1%) drops applied hourly and moxifloxacin (Vigamox®) drops 5id. Dexamethasone phosphate drops were tapered by one drop per day and oral prednisolone was tapered from 60mg/day, by steps of 20mg, every 3 days. The flap lift approach was postponed.Figure 1 Slit-lamp examination, day 25.
After three days (day 28), clinical improvement was perceived [e-Figures 4 and 5] and the treatment plan was maintained. Continued gradual progress was observed in the following days (day 33), with a visual recovery to 20/40 [e-Figure 6]. One week later (day 40), after oral and topical corticosteroid withdrawal, improvement was sustained, with a residual mild to moderate central double-ring shaped opacity with defined edges [e-Figures 7 and 8]. The morphologic analysis of the cultural media from the initial ulcer scraping by an experienced microbiologist revealed the presence of Scopulariopsis brevicaulis fungus. The fungus was sensible to Voriconazole. After confirmation of the suspected diagnosis, moxifloxacin was suspended, and only topical Voriconazole 1% 5id was maintained.
After 50 days of treatment (day 75), the corneal infiltrate had resolved with mild scarring and the topical fortified voriconazole was stopped. There were no side effects reported from medication. More than one year after the infection, the patient maintains a mild density leucoma, with 20/20 of UCVA [Figure 2].Figure 2 (A) Slit-lamp examination, one year and a half after the infection; (B) anterior segment OCT, one year and a half after the infection.
Discussion
The authors present a very rare case of unilateral fungal infection by Scopulariopsis brevicaulis. As these species are soil saprophytes,7 the authors hypothesize that the contact with cereal seeds and jogging activity in the park, 4 and 10 days after the surgery, respectively, might have played a role as risk factors; however, intraoperative contamination from adjacent structures like the conjunctiva, eyelids and eyelashes, or even from surgical gloves, operative drapes and room air during the procedure should not be neglected.8 Additionally, the risk can be increased by other factors, such as an epithelial break after LASIK, allowing the penetration of pathogens,9 or the long-term use of steroids, decreasing the host immune response. Moreover, these pathogens are usually associated to mild onychomycosis in humans,7 so a possible source of infection could be the hands of both healthcare professionals or the patient.
Only few cases3–6 of Scopulariopsis spp. keratitis have been reported, of which only one case described after laser refractive surgery. In the present case, hypopyon was never observed and the infection was initially misdiagnosed as a DLK, justified by the presence of a pattern of diffuse inflammatory infiltrates, rather than satellite lesions. Thus, the initial treatment with a large dose of local corticosteroids, could have allowed the fungus to spread, as reported in the literature.10
The rapid progression and the difficulties in the treatment of corneal fungal infections make a timely microbiological workup, including sensitivity tests, of utmost importance when post-LASIK infection is suspected; however, it is crucial to be aware of the time-consuming cultural exams and its high rate of false negative results, which may contribute to a challenging diagnosis and delayed directed treatment. A careful clinical biomicroscopic examination is helpful towards reaching a diagnosis and the subsequent decision of antifungal treatment. In this case, considering the initial suspicion of a possible fungal etiology, broad spectrum fortified topical antifungal agent was promptly initiated and corticotherapy was tapered, in order to decrease the risk of rebound inflammation due to complete withdrawal.
Flap lifting for culturing and irrigation with directed antimicrobial solution is recommended by the American Society of Cataract and Refractive Surgery.11 In this case, the central infiltrate almost occupying the complete flap thickness and its communication with the corneal ulcer raised the risk of flap break during surgical lift, with subsequent amputation and its severe visual function implications. Therefore, a conservative approach with close monitoring was preferred, and ulcer scraps were collected for culture.
In fact, usually, fungal keratitis requires long-term administration of antifungal treatment and the possibility of clinical relapse, even after complete clinical improvement, should not be neglected. In this case, we experienced a good and fast clinical response based on topical, fortified Voriconazole, which was maintained for fifty days. Plus, more than one year after antifungal discontinuation and without chemoprophylaxis, the patient did not present any sign of relapse and conserved a very good visual function after the keratorefractive procedure.
The strengths of the present case-report are the rarity of the etiological agent and the good clinical response and outcome to medical treatment, without the need for a more invasive intervention, such as flap lifting. The main limitation is the absence of photographic data from ophthalmological examination before the first evaluation in our department.
Conclusions
Despite being an extremely rare complication, post-LASIK fungal keratitis is a severe complication that can lead to poor visual outcomes. This report shows that despite the initial difficulty in the differential diagnosis with DLK, an early diagnostic suspicion, combined with early microbiological diagnosis and appropriate conservative management can result in good clinical outcomes. Furthermore, voriconazole seems to be effective and safe to treat such cases.
Acknowledgments
We want to express our gratitude to the chief of the Ophthalmology department from the Centro Hospitalar e Universitário do Porto, Prof. Dr. Pedro Menéres, for his vision and enthusiasm with new technologies and resources to improve the ophthalmic care of the population.
Data Sharing Statement
The data used in the current study are available from the corresponding author on reasonable request. The abstract of this paper was presented at the European Society of Cataract and Refractive Surgeons as a poster presentation with interim findings.
Ethics Approval and Consent to Participate
The ethics committee of the Centro Hospitalar e Universitário do Porto approved the study (nr. 2020.167 (130-DEFI/132-CE)). Consent to participate was signed by the patient.
Consent for Publication
Consent to publish the case report with anonymized data, including images, was signed by the patient.
Disclosure
The authors report no conflicts of interest in this work. | Sunconjunctival | DrugAdministrationRoute | CC BY-NC | 33633469 | 19,950,282 | 2021 |
What was the dosage of drug 'TRIAMCINOLONE'? | Keratitis by Scopulariopsis brevicaulis Fungus After LASIK - A Case Report.
To describe a rare case of an interface filamentous fungal keratitis and its successful clinical approach and management.
Retrospective case report. Analysis of the patient's clinical records.
A healthy 30-year-old woman presenting with complaints of blurred vision, photophobia and intense pain, was previously diagnosed with a suspected unilateral diffuse lamellar keratitis after laser in situ keratomileusis surgery, and accordingly treated with a scheme of oral and subconjunctival corticosteroids. Due to worsening of symptoms, the patient was later referred to our ophthalmology department. Upon examination, a corneal infiltration was observed and a fungal infection was suspected. Treatment with fortified Voriconazole (1%) was initiated and both topical and oral corticosteroids were tapered. The infiltrate resolved after 6 weeks of antifungal topical treatment. Scopulariopsis brevicaulis was isolated on culture media. At the end of follow-up, the uncorrected distance visual acuity was 20/20 with mild scarring.
Scopulariopsis brevicaulis can be associated with post-laser in situ keratomileusis interface infection. A quick intervention may dictate a good outcome, when combining early suspicion and microbiological diagnosis, and an appropriate conservative management. Furthermore, Voriconazole seems to be effective and safe in the treatment of such cases.
Introduction
Laser in situ keratomileusis (LASIK) is an effective and safe procedure applied to correct low to moderate ametropia, commonly used worldwide. Despite being very rare, any infection after the procedure, mainly those related to flap interface, can be a sight-threatening complication in previously otherwise healthy eyes, in young individuals.1
Over time, the main cause of non-viral infectious keratitis after LASIK has changed from the atypical Mycobacterium to gram-positive organisms, particularly Methicillin-resistant Staphylococcus aureus (MRSA). Additionally, the postoperative intensive steroid use increases host susceptibility to opportunistic agents, including fungi.2 Only a few cases3–6 of Scopulariopsis spp. fungal keratitis have been reported in the literature, with only one case describing infection after laser refractive surgery.
In this report, we present a rare case of post-LASIK interface filamentous fungal keratitis and its successful clinical management.
Patients and Methods
Retrospective case-report. Data were collected from the patient’s clinical records.
Results
A healthy 30-year-old woman underwent uncomplicated bilateral LASIK surgery for myopia at a private medical center (day 1). In the postoperative period, she was medicated with topical ofloxacin 5id (Floxedol®), dexamethasone phosphate 5id (Ronic®) and artificial tears.
Two weeks after surgery (day 14), the patient presented complaints of blurred vision, photophobia and intense pain on her left eye (LE). As diffuse lamellar keratitis (DLK) diagnosis was postulated, in addition to the previously established medication, oral prednisolone (Lepicortinolo®) 60mg/day was initiated and two injections of subconjunctival triamcinolone (Kenalog A-40®) were applied in two consecutive days (day 15 and 16). Despite only mild clinical improvement, a third subconjunctival injection of triamcinolone was applied to the patient (day 18) and a flap lift was proposed.
Due to worsening of symptoms and clinical deterioration, seven days after the third subconjunctival corticosteroid injection, the patient came to our department, seeking second medical opinion (day 25). A complete medical history was then carried out, highlighting close contact to cereal seeds for a short period of time, when cooking, and jogging in a natural park, 4 and 10 days after surgery, respectively. Uncorrected distance visual acuity (UDVA) of the LE was 20/100. Slit-lamp examination revealed diffuse corneal edema, a central and irregular white nodular infiltrate with corneal ulceration and the presence of numerous inflammatory cells on the flap’s interface [Figure 1] [e-Figures 1–3]. As infectious etiology (namely fungal or acanthamoeba) was suspected, corneal scrapings were taken from the ulcer and the treatment scheme was altered to fortified voriconazole (1%) drops applied hourly and moxifloxacin (Vigamox®) drops 5id. Dexamethasone phosphate drops were tapered by one drop per day and oral prednisolone was tapered from 60mg/day, by steps of 20mg, every 3 days. The flap lift approach was postponed.Figure 1 Slit-lamp examination, day 25.
After three days (day 28), clinical improvement was perceived [e-Figures 4 and 5] and the treatment plan was maintained. Continued gradual progress was observed in the following days (day 33), with a visual recovery to 20/40 [e-Figure 6]. One week later (day 40), after oral and topical corticosteroid withdrawal, improvement was sustained, with a residual mild to moderate central double-ring shaped opacity with defined edges [e-Figures 7 and 8]. The morphologic analysis of the cultural media from the initial ulcer scraping by an experienced microbiologist revealed the presence of Scopulariopsis brevicaulis fungus. The fungus was sensible to Voriconazole. After confirmation of the suspected diagnosis, moxifloxacin was suspended, and only topical Voriconazole 1% 5id was maintained.
After 50 days of treatment (day 75), the corneal infiltrate had resolved with mild scarring and the topical fortified voriconazole was stopped. There were no side effects reported from medication. More than one year after the infection, the patient maintains a mild density leucoma, with 20/20 of UCVA [Figure 2].Figure 2 (A) Slit-lamp examination, one year and a half after the infection; (B) anterior segment OCT, one year and a half after the infection.
Discussion
The authors present a very rare case of unilateral fungal infection by Scopulariopsis brevicaulis. As these species are soil saprophytes,7 the authors hypothesize that the contact with cereal seeds and jogging activity in the park, 4 and 10 days after the surgery, respectively, might have played a role as risk factors; however, intraoperative contamination from adjacent structures like the conjunctiva, eyelids and eyelashes, or even from surgical gloves, operative drapes and room air during the procedure should not be neglected.8 Additionally, the risk can be increased by other factors, such as an epithelial break after LASIK, allowing the penetration of pathogens,9 or the long-term use of steroids, decreasing the host immune response. Moreover, these pathogens are usually associated to mild onychomycosis in humans,7 so a possible source of infection could be the hands of both healthcare professionals or the patient.
Only few cases3–6 of Scopulariopsis spp. keratitis have been reported, of which only one case described after laser refractive surgery. In the present case, hypopyon was never observed and the infection was initially misdiagnosed as a DLK, justified by the presence of a pattern of diffuse inflammatory infiltrates, rather than satellite lesions. Thus, the initial treatment with a large dose of local corticosteroids, could have allowed the fungus to spread, as reported in the literature.10
The rapid progression and the difficulties in the treatment of corneal fungal infections make a timely microbiological workup, including sensitivity tests, of utmost importance when post-LASIK infection is suspected; however, it is crucial to be aware of the time-consuming cultural exams and its high rate of false negative results, which may contribute to a challenging diagnosis and delayed directed treatment. A careful clinical biomicroscopic examination is helpful towards reaching a diagnosis and the subsequent decision of antifungal treatment. In this case, considering the initial suspicion of a possible fungal etiology, broad spectrum fortified topical antifungal agent was promptly initiated and corticotherapy was tapered, in order to decrease the risk of rebound inflammation due to complete withdrawal.
Flap lifting for culturing and irrigation with directed antimicrobial solution is recommended by the American Society of Cataract and Refractive Surgery.11 In this case, the central infiltrate almost occupying the complete flap thickness and its communication with the corneal ulcer raised the risk of flap break during surgical lift, with subsequent amputation and its severe visual function implications. Therefore, a conservative approach with close monitoring was preferred, and ulcer scraps were collected for culture.
In fact, usually, fungal keratitis requires long-term administration of antifungal treatment and the possibility of clinical relapse, even after complete clinical improvement, should not be neglected. In this case, we experienced a good and fast clinical response based on topical, fortified Voriconazole, which was maintained for fifty days. Plus, more than one year after antifungal discontinuation and without chemoprophylaxis, the patient did not present any sign of relapse and conserved a very good visual function after the keratorefractive procedure.
The strengths of the present case-report are the rarity of the etiological agent and the good clinical response and outcome to medical treatment, without the need for a more invasive intervention, such as flap lifting. The main limitation is the absence of photographic data from ophthalmological examination before the first evaluation in our department.
Conclusions
Despite being an extremely rare complication, post-LASIK fungal keratitis is a severe complication that can lead to poor visual outcomes. This report shows that despite the initial difficulty in the differential diagnosis with DLK, an early diagnostic suspicion, combined with early microbiological diagnosis and appropriate conservative management can result in good clinical outcomes. Furthermore, voriconazole seems to be effective and safe to treat such cases.
Acknowledgments
We want to express our gratitude to the chief of the Ophthalmology department from the Centro Hospitalar e Universitário do Porto, Prof. Dr. Pedro Menéres, for his vision and enthusiasm with new technologies and resources to improve the ophthalmic care of the population.
Data Sharing Statement
The data used in the current study are available from the corresponding author on reasonable request. The abstract of this paper was presented at the European Society of Cataract and Refractive Surgeons as a poster presentation with interim findings.
Ethics Approval and Consent to Participate
The ethics committee of the Centro Hospitalar e Universitário do Porto approved the study (nr. 2020.167 (130-DEFI/132-CE)). Consent to participate was signed by the patient.
Consent for Publication
Consent to publish the case report with anonymized data, including images, was signed by the patient.
Disclosure
The authors report no conflicts of interest in this work. | TWO INJECTIONS WERE ADMINISTERED ON TWO CONSECUTIVE DAYS (DAY 15 AND 16) AND THIRD INJECTION WAS ADM | DrugDosageText | CC BY-NC | 33633469 | 19,950,282 | 2021 |
What was the outcome of reaction 'Keratitis fungal'? | Keratitis by Scopulariopsis brevicaulis Fungus After LASIK - A Case Report.
To describe a rare case of an interface filamentous fungal keratitis and its successful clinical approach and management.
Retrospective case report. Analysis of the patient's clinical records.
A healthy 30-year-old woman presenting with complaints of blurred vision, photophobia and intense pain, was previously diagnosed with a suspected unilateral diffuse lamellar keratitis after laser in situ keratomileusis surgery, and accordingly treated with a scheme of oral and subconjunctival corticosteroids. Due to worsening of symptoms, the patient was later referred to our ophthalmology department. Upon examination, a corneal infiltration was observed and a fungal infection was suspected. Treatment with fortified Voriconazole (1%) was initiated and both topical and oral corticosteroids were tapered. The infiltrate resolved after 6 weeks of antifungal topical treatment. Scopulariopsis brevicaulis was isolated on culture media. At the end of follow-up, the uncorrected distance visual acuity was 20/20 with mild scarring.
Scopulariopsis brevicaulis can be associated with post-laser in situ keratomileusis interface infection. A quick intervention may dictate a good outcome, when combining early suspicion and microbiological diagnosis, and an appropriate conservative management. Furthermore, Voriconazole seems to be effective and safe in the treatment of such cases.
Introduction
Laser in situ keratomileusis (LASIK) is an effective and safe procedure applied to correct low to moderate ametropia, commonly used worldwide. Despite being very rare, any infection after the procedure, mainly those related to flap interface, can be a sight-threatening complication in previously otherwise healthy eyes, in young individuals.1
Over time, the main cause of non-viral infectious keratitis after LASIK has changed from the atypical Mycobacterium to gram-positive organisms, particularly Methicillin-resistant Staphylococcus aureus (MRSA). Additionally, the postoperative intensive steroid use increases host susceptibility to opportunistic agents, including fungi.2 Only a few cases3–6 of Scopulariopsis spp. fungal keratitis have been reported in the literature, with only one case describing infection after laser refractive surgery.
In this report, we present a rare case of post-LASIK interface filamentous fungal keratitis and its successful clinical management.
Patients and Methods
Retrospective case-report. Data were collected from the patient’s clinical records.
Results
A healthy 30-year-old woman underwent uncomplicated bilateral LASIK surgery for myopia at a private medical center (day 1). In the postoperative period, she was medicated with topical ofloxacin 5id (Floxedol®), dexamethasone phosphate 5id (Ronic®) and artificial tears.
Two weeks after surgery (day 14), the patient presented complaints of blurred vision, photophobia and intense pain on her left eye (LE). As diffuse lamellar keratitis (DLK) diagnosis was postulated, in addition to the previously established medication, oral prednisolone (Lepicortinolo®) 60mg/day was initiated and two injections of subconjunctival triamcinolone (Kenalog A-40®) were applied in two consecutive days (day 15 and 16). Despite only mild clinical improvement, a third subconjunctival injection of triamcinolone was applied to the patient (day 18) and a flap lift was proposed.
Due to worsening of symptoms and clinical deterioration, seven days after the third subconjunctival corticosteroid injection, the patient came to our department, seeking second medical opinion (day 25). A complete medical history was then carried out, highlighting close contact to cereal seeds for a short period of time, when cooking, and jogging in a natural park, 4 and 10 days after surgery, respectively. Uncorrected distance visual acuity (UDVA) of the LE was 20/100. Slit-lamp examination revealed diffuse corneal edema, a central and irregular white nodular infiltrate with corneal ulceration and the presence of numerous inflammatory cells on the flap’s interface [Figure 1] [e-Figures 1–3]. As infectious etiology (namely fungal or acanthamoeba) was suspected, corneal scrapings were taken from the ulcer and the treatment scheme was altered to fortified voriconazole (1%) drops applied hourly and moxifloxacin (Vigamox®) drops 5id. Dexamethasone phosphate drops were tapered by one drop per day and oral prednisolone was tapered from 60mg/day, by steps of 20mg, every 3 days. The flap lift approach was postponed.Figure 1 Slit-lamp examination, day 25.
After three days (day 28), clinical improvement was perceived [e-Figures 4 and 5] and the treatment plan was maintained. Continued gradual progress was observed in the following days (day 33), with a visual recovery to 20/40 [e-Figure 6]. One week later (day 40), after oral and topical corticosteroid withdrawal, improvement was sustained, with a residual mild to moderate central double-ring shaped opacity with defined edges [e-Figures 7 and 8]. The morphologic analysis of the cultural media from the initial ulcer scraping by an experienced microbiologist revealed the presence of Scopulariopsis brevicaulis fungus. The fungus was sensible to Voriconazole. After confirmation of the suspected diagnosis, moxifloxacin was suspended, and only topical Voriconazole 1% 5id was maintained.
After 50 days of treatment (day 75), the corneal infiltrate had resolved with mild scarring and the topical fortified voriconazole was stopped. There were no side effects reported from medication. More than one year after the infection, the patient maintains a mild density leucoma, with 20/20 of UCVA [Figure 2].Figure 2 (A) Slit-lamp examination, one year and a half after the infection; (B) anterior segment OCT, one year and a half after the infection.
Discussion
The authors present a very rare case of unilateral fungal infection by Scopulariopsis brevicaulis. As these species are soil saprophytes,7 the authors hypothesize that the contact with cereal seeds and jogging activity in the park, 4 and 10 days after the surgery, respectively, might have played a role as risk factors; however, intraoperative contamination from adjacent structures like the conjunctiva, eyelids and eyelashes, or even from surgical gloves, operative drapes and room air during the procedure should not be neglected.8 Additionally, the risk can be increased by other factors, such as an epithelial break after LASIK, allowing the penetration of pathogens,9 or the long-term use of steroids, decreasing the host immune response. Moreover, these pathogens are usually associated to mild onychomycosis in humans,7 so a possible source of infection could be the hands of both healthcare professionals or the patient.
Only few cases3–6 of Scopulariopsis spp. keratitis have been reported, of which only one case described after laser refractive surgery. In the present case, hypopyon was never observed and the infection was initially misdiagnosed as a DLK, justified by the presence of a pattern of diffuse inflammatory infiltrates, rather than satellite lesions. Thus, the initial treatment with a large dose of local corticosteroids, could have allowed the fungus to spread, as reported in the literature.10
The rapid progression and the difficulties in the treatment of corneal fungal infections make a timely microbiological workup, including sensitivity tests, of utmost importance when post-LASIK infection is suspected; however, it is crucial to be aware of the time-consuming cultural exams and its high rate of false negative results, which may contribute to a challenging diagnosis and delayed directed treatment. A careful clinical biomicroscopic examination is helpful towards reaching a diagnosis and the subsequent decision of antifungal treatment. In this case, considering the initial suspicion of a possible fungal etiology, broad spectrum fortified topical antifungal agent was promptly initiated and corticotherapy was tapered, in order to decrease the risk of rebound inflammation due to complete withdrawal.
Flap lifting for culturing and irrigation with directed antimicrobial solution is recommended by the American Society of Cataract and Refractive Surgery.11 In this case, the central infiltrate almost occupying the complete flap thickness and its communication with the corneal ulcer raised the risk of flap break during surgical lift, with subsequent amputation and its severe visual function implications. Therefore, a conservative approach with close monitoring was preferred, and ulcer scraps were collected for culture.
In fact, usually, fungal keratitis requires long-term administration of antifungal treatment and the possibility of clinical relapse, even after complete clinical improvement, should not be neglected. In this case, we experienced a good and fast clinical response based on topical, fortified Voriconazole, which was maintained for fifty days. Plus, more than one year after antifungal discontinuation and without chemoprophylaxis, the patient did not present any sign of relapse and conserved a very good visual function after the keratorefractive procedure.
The strengths of the present case-report are the rarity of the etiological agent and the good clinical response and outcome to medical treatment, without the need for a more invasive intervention, such as flap lifting. The main limitation is the absence of photographic data from ophthalmological examination before the first evaluation in our department.
Conclusions
Despite being an extremely rare complication, post-LASIK fungal keratitis is a severe complication that can lead to poor visual outcomes. This report shows that despite the initial difficulty in the differential diagnosis with DLK, an early diagnostic suspicion, combined with early microbiological diagnosis and appropriate conservative management can result in good clinical outcomes. Furthermore, voriconazole seems to be effective and safe to treat such cases.
Acknowledgments
We want to express our gratitude to the chief of the Ophthalmology department from the Centro Hospitalar e Universitário do Porto, Prof. Dr. Pedro Menéres, for his vision and enthusiasm with new technologies and resources to improve the ophthalmic care of the population.
Data Sharing Statement
The data used in the current study are available from the corresponding author on reasonable request. The abstract of this paper was presented at the European Society of Cataract and Refractive Surgeons as a poster presentation with interim findings.
Ethics Approval and Consent to Participate
The ethics committee of the Centro Hospitalar e Universitário do Porto approved the study (nr. 2020.167 (130-DEFI/132-CE)). Consent to participate was signed by the patient.
Consent for Publication
Consent to publish the case report with anonymized data, including images, was signed by the patient.
Disclosure
The authors report no conflicts of interest in this work. | Recovered | ReactionOutcome | CC BY-NC | 33633469 | 19,950,282 | 2021 |
What was the outcome of reaction 'Scopulariopsis infection'? | Keratitis by Scopulariopsis brevicaulis Fungus After LASIK - A Case Report.
To describe a rare case of an interface filamentous fungal keratitis and its successful clinical approach and management.
Retrospective case report. Analysis of the patient's clinical records.
A healthy 30-year-old woman presenting with complaints of blurred vision, photophobia and intense pain, was previously diagnosed with a suspected unilateral diffuse lamellar keratitis after laser in situ keratomileusis surgery, and accordingly treated with a scheme of oral and subconjunctival corticosteroids. Due to worsening of symptoms, the patient was later referred to our ophthalmology department. Upon examination, a corneal infiltration was observed and a fungal infection was suspected. Treatment with fortified Voriconazole (1%) was initiated and both topical and oral corticosteroids were tapered. The infiltrate resolved after 6 weeks of antifungal topical treatment. Scopulariopsis brevicaulis was isolated on culture media. At the end of follow-up, the uncorrected distance visual acuity was 20/20 with mild scarring.
Scopulariopsis brevicaulis can be associated with post-laser in situ keratomileusis interface infection. A quick intervention may dictate a good outcome, when combining early suspicion and microbiological diagnosis, and an appropriate conservative management. Furthermore, Voriconazole seems to be effective and safe in the treatment of such cases.
Introduction
Laser in situ keratomileusis (LASIK) is an effective and safe procedure applied to correct low to moderate ametropia, commonly used worldwide. Despite being very rare, any infection after the procedure, mainly those related to flap interface, can be a sight-threatening complication in previously otherwise healthy eyes, in young individuals.1
Over time, the main cause of non-viral infectious keratitis after LASIK has changed from the atypical Mycobacterium to gram-positive organisms, particularly Methicillin-resistant Staphylococcus aureus (MRSA). Additionally, the postoperative intensive steroid use increases host susceptibility to opportunistic agents, including fungi.2 Only a few cases3–6 of Scopulariopsis spp. fungal keratitis have been reported in the literature, with only one case describing infection after laser refractive surgery.
In this report, we present a rare case of post-LASIK interface filamentous fungal keratitis and its successful clinical management.
Patients and Methods
Retrospective case-report. Data were collected from the patient’s clinical records.
Results
A healthy 30-year-old woman underwent uncomplicated bilateral LASIK surgery for myopia at a private medical center (day 1). In the postoperative period, she was medicated with topical ofloxacin 5id (Floxedol®), dexamethasone phosphate 5id (Ronic®) and artificial tears.
Two weeks after surgery (day 14), the patient presented complaints of blurred vision, photophobia and intense pain on her left eye (LE). As diffuse lamellar keratitis (DLK) diagnosis was postulated, in addition to the previously established medication, oral prednisolone (Lepicortinolo®) 60mg/day was initiated and two injections of subconjunctival triamcinolone (Kenalog A-40®) were applied in two consecutive days (day 15 and 16). Despite only mild clinical improvement, a third subconjunctival injection of triamcinolone was applied to the patient (day 18) and a flap lift was proposed.
Due to worsening of symptoms and clinical deterioration, seven days after the third subconjunctival corticosteroid injection, the patient came to our department, seeking second medical opinion (day 25). A complete medical history was then carried out, highlighting close contact to cereal seeds for a short period of time, when cooking, and jogging in a natural park, 4 and 10 days after surgery, respectively. Uncorrected distance visual acuity (UDVA) of the LE was 20/100. Slit-lamp examination revealed diffuse corneal edema, a central and irregular white nodular infiltrate with corneal ulceration and the presence of numerous inflammatory cells on the flap’s interface [Figure 1] [e-Figures 1–3]. As infectious etiology (namely fungal or acanthamoeba) was suspected, corneal scrapings were taken from the ulcer and the treatment scheme was altered to fortified voriconazole (1%) drops applied hourly and moxifloxacin (Vigamox®) drops 5id. Dexamethasone phosphate drops were tapered by one drop per day and oral prednisolone was tapered from 60mg/day, by steps of 20mg, every 3 days. The flap lift approach was postponed.Figure 1 Slit-lamp examination, day 25.
After three days (day 28), clinical improvement was perceived [e-Figures 4 and 5] and the treatment plan was maintained. Continued gradual progress was observed in the following days (day 33), with a visual recovery to 20/40 [e-Figure 6]. One week later (day 40), after oral and topical corticosteroid withdrawal, improvement was sustained, with a residual mild to moderate central double-ring shaped opacity with defined edges [e-Figures 7 and 8]. The morphologic analysis of the cultural media from the initial ulcer scraping by an experienced microbiologist revealed the presence of Scopulariopsis brevicaulis fungus. The fungus was sensible to Voriconazole. After confirmation of the suspected diagnosis, moxifloxacin was suspended, and only topical Voriconazole 1% 5id was maintained.
After 50 days of treatment (day 75), the corneal infiltrate had resolved with mild scarring and the topical fortified voriconazole was stopped. There were no side effects reported from medication. More than one year after the infection, the patient maintains a mild density leucoma, with 20/20 of UCVA [Figure 2].Figure 2 (A) Slit-lamp examination, one year and a half after the infection; (B) anterior segment OCT, one year and a half after the infection.
Discussion
The authors present a very rare case of unilateral fungal infection by Scopulariopsis brevicaulis. As these species are soil saprophytes,7 the authors hypothesize that the contact with cereal seeds and jogging activity in the park, 4 and 10 days after the surgery, respectively, might have played a role as risk factors; however, intraoperative contamination from adjacent structures like the conjunctiva, eyelids and eyelashes, or even from surgical gloves, operative drapes and room air during the procedure should not be neglected.8 Additionally, the risk can be increased by other factors, such as an epithelial break after LASIK, allowing the penetration of pathogens,9 or the long-term use of steroids, decreasing the host immune response. Moreover, these pathogens are usually associated to mild onychomycosis in humans,7 so a possible source of infection could be the hands of both healthcare professionals or the patient.
Only few cases3–6 of Scopulariopsis spp. keratitis have been reported, of which only one case described after laser refractive surgery. In the present case, hypopyon was never observed and the infection was initially misdiagnosed as a DLK, justified by the presence of a pattern of diffuse inflammatory infiltrates, rather than satellite lesions. Thus, the initial treatment with a large dose of local corticosteroids, could have allowed the fungus to spread, as reported in the literature.10
The rapid progression and the difficulties in the treatment of corneal fungal infections make a timely microbiological workup, including sensitivity tests, of utmost importance when post-LASIK infection is suspected; however, it is crucial to be aware of the time-consuming cultural exams and its high rate of false negative results, which may contribute to a challenging diagnosis and delayed directed treatment. A careful clinical biomicroscopic examination is helpful towards reaching a diagnosis and the subsequent decision of antifungal treatment. In this case, considering the initial suspicion of a possible fungal etiology, broad spectrum fortified topical antifungal agent was promptly initiated and corticotherapy was tapered, in order to decrease the risk of rebound inflammation due to complete withdrawal.
Flap lifting for culturing and irrigation with directed antimicrobial solution is recommended by the American Society of Cataract and Refractive Surgery.11 In this case, the central infiltrate almost occupying the complete flap thickness and its communication with the corneal ulcer raised the risk of flap break during surgical lift, with subsequent amputation and its severe visual function implications. Therefore, a conservative approach with close monitoring was preferred, and ulcer scraps were collected for culture.
In fact, usually, fungal keratitis requires long-term administration of antifungal treatment and the possibility of clinical relapse, even after complete clinical improvement, should not be neglected. In this case, we experienced a good and fast clinical response based on topical, fortified Voriconazole, which was maintained for fifty days. Plus, more than one year after antifungal discontinuation and without chemoprophylaxis, the patient did not present any sign of relapse and conserved a very good visual function after the keratorefractive procedure.
The strengths of the present case-report are the rarity of the etiological agent and the good clinical response and outcome to medical treatment, without the need for a more invasive intervention, such as flap lifting. The main limitation is the absence of photographic data from ophthalmological examination before the first evaluation in our department.
Conclusions
Despite being an extremely rare complication, post-LASIK fungal keratitis is a severe complication that can lead to poor visual outcomes. This report shows that despite the initial difficulty in the differential diagnosis with DLK, an early diagnostic suspicion, combined with early microbiological diagnosis and appropriate conservative management can result in good clinical outcomes. Furthermore, voriconazole seems to be effective and safe to treat such cases.
Acknowledgments
We want to express our gratitude to the chief of the Ophthalmology department from the Centro Hospitalar e Universitário do Porto, Prof. Dr. Pedro Menéres, for his vision and enthusiasm with new technologies and resources to improve the ophthalmic care of the population.
Data Sharing Statement
The data used in the current study are available from the corresponding author on reasonable request. The abstract of this paper was presented at the European Society of Cataract and Refractive Surgeons as a poster presentation with interim findings.
Ethics Approval and Consent to Participate
The ethics committee of the Centro Hospitalar e Universitário do Porto approved the study (nr. 2020.167 (130-DEFI/132-CE)). Consent to participate was signed by the patient.
Consent for Publication
Consent to publish the case report with anonymized data, including images, was signed by the patient.
Disclosure
The authors report no conflicts of interest in this work. | Recovered | ReactionOutcome | CC BY-NC | 33633469 | 19,950,282 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Case Report: Late-Onset Temporal Lobe Epilepsy Following Subarachnoid Hemorrhage: An Interplay Between Pre-existing Cortical Development Abnormality and Tissue Damage.
Epileptogenicity following brain insult depends on various factors including severity of the resulting lesion and extent of brain damage. We report a 54-year-old female patient who developed medically refractory epilepsy resulting from the interplay of pre-existing and post-insult pathologies. She presented with subarachnoid hemorrhage (SAH) due to a ruptured aneurysm and underwent clipping surgery. Seizures started 3 months post-operatively. MRI revealed cerebral ischemia and hemosiderin deposits in the left temporal lobes, and left hippocampal atrophy was suspected. As anti-seizure medications and vagus nerve stimulation failed to control her seizures, she underwent left temporal lobe resection and placement of a ventriculoperitoneal shunt for the post-operative complication of hydrocephalus. She remains seizure-free to date. Neuropathology revealed a previously undiagnosed focal cortical dysplasia (FCD) type 1a. Brain insult likely had a second hit effect in the late onset of epilepsy in this patient with pre-existing mild MCD, in whom secondary epilepsy can be attributed to the interplay of multiple underlying pathologies.
Highlights
- Pre-existing and post-insult pathologies induced epileptogenicity
- Late-onset medically refractory epilepsy with undiagnosed FCD
Background
Parenchymal hemosiderosis is a risk factor for focal epilepsy after intracerebral bleeding (1, 2). Epileptogenicity due to hemosiderosis is well-known and can be related to cavernous malformation (3), brain tumor (4), or intracranial hemorrhage (5, 6). The mechanism of epileptogenicity due to hemosiderosis includes abnormalities in neurotransmission and free radical formation (7).
In neuropathology of temporal lobe epilepsy, epileptogenicity has been attributed to various lesions including hippocampal sclerosis, malformation of cortical development (focal cortical dysplasia—FCD—and gray matter heterotopia), as well low-grade tumors (8, 9).
In daily practice, acute or remote damage resulting from a previous insult is considered as the sole cause of epileptogenicity. As many patients do not require surgery, information on etiology derives solely from magnetic resonance imaging (MRI). However, many pre-existing and yet undiagnosed factors as well as complications from an acute insult can impact the establishment of an epilepsy network by affecting the neurotransmitter system and intracellular and extracellular homeostasis. Indeed, it is common clinical experience that some patients develop epilepsy following an insult and others do not, even though they have the same degree of brain damage.
We have previously identified the presence of an underlying FCD as a significant factor associated with epilepsy in patients who developed post-traumatic epilepsy following severe head trauma (10). We postulated that multifactorial mechanisms might be involved in epileptogenicity following an insult, and this further applies to patients with chronic seizures following subarachnoid hemorrhage (SAH).
Here, we describe the management of a patient who developed epilepsy and who initially presented for medical care due to a ruptured aneurysmal SAH. In addition to multiple complications due to her SAH (which included acute ischemic stroke with hemorrhagic transformation, hemosiderosis and hydrocephalus), her seizures became medically refractory and warranted resection surgery, leading to the discovery of a previously unknown area suggestive of FCD type 1a.
Case Presentation
A 54-year-old right-handed female was evaluated at the Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital (Hamamatsu, Japan) due to medically refractory weekly epileptic seizures.
Past medical history was relevant for a SAH due to a ruptured left middle cerebral artery aneurysm and status post-aneurysm clipping 11 months prior. Her clinical evolution during acute care was complicated by a hemorrhagic cerebral infarction in the left temporal lobes due to symptomatic cerebral vasospasm.
Focal aware and unaware seizures started 3 months after the surgery. Seizure semiology consisted of an epigastric sensation followed by aphasia and then loss of awareness, with occasional focal to bilateral tonic-clonic seizures. The electroencephalogram (EEG) showed interictal epileptiform discharges over the left fronto-temporal region, in keeping with topography of the bleeding and complications.
Levetiracetam, Zonisamide, Valproic acid, and Lamotrigine did not control her seizures, thus fulfilling criteria for drug-resistant seizures (11, 12). The patient was considered a candidate for surgical intervention and was offered the option of either resection surgery or vagus nerve stimulation (VNS). In view of focal aware seizures, the possibility of effective application of the magnet at the onset of seizures to abort their progression was preferred by the patient and her family. Therefore, she underwent VNS implantation at the age of 55-years and 3 months. VNS reduced her seizure intensity and frequency from weekly to monthly, and aiming at seizure freedom, the patient thereafter elected to undergo resection surgery.
Pre-surgical evaluation included MRI, 2-[18F]fluoro-2-deoxy-D-glucose (18FDG)-positron emission tomography (PET), and video EEG monitoring (VEEG). MRI showed T2 signal hyperintensity lesions in the frontal and temporal lobes, with hemosiderin deposits in the temporal area, as well as severe left hippocampal atrophy. 18FDG-PET showed hypometabolism in the left frontal and temporal lobe (Figure 1). VEEG captured her habitual seizures with loss of awareness preceded by an epigastric sensation and aphasia, arising electrographically from the left fronto-temporal area.
Figure 1 Pre-operative and post-operative neuroimaging. MRI FLAIR axial image (A) showing a hyperintense signal at the left temporal pole (arrow) and hippocampal atrophy (arrowhead). T2-weighted coronal image (B) showing a hypointense signal along the lower insula cortex and the roof of the inferior horn. Positron emission tomography (C,D) showing reduced glucose uptake in the left frontal and temporal lobes (arrow). T2-weighted coronal image (E) at the level of the hippocampal body showing hippocampal atrophy (arrow). T2-weighted coronal image at frontal region (F) showing a change in intensity.
Based on the comprehensive pre-surgical evaluation, we hypothesized that her seizures were consistent with mesial temporal lobe epilepsy with a generator in the mesial temporal lobe structures from her dominant hemisphere, and we performed Spencer's anteromedial temporal lobectomy (a left hippocampal and amygdala resection with a temporal lobectomy from the middle temporal gyrus) (13, 14) at age 56. Surgery was complicated by subacute hydrocephalus at post-operative week 1, and she underwent ventriculoperitoneal shunting. She has remained seizure-free for more than 2-years, and remains on Levetiracetam monotherapy.
Neuropathology revealed a small number of ectopic neurons in the white matter of the temporal lobe, as well as satellite oligogenesis growth, suggestive of FCD type 1a (Figure 2). Despite MRI evidence of hippocampal atrophy, the hippocampal specimen showed no neuronal loss or gliosis in CA sectors or in the dentate gyrus, and thus, no neuropathological diagnosis of hippocampal sclerosis could be confirmed.
Figure 2 Histopathology of the left temporal lobe. The cortical-white matter border is ill-defined and indicated as a dotted line (A). Sporadic ectopic neurons accompanied by glial cell proliferation (satellite oligogenesis equivalent to oligodendrocytes) surrounding the neurons (arrows) are seen at high magnification (×200) (B).
Discussion
In this patient, her late-onset epilepsy was at first attributed to prior SAH complicated with left frontal and temporal ischemic stroke with hemorrhagic transformation due to severe vasospasm. However, upon development of drug resistance and partial response to VNS, a full work-up for possible resection surgery, including resection of a generator in the mesial temporal structures, was postulated based on MRI signs that indicated hippocampal atrophy. Although hippocampal pathology did not confirm the presence of hippocampal sclerosis, the decision for resection surgery as the next step in this patient's management revealed FCD 1a in the temporal neocortex. This pre-existing and not yet diagnosed epileptogenic lesion could play a role in the development of epilepsy in this patient, as not all patients with a prior vascular insult will present with chronic unprovoked seizures.
Many patients, like ours, will present with recurrent seizures that develop following the diagnosis of an insult, such as stroke, head trauma, or tumors (15–21). The current use of terms such as “post-stroke epilepsy,” “post-traumatic epilepsy,” and “brain tumor-related epilepsy” can guide our management decisions and allows us to provide patients and families an overview of the predicted outcome. However, the interplay with other underlying known and unknown neuropathological factors might lead to unexpected directions, and attention needs to be paid to patients with rather poor clinical evolution.
An imbalance between excitatory and inhibitory neurotransmission causing epileptic seizures (22–24) is a common mechanism in the various etiologies of epilepsy. It is however possible that even in the presence of a highly epileptogenic brain lesion such as FCD, epileptogenicity and clinically manifested seizures in some patients only occur after a second hit/insult. Indeed, the “two-hit theory” (25) or “multiple-hit theory” (26) may explain this situation (27, 28). In our patient, seizures became controlled after resection surgery, including resection of the cortical malformation and of areas bearing hemosiderin deposits.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by Submission of this case report was approved by the ethics review board at Seirei Hamamatsu General Hospital, and written informed consent was obtained from the patient. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
All authors made substantial contributions to the conception, validation, design, acquisition of data, or analysis and interpretation of data.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
EEGelectroencephalogram
18FDG2-[18F]fluoro-2-deoxy-D-glucose
MCDmalformation of cortical development
MRImagnetic resonance imaging
PETpositron emission tomography
SAHsubarachnoid hemorrhage
VEEGvideo electroencephalogram
VNSvagus nerve stimulation. | LAMOTRIGINE, LEVETIRACETAM, VALPROIC ACID, ZONISAMIDE | DrugsGivenReaction | CC BY | 33633663 | 20,672,527 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | Case Report: Late-Onset Temporal Lobe Epilepsy Following Subarachnoid Hemorrhage: An Interplay Between Pre-existing Cortical Development Abnormality and Tissue Damage.
Epileptogenicity following brain insult depends on various factors including severity of the resulting lesion and extent of brain damage. We report a 54-year-old female patient who developed medically refractory epilepsy resulting from the interplay of pre-existing and post-insult pathologies. She presented with subarachnoid hemorrhage (SAH) due to a ruptured aneurysm and underwent clipping surgery. Seizures started 3 months post-operatively. MRI revealed cerebral ischemia and hemosiderin deposits in the left temporal lobes, and left hippocampal atrophy was suspected. As anti-seizure medications and vagus nerve stimulation failed to control her seizures, she underwent left temporal lobe resection and placement of a ventriculoperitoneal shunt for the post-operative complication of hydrocephalus. She remains seizure-free to date. Neuropathology revealed a previously undiagnosed focal cortical dysplasia (FCD) type 1a. Brain insult likely had a second hit effect in the late onset of epilepsy in this patient with pre-existing mild MCD, in whom secondary epilepsy can be attributed to the interplay of multiple underlying pathologies.
Highlights
- Pre-existing and post-insult pathologies induced epileptogenicity
- Late-onset medically refractory epilepsy with undiagnosed FCD
Background
Parenchymal hemosiderosis is a risk factor for focal epilepsy after intracerebral bleeding (1, 2). Epileptogenicity due to hemosiderosis is well-known and can be related to cavernous malformation (3), brain tumor (4), or intracranial hemorrhage (5, 6). The mechanism of epileptogenicity due to hemosiderosis includes abnormalities in neurotransmission and free radical formation (7).
In neuropathology of temporal lobe epilepsy, epileptogenicity has been attributed to various lesions including hippocampal sclerosis, malformation of cortical development (focal cortical dysplasia—FCD—and gray matter heterotopia), as well low-grade tumors (8, 9).
In daily practice, acute or remote damage resulting from a previous insult is considered as the sole cause of epileptogenicity. As many patients do not require surgery, information on etiology derives solely from magnetic resonance imaging (MRI). However, many pre-existing and yet undiagnosed factors as well as complications from an acute insult can impact the establishment of an epilepsy network by affecting the neurotransmitter system and intracellular and extracellular homeostasis. Indeed, it is common clinical experience that some patients develop epilepsy following an insult and others do not, even though they have the same degree of brain damage.
We have previously identified the presence of an underlying FCD as a significant factor associated with epilepsy in patients who developed post-traumatic epilepsy following severe head trauma (10). We postulated that multifactorial mechanisms might be involved in epileptogenicity following an insult, and this further applies to patients with chronic seizures following subarachnoid hemorrhage (SAH).
Here, we describe the management of a patient who developed epilepsy and who initially presented for medical care due to a ruptured aneurysmal SAH. In addition to multiple complications due to her SAH (which included acute ischemic stroke with hemorrhagic transformation, hemosiderosis and hydrocephalus), her seizures became medically refractory and warranted resection surgery, leading to the discovery of a previously unknown area suggestive of FCD type 1a.
Case Presentation
A 54-year-old right-handed female was evaluated at the Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital (Hamamatsu, Japan) due to medically refractory weekly epileptic seizures.
Past medical history was relevant for a SAH due to a ruptured left middle cerebral artery aneurysm and status post-aneurysm clipping 11 months prior. Her clinical evolution during acute care was complicated by a hemorrhagic cerebral infarction in the left temporal lobes due to symptomatic cerebral vasospasm.
Focal aware and unaware seizures started 3 months after the surgery. Seizure semiology consisted of an epigastric sensation followed by aphasia and then loss of awareness, with occasional focal to bilateral tonic-clonic seizures. The electroencephalogram (EEG) showed interictal epileptiform discharges over the left fronto-temporal region, in keeping with topography of the bleeding and complications.
Levetiracetam, Zonisamide, Valproic acid, and Lamotrigine did not control her seizures, thus fulfilling criteria for drug-resistant seizures (11, 12). The patient was considered a candidate for surgical intervention and was offered the option of either resection surgery or vagus nerve stimulation (VNS). In view of focal aware seizures, the possibility of effective application of the magnet at the onset of seizures to abort their progression was preferred by the patient and her family. Therefore, she underwent VNS implantation at the age of 55-years and 3 months. VNS reduced her seizure intensity and frequency from weekly to monthly, and aiming at seizure freedom, the patient thereafter elected to undergo resection surgery.
Pre-surgical evaluation included MRI, 2-[18F]fluoro-2-deoxy-D-glucose (18FDG)-positron emission tomography (PET), and video EEG monitoring (VEEG). MRI showed T2 signal hyperintensity lesions in the frontal and temporal lobes, with hemosiderin deposits in the temporal area, as well as severe left hippocampal atrophy. 18FDG-PET showed hypometabolism in the left frontal and temporal lobe (Figure 1). VEEG captured her habitual seizures with loss of awareness preceded by an epigastric sensation and aphasia, arising electrographically from the left fronto-temporal area.
Figure 1 Pre-operative and post-operative neuroimaging. MRI FLAIR axial image (A) showing a hyperintense signal at the left temporal pole (arrow) and hippocampal atrophy (arrowhead). T2-weighted coronal image (B) showing a hypointense signal along the lower insula cortex and the roof of the inferior horn. Positron emission tomography (C,D) showing reduced glucose uptake in the left frontal and temporal lobes (arrow). T2-weighted coronal image (E) at the level of the hippocampal body showing hippocampal atrophy (arrow). T2-weighted coronal image at frontal region (F) showing a change in intensity.
Based on the comprehensive pre-surgical evaluation, we hypothesized that her seizures were consistent with mesial temporal lobe epilepsy with a generator in the mesial temporal lobe structures from her dominant hemisphere, and we performed Spencer's anteromedial temporal lobectomy (a left hippocampal and amygdala resection with a temporal lobectomy from the middle temporal gyrus) (13, 14) at age 56. Surgery was complicated by subacute hydrocephalus at post-operative week 1, and she underwent ventriculoperitoneal shunting. She has remained seizure-free for more than 2-years, and remains on Levetiracetam monotherapy.
Neuropathology revealed a small number of ectopic neurons in the white matter of the temporal lobe, as well as satellite oligogenesis growth, suggestive of FCD type 1a (Figure 2). Despite MRI evidence of hippocampal atrophy, the hippocampal specimen showed no neuronal loss or gliosis in CA sectors or in the dentate gyrus, and thus, no neuropathological diagnosis of hippocampal sclerosis could be confirmed.
Figure 2 Histopathology of the left temporal lobe. The cortical-white matter border is ill-defined and indicated as a dotted line (A). Sporadic ectopic neurons accompanied by glial cell proliferation (satellite oligogenesis equivalent to oligodendrocytes) surrounding the neurons (arrows) are seen at high magnification (×200) (B).
Discussion
In this patient, her late-onset epilepsy was at first attributed to prior SAH complicated with left frontal and temporal ischemic stroke with hemorrhagic transformation due to severe vasospasm. However, upon development of drug resistance and partial response to VNS, a full work-up for possible resection surgery, including resection of a generator in the mesial temporal structures, was postulated based on MRI signs that indicated hippocampal atrophy. Although hippocampal pathology did not confirm the presence of hippocampal sclerosis, the decision for resection surgery as the next step in this patient's management revealed FCD 1a in the temporal neocortex. This pre-existing and not yet diagnosed epileptogenic lesion could play a role in the development of epilepsy in this patient, as not all patients with a prior vascular insult will present with chronic unprovoked seizures.
Many patients, like ours, will present with recurrent seizures that develop following the diagnosis of an insult, such as stroke, head trauma, or tumors (15–21). The current use of terms such as “post-stroke epilepsy,” “post-traumatic epilepsy,” and “brain tumor-related epilepsy” can guide our management decisions and allows us to provide patients and families an overview of the predicted outcome. However, the interplay with other underlying known and unknown neuropathological factors might lead to unexpected directions, and attention needs to be paid to patients with rather poor clinical evolution.
An imbalance between excitatory and inhibitory neurotransmission causing epileptic seizures (22–24) is a common mechanism in the various etiologies of epilepsy. It is however possible that even in the presence of a highly epileptogenic brain lesion such as FCD, epileptogenicity and clinically manifested seizures in some patients only occur after a second hit/insult. Indeed, the “two-hit theory” (25) or “multiple-hit theory” (26) may explain this situation (27, 28). In our patient, seizures became controlled after resection surgery, including resection of the cortical malformation and of areas bearing hemosiderin deposits.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by Submission of this case report was approved by the ethics review board at Seirei Hamamatsu General Hospital, and written informed consent was obtained from the patient. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
All authors made substantial contributions to the conception, validation, design, acquisition of data, or analysis and interpretation of data.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
EEGelectroencephalogram
18FDG2-[18F]fluoro-2-deoxy-D-glucose
MCDmalformation of cortical development
MRImagnetic resonance imaging
PETpositron emission tomography
SAHsubarachnoid hemorrhage
VEEGvideo electroencephalogram
VNSvagus nerve stimulation. | LAMOTRIGINE, LEVETIRACETAM, VALPROIC ACID, ZONISAMIDE | DrugsGivenReaction | CC BY | 33633663 | 20,681,904 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arthritis'. | Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm.
Ocular immune-related adverse events (IrAEs) associated with use of checkpoint inhibitors (CPIs) in cancer therapeutics are relatively rare, occurring in approximately 1% of treated patients. Recognition and early intervention are essential because the degree of tissue damage may be disproportionate to the symptoms, and lack of appropriate treatment risks permanent loss of vision. International guidelines on managing ocular IrAEs provide limited advice only. Importantly, local interventions can be effective and may avoid the need for systemic corticosteroids, thereby permitting the continuation of CPIs. We present a single institution case series of eight affected patients managed by our multidisciplinary team. Consistent with previously published series and case reports, we identified anterior uveitis as the most common ocular IrAE associated with CPIs requiring intervention. Based on our experience, as well as published guidance, we generated a simple algorithm to assist clinicians efficiently manage patients developing ocular symptoms during treatment with CPIs. In addition, we make recommendations for optimising treatment of uveitis and address implications for ongoing CPI therapy.
Background
Immunotherapy with checkpoint inhibitors (CPIs) has transformed the treatment of a wide range of malignancies.1,2 These drugs work by enabling the host immune system to eliminate malignant cells, recognisable through the expression of neoantigens. The CPIs currently in clinical use are antibodies which target the cytotoxic T-lymphocyte antigen-4 receptor (anti-CTLA-4), the programmed death-1 receptor (anti-PD-1) and its ligand (anti-PD-L1). The CTLA-4 receptor downregulates T-cell activation, whereas the PD-1 receptor inhibits T-cell proliferation, cytokine release, and cytotoxicity. Blocking their function can enhance T-cell response and allow immune-mediated tumour killing.
CPIs generate side effects termed immune-related adverse events (IrAEs), which stem from their mechanism of action, being predominantly autoimmune in nature and having the potential to affect any body organ. IrAEs range from being mild to life-threatening, or life-changing in some instances.3 Since their first introduction into clinical practice in 2011 as treatment for metastatic melanoma, the use of anti-CTLA-4 and anti-PD-L1 antibodies has expanded to include multiple cancer types including lung and urological cancers as well as lymphomas, with new treatment indications being added frequently. Their increasing use has resulted in greater awareness of both common and rarely seen IrAEs, ranging from mild presentations to severe reactions requiring prompt intervention.4
Optimal management of IrAEs is still in its infancy, with limited evidence to inform international guidelines which have been generated to assist clinical practice.5,6 The mainstay of treatment for what appear to be inflammatory conditions is immunosuppression with corticosteroids, prompting concerns about their effect on CPI efficacy.7 Moreover, the long-term effects on cancer survivors of high dose steroids, sometimes administered for protracted periods of time, have yet to be fully understood. The European Society of Medical Oncology (ESMO) clinical practice guidelines5 provide helpful algorithms for managing the more commonly occurring IrAEs, but consensus advice on managing less common IrAEs, such as those affecting the eyes, is also needed to minimise any negative impact of anti-cancer interventions.
Ocular IrAEs occur with an estimated prevalence of 1–3% of all treated patients.8,9 While the spectrum of severity is broad, they are highly significant as they can threaten vision. Reports of ocular IrAEs associated with CPIs are limited to small, single-digit case series and individual case reports, which principally report patients experiencing varying degrees of uveitis.8,10–13
Uveitis is a term used to describe inflammation of the uvea, the middle layer of the eye comprising the iris, ciliary body and choroid. It is classified as anterior, intermediate, posterior, or panuveitis, according to the predominant site of inflammation within the eye.14 Anterior uveitis is characterised by an infiltrate of white blood cells in the anterior chamber of the eye; intermediate uveitis is associated with inflammation in the vitreous gel, resulting in visual blurring, haze and floaters; posterior uveitis is characterised by retinal and/or choroidal inflammation.15,16 Symptoms of uveitis include pain, blurred vision and red eye. Involvement of the posterior segment can produce symptoms of floaters, flickering and shimmering lights (photopsias), as well as blind spots.
Anterior uveitis, whether acute or chronic, can often be managed with topical steroid drops alone. Severe uveitis of any subtype may lead to macular oedema, with accumulation of fluid at the most sensitive part of the retina, causing visual distortion and blurring. Severe ocular inflammation requires prompt intervention to avoid permanent loss of vision, and may require periocular or intravitreal steroid injections. More severe cases require systemic steroids, including oral, or pulsed intravenous methylprednisolone. Recalcitrant, chronic inflammatory eye diseases can be managed with secondary non-corticosteroid immunomodulatory therapeutic agents, including anti-metabolites like mycophenolate mofetil and methotrexate, or biological drugs like adalimumab.17 Common complications of uveitis and its treatment include cataract, glaucoma and choroidal neovascularisation. While most reports suggest a good response to therapy with complete resolution of inflammation, a minority of patients may develop permanent visual loss.
Other less common ocular IrAEs include ocular myasthenia, optic neuritis and auto-immune retinopathy. Dry eyes are described by up to one in four treated patients, but this is a common condition that is often not reported in clinical trials and is frequently undertreated, even in clinical practice.8,9 The risk of ocular IrAEs associated with CPIs was recently quantified using disproportionality analysis; odds ratios for uveitis ranged from 4.6 to 10.8, while that of any ocular IrAE was 2.5 compared with reported events associated with all other drugs.18
Uncertainties about optimal management of ocular IrAEs persist, such as when to interrupt or discontinue potentially life-saving CPI therapy and whether systemic steroids can influence the efficacy of CPIs. We report our experience of managing ocular IrAEs in a cohort of cancer patients receiving CPIs in a single institution and make management recommendations in a novel treatment algorithm.
Methods
We reviewed the electronic patient records of patients treated with CPIs from January to December 2019, and identified all cases referred to the ophthalmology service. The clinical characteristics, treatment and course of IrAEs over time were recorded. Details of their CPI treatment, other non-ocular irAEs, and disease response (based on routine radiological imaging and applying RECIST 1.1 response criteria) were also recorded. Survival was measured from the date of first CPI infusion until data cut-off, on 17 March, 2020.
Based on our case series and information contained in published international guidelines,5,6 we generated a simple assessment and treatment algorithm for use in routine clinical practice to guide the multidisciplinary team managing ocular symptoms and uveitis; the most common ocular IrAE reported.
This project was registered as a health service evaluation at Cambridge University Hospitals NHS Foundation Trust (CUHFT). The CUHFT research governance lead confirmed that, under the UK Policy Framework for Health and Social Care Research 2017, this project would not be classified or managed as research within the National Health Service and therefore did not require ethical review by a research ethics committee. Written informed consent to publish was obtained from the surviving case study patient.
Results
Patient characteristics
We identified eight patients (three women and five men, aged between 39 and 81 years) who developed ocular IrAEs after starting CPIs (Table 1). Seven patients were treated for advanced cancer; four for metastatic melanoma, two metastatic renal-cell carcinoma and one advanced ovarian carcinoma. One melanoma patient received CPI as an adjuvant therapy, after resection of regional lymph node disease. None had a previous history of uveitis. One patient had a history of glaucoma. Five patients received combination anti-CTLA-4 plus anti-PD-1 antibodies (ipilimumab + nivolumab), two patients received a single agent anti-PD-1 antibody (one pembrolizumab, one nivolumab) and one patient received anti-PD-1 antibody (nivolumab) in combination with a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor (rucaparib). Seven patients had their treatment discontinued early due to treatment-related adverse events; their treatment duration ranged from 3 to 9 weeks. The median number of adverse events contributing to treatment discontinuation was three (range 1–3). One patient completed 2 years of planned anti-PD-1 antibody therapy.
Table 1. Patient characteristics of patients experiencing ocular IrAEs associated with CPI treatment.
Patient case CPI regimen Duration of CPI therapy Reason for discontinuation AEs leading to discontinuation Best response to CPI Survival outcome
Melanoma-1
Metastatic
50-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Ocular IrAE Ocular
Skin
Fatigue Partial response Alive 16 months+
Kidney-1
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 3 weeks Multiple IrAE Ocular
Skin
Liver Stable disease Alive 15 months+
Kidney-2
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 4 weeks Multiple IrAEs Ocular
Liver
Arthritis Partial response Alive 16 months+
Ovarian
Metastatic
40-yo woman Nivolumab + rucaparib 8 weeks Multiple IrAE Ocular
Liver
Neutropaenia* Partial response Alive 10 months+
Melanoma-2
Resected stage III
74-yo woman Pembrolizumab
200 mg IV q3w 3 weeks Ocular IrAE Ocular Recurrence Treated with ipilimumab on recurrence; aborted after 6 weeks due to colitis.
Alive with stable disease:
14 months+
Melanoma-3
Metastatic
56-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Multiple IrAEs Ocular
Lung Partial response Alive 22 months+
Melanoma-4
Metastatic
40-yo woman Ipilimumab
1 mg/kg+ nivolumab 3 mg/kg 6 weeks Multiple IrAEs Ocular
Liver Partial response Rechallenged with 2 further cycles of ipilimumab+nivolumab on disease progression without significant IrAEs; progressive brain metastases.
Died after 11 months
Melanoma-5
Metastatic
81-yo man Nivolumab 240 mg 2 years Completed planned treatment – Near complete response Alive 5 years+
* Likely due to PARP inhibitor, not CPI.
AEs, adverse events; CPI, checkpoint inhibitor; IrEAs, immune-related adverse events; yo, year-old; PARP, poly-adenosine diphosphate ribose polymerase.
Ocular IrAE characteristics
The median time to the onset of ocular IrAE was 5 weeks from starting CPIs, although one patient developed symptoms after 18 months of treatment (Table 2). In all seven patients who discontinued CPIs early, ocular IrAE contributed to the decision to discontinue therapy. One patient with pre-existing glaucoma experienced ocular IrAE as the only IrAE, occurring after her first dose of pembrolizumab, and this led to treatment discontinuation. Four patients were diagnosed with anterior uveitis, one had intermediate uveitis, one had melanoma-associated retinopathy (MAR)19,20 and one had suspected ocular ischaemic syndrome.21 All patients had bilateral eye involvement. There were no hospitalisations associated with ocular IrAEs.
Table 2. Characteristics of ocular IrAEs experienced and their treatment.
Patient case Presenting symptoms Ocular IrAE Worst
CTCAE
grade Time to onset/resolution of ocular IrAE Worst visual acuity Visual acuity on resolution Local treatment Systemic steroids (starting dose) Outcome of ocular IrAE
Melanoma 1 Bilateral blurred vision, painful eyes Anterior uveitis 2 3 weeks/8 weeks R 6/19
L Normal R Normal
L Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Kidney 1 Bilateral blurred vision, painful eyes, headache Anterior uveitis
High IO pressures 2 5 weeks/11 weeks (uveitis)
6 months
(IO pressures) R 6/9.5
L 6/7.5 R Normal
L Normal Dexamethasone 0.1% drops
Timolol
Latanprost None Complete resolution
Kidney 2 Bilateral painful red eyes, light sensitivity Anterior uveitis
Left disc swelling 2 5 weeks/8 weeks Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Ovarian Bilateral blurred vision. Painful to focus Anterior uveitis 2 5 weeks/8 months Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Melanoma 2 Deterioration in vision Intermediate
uveitis 3 1 week/10 weeks R 6/9
L Normal R 6/9
L Normal None 40 mg prednisolone Resolved on 10 mg prednisolone; following 2 cycles of ipilimumab,
received IV steroids and infliximab for enteritis
Melanoma 3 Flashing lights, visual aura Melanoma associated retinopathy 4 3 weeks/18 months R 6/18 R 6/5 Anti-VEGF injections
Intra-ocular dexamethasone 50 mg prednisolone Permanent loss of vision; macular scarring
Melanoma 4 Rapid onset loss of vision in both eyes Suspected ocular ischaemic syndrome 4 7 weeks/4 weeks R 6/15
L 6/9 R Normal
L Normal Dexamethasone 0.1% drops
Mydrilate 1% drops 40 mg prednisolone Complete resolution
Melanoma 5 Red, eyes
Loss of vision in left eye
Blurred vision Conjunctivitis
Left retinal detachment*
Anterior uveitis 2
2 18 months
21 months
4 years/10 months R 6/12
L 6/7.5 R 6/12
L 6/7.5 Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Quiescent
* Association of retinal detachment as an IrAE could not be confirmed.
CTCAE, common toxicity criteria; IO, intra-ocular; IrEA, immune-related adverse event; IV, intravenous; L, left; R, right; VEGF, vascular endothelial growth factor.
The patient completing 2 years of nivolumab experienced ocular IrAEs both during and after completing CPI treatment. As the symptoms were manageable and no other IrAEs occurred, his planned treatment was not interrupted. He experienced conjunctivitis and left retinal detachment during treatment, both of which were managed successfully. Two years after completing CPIs, he developed bilateral anterior uveitis.
Treatment of ocular IrAEs
All five patients who developed anterior uveitis were treated with topical steroids only. The three other ocular conditions (intermediate uveitis, MAR and suspected ocular ischaemic syndrome) were treated with oral corticosteroids. No patients received intravenous steroids or other immunosuppressive agents to treat their ocular IrAEs. One patient diagnosed with MAR received intravitreal anti-vascular endothelial growth factor injections to treat a juxtafoveal choroidal neovascular membrane, as well as intra-ocular steroid implants to treat chronic photopsia in his only remaining eye.
The median ocular IrAE treatment duration was 11 weeks (range 8 weeks–10 months) with topical steroids and 10 weeks (range 4 weeks–6 months) with oral steroids. Two patients with anterior uveitis had rapid, complete resolution of their symptoms by 8 and 11 weeks. One patient had persistently raised intra-ocular pressures for approximately 6 months. Two patients had a protracted course of inflammatory eye disease, with recurrent episodes lasting 8 and 10 months, respectively. Of two patients re-challenged with CPIs at a later date, (one with ipilimumab, one with ipilimumab + nivolumab), neither had recurrence of ocular IrAEs.
Oncological response to CPIs
Overall, six out of the eight treated patients experienced a partial or near complete response to CPI therapy and seven remain alive and well at data cut-off. One melanoma patient whose adjuvant pembrolizumab treatment was aborted due to uveitis had disease recurrence documented 10 weeks after her first CPI administration, then received ipilimumab, which was aborted after teo cycles due to severe colitis, but her disease has remained stable since that time (15 months at data cut-off). A second melanoma patient who progressed on completing adjuvant pembrolizumab initially responded to ipilimumab + nivolumab, but died of metastatic disease 19 months after her first CPI administration.
Non-uveitis case studies
Case 1: (‘Melanoma 3’ in Tables 1 and 2)
A 56-year-old man received treatment with ipilimumab + nivolumab for metastatic uveal melanoma, having had exenteration of his left eye 4 years previously. Three weeks after his first CPI administration he complained of severe flashing lights in his remaining eye, and he was referred urgently for an ophthalmological assessment.
On slit lamp biomicroscopy, pale lesions were noted in the fundus, and these were presumed to be benign. He continued immunotherapy, but after 9 weeks (three cycles of CPI), he developed moderately severe pneumonitis which was initially treated with 50 mg oral prednisolone daily and CPI therapy was permanently discontinued. The pneumonitis resolved over 12 weeks and he was gradually weaned off steroids. While tapering his steroids, he noticed that his vision was deteriorating and a visual field defect was detected on formal testing.
Optical coherence tomography (OCT) scanning indicated a choroidal lesion next to the fovea, suggesting a possible neovascular membrane (Figure 1a), which could cause visual loss. This suspicion was confirmed by the presence of early leakage during fundus fluorescein angiography (FFA) (Figure 1b). The choroidal neovascular membrane was treated with a series of intravitreal anti-vascular endothelial growth factor (ranibizumab) injections, until it was deemed to be inactive.
Figure 1. Non-uveitis case study. (a) Optical coherence tomography scan showing a choroidal lesion next to the fovea, possibly representing a neovascular membrane. (b) Fundus fluorescein angiography demonstrating early hyperfluorescence of the juxtafoveal lesion, supporting a diagnosis of choroidal neovascularisation. (c) Pseudocolour image of the fundus showing the dexamethasone 0.7 mg steroid implant.
Electrodiagnostic testing subsequently revealed widespread post-phototransduction cone and rod dysfunction, compatible with MAR. His symptoms partially improved on restarting oral steroids (10 mg prednisolone daily), pointing to an inflammatory cause of his visual symptoms. On the basis of this evidence, he was offered short-acting and long-acting intravitreal steroid implants,22 (dexamethasone 0.7 mg and fluocinolone acetonide, respectively, Figure 1c) to avoid chronic side effects of long-term systemic steroids. At the time of data cut-off, the patient remained disease free, with relatively minor persistent visual impairment.
Case 2: (‘Melanoma 4’ in Tables 1 and 2)
A 40-year-old woman received adjuvant pembrolizumab for stage IIID BRAF wild type melanoma, which was well tolerated, without any IrAEs. After 11 months of treatment, she complained of generalised musculoskeletal pains and fatigue. Restaging scans identified widespread metastases including to liver and bone. She was commenced on ipilimumab + nivolumab. After 6 weeks (post cycle 2), her overall condition deteriorated, with severe fatigue and deterioration in liver function and performance status, although her serum lactate dehydrogenase dropped markedly from 1956 to 498 IU/L during the same time period. Her third cycle of ipilimumab + nivolumab was deferred.
One week later, she presented to the emergency department complaining of sudden onset bilateral loss of vision, worse in the right eye. Visual acuity was 6/15 in the right eye and 6/9 in the left eye, and intraocular pressure was within normal parameters. Iris neovascularisation and a swollen right optic disc were found on slit lamp biomicroscopy and fundoscopy. Brain imaging was requested, and confirmed the absence of metastases. A diagnosis of ocular ischaemic syndrome21 was suggested, but after discussion with the oncology specialist, a possible inflammatory aetiology was considered.
The patient was treated with 40 mg oral prednisolone daily, 0.1% dexamethasone eye drops and 1% mydrilate drops. She responded well to treatment, and was gradually weaned off steroids, and her vision recovered. Her liver function normalised and her performance status improved sufficiently for a return to normal activities of daily living. Subsequent staging compueterised tomography (CT) images indicated a partial response to CPIs. Six months later, despite the patient remaining well and asymptomatic, surveillance imaging identified disease recurrence in previously involved body sites with four new brain metastases. She was re-challenged with ipilimumab + nivolumab. No new IrAEs occurred, but after the second cycle, she was admitted to hospital with seizures due to haemorrhage into the brain metastases and died 10 weeks later, 11 months after starting CPIs for metastatic disease.
Ocular symptom management algorithm
Based on our own experience, review of the literature and international guidelines, we generated a management algorithm designed for multidisciplinary teams to use in clinical practice (Figure 2).
Figure 2. Management algorithm for patients treated with CPIs who present with ocular symptoms.
CPI, checkpoint inhibitor; FAF, fundus autofluorescence; FFA, fundus fluorescein angiography; ICG, indocyanine angiography; OCT, optical coherence tomography.
Patient symptoms and signs are classified according to international common toxicity criteria (CTCAE version 5.0)23 and management is determined by the severity of the condition. The international CTCAE grades classify the severity of ocular conditions from 1 (mild) to 4 (severe, with sight-threatening consequences). Anterior uveitis is graded in correspondence with the number of cells seen on slit lamp examination of the anterior chamber, as defined by the standardisation of uveitis nomenclature.12 Thus, grade 1 uveitis corresponds to a ‘trace’ of cells (1–5 cells in a 1 mm × 1 mm slit beam), and grade 3 uveitis corresponds to ‘3+’ (26–50 cells per field). Posterior uveitis is graded 3. In addition, a visual acuity of 20/200 (6/60 in European terminology) or less, meeting criteria for blindness in the affected eye, is graded as 4.
The ophthalmological assessments of patients with visual disturbance include visual acuity, colour vision and intraocular pressure measurement. A relative afferent pupillary defect can be tested for by carrying out the swinging flashlight test before dilating drops are instilled into the eyes. Our algorithm includes a pathway for specialist ophthalmic investigations used to diagnose uveitis, which may include FFA and indocyanine angiography (ICG), fundus autofluorescence (FAF) and OCT, depending on the individual case.
In the absence of intermediate or posterior signs, invasive dye-based angiography tests would not normally be indicated, but can be used to exclude retinal vasculitis and leakage (FFA) or undiagnosed choroiditis (ICG) in challenging cases. This can be valuable in both the diagnosis and monitoring of inflammatory eye disease.24 Non-invasive FAF imaging is used to map metabolic activity in the retinal photoreceptor and pigment epithelial layers, and can be useful in identifying inflammatory processes occurring in the outer retina.25 OCT scanning provides high resolution images of the retina in cross-section and has transformed modern ophthalmological practice.
In contrast to recommendations in current international guidelines, we have used clinical evidence to justify avoiding the discontinuation of CPIs as much as possible. The algorithm aims to emphasise the need for close liaison between oncologist and specialist ophthalmologist from the point of recognition to resolution of ocular symptoms, as well as the benefit of a multidisciplinary approach involving good communication between the specialties to balance the need for cancer control alongside patient safety and vision preservation.
Discussion
This report of eight patients experiencing ocular IrAEs associated with CPI treatment is one of the largest series published to date. Anterior uveitis was the most common ocular IrAE that we identified, occurring in five of our eight cases. The onset of uveitis is reported mainly to occur within 2 months of starting CPIs.7,13,26 This was generally the case in our cohort, with a median time to onset of 5 weeks (range 1–7 weeks). The exception was a single patient who developed anterior uveitis 2 years after completing 2 years of nivolumab treatment. It is noteworthy that he had other ocular IrAEs while on treatment that did not lead to CPI discontinuation, while his anterior uveitis was difficult to control. It is well recognised that some IrAEs (including ocular IrAEs)13 can occur months and years after stopping CPIs, and this case is a reminder to consider the need for ongoing follow-up, even in patients apparently entering long-term remission after completing treatment.
Ocular IrAEs may occur as the only IrAE, or in association with multiple body system IrAEs. In our series, their occurrence influenced the decision to interrupt CPI treatment in all seven patients who discontinued treatment early: uveitis was the primary reason for discontinuation in two (29%) patients, but contributed to the decision to stop treatment in the remaining five patients, all of whom experienced multiple IrAEs.
A literature review of 33 cases of uveitis secondary to CPIs10 concluded that one-third of patients experienced anterior uveitis alone, one-third had anterior uveitis plus posterior segment changes including macular oedema, retinal detachment, vitritis or papillitis, and one-third had panuveitis. A very recent larger review of 126 cases of CPI-associated uveitis was broadly consistent, noting that 35% of panuveitis cases occurred as part of a Vogt–Koyanagi–Harada (VKH)-like syndrome.27–30 VKH disease is a multisystem disease affecting melanin-containing tissues, which is thought to be autoimmune in origin. The most significant ocular manifestation is bilateral diffuse panuveitis with exudative retinal detachment, often accompanied by a variable spectrum of symptoms involving the skin, nervous system and inner ear.
Recognition of the different presentations of the subtypes of uveitis is clearly important, as this influences whether topical steroids alone can be used for treatment, sparing patients the need for systemic steroids which may adversely affect the outcome of anti-cancer treatment.7 As in our own series, most published series describe initial intervention with topical and/or oral corticosteroids. Although outcomes are generally good, with complete resolution of inflammation in most cases, some cases are recalcitrant, warranting alternative immunomodulatory agents, while peri-ocular or intravitreal steroids22 have been employed as steroid-sparing strategies.
Prompt recognition of ocular and visual symptoms by oncologists and referral to ophthalmology specialists is necessary to ensure rapid investigation, diagnosis and sight-preserving treatment, as well as to inform multidisciplinary team opinion concerning ongoing treatment with CPIs. This can be challenging, because the ocular symptoms experienced may not directly correlate with the severity of inflammation identified.14 Even so, in most of the case series published to date, the overwhelming majority of patients experiencing ocular irAEs have had their CPIs discontinued,12,13 and uncertainty exists whether this line of action may impact overall treatment outcomes.
Perhaps because of its low incidence relative to other IrAEs, the ESMO guidelines5 offer very little advice on how to manage ocular IrAEs. The American Society of Clinical Oncology (ASCO) guidelines,6 on the other hand, are far more extensive and recommend referral to ophthalmology services for new onset visual symptoms, while they also recognise that symptoms may not always correlate with severity. The guidelines make use of the CTCAE grading system for ocular IrAEs and include management recommendations on whether to withhold, or discontinue, immunotherapy. While these constitute a welcome framework, they may also prove unnecessarily restrictive.
The ASCO guidelines recommend that for grade 1 ocular IrAEs, CPIs can be continued, for grade 2 events CPIs should be withheld and for grades 3 and 4 events they should be permanently discontinued. Ocular IrAEs, while not usually life threatening, may be life changing, so urgent intervention aimed at avoiding permanent loss of eyesight is certainly warranted. However, it is important to note that even severe deterioration in visual acuity can sometimes be reversible. For example, significant visual impairment associated with macular oedema may recover following prompt treatment with oral or intravitreal steroids. In adherence to ASCO guidance, loss of visual acuity may result in an adverse event grading of 3 or 4, which we consider could unnecessarily lead to permanent cessation of immunotherapy.
In some patients who resume CPIs after treatment for IrAEs, relapse with the same symptoms has been observed.9,13 We argue that permanent discontinuation of immunotherapy may not always be justified in these circumstances. In our own series, one patient experienced significant bilateral loss of vision associated with an ocular IrAE after two cycles of CPI with ipilimumab + nivolumab, but did not experience further ocular symptoms on retreatment several months later. Moreover, a severe or acute drop in visual acuity may be due to other pathologies unrelated to CPI (for example, incidental retinal detachment, which has a lifetime risk in normal individuals of one in 300).31 On the other hand, a patient could have apparently mild visual impairment but severe intra-ocular inflammation.
We recommend early referral to an ophthalmology specialist on recognition of ocular symptoms to diagnose the possible ocular IrAE and accurately grade its severity. We further recommend that both eye treatment and the ongoing use of CPIs are discussed on an individual case basis within a multidisciplinary team of oncologists and ophthalmologists, keeping the option open for retreatment in situations in which the possible benefits outweigh the risks, assuming appropriate patient counselling and support.
Most cases of uveitis associated with CPI, including the majority of our cases, are mild and would be categorised as CTCAE grade 2. These cases do not require cessation of CPI and neither should they require systemic steroids, in general. The outcomes from topical treatment are mainly good, with either a limited course, or sometimes ongoing topical steroids. If systemic steroids are used, the ASCO guidelines recommend that CPIs are withheld until the patient is either off all steroids or is receiving a daily dose of 10 mg oral prednisolone (or equivalent) or less. As far as possible, the aim should be to treat ocular IrAEs with local options in order to avoid systemic steroids and cessation of CPI therapy. Aside from concerns regarding their impact on CPI efficacy, long-term steroid use is associated with many well-known harmful effects.
The goal of avoiding the interruption of CPI therapy is best achieved by taking a multidisciplinary approach, with close liaison between ophthalmology and oncology teams, remembering that patients may have a high degree of anxiety about stopping potentially life-saving anti-cancer therapy. In our cohort, five patients stopped CPIs due to ocular IrAEs, despite being categorised as grade 2, which does not necessarily mandate permanent discontinuation. Three of these patients were treated solely with topical steroids, which suggests a low threat to vision, and which would not normally interfere with CPIs. In cases where topical steroids are not sufficient, intravitreal or periocular steroids should be considered to enable patients to remain on CPIs.
It is possible that patients diagnosed with melanoma may be at increased risk of developing uveitis due to the presence of melanin in the retinal pigment epithelium. An immune-mediated response to melanin-producing cells in the eye may occur both in patients on treatment and in those who develop an immunological reaction to their cancer independent of treatment. In our series, MAR was the most likely diagnosis in one of two patients reporting ocular toxicities that were not due to uveitis, based on symptoms described and investigations performed. The pathology is thought to be due to shared neuroectodermal lineage of melanocytes and retinal cells. Conversely, uveitis is not unique to patients with a diagnosis of melanoma. Patients at increased risk of uveitis may include those with other immune-related side effects and those predisposed to autoimmune disease or with a significant family history.32
Four of our patients, of whom two had other IrAEs, responded very well to retreatment with CPIs, highlighting a key unanswered question concerning whether the occurrence of IrAEs can predict a therapeutic response.32,33 Several studies have reported increased progression-free and overall survival in patients who experienced IrAEs with CPIs compared to those who did not.34,35 To date, it remains unclear whether the development of uveitis or other specific IrAEs is associated with better outcomes from treatment with CPIs,34,36 although it is quite plausible that an observed inflammatory response within the eye or elsewhere might reflect an enhanced immune response against cancer. The number of patients in our study is insufficient to answer this question, but further study is warranted and, if proved, this could be reassuring for patients who have previously stopped immunotherapy while being treated for inflammatory side effects.
In conclusion, ocular IrAEs are relatively uncommon IrAEs associated with CPIs, but can be dramatic and may lead to permanent visual loss. Prompt recognition in oncology clinics and early referral to an ophthalmologist is essential. Patients with confirmed ocular inflammation require close monitoring in the eye clinic and ongoing liaison with their oncologist regarding optimal treatment and the use of corticosteroids. The option of intraocular steroid implants should be considered as an alternative to systemic steroids when IrAEs do not resolve with topical steroids alone, with the potential benefit of being able to continue on CPIs.
In conjunction with our ocular IrAE management algorithm (Figure 2), we propose the following basic steps to follow when seeing immunotherapy patients with ocular symptoms in the clinic:
document the symptoms and signs and their severity
escalate by referral to an ophthalmologist; consider urgency of referral and the need to interrupt CPI therapy depending on symptom severity
obtain an ophthalmological diagnosis
take a multidisciplinary approach to managing the ocular symptoms and the need or otherwise to restart CPIs, based on risk/benefit considerations.
The authors would like to thank the patients and their families for allowing us to share their case studies. Thanks also to the CUHFT research governance and audit teams for their assistance in the conduct of this study.
Conflict of interest: The authors declare that there is no conflict of interest.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Philippa Corrie
https://orcid.org/0000-0003-4875-7021 | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY-NC | 33633802 | 19,074,033 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Conjunctivitis'. | Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm.
Ocular immune-related adverse events (IrAEs) associated with use of checkpoint inhibitors (CPIs) in cancer therapeutics are relatively rare, occurring in approximately 1% of treated patients. Recognition and early intervention are essential because the degree of tissue damage may be disproportionate to the symptoms, and lack of appropriate treatment risks permanent loss of vision. International guidelines on managing ocular IrAEs provide limited advice only. Importantly, local interventions can be effective and may avoid the need for systemic corticosteroids, thereby permitting the continuation of CPIs. We present a single institution case series of eight affected patients managed by our multidisciplinary team. Consistent with previously published series and case reports, we identified anterior uveitis as the most common ocular IrAE associated with CPIs requiring intervention. Based on our experience, as well as published guidance, we generated a simple algorithm to assist clinicians efficiently manage patients developing ocular symptoms during treatment with CPIs. In addition, we make recommendations for optimising treatment of uveitis and address implications for ongoing CPI therapy.
Background
Immunotherapy with checkpoint inhibitors (CPIs) has transformed the treatment of a wide range of malignancies.1,2 These drugs work by enabling the host immune system to eliminate malignant cells, recognisable through the expression of neoantigens. The CPIs currently in clinical use are antibodies which target the cytotoxic T-lymphocyte antigen-4 receptor (anti-CTLA-4), the programmed death-1 receptor (anti-PD-1) and its ligand (anti-PD-L1). The CTLA-4 receptor downregulates T-cell activation, whereas the PD-1 receptor inhibits T-cell proliferation, cytokine release, and cytotoxicity. Blocking their function can enhance T-cell response and allow immune-mediated tumour killing.
CPIs generate side effects termed immune-related adverse events (IrAEs), which stem from their mechanism of action, being predominantly autoimmune in nature and having the potential to affect any body organ. IrAEs range from being mild to life-threatening, or life-changing in some instances.3 Since their first introduction into clinical practice in 2011 as treatment for metastatic melanoma, the use of anti-CTLA-4 and anti-PD-L1 antibodies has expanded to include multiple cancer types including lung and urological cancers as well as lymphomas, with new treatment indications being added frequently. Their increasing use has resulted in greater awareness of both common and rarely seen IrAEs, ranging from mild presentations to severe reactions requiring prompt intervention.4
Optimal management of IrAEs is still in its infancy, with limited evidence to inform international guidelines which have been generated to assist clinical practice.5,6 The mainstay of treatment for what appear to be inflammatory conditions is immunosuppression with corticosteroids, prompting concerns about their effect on CPI efficacy.7 Moreover, the long-term effects on cancer survivors of high dose steroids, sometimes administered for protracted periods of time, have yet to be fully understood. The European Society of Medical Oncology (ESMO) clinical practice guidelines5 provide helpful algorithms for managing the more commonly occurring IrAEs, but consensus advice on managing less common IrAEs, such as those affecting the eyes, is also needed to minimise any negative impact of anti-cancer interventions.
Ocular IrAEs occur with an estimated prevalence of 1–3% of all treated patients.8,9 While the spectrum of severity is broad, they are highly significant as they can threaten vision. Reports of ocular IrAEs associated with CPIs are limited to small, single-digit case series and individual case reports, which principally report patients experiencing varying degrees of uveitis.8,10–13
Uveitis is a term used to describe inflammation of the uvea, the middle layer of the eye comprising the iris, ciliary body and choroid. It is classified as anterior, intermediate, posterior, or panuveitis, according to the predominant site of inflammation within the eye.14 Anterior uveitis is characterised by an infiltrate of white blood cells in the anterior chamber of the eye; intermediate uveitis is associated with inflammation in the vitreous gel, resulting in visual blurring, haze and floaters; posterior uveitis is characterised by retinal and/or choroidal inflammation.15,16 Symptoms of uveitis include pain, blurred vision and red eye. Involvement of the posterior segment can produce symptoms of floaters, flickering and shimmering lights (photopsias), as well as blind spots.
Anterior uveitis, whether acute or chronic, can often be managed with topical steroid drops alone. Severe uveitis of any subtype may lead to macular oedema, with accumulation of fluid at the most sensitive part of the retina, causing visual distortion and blurring. Severe ocular inflammation requires prompt intervention to avoid permanent loss of vision, and may require periocular or intravitreal steroid injections. More severe cases require systemic steroids, including oral, or pulsed intravenous methylprednisolone. Recalcitrant, chronic inflammatory eye diseases can be managed with secondary non-corticosteroid immunomodulatory therapeutic agents, including anti-metabolites like mycophenolate mofetil and methotrexate, or biological drugs like adalimumab.17 Common complications of uveitis and its treatment include cataract, glaucoma and choroidal neovascularisation. While most reports suggest a good response to therapy with complete resolution of inflammation, a minority of patients may develop permanent visual loss.
Other less common ocular IrAEs include ocular myasthenia, optic neuritis and auto-immune retinopathy. Dry eyes are described by up to one in four treated patients, but this is a common condition that is often not reported in clinical trials and is frequently undertreated, even in clinical practice.8,9 The risk of ocular IrAEs associated with CPIs was recently quantified using disproportionality analysis; odds ratios for uveitis ranged from 4.6 to 10.8, while that of any ocular IrAE was 2.5 compared with reported events associated with all other drugs.18
Uncertainties about optimal management of ocular IrAEs persist, such as when to interrupt or discontinue potentially life-saving CPI therapy and whether systemic steroids can influence the efficacy of CPIs. We report our experience of managing ocular IrAEs in a cohort of cancer patients receiving CPIs in a single institution and make management recommendations in a novel treatment algorithm.
Methods
We reviewed the electronic patient records of patients treated with CPIs from January to December 2019, and identified all cases referred to the ophthalmology service. The clinical characteristics, treatment and course of IrAEs over time were recorded. Details of their CPI treatment, other non-ocular irAEs, and disease response (based on routine radiological imaging and applying RECIST 1.1 response criteria) were also recorded. Survival was measured from the date of first CPI infusion until data cut-off, on 17 March, 2020.
Based on our case series and information contained in published international guidelines,5,6 we generated a simple assessment and treatment algorithm for use in routine clinical practice to guide the multidisciplinary team managing ocular symptoms and uveitis; the most common ocular IrAE reported.
This project was registered as a health service evaluation at Cambridge University Hospitals NHS Foundation Trust (CUHFT). The CUHFT research governance lead confirmed that, under the UK Policy Framework for Health and Social Care Research 2017, this project would not be classified or managed as research within the National Health Service and therefore did not require ethical review by a research ethics committee. Written informed consent to publish was obtained from the surviving case study patient.
Results
Patient characteristics
We identified eight patients (three women and five men, aged between 39 and 81 years) who developed ocular IrAEs after starting CPIs (Table 1). Seven patients were treated for advanced cancer; four for metastatic melanoma, two metastatic renal-cell carcinoma and one advanced ovarian carcinoma. One melanoma patient received CPI as an adjuvant therapy, after resection of regional lymph node disease. None had a previous history of uveitis. One patient had a history of glaucoma. Five patients received combination anti-CTLA-4 plus anti-PD-1 antibodies (ipilimumab + nivolumab), two patients received a single agent anti-PD-1 antibody (one pembrolizumab, one nivolumab) and one patient received anti-PD-1 antibody (nivolumab) in combination with a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor (rucaparib). Seven patients had their treatment discontinued early due to treatment-related adverse events; their treatment duration ranged from 3 to 9 weeks. The median number of adverse events contributing to treatment discontinuation was three (range 1–3). One patient completed 2 years of planned anti-PD-1 antibody therapy.
Table 1. Patient characteristics of patients experiencing ocular IrAEs associated with CPI treatment.
Patient case CPI regimen Duration of CPI therapy Reason for discontinuation AEs leading to discontinuation Best response to CPI Survival outcome
Melanoma-1
Metastatic
50-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Ocular IrAE Ocular
Skin
Fatigue Partial response Alive 16 months+
Kidney-1
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 3 weeks Multiple IrAE Ocular
Skin
Liver Stable disease Alive 15 months+
Kidney-2
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 4 weeks Multiple IrAEs Ocular
Liver
Arthritis Partial response Alive 16 months+
Ovarian
Metastatic
40-yo woman Nivolumab + rucaparib 8 weeks Multiple IrAE Ocular
Liver
Neutropaenia* Partial response Alive 10 months+
Melanoma-2
Resected stage III
74-yo woman Pembrolizumab
200 mg IV q3w 3 weeks Ocular IrAE Ocular Recurrence Treated with ipilimumab on recurrence; aborted after 6 weeks due to colitis.
Alive with stable disease:
14 months+
Melanoma-3
Metastatic
56-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Multiple IrAEs Ocular
Lung Partial response Alive 22 months+
Melanoma-4
Metastatic
40-yo woman Ipilimumab
1 mg/kg+ nivolumab 3 mg/kg 6 weeks Multiple IrAEs Ocular
Liver Partial response Rechallenged with 2 further cycles of ipilimumab+nivolumab on disease progression without significant IrAEs; progressive brain metastases.
Died after 11 months
Melanoma-5
Metastatic
81-yo man Nivolumab 240 mg 2 years Completed planned treatment – Near complete response Alive 5 years+
* Likely due to PARP inhibitor, not CPI.
AEs, adverse events; CPI, checkpoint inhibitor; IrEAs, immune-related adverse events; yo, year-old; PARP, poly-adenosine diphosphate ribose polymerase.
Ocular IrAE characteristics
The median time to the onset of ocular IrAE was 5 weeks from starting CPIs, although one patient developed symptoms after 18 months of treatment (Table 2). In all seven patients who discontinued CPIs early, ocular IrAE contributed to the decision to discontinue therapy. One patient with pre-existing glaucoma experienced ocular IrAE as the only IrAE, occurring after her first dose of pembrolizumab, and this led to treatment discontinuation. Four patients were diagnosed with anterior uveitis, one had intermediate uveitis, one had melanoma-associated retinopathy (MAR)19,20 and one had suspected ocular ischaemic syndrome.21 All patients had bilateral eye involvement. There were no hospitalisations associated with ocular IrAEs.
Table 2. Characteristics of ocular IrAEs experienced and their treatment.
Patient case Presenting symptoms Ocular IrAE Worst
CTCAE
grade Time to onset/resolution of ocular IrAE Worst visual acuity Visual acuity on resolution Local treatment Systemic steroids (starting dose) Outcome of ocular IrAE
Melanoma 1 Bilateral blurred vision, painful eyes Anterior uveitis 2 3 weeks/8 weeks R 6/19
L Normal R Normal
L Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Kidney 1 Bilateral blurred vision, painful eyes, headache Anterior uveitis
High IO pressures 2 5 weeks/11 weeks (uveitis)
6 months
(IO pressures) R 6/9.5
L 6/7.5 R Normal
L Normal Dexamethasone 0.1% drops
Timolol
Latanprost None Complete resolution
Kidney 2 Bilateral painful red eyes, light sensitivity Anterior uveitis
Left disc swelling 2 5 weeks/8 weeks Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Ovarian Bilateral blurred vision. Painful to focus Anterior uveitis 2 5 weeks/8 months Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Melanoma 2 Deterioration in vision Intermediate
uveitis 3 1 week/10 weeks R 6/9
L Normal R 6/9
L Normal None 40 mg prednisolone Resolved on 10 mg prednisolone; following 2 cycles of ipilimumab,
received IV steroids and infliximab for enteritis
Melanoma 3 Flashing lights, visual aura Melanoma associated retinopathy 4 3 weeks/18 months R 6/18 R 6/5 Anti-VEGF injections
Intra-ocular dexamethasone 50 mg prednisolone Permanent loss of vision; macular scarring
Melanoma 4 Rapid onset loss of vision in both eyes Suspected ocular ischaemic syndrome 4 7 weeks/4 weeks R 6/15
L 6/9 R Normal
L Normal Dexamethasone 0.1% drops
Mydrilate 1% drops 40 mg prednisolone Complete resolution
Melanoma 5 Red, eyes
Loss of vision in left eye
Blurred vision Conjunctivitis
Left retinal detachment*
Anterior uveitis 2
2 18 months
21 months
4 years/10 months R 6/12
L 6/7.5 R 6/12
L 6/7.5 Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Quiescent
* Association of retinal detachment as an IrAE could not be confirmed.
CTCAE, common toxicity criteria; IO, intra-ocular; IrEA, immune-related adverse event; IV, intravenous; L, left; R, right; VEGF, vascular endothelial growth factor.
The patient completing 2 years of nivolumab experienced ocular IrAEs both during and after completing CPI treatment. As the symptoms were manageable and no other IrAEs occurred, his planned treatment was not interrupted. He experienced conjunctivitis and left retinal detachment during treatment, both of which were managed successfully. Two years after completing CPIs, he developed bilateral anterior uveitis.
Treatment of ocular IrAEs
All five patients who developed anterior uveitis were treated with topical steroids only. The three other ocular conditions (intermediate uveitis, MAR and suspected ocular ischaemic syndrome) were treated with oral corticosteroids. No patients received intravenous steroids or other immunosuppressive agents to treat their ocular IrAEs. One patient diagnosed with MAR received intravitreal anti-vascular endothelial growth factor injections to treat a juxtafoveal choroidal neovascular membrane, as well as intra-ocular steroid implants to treat chronic photopsia in his only remaining eye.
The median ocular IrAE treatment duration was 11 weeks (range 8 weeks–10 months) with topical steroids and 10 weeks (range 4 weeks–6 months) with oral steroids. Two patients with anterior uveitis had rapid, complete resolution of their symptoms by 8 and 11 weeks. One patient had persistently raised intra-ocular pressures for approximately 6 months. Two patients had a protracted course of inflammatory eye disease, with recurrent episodes lasting 8 and 10 months, respectively. Of two patients re-challenged with CPIs at a later date, (one with ipilimumab, one with ipilimumab + nivolumab), neither had recurrence of ocular IrAEs.
Oncological response to CPIs
Overall, six out of the eight treated patients experienced a partial or near complete response to CPI therapy and seven remain alive and well at data cut-off. One melanoma patient whose adjuvant pembrolizumab treatment was aborted due to uveitis had disease recurrence documented 10 weeks after her first CPI administration, then received ipilimumab, which was aborted after teo cycles due to severe colitis, but her disease has remained stable since that time (15 months at data cut-off). A second melanoma patient who progressed on completing adjuvant pembrolizumab initially responded to ipilimumab + nivolumab, but died of metastatic disease 19 months after her first CPI administration.
Non-uveitis case studies
Case 1: (‘Melanoma 3’ in Tables 1 and 2)
A 56-year-old man received treatment with ipilimumab + nivolumab for metastatic uveal melanoma, having had exenteration of his left eye 4 years previously. Three weeks after his first CPI administration he complained of severe flashing lights in his remaining eye, and he was referred urgently for an ophthalmological assessment.
On slit lamp biomicroscopy, pale lesions were noted in the fundus, and these were presumed to be benign. He continued immunotherapy, but after 9 weeks (three cycles of CPI), he developed moderately severe pneumonitis which was initially treated with 50 mg oral prednisolone daily and CPI therapy was permanently discontinued. The pneumonitis resolved over 12 weeks and he was gradually weaned off steroids. While tapering his steroids, he noticed that his vision was deteriorating and a visual field defect was detected on formal testing.
Optical coherence tomography (OCT) scanning indicated a choroidal lesion next to the fovea, suggesting a possible neovascular membrane (Figure 1a), which could cause visual loss. This suspicion was confirmed by the presence of early leakage during fundus fluorescein angiography (FFA) (Figure 1b). The choroidal neovascular membrane was treated with a series of intravitreal anti-vascular endothelial growth factor (ranibizumab) injections, until it was deemed to be inactive.
Figure 1. Non-uveitis case study. (a) Optical coherence tomography scan showing a choroidal lesion next to the fovea, possibly representing a neovascular membrane. (b) Fundus fluorescein angiography demonstrating early hyperfluorescence of the juxtafoveal lesion, supporting a diagnosis of choroidal neovascularisation. (c) Pseudocolour image of the fundus showing the dexamethasone 0.7 mg steroid implant.
Electrodiagnostic testing subsequently revealed widespread post-phototransduction cone and rod dysfunction, compatible with MAR. His symptoms partially improved on restarting oral steroids (10 mg prednisolone daily), pointing to an inflammatory cause of his visual symptoms. On the basis of this evidence, he was offered short-acting and long-acting intravitreal steroid implants,22 (dexamethasone 0.7 mg and fluocinolone acetonide, respectively, Figure 1c) to avoid chronic side effects of long-term systemic steroids. At the time of data cut-off, the patient remained disease free, with relatively minor persistent visual impairment.
Case 2: (‘Melanoma 4’ in Tables 1 and 2)
A 40-year-old woman received adjuvant pembrolizumab for stage IIID BRAF wild type melanoma, which was well tolerated, without any IrAEs. After 11 months of treatment, she complained of generalised musculoskeletal pains and fatigue. Restaging scans identified widespread metastases including to liver and bone. She was commenced on ipilimumab + nivolumab. After 6 weeks (post cycle 2), her overall condition deteriorated, with severe fatigue and deterioration in liver function and performance status, although her serum lactate dehydrogenase dropped markedly from 1956 to 498 IU/L during the same time period. Her third cycle of ipilimumab + nivolumab was deferred.
One week later, she presented to the emergency department complaining of sudden onset bilateral loss of vision, worse in the right eye. Visual acuity was 6/15 in the right eye and 6/9 in the left eye, and intraocular pressure was within normal parameters. Iris neovascularisation and a swollen right optic disc were found on slit lamp biomicroscopy and fundoscopy. Brain imaging was requested, and confirmed the absence of metastases. A diagnosis of ocular ischaemic syndrome21 was suggested, but after discussion with the oncology specialist, a possible inflammatory aetiology was considered.
The patient was treated with 40 mg oral prednisolone daily, 0.1% dexamethasone eye drops and 1% mydrilate drops. She responded well to treatment, and was gradually weaned off steroids, and her vision recovered. Her liver function normalised and her performance status improved sufficiently for a return to normal activities of daily living. Subsequent staging compueterised tomography (CT) images indicated a partial response to CPIs. Six months later, despite the patient remaining well and asymptomatic, surveillance imaging identified disease recurrence in previously involved body sites with four new brain metastases. She was re-challenged with ipilimumab + nivolumab. No new IrAEs occurred, but after the second cycle, she was admitted to hospital with seizures due to haemorrhage into the brain metastases and died 10 weeks later, 11 months after starting CPIs for metastatic disease.
Ocular symptom management algorithm
Based on our own experience, review of the literature and international guidelines, we generated a management algorithm designed for multidisciplinary teams to use in clinical practice (Figure 2).
Figure 2. Management algorithm for patients treated with CPIs who present with ocular symptoms.
CPI, checkpoint inhibitor; FAF, fundus autofluorescence; FFA, fundus fluorescein angiography; ICG, indocyanine angiography; OCT, optical coherence tomography.
Patient symptoms and signs are classified according to international common toxicity criteria (CTCAE version 5.0)23 and management is determined by the severity of the condition. The international CTCAE grades classify the severity of ocular conditions from 1 (mild) to 4 (severe, with sight-threatening consequences). Anterior uveitis is graded in correspondence with the number of cells seen on slit lamp examination of the anterior chamber, as defined by the standardisation of uveitis nomenclature.12 Thus, grade 1 uveitis corresponds to a ‘trace’ of cells (1–5 cells in a 1 mm × 1 mm slit beam), and grade 3 uveitis corresponds to ‘3+’ (26–50 cells per field). Posterior uveitis is graded 3. In addition, a visual acuity of 20/200 (6/60 in European terminology) or less, meeting criteria for blindness in the affected eye, is graded as 4.
The ophthalmological assessments of patients with visual disturbance include visual acuity, colour vision and intraocular pressure measurement. A relative afferent pupillary defect can be tested for by carrying out the swinging flashlight test before dilating drops are instilled into the eyes. Our algorithm includes a pathway for specialist ophthalmic investigations used to diagnose uveitis, which may include FFA and indocyanine angiography (ICG), fundus autofluorescence (FAF) and OCT, depending on the individual case.
In the absence of intermediate or posterior signs, invasive dye-based angiography tests would not normally be indicated, but can be used to exclude retinal vasculitis and leakage (FFA) or undiagnosed choroiditis (ICG) in challenging cases. This can be valuable in both the diagnosis and monitoring of inflammatory eye disease.24 Non-invasive FAF imaging is used to map metabolic activity in the retinal photoreceptor and pigment epithelial layers, and can be useful in identifying inflammatory processes occurring in the outer retina.25 OCT scanning provides high resolution images of the retina in cross-section and has transformed modern ophthalmological practice.
In contrast to recommendations in current international guidelines, we have used clinical evidence to justify avoiding the discontinuation of CPIs as much as possible. The algorithm aims to emphasise the need for close liaison between oncologist and specialist ophthalmologist from the point of recognition to resolution of ocular symptoms, as well as the benefit of a multidisciplinary approach involving good communication between the specialties to balance the need for cancer control alongside patient safety and vision preservation.
Discussion
This report of eight patients experiencing ocular IrAEs associated with CPI treatment is one of the largest series published to date. Anterior uveitis was the most common ocular IrAE that we identified, occurring in five of our eight cases. The onset of uveitis is reported mainly to occur within 2 months of starting CPIs.7,13,26 This was generally the case in our cohort, with a median time to onset of 5 weeks (range 1–7 weeks). The exception was a single patient who developed anterior uveitis 2 years after completing 2 years of nivolumab treatment. It is noteworthy that he had other ocular IrAEs while on treatment that did not lead to CPI discontinuation, while his anterior uveitis was difficult to control. It is well recognised that some IrAEs (including ocular IrAEs)13 can occur months and years after stopping CPIs, and this case is a reminder to consider the need for ongoing follow-up, even in patients apparently entering long-term remission after completing treatment.
Ocular IrAEs may occur as the only IrAE, or in association with multiple body system IrAEs. In our series, their occurrence influenced the decision to interrupt CPI treatment in all seven patients who discontinued treatment early: uveitis was the primary reason for discontinuation in two (29%) patients, but contributed to the decision to stop treatment in the remaining five patients, all of whom experienced multiple IrAEs.
A literature review of 33 cases of uveitis secondary to CPIs10 concluded that one-third of patients experienced anterior uveitis alone, one-third had anterior uveitis plus posterior segment changes including macular oedema, retinal detachment, vitritis or papillitis, and one-third had panuveitis. A very recent larger review of 126 cases of CPI-associated uveitis was broadly consistent, noting that 35% of panuveitis cases occurred as part of a Vogt–Koyanagi–Harada (VKH)-like syndrome.27–30 VKH disease is a multisystem disease affecting melanin-containing tissues, which is thought to be autoimmune in origin. The most significant ocular manifestation is bilateral diffuse panuveitis with exudative retinal detachment, often accompanied by a variable spectrum of symptoms involving the skin, nervous system and inner ear.
Recognition of the different presentations of the subtypes of uveitis is clearly important, as this influences whether topical steroids alone can be used for treatment, sparing patients the need for systemic steroids which may adversely affect the outcome of anti-cancer treatment.7 As in our own series, most published series describe initial intervention with topical and/or oral corticosteroids. Although outcomes are generally good, with complete resolution of inflammation in most cases, some cases are recalcitrant, warranting alternative immunomodulatory agents, while peri-ocular or intravitreal steroids22 have been employed as steroid-sparing strategies.
Prompt recognition of ocular and visual symptoms by oncologists and referral to ophthalmology specialists is necessary to ensure rapid investigation, diagnosis and sight-preserving treatment, as well as to inform multidisciplinary team opinion concerning ongoing treatment with CPIs. This can be challenging, because the ocular symptoms experienced may not directly correlate with the severity of inflammation identified.14 Even so, in most of the case series published to date, the overwhelming majority of patients experiencing ocular irAEs have had their CPIs discontinued,12,13 and uncertainty exists whether this line of action may impact overall treatment outcomes.
Perhaps because of its low incidence relative to other IrAEs, the ESMO guidelines5 offer very little advice on how to manage ocular IrAEs. The American Society of Clinical Oncology (ASCO) guidelines,6 on the other hand, are far more extensive and recommend referral to ophthalmology services for new onset visual symptoms, while they also recognise that symptoms may not always correlate with severity. The guidelines make use of the CTCAE grading system for ocular IrAEs and include management recommendations on whether to withhold, or discontinue, immunotherapy. While these constitute a welcome framework, they may also prove unnecessarily restrictive.
The ASCO guidelines recommend that for grade 1 ocular IrAEs, CPIs can be continued, for grade 2 events CPIs should be withheld and for grades 3 and 4 events they should be permanently discontinued. Ocular IrAEs, while not usually life threatening, may be life changing, so urgent intervention aimed at avoiding permanent loss of eyesight is certainly warranted. However, it is important to note that even severe deterioration in visual acuity can sometimes be reversible. For example, significant visual impairment associated with macular oedema may recover following prompt treatment with oral or intravitreal steroids. In adherence to ASCO guidance, loss of visual acuity may result in an adverse event grading of 3 or 4, which we consider could unnecessarily lead to permanent cessation of immunotherapy.
In some patients who resume CPIs after treatment for IrAEs, relapse with the same symptoms has been observed.9,13 We argue that permanent discontinuation of immunotherapy may not always be justified in these circumstances. In our own series, one patient experienced significant bilateral loss of vision associated with an ocular IrAE after two cycles of CPI with ipilimumab + nivolumab, but did not experience further ocular symptoms on retreatment several months later. Moreover, a severe or acute drop in visual acuity may be due to other pathologies unrelated to CPI (for example, incidental retinal detachment, which has a lifetime risk in normal individuals of one in 300).31 On the other hand, a patient could have apparently mild visual impairment but severe intra-ocular inflammation.
We recommend early referral to an ophthalmology specialist on recognition of ocular symptoms to diagnose the possible ocular IrAE and accurately grade its severity. We further recommend that both eye treatment and the ongoing use of CPIs are discussed on an individual case basis within a multidisciplinary team of oncologists and ophthalmologists, keeping the option open for retreatment in situations in which the possible benefits outweigh the risks, assuming appropriate patient counselling and support.
Most cases of uveitis associated with CPI, including the majority of our cases, are mild and would be categorised as CTCAE grade 2. These cases do not require cessation of CPI and neither should they require systemic steroids, in general. The outcomes from topical treatment are mainly good, with either a limited course, or sometimes ongoing topical steroids. If systemic steroids are used, the ASCO guidelines recommend that CPIs are withheld until the patient is either off all steroids or is receiving a daily dose of 10 mg oral prednisolone (or equivalent) or less. As far as possible, the aim should be to treat ocular IrAEs with local options in order to avoid systemic steroids and cessation of CPI therapy. Aside from concerns regarding their impact on CPI efficacy, long-term steroid use is associated with many well-known harmful effects.
The goal of avoiding the interruption of CPI therapy is best achieved by taking a multidisciplinary approach, with close liaison between ophthalmology and oncology teams, remembering that patients may have a high degree of anxiety about stopping potentially life-saving anti-cancer therapy. In our cohort, five patients stopped CPIs due to ocular IrAEs, despite being categorised as grade 2, which does not necessarily mandate permanent discontinuation. Three of these patients were treated solely with topical steroids, which suggests a low threat to vision, and which would not normally interfere with CPIs. In cases where topical steroids are not sufficient, intravitreal or periocular steroids should be considered to enable patients to remain on CPIs.
It is possible that patients diagnosed with melanoma may be at increased risk of developing uveitis due to the presence of melanin in the retinal pigment epithelium. An immune-mediated response to melanin-producing cells in the eye may occur both in patients on treatment and in those who develop an immunological reaction to their cancer independent of treatment. In our series, MAR was the most likely diagnosis in one of two patients reporting ocular toxicities that were not due to uveitis, based on symptoms described and investigations performed. The pathology is thought to be due to shared neuroectodermal lineage of melanocytes and retinal cells. Conversely, uveitis is not unique to patients with a diagnosis of melanoma. Patients at increased risk of uveitis may include those with other immune-related side effects and those predisposed to autoimmune disease or with a significant family history.32
Four of our patients, of whom two had other IrAEs, responded very well to retreatment with CPIs, highlighting a key unanswered question concerning whether the occurrence of IrAEs can predict a therapeutic response.32,33 Several studies have reported increased progression-free and overall survival in patients who experienced IrAEs with CPIs compared to those who did not.34,35 To date, it remains unclear whether the development of uveitis or other specific IrAEs is associated with better outcomes from treatment with CPIs,34,36 although it is quite plausible that an observed inflammatory response within the eye or elsewhere might reflect an enhanced immune response against cancer. The number of patients in our study is insufficient to answer this question, but further study is warranted and, if proved, this could be reassuring for patients who have previously stopped immunotherapy while being treated for inflammatory side effects.
In conclusion, ocular IrAEs are relatively uncommon IrAEs associated with CPIs, but can be dramatic and may lead to permanent visual loss. Prompt recognition in oncology clinics and early referral to an ophthalmologist is essential. Patients with confirmed ocular inflammation require close monitoring in the eye clinic and ongoing liaison with their oncologist regarding optimal treatment and the use of corticosteroids. The option of intraocular steroid implants should be considered as an alternative to systemic steroids when IrAEs do not resolve with topical steroids alone, with the potential benefit of being able to continue on CPIs.
In conjunction with our ocular IrAE management algorithm (Figure 2), we propose the following basic steps to follow when seeing immunotherapy patients with ocular symptoms in the clinic:
document the symptoms and signs and their severity
escalate by referral to an ophthalmologist; consider urgency of referral and the need to interrupt CPI therapy depending on symptom severity
obtain an ophthalmological diagnosis
take a multidisciplinary approach to managing the ocular symptoms and the need or otherwise to restart CPIs, based on risk/benefit considerations.
The authors would like to thank the patients and their families for allowing us to share their case studies. Thanks also to the CUHFT research governance and audit teams for their assistance in the conduct of this study.
Conflict of interest: The authors declare that there is no conflict of interest.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Philippa Corrie
https://orcid.org/0000-0003-4875-7021 | NIVOLUMAB | DrugsGivenReaction | CC BY-NC | 33633802 | 19,074,234 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Liver disorder'. | Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm.
Ocular immune-related adverse events (IrAEs) associated with use of checkpoint inhibitors (CPIs) in cancer therapeutics are relatively rare, occurring in approximately 1% of treated patients. Recognition and early intervention are essential because the degree of tissue damage may be disproportionate to the symptoms, and lack of appropriate treatment risks permanent loss of vision. International guidelines on managing ocular IrAEs provide limited advice only. Importantly, local interventions can be effective and may avoid the need for systemic corticosteroids, thereby permitting the continuation of CPIs. We present a single institution case series of eight affected patients managed by our multidisciplinary team. Consistent with previously published series and case reports, we identified anterior uveitis as the most common ocular IrAE associated with CPIs requiring intervention. Based on our experience, as well as published guidance, we generated a simple algorithm to assist clinicians efficiently manage patients developing ocular symptoms during treatment with CPIs. In addition, we make recommendations for optimising treatment of uveitis and address implications for ongoing CPI therapy.
Background
Immunotherapy with checkpoint inhibitors (CPIs) has transformed the treatment of a wide range of malignancies.1,2 These drugs work by enabling the host immune system to eliminate malignant cells, recognisable through the expression of neoantigens. The CPIs currently in clinical use are antibodies which target the cytotoxic T-lymphocyte antigen-4 receptor (anti-CTLA-4), the programmed death-1 receptor (anti-PD-1) and its ligand (anti-PD-L1). The CTLA-4 receptor downregulates T-cell activation, whereas the PD-1 receptor inhibits T-cell proliferation, cytokine release, and cytotoxicity. Blocking their function can enhance T-cell response and allow immune-mediated tumour killing.
CPIs generate side effects termed immune-related adverse events (IrAEs), which stem from their mechanism of action, being predominantly autoimmune in nature and having the potential to affect any body organ. IrAEs range from being mild to life-threatening, or life-changing in some instances.3 Since their first introduction into clinical practice in 2011 as treatment for metastatic melanoma, the use of anti-CTLA-4 and anti-PD-L1 antibodies has expanded to include multiple cancer types including lung and urological cancers as well as lymphomas, with new treatment indications being added frequently. Their increasing use has resulted in greater awareness of both common and rarely seen IrAEs, ranging from mild presentations to severe reactions requiring prompt intervention.4
Optimal management of IrAEs is still in its infancy, with limited evidence to inform international guidelines which have been generated to assist clinical practice.5,6 The mainstay of treatment for what appear to be inflammatory conditions is immunosuppression with corticosteroids, prompting concerns about their effect on CPI efficacy.7 Moreover, the long-term effects on cancer survivors of high dose steroids, sometimes administered for protracted periods of time, have yet to be fully understood. The European Society of Medical Oncology (ESMO) clinical practice guidelines5 provide helpful algorithms for managing the more commonly occurring IrAEs, but consensus advice on managing less common IrAEs, such as those affecting the eyes, is also needed to minimise any negative impact of anti-cancer interventions.
Ocular IrAEs occur with an estimated prevalence of 1–3% of all treated patients.8,9 While the spectrum of severity is broad, they are highly significant as they can threaten vision. Reports of ocular IrAEs associated with CPIs are limited to small, single-digit case series and individual case reports, which principally report patients experiencing varying degrees of uveitis.8,10–13
Uveitis is a term used to describe inflammation of the uvea, the middle layer of the eye comprising the iris, ciliary body and choroid. It is classified as anterior, intermediate, posterior, or panuveitis, according to the predominant site of inflammation within the eye.14 Anterior uveitis is characterised by an infiltrate of white blood cells in the anterior chamber of the eye; intermediate uveitis is associated with inflammation in the vitreous gel, resulting in visual blurring, haze and floaters; posterior uveitis is characterised by retinal and/or choroidal inflammation.15,16 Symptoms of uveitis include pain, blurred vision and red eye. Involvement of the posterior segment can produce symptoms of floaters, flickering and shimmering lights (photopsias), as well as blind spots.
Anterior uveitis, whether acute or chronic, can often be managed with topical steroid drops alone. Severe uveitis of any subtype may lead to macular oedema, with accumulation of fluid at the most sensitive part of the retina, causing visual distortion and blurring. Severe ocular inflammation requires prompt intervention to avoid permanent loss of vision, and may require periocular or intravitreal steroid injections. More severe cases require systemic steroids, including oral, or pulsed intravenous methylprednisolone. Recalcitrant, chronic inflammatory eye diseases can be managed with secondary non-corticosteroid immunomodulatory therapeutic agents, including anti-metabolites like mycophenolate mofetil and methotrexate, or biological drugs like adalimumab.17 Common complications of uveitis and its treatment include cataract, glaucoma and choroidal neovascularisation. While most reports suggest a good response to therapy with complete resolution of inflammation, a minority of patients may develop permanent visual loss.
Other less common ocular IrAEs include ocular myasthenia, optic neuritis and auto-immune retinopathy. Dry eyes are described by up to one in four treated patients, but this is a common condition that is often not reported in clinical trials and is frequently undertreated, even in clinical practice.8,9 The risk of ocular IrAEs associated with CPIs was recently quantified using disproportionality analysis; odds ratios for uveitis ranged from 4.6 to 10.8, while that of any ocular IrAE was 2.5 compared with reported events associated with all other drugs.18
Uncertainties about optimal management of ocular IrAEs persist, such as when to interrupt or discontinue potentially life-saving CPI therapy and whether systemic steroids can influence the efficacy of CPIs. We report our experience of managing ocular IrAEs in a cohort of cancer patients receiving CPIs in a single institution and make management recommendations in a novel treatment algorithm.
Methods
We reviewed the electronic patient records of patients treated with CPIs from January to December 2019, and identified all cases referred to the ophthalmology service. The clinical characteristics, treatment and course of IrAEs over time were recorded. Details of their CPI treatment, other non-ocular irAEs, and disease response (based on routine radiological imaging and applying RECIST 1.1 response criteria) were also recorded. Survival was measured from the date of first CPI infusion until data cut-off, on 17 March, 2020.
Based on our case series and information contained in published international guidelines,5,6 we generated a simple assessment and treatment algorithm for use in routine clinical practice to guide the multidisciplinary team managing ocular symptoms and uveitis; the most common ocular IrAE reported.
This project was registered as a health service evaluation at Cambridge University Hospitals NHS Foundation Trust (CUHFT). The CUHFT research governance lead confirmed that, under the UK Policy Framework for Health and Social Care Research 2017, this project would not be classified or managed as research within the National Health Service and therefore did not require ethical review by a research ethics committee. Written informed consent to publish was obtained from the surviving case study patient.
Results
Patient characteristics
We identified eight patients (three women and five men, aged between 39 and 81 years) who developed ocular IrAEs after starting CPIs (Table 1). Seven patients were treated for advanced cancer; four for metastatic melanoma, two metastatic renal-cell carcinoma and one advanced ovarian carcinoma. One melanoma patient received CPI as an adjuvant therapy, after resection of regional lymph node disease. None had a previous history of uveitis. One patient had a history of glaucoma. Five patients received combination anti-CTLA-4 plus anti-PD-1 antibodies (ipilimumab + nivolumab), two patients received a single agent anti-PD-1 antibody (one pembrolizumab, one nivolumab) and one patient received anti-PD-1 antibody (nivolumab) in combination with a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor (rucaparib). Seven patients had their treatment discontinued early due to treatment-related adverse events; their treatment duration ranged from 3 to 9 weeks. The median number of adverse events contributing to treatment discontinuation was three (range 1–3). One patient completed 2 years of planned anti-PD-1 antibody therapy.
Table 1. Patient characteristics of patients experiencing ocular IrAEs associated with CPI treatment.
Patient case CPI regimen Duration of CPI therapy Reason for discontinuation AEs leading to discontinuation Best response to CPI Survival outcome
Melanoma-1
Metastatic
50-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Ocular IrAE Ocular
Skin
Fatigue Partial response Alive 16 months+
Kidney-1
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 3 weeks Multiple IrAE Ocular
Skin
Liver Stable disease Alive 15 months+
Kidney-2
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 4 weeks Multiple IrAEs Ocular
Liver
Arthritis Partial response Alive 16 months+
Ovarian
Metastatic
40-yo woman Nivolumab + rucaparib 8 weeks Multiple IrAE Ocular
Liver
Neutropaenia* Partial response Alive 10 months+
Melanoma-2
Resected stage III
74-yo woman Pembrolizumab
200 mg IV q3w 3 weeks Ocular IrAE Ocular Recurrence Treated with ipilimumab on recurrence; aborted after 6 weeks due to colitis.
Alive with stable disease:
14 months+
Melanoma-3
Metastatic
56-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Multiple IrAEs Ocular
Lung Partial response Alive 22 months+
Melanoma-4
Metastatic
40-yo woman Ipilimumab
1 mg/kg+ nivolumab 3 mg/kg 6 weeks Multiple IrAEs Ocular
Liver Partial response Rechallenged with 2 further cycles of ipilimumab+nivolumab on disease progression without significant IrAEs; progressive brain metastases.
Died after 11 months
Melanoma-5
Metastatic
81-yo man Nivolumab 240 mg 2 years Completed planned treatment – Near complete response Alive 5 years+
* Likely due to PARP inhibitor, not CPI.
AEs, adverse events; CPI, checkpoint inhibitor; IrEAs, immune-related adverse events; yo, year-old; PARP, poly-adenosine diphosphate ribose polymerase.
Ocular IrAE characteristics
The median time to the onset of ocular IrAE was 5 weeks from starting CPIs, although one patient developed symptoms after 18 months of treatment (Table 2). In all seven patients who discontinued CPIs early, ocular IrAE contributed to the decision to discontinue therapy. One patient with pre-existing glaucoma experienced ocular IrAE as the only IrAE, occurring after her first dose of pembrolizumab, and this led to treatment discontinuation. Four patients were diagnosed with anterior uveitis, one had intermediate uveitis, one had melanoma-associated retinopathy (MAR)19,20 and one had suspected ocular ischaemic syndrome.21 All patients had bilateral eye involvement. There were no hospitalisations associated with ocular IrAEs.
Table 2. Characteristics of ocular IrAEs experienced and their treatment.
Patient case Presenting symptoms Ocular IrAE Worst
CTCAE
grade Time to onset/resolution of ocular IrAE Worst visual acuity Visual acuity on resolution Local treatment Systemic steroids (starting dose) Outcome of ocular IrAE
Melanoma 1 Bilateral blurred vision, painful eyes Anterior uveitis 2 3 weeks/8 weeks R 6/19
L Normal R Normal
L Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Kidney 1 Bilateral blurred vision, painful eyes, headache Anterior uveitis
High IO pressures 2 5 weeks/11 weeks (uveitis)
6 months
(IO pressures) R 6/9.5
L 6/7.5 R Normal
L Normal Dexamethasone 0.1% drops
Timolol
Latanprost None Complete resolution
Kidney 2 Bilateral painful red eyes, light sensitivity Anterior uveitis
Left disc swelling 2 5 weeks/8 weeks Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Ovarian Bilateral blurred vision. Painful to focus Anterior uveitis 2 5 weeks/8 months Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Melanoma 2 Deterioration in vision Intermediate
uveitis 3 1 week/10 weeks R 6/9
L Normal R 6/9
L Normal None 40 mg prednisolone Resolved on 10 mg prednisolone; following 2 cycles of ipilimumab,
received IV steroids and infliximab for enteritis
Melanoma 3 Flashing lights, visual aura Melanoma associated retinopathy 4 3 weeks/18 months R 6/18 R 6/5 Anti-VEGF injections
Intra-ocular dexamethasone 50 mg prednisolone Permanent loss of vision; macular scarring
Melanoma 4 Rapid onset loss of vision in both eyes Suspected ocular ischaemic syndrome 4 7 weeks/4 weeks R 6/15
L 6/9 R Normal
L Normal Dexamethasone 0.1% drops
Mydrilate 1% drops 40 mg prednisolone Complete resolution
Melanoma 5 Red, eyes
Loss of vision in left eye
Blurred vision Conjunctivitis
Left retinal detachment*
Anterior uveitis 2
2 18 months
21 months
4 years/10 months R 6/12
L 6/7.5 R 6/12
L 6/7.5 Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Quiescent
* Association of retinal detachment as an IrAE could not be confirmed.
CTCAE, common toxicity criteria; IO, intra-ocular; IrEA, immune-related adverse event; IV, intravenous; L, left; R, right; VEGF, vascular endothelial growth factor.
The patient completing 2 years of nivolumab experienced ocular IrAEs both during and after completing CPI treatment. As the symptoms were manageable and no other IrAEs occurred, his planned treatment was not interrupted. He experienced conjunctivitis and left retinal detachment during treatment, both of which were managed successfully. Two years after completing CPIs, he developed bilateral anterior uveitis.
Treatment of ocular IrAEs
All five patients who developed anterior uveitis were treated with topical steroids only. The three other ocular conditions (intermediate uveitis, MAR and suspected ocular ischaemic syndrome) were treated with oral corticosteroids. No patients received intravenous steroids or other immunosuppressive agents to treat their ocular IrAEs. One patient diagnosed with MAR received intravitreal anti-vascular endothelial growth factor injections to treat a juxtafoveal choroidal neovascular membrane, as well as intra-ocular steroid implants to treat chronic photopsia in his only remaining eye.
The median ocular IrAE treatment duration was 11 weeks (range 8 weeks–10 months) with topical steroids and 10 weeks (range 4 weeks–6 months) with oral steroids. Two patients with anterior uveitis had rapid, complete resolution of their symptoms by 8 and 11 weeks. One patient had persistently raised intra-ocular pressures for approximately 6 months. Two patients had a protracted course of inflammatory eye disease, with recurrent episodes lasting 8 and 10 months, respectively. Of two patients re-challenged with CPIs at a later date, (one with ipilimumab, one with ipilimumab + nivolumab), neither had recurrence of ocular IrAEs.
Oncological response to CPIs
Overall, six out of the eight treated patients experienced a partial or near complete response to CPI therapy and seven remain alive and well at data cut-off. One melanoma patient whose adjuvant pembrolizumab treatment was aborted due to uveitis had disease recurrence documented 10 weeks after her first CPI administration, then received ipilimumab, which was aborted after teo cycles due to severe colitis, but her disease has remained stable since that time (15 months at data cut-off). A second melanoma patient who progressed on completing adjuvant pembrolizumab initially responded to ipilimumab + nivolumab, but died of metastatic disease 19 months after her first CPI administration.
Non-uveitis case studies
Case 1: (‘Melanoma 3’ in Tables 1 and 2)
A 56-year-old man received treatment with ipilimumab + nivolumab for metastatic uveal melanoma, having had exenteration of his left eye 4 years previously. Three weeks after his first CPI administration he complained of severe flashing lights in his remaining eye, and he was referred urgently for an ophthalmological assessment.
On slit lamp biomicroscopy, pale lesions were noted in the fundus, and these were presumed to be benign. He continued immunotherapy, but after 9 weeks (three cycles of CPI), he developed moderately severe pneumonitis which was initially treated with 50 mg oral prednisolone daily and CPI therapy was permanently discontinued. The pneumonitis resolved over 12 weeks and he was gradually weaned off steroids. While tapering his steroids, he noticed that his vision was deteriorating and a visual field defect was detected on formal testing.
Optical coherence tomography (OCT) scanning indicated a choroidal lesion next to the fovea, suggesting a possible neovascular membrane (Figure 1a), which could cause visual loss. This suspicion was confirmed by the presence of early leakage during fundus fluorescein angiography (FFA) (Figure 1b). The choroidal neovascular membrane was treated with a series of intravitreal anti-vascular endothelial growth factor (ranibizumab) injections, until it was deemed to be inactive.
Figure 1. Non-uveitis case study. (a) Optical coherence tomography scan showing a choroidal lesion next to the fovea, possibly representing a neovascular membrane. (b) Fundus fluorescein angiography demonstrating early hyperfluorescence of the juxtafoveal lesion, supporting a diagnosis of choroidal neovascularisation. (c) Pseudocolour image of the fundus showing the dexamethasone 0.7 mg steroid implant.
Electrodiagnostic testing subsequently revealed widespread post-phototransduction cone and rod dysfunction, compatible with MAR. His symptoms partially improved on restarting oral steroids (10 mg prednisolone daily), pointing to an inflammatory cause of his visual symptoms. On the basis of this evidence, he was offered short-acting and long-acting intravitreal steroid implants,22 (dexamethasone 0.7 mg and fluocinolone acetonide, respectively, Figure 1c) to avoid chronic side effects of long-term systemic steroids. At the time of data cut-off, the patient remained disease free, with relatively minor persistent visual impairment.
Case 2: (‘Melanoma 4’ in Tables 1 and 2)
A 40-year-old woman received adjuvant pembrolizumab for stage IIID BRAF wild type melanoma, which was well tolerated, without any IrAEs. After 11 months of treatment, she complained of generalised musculoskeletal pains and fatigue. Restaging scans identified widespread metastases including to liver and bone. She was commenced on ipilimumab + nivolumab. After 6 weeks (post cycle 2), her overall condition deteriorated, with severe fatigue and deterioration in liver function and performance status, although her serum lactate dehydrogenase dropped markedly from 1956 to 498 IU/L during the same time period. Her third cycle of ipilimumab + nivolumab was deferred.
One week later, she presented to the emergency department complaining of sudden onset bilateral loss of vision, worse in the right eye. Visual acuity was 6/15 in the right eye and 6/9 in the left eye, and intraocular pressure was within normal parameters. Iris neovascularisation and a swollen right optic disc were found on slit lamp biomicroscopy and fundoscopy. Brain imaging was requested, and confirmed the absence of metastases. A diagnosis of ocular ischaemic syndrome21 was suggested, but after discussion with the oncology specialist, a possible inflammatory aetiology was considered.
The patient was treated with 40 mg oral prednisolone daily, 0.1% dexamethasone eye drops and 1% mydrilate drops. She responded well to treatment, and was gradually weaned off steroids, and her vision recovered. Her liver function normalised and her performance status improved sufficiently for a return to normal activities of daily living. Subsequent staging compueterised tomography (CT) images indicated a partial response to CPIs. Six months later, despite the patient remaining well and asymptomatic, surveillance imaging identified disease recurrence in previously involved body sites with four new brain metastases. She was re-challenged with ipilimumab + nivolumab. No new IrAEs occurred, but after the second cycle, she was admitted to hospital with seizures due to haemorrhage into the brain metastases and died 10 weeks later, 11 months after starting CPIs for metastatic disease.
Ocular symptom management algorithm
Based on our own experience, review of the literature and international guidelines, we generated a management algorithm designed for multidisciplinary teams to use in clinical practice (Figure 2).
Figure 2. Management algorithm for patients treated with CPIs who present with ocular symptoms.
CPI, checkpoint inhibitor; FAF, fundus autofluorescence; FFA, fundus fluorescein angiography; ICG, indocyanine angiography; OCT, optical coherence tomography.
Patient symptoms and signs are classified according to international common toxicity criteria (CTCAE version 5.0)23 and management is determined by the severity of the condition. The international CTCAE grades classify the severity of ocular conditions from 1 (mild) to 4 (severe, with sight-threatening consequences). Anterior uveitis is graded in correspondence with the number of cells seen on slit lamp examination of the anterior chamber, as defined by the standardisation of uveitis nomenclature.12 Thus, grade 1 uveitis corresponds to a ‘trace’ of cells (1–5 cells in a 1 mm × 1 mm slit beam), and grade 3 uveitis corresponds to ‘3+’ (26–50 cells per field). Posterior uveitis is graded 3. In addition, a visual acuity of 20/200 (6/60 in European terminology) or less, meeting criteria for blindness in the affected eye, is graded as 4.
The ophthalmological assessments of patients with visual disturbance include visual acuity, colour vision and intraocular pressure measurement. A relative afferent pupillary defect can be tested for by carrying out the swinging flashlight test before dilating drops are instilled into the eyes. Our algorithm includes a pathway for specialist ophthalmic investigations used to diagnose uveitis, which may include FFA and indocyanine angiography (ICG), fundus autofluorescence (FAF) and OCT, depending on the individual case.
In the absence of intermediate or posterior signs, invasive dye-based angiography tests would not normally be indicated, but can be used to exclude retinal vasculitis and leakage (FFA) or undiagnosed choroiditis (ICG) in challenging cases. This can be valuable in both the diagnosis and monitoring of inflammatory eye disease.24 Non-invasive FAF imaging is used to map metabolic activity in the retinal photoreceptor and pigment epithelial layers, and can be useful in identifying inflammatory processes occurring in the outer retina.25 OCT scanning provides high resolution images of the retina in cross-section and has transformed modern ophthalmological practice.
In contrast to recommendations in current international guidelines, we have used clinical evidence to justify avoiding the discontinuation of CPIs as much as possible. The algorithm aims to emphasise the need for close liaison between oncologist and specialist ophthalmologist from the point of recognition to resolution of ocular symptoms, as well as the benefit of a multidisciplinary approach involving good communication between the specialties to balance the need for cancer control alongside patient safety and vision preservation.
Discussion
This report of eight patients experiencing ocular IrAEs associated with CPI treatment is one of the largest series published to date. Anterior uveitis was the most common ocular IrAE that we identified, occurring in five of our eight cases. The onset of uveitis is reported mainly to occur within 2 months of starting CPIs.7,13,26 This was generally the case in our cohort, with a median time to onset of 5 weeks (range 1–7 weeks). The exception was a single patient who developed anterior uveitis 2 years after completing 2 years of nivolumab treatment. It is noteworthy that he had other ocular IrAEs while on treatment that did not lead to CPI discontinuation, while his anterior uveitis was difficult to control. It is well recognised that some IrAEs (including ocular IrAEs)13 can occur months and years after stopping CPIs, and this case is a reminder to consider the need for ongoing follow-up, even in patients apparently entering long-term remission after completing treatment.
Ocular IrAEs may occur as the only IrAE, or in association with multiple body system IrAEs. In our series, their occurrence influenced the decision to interrupt CPI treatment in all seven patients who discontinued treatment early: uveitis was the primary reason for discontinuation in two (29%) patients, but contributed to the decision to stop treatment in the remaining five patients, all of whom experienced multiple IrAEs.
A literature review of 33 cases of uveitis secondary to CPIs10 concluded that one-third of patients experienced anterior uveitis alone, one-third had anterior uveitis plus posterior segment changes including macular oedema, retinal detachment, vitritis or papillitis, and one-third had panuveitis. A very recent larger review of 126 cases of CPI-associated uveitis was broadly consistent, noting that 35% of panuveitis cases occurred as part of a Vogt–Koyanagi–Harada (VKH)-like syndrome.27–30 VKH disease is a multisystem disease affecting melanin-containing tissues, which is thought to be autoimmune in origin. The most significant ocular manifestation is bilateral diffuse panuveitis with exudative retinal detachment, often accompanied by a variable spectrum of symptoms involving the skin, nervous system and inner ear.
Recognition of the different presentations of the subtypes of uveitis is clearly important, as this influences whether topical steroids alone can be used for treatment, sparing patients the need for systemic steroids which may adversely affect the outcome of anti-cancer treatment.7 As in our own series, most published series describe initial intervention with topical and/or oral corticosteroids. Although outcomes are generally good, with complete resolution of inflammation in most cases, some cases are recalcitrant, warranting alternative immunomodulatory agents, while peri-ocular or intravitreal steroids22 have been employed as steroid-sparing strategies.
Prompt recognition of ocular and visual symptoms by oncologists and referral to ophthalmology specialists is necessary to ensure rapid investigation, diagnosis and sight-preserving treatment, as well as to inform multidisciplinary team opinion concerning ongoing treatment with CPIs. This can be challenging, because the ocular symptoms experienced may not directly correlate with the severity of inflammation identified.14 Even so, in most of the case series published to date, the overwhelming majority of patients experiencing ocular irAEs have had their CPIs discontinued,12,13 and uncertainty exists whether this line of action may impact overall treatment outcomes.
Perhaps because of its low incidence relative to other IrAEs, the ESMO guidelines5 offer very little advice on how to manage ocular IrAEs. The American Society of Clinical Oncology (ASCO) guidelines,6 on the other hand, are far more extensive and recommend referral to ophthalmology services for new onset visual symptoms, while they also recognise that symptoms may not always correlate with severity. The guidelines make use of the CTCAE grading system for ocular IrAEs and include management recommendations on whether to withhold, or discontinue, immunotherapy. While these constitute a welcome framework, they may also prove unnecessarily restrictive.
The ASCO guidelines recommend that for grade 1 ocular IrAEs, CPIs can be continued, for grade 2 events CPIs should be withheld and for grades 3 and 4 events they should be permanently discontinued. Ocular IrAEs, while not usually life threatening, may be life changing, so urgent intervention aimed at avoiding permanent loss of eyesight is certainly warranted. However, it is important to note that even severe deterioration in visual acuity can sometimes be reversible. For example, significant visual impairment associated with macular oedema may recover following prompt treatment with oral or intravitreal steroids. In adherence to ASCO guidance, loss of visual acuity may result in an adverse event grading of 3 or 4, which we consider could unnecessarily lead to permanent cessation of immunotherapy.
In some patients who resume CPIs after treatment for IrAEs, relapse with the same symptoms has been observed.9,13 We argue that permanent discontinuation of immunotherapy may not always be justified in these circumstances. In our own series, one patient experienced significant bilateral loss of vision associated with an ocular IrAE after two cycles of CPI with ipilimumab + nivolumab, but did not experience further ocular symptoms on retreatment several months later. Moreover, a severe or acute drop in visual acuity may be due to other pathologies unrelated to CPI (for example, incidental retinal detachment, which has a lifetime risk in normal individuals of one in 300).31 On the other hand, a patient could have apparently mild visual impairment but severe intra-ocular inflammation.
We recommend early referral to an ophthalmology specialist on recognition of ocular symptoms to diagnose the possible ocular IrAE and accurately grade its severity. We further recommend that both eye treatment and the ongoing use of CPIs are discussed on an individual case basis within a multidisciplinary team of oncologists and ophthalmologists, keeping the option open for retreatment in situations in which the possible benefits outweigh the risks, assuming appropriate patient counselling and support.
Most cases of uveitis associated with CPI, including the majority of our cases, are mild and would be categorised as CTCAE grade 2. These cases do not require cessation of CPI and neither should they require systemic steroids, in general. The outcomes from topical treatment are mainly good, with either a limited course, or sometimes ongoing topical steroids. If systemic steroids are used, the ASCO guidelines recommend that CPIs are withheld until the patient is either off all steroids or is receiving a daily dose of 10 mg oral prednisolone (or equivalent) or less. As far as possible, the aim should be to treat ocular IrAEs with local options in order to avoid systemic steroids and cessation of CPI therapy. Aside from concerns regarding their impact on CPI efficacy, long-term steroid use is associated with many well-known harmful effects.
The goal of avoiding the interruption of CPI therapy is best achieved by taking a multidisciplinary approach, with close liaison between ophthalmology and oncology teams, remembering that patients may have a high degree of anxiety about stopping potentially life-saving anti-cancer therapy. In our cohort, five patients stopped CPIs due to ocular IrAEs, despite being categorised as grade 2, which does not necessarily mandate permanent discontinuation. Three of these patients were treated solely with topical steroids, which suggests a low threat to vision, and which would not normally interfere with CPIs. In cases where topical steroids are not sufficient, intravitreal or periocular steroids should be considered to enable patients to remain on CPIs.
It is possible that patients diagnosed with melanoma may be at increased risk of developing uveitis due to the presence of melanin in the retinal pigment epithelium. An immune-mediated response to melanin-producing cells in the eye may occur both in patients on treatment and in those who develop an immunological reaction to their cancer independent of treatment. In our series, MAR was the most likely diagnosis in one of two patients reporting ocular toxicities that were not due to uveitis, based on symptoms described and investigations performed. The pathology is thought to be due to shared neuroectodermal lineage of melanocytes and retinal cells. Conversely, uveitis is not unique to patients with a diagnosis of melanoma. Patients at increased risk of uveitis may include those with other immune-related side effects and those predisposed to autoimmune disease or with a significant family history.32
Four of our patients, of whom two had other IrAEs, responded very well to retreatment with CPIs, highlighting a key unanswered question concerning whether the occurrence of IrAEs can predict a therapeutic response.32,33 Several studies have reported increased progression-free and overall survival in patients who experienced IrAEs with CPIs compared to those who did not.34,35 To date, it remains unclear whether the development of uveitis or other specific IrAEs is associated with better outcomes from treatment with CPIs,34,36 although it is quite plausible that an observed inflammatory response within the eye or elsewhere might reflect an enhanced immune response against cancer. The number of patients in our study is insufficient to answer this question, but further study is warranted and, if proved, this could be reassuring for patients who have previously stopped immunotherapy while being treated for inflammatory side effects.
In conclusion, ocular IrAEs are relatively uncommon IrAEs associated with CPIs, but can be dramatic and may lead to permanent visual loss. Prompt recognition in oncology clinics and early referral to an ophthalmologist is essential. Patients with confirmed ocular inflammation require close monitoring in the eye clinic and ongoing liaison with their oncologist regarding optimal treatment and the use of corticosteroids. The option of intraocular steroid implants should be considered as an alternative to systemic steroids when IrAEs do not resolve with topical steroids alone, with the potential benefit of being able to continue on CPIs.
In conjunction with our ocular IrAE management algorithm (Figure 2), we propose the following basic steps to follow when seeing immunotherapy patients with ocular symptoms in the clinic:
document the symptoms and signs and their severity
escalate by referral to an ophthalmologist; consider urgency of referral and the need to interrupt CPI therapy depending on symptom severity
obtain an ophthalmological diagnosis
take a multidisciplinary approach to managing the ocular symptoms and the need or otherwise to restart CPIs, based on risk/benefit considerations.
The authors would like to thank the patients and their families for allowing us to share their case studies. Thanks also to the CUHFT research governance and audit teams for their assistance in the conduct of this study.
Conflict of interest: The authors declare that there is no conflict of interest.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Philippa Corrie
https://orcid.org/0000-0003-4875-7021 | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY-NC | 33633802 | 19,074,441 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ocular ischaemic syndrome'. | Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm.
Ocular immune-related adverse events (IrAEs) associated with use of checkpoint inhibitors (CPIs) in cancer therapeutics are relatively rare, occurring in approximately 1% of treated patients. Recognition and early intervention are essential because the degree of tissue damage may be disproportionate to the symptoms, and lack of appropriate treatment risks permanent loss of vision. International guidelines on managing ocular IrAEs provide limited advice only. Importantly, local interventions can be effective and may avoid the need for systemic corticosteroids, thereby permitting the continuation of CPIs. We present a single institution case series of eight affected patients managed by our multidisciplinary team. Consistent with previously published series and case reports, we identified anterior uveitis as the most common ocular IrAE associated with CPIs requiring intervention. Based on our experience, as well as published guidance, we generated a simple algorithm to assist clinicians efficiently manage patients developing ocular symptoms during treatment with CPIs. In addition, we make recommendations for optimising treatment of uveitis and address implications for ongoing CPI therapy.
Background
Immunotherapy with checkpoint inhibitors (CPIs) has transformed the treatment of a wide range of malignancies.1,2 These drugs work by enabling the host immune system to eliminate malignant cells, recognisable through the expression of neoantigens. The CPIs currently in clinical use are antibodies which target the cytotoxic T-lymphocyte antigen-4 receptor (anti-CTLA-4), the programmed death-1 receptor (anti-PD-1) and its ligand (anti-PD-L1). The CTLA-4 receptor downregulates T-cell activation, whereas the PD-1 receptor inhibits T-cell proliferation, cytokine release, and cytotoxicity. Blocking their function can enhance T-cell response and allow immune-mediated tumour killing.
CPIs generate side effects termed immune-related adverse events (IrAEs), which stem from their mechanism of action, being predominantly autoimmune in nature and having the potential to affect any body organ. IrAEs range from being mild to life-threatening, or life-changing in some instances.3 Since their first introduction into clinical practice in 2011 as treatment for metastatic melanoma, the use of anti-CTLA-4 and anti-PD-L1 antibodies has expanded to include multiple cancer types including lung and urological cancers as well as lymphomas, with new treatment indications being added frequently. Their increasing use has resulted in greater awareness of both common and rarely seen IrAEs, ranging from mild presentations to severe reactions requiring prompt intervention.4
Optimal management of IrAEs is still in its infancy, with limited evidence to inform international guidelines which have been generated to assist clinical practice.5,6 The mainstay of treatment for what appear to be inflammatory conditions is immunosuppression with corticosteroids, prompting concerns about their effect on CPI efficacy.7 Moreover, the long-term effects on cancer survivors of high dose steroids, sometimes administered for protracted periods of time, have yet to be fully understood. The European Society of Medical Oncology (ESMO) clinical practice guidelines5 provide helpful algorithms for managing the more commonly occurring IrAEs, but consensus advice on managing less common IrAEs, such as those affecting the eyes, is also needed to minimise any negative impact of anti-cancer interventions.
Ocular IrAEs occur with an estimated prevalence of 1–3% of all treated patients.8,9 While the spectrum of severity is broad, they are highly significant as they can threaten vision. Reports of ocular IrAEs associated with CPIs are limited to small, single-digit case series and individual case reports, which principally report patients experiencing varying degrees of uveitis.8,10–13
Uveitis is a term used to describe inflammation of the uvea, the middle layer of the eye comprising the iris, ciliary body and choroid. It is classified as anterior, intermediate, posterior, or panuveitis, according to the predominant site of inflammation within the eye.14 Anterior uveitis is characterised by an infiltrate of white blood cells in the anterior chamber of the eye; intermediate uveitis is associated with inflammation in the vitreous gel, resulting in visual blurring, haze and floaters; posterior uveitis is characterised by retinal and/or choroidal inflammation.15,16 Symptoms of uveitis include pain, blurred vision and red eye. Involvement of the posterior segment can produce symptoms of floaters, flickering and shimmering lights (photopsias), as well as blind spots.
Anterior uveitis, whether acute or chronic, can often be managed with topical steroid drops alone. Severe uveitis of any subtype may lead to macular oedema, with accumulation of fluid at the most sensitive part of the retina, causing visual distortion and blurring. Severe ocular inflammation requires prompt intervention to avoid permanent loss of vision, and may require periocular or intravitreal steroid injections. More severe cases require systemic steroids, including oral, or pulsed intravenous methylprednisolone. Recalcitrant, chronic inflammatory eye diseases can be managed with secondary non-corticosteroid immunomodulatory therapeutic agents, including anti-metabolites like mycophenolate mofetil and methotrexate, or biological drugs like adalimumab.17 Common complications of uveitis and its treatment include cataract, glaucoma and choroidal neovascularisation. While most reports suggest a good response to therapy with complete resolution of inflammation, a minority of patients may develop permanent visual loss.
Other less common ocular IrAEs include ocular myasthenia, optic neuritis and auto-immune retinopathy. Dry eyes are described by up to one in four treated patients, but this is a common condition that is often not reported in clinical trials and is frequently undertreated, even in clinical practice.8,9 The risk of ocular IrAEs associated with CPIs was recently quantified using disproportionality analysis; odds ratios for uveitis ranged from 4.6 to 10.8, while that of any ocular IrAE was 2.5 compared with reported events associated with all other drugs.18
Uncertainties about optimal management of ocular IrAEs persist, such as when to interrupt or discontinue potentially life-saving CPI therapy and whether systemic steroids can influence the efficacy of CPIs. We report our experience of managing ocular IrAEs in a cohort of cancer patients receiving CPIs in a single institution and make management recommendations in a novel treatment algorithm.
Methods
We reviewed the electronic patient records of patients treated with CPIs from January to December 2019, and identified all cases referred to the ophthalmology service. The clinical characteristics, treatment and course of IrAEs over time were recorded. Details of their CPI treatment, other non-ocular irAEs, and disease response (based on routine radiological imaging and applying RECIST 1.1 response criteria) were also recorded. Survival was measured from the date of first CPI infusion until data cut-off, on 17 March, 2020.
Based on our case series and information contained in published international guidelines,5,6 we generated a simple assessment and treatment algorithm for use in routine clinical practice to guide the multidisciplinary team managing ocular symptoms and uveitis; the most common ocular IrAE reported.
This project was registered as a health service evaluation at Cambridge University Hospitals NHS Foundation Trust (CUHFT). The CUHFT research governance lead confirmed that, under the UK Policy Framework for Health and Social Care Research 2017, this project would not be classified or managed as research within the National Health Service and therefore did not require ethical review by a research ethics committee. Written informed consent to publish was obtained from the surviving case study patient.
Results
Patient characteristics
We identified eight patients (three women and five men, aged between 39 and 81 years) who developed ocular IrAEs after starting CPIs (Table 1). Seven patients were treated for advanced cancer; four for metastatic melanoma, two metastatic renal-cell carcinoma and one advanced ovarian carcinoma. One melanoma patient received CPI as an adjuvant therapy, after resection of regional lymph node disease. None had a previous history of uveitis. One patient had a history of glaucoma. Five patients received combination anti-CTLA-4 plus anti-PD-1 antibodies (ipilimumab + nivolumab), two patients received a single agent anti-PD-1 antibody (one pembrolizumab, one nivolumab) and one patient received anti-PD-1 antibody (nivolumab) in combination with a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor (rucaparib). Seven patients had their treatment discontinued early due to treatment-related adverse events; their treatment duration ranged from 3 to 9 weeks. The median number of adverse events contributing to treatment discontinuation was three (range 1–3). One patient completed 2 years of planned anti-PD-1 antibody therapy.
Table 1. Patient characteristics of patients experiencing ocular IrAEs associated with CPI treatment.
Patient case CPI regimen Duration of CPI therapy Reason for discontinuation AEs leading to discontinuation Best response to CPI Survival outcome
Melanoma-1
Metastatic
50-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Ocular IrAE Ocular
Skin
Fatigue Partial response Alive 16 months+
Kidney-1
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 3 weeks Multiple IrAE Ocular
Skin
Liver Stable disease Alive 15 months+
Kidney-2
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 4 weeks Multiple IrAEs Ocular
Liver
Arthritis Partial response Alive 16 months+
Ovarian
Metastatic
40-yo woman Nivolumab + rucaparib 8 weeks Multiple IrAE Ocular
Liver
Neutropaenia* Partial response Alive 10 months+
Melanoma-2
Resected stage III
74-yo woman Pembrolizumab
200 mg IV q3w 3 weeks Ocular IrAE Ocular Recurrence Treated with ipilimumab on recurrence; aborted after 6 weeks due to colitis.
Alive with stable disease:
14 months+
Melanoma-3
Metastatic
56-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Multiple IrAEs Ocular
Lung Partial response Alive 22 months+
Melanoma-4
Metastatic
40-yo woman Ipilimumab
1 mg/kg+ nivolumab 3 mg/kg 6 weeks Multiple IrAEs Ocular
Liver Partial response Rechallenged with 2 further cycles of ipilimumab+nivolumab on disease progression without significant IrAEs; progressive brain metastases.
Died after 11 months
Melanoma-5
Metastatic
81-yo man Nivolumab 240 mg 2 years Completed planned treatment – Near complete response Alive 5 years+
* Likely due to PARP inhibitor, not CPI.
AEs, adverse events; CPI, checkpoint inhibitor; IrEAs, immune-related adverse events; yo, year-old; PARP, poly-adenosine diphosphate ribose polymerase.
Ocular IrAE characteristics
The median time to the onset of ocular IrAE was 5 weeks from starting CPIs, although one patient developed symptoms after 18 months of treatment (Table 2). In all seven patients who discontinued CPIs early, ocular IrAE contributed to the decision to discontinue therapy. One patient with pre-existing glaucoma experienced ocular IrAE as the only IrAE, occurring after her first dose of pembrolizumab, and this led to treatment discontinuation. Four patients were diagnosed with anterior uveitis, one had intermediate uveitis, one had melanoma-associated retinopathy (MAR)19,20 and one had suspected ocular ischaemic syndrome.21 All patients had bilateral eye involvement. There were no hospitalisations associated with ocular IrAEs.
Table 2. Characteristics of ocular IrAEs experienced and their treatment.
Patient case Presenting symptoms Ocular IrAE Worst
CTCAE
grade Time to onset/resolution of ocular IrAE Worst visual acuity Visual acuity on resolution Local treatment Systemic steroids (starting dose) Outcome of ocular IrAE
Melanoma 1 Bilateral blurred vision, painful eyes Anterior uveitis 2 3 weeks/8 weeks R 6/19
L Normal R Normal
L Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Kidney 1 Bilateral blurred vision, painful eyes, headache Anterior uveitis
High IO pressures 2 5 weeks/11 weeks (uveitis)
6 months
(IO pressures) R 6/9.5
L 6/7.5 R Normal
L Normal Dexamethasone 0.1% drops
Timolol
Latanprost None Complete resolution
Kidney 2 Bilateral painful red eyes, light sensitivity Anterior uveitis
Left disc swelling 2 5 weeks/8 weeks Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Ovarian Bilateral blurred vision. Painful to focus Anterior uveitis 2 5 weeks/8 months Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Melanoma 2 Deterioration in vision Intermediate
uveitis 3 1 week/10 weeks R 6/9
L Normal R 6/9
L Normal None 40 mg prednisolone Resolved on 10 mg prednisolone; following 2 cycles of ipilimumab,
received IV steroids and infliximab for enteritis
Melanoma 3 Flashing lights, visual aura Melanoma associated retinopathy 4 3 weeks/18 months R 6/18 R 6/5 Anti-VEGF injections
Intra-ocular dexamethasone 50 mg prednisolone Permanent loss of vision; macular scarring
Melanoma 4 Rapid onset loss of vision in both eyes Suspected ocular ischaemic syndrome 4 7 weeks/4 weeks R 6/15
L 6/9 R Normal
L Normal Dexamethasone 0.1% drops
Mydrilate 1% drops 40 mg prednisolone Complete resolution
Melanoma 5 Red, eyes
Loss of vision in left eye
Blurred vision Conjunctivitis
Left retinal detachment*
Anterior uveitis 2
2 18 months
21 months
4 years/10 months R 6/12
L 6/7.5 R 6/12
L 6/7.5 Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Quiescent
* Association of retinal detachment as an IrAE could not be confirmed.
CTCAE, common toxicity criteria; IO, intra-ocular; IrEA, immune-related adverse event; IV, intravenous; L, left; R, right; VEGF, vascular endothelial growth factor.
The patient completing 2 years of nivolumab experienced ocular IrAEs both during and after completing CPI treatment. As the symptoms were manageable and no other IrAEs occurred, his planned treatment was not interrupted. He experienced conjunctivitis and left retinal detachment during treatment, both of which were managed successfully. Two years after completing CPIs, he developed bilateral anterior uveitis.
Treatment of ocular IrAEs
All five patients who developed anterior uveitis were treated with topical steroids only. The three other ocular conditions (intermediate uveitis, MAR and suspected ocular ischaemic syndrome) were treated with oral corticosteroids. No patients received intravenous steroids or other immunosuppressive agents to treat their ocular IrAEs. One patient diagnosed with MAR received intravitreal anti-vascular endothelial growth factor injections to treat a juxtafoveal choroidal neovascular membrane, as well as intra-ocular steroid implants to treat chronic photopsia in his only remaining eye.
The median ocular IrAE treatment duration was 11 weeks (range 8 weeks–10 months) with topical steroids and 10 weeks (range 4 weeks–6 months) with oral steroids. Two patients with anterior uveitis had rapid, complete resolution of their symptoms by 8 and 11 weeks. One patient had persistently raised intra-ocular pressures for approximately 6 months. Two patients had a protracted course of inflammatory eye disease, with recurrent episodes lasting 8 and 10 months, respectively. Of two patients re-challenged with CPIs at a later date, (one with ipilimumab, one with ipilimumab + nivolumab), neither had recurrence of ocular IrAEs.
Oncological response to CPIs
Overall, six out of the eight treated patients experienced a partial or near complete response to CPI therapy and seven remain alive and well at data cut-off. One melanoma patient whose adjuvant pembrolizumab treatment was aborted due to uveitis had disease recurrence documented 10 weeks after her first CPI administration, then received ipilimumab, which was aborted after teo cycles due to severe colitis, but her disease has remained stable since that time (15 months at data cut-off). A second melanoma patient who progressed on completing adjuvant pembrolizumab initially responded to ipilimumab + nivolumab, but died of metastatic disease 19 months after her first CPI administration.
Non-uveitis case studies
Case 1: (‘Melanoma 3’ in Tables 1 and 2)
A 56-year-old man received treatment with ipilimumab + nivolumab for metastatic uveal melanoma, having had exenteration of his left eye 4 years previously. Three weeks after his first CPI administration he complained of severe flashing lights in his remaining eye, and he was referred urgently for an ophthalmological assessment.
On slit lamp biomicroscopy, pale lesions were noted in the fundus, and these were presumed to be benign. He continued immunotherapy, but after 9 weeks (three cycles of CPI), he developed moderately severe pneumonitis which was initially treated with 50 mg oral prednisolone daily and CPI therapy was permanently discontinued. The pneumonitis resolved over 12 weeks and he was gradually weaned off steroids. While tapering his steroids, he noticed that his vision was deteriorating and a visual field defect was detected on formal testing.
Optical coherence tomography (OCT) scanning indicated a choroidal lesion next to the fovea, suggesting a possible neovascular membrane (Figure 1a), which could cause visual loss. This suspicion was confirmed by the presence of early leakage during fundus fluorescein angiography (FFA) (Figure 1b). The choroidal neovascular membrane was treated with a series of intravitreal anti-vascular endothelial growth factor (ranibizumab) injections, until it was deemed to be inactive.
Figure 1. Non-uveitis case study. (a) Optical coherence tomography scan showing a choroidal lesion next to the fovea, possibly representing a neovascular membrane. (b) Fundus fluorescein angiography demonstrating early hyperfluorescence of the juxtafoveal lesion, supporting a diagnosis of choroidal neovascularisation. (c) Pseudocolour image of the fundus showing the dexamethasone 0.7 mg steroid implant.
Electrodiagnostic testing subsequently revealed widespread post-phototransduction cone and rod dysfunction, compatible with MAR. His symptoms partially improved on restarting oral steroids (10 mg prednisolone daily), pointing to an inflammatory cause of his visual symptoms. On the basis of this evidence, he was offered short-acting and long-acting intravitreal steroid implants,22 (dexamethasone 0.7 mg and fluocinolone acetonide, respectively, Figure 1c) to avoid chronic side effects of long-term systemic steroids. At the time of data cut-off, the patient remained disease free, with relatively minor persistent visual impairment.
Case 2: (‘Melanoma 4’ in Tables 1 and 2)
A 40-year-old woman received adjuvant pembrolizumab for stage IIID BRAF wild type melanoma, which was well tolerated, without any IrAEs. After 11 months of treatment, she complained of generalised musculoskeletal pains and fatigue. Restaging scans identified widespread metastases including to liver and bone. She was commenced on ipilimumab + nivolumab. After 6 weeks (post cycle 2), her overall condition deteriorated, with severe fatigue and deterioration in liver function and performance status, although her serum lactate dehydrogenase dropped markedly from 1956 to 498 IU/L during the same time period. Her third cycle of ipilimumab + nivolumab was deferred.
One week later, she presented to the emergency department complaining of sudden onset bilateral loss of vision, worse in the right eye. Visual acuity was 6/15 in the right eye and 6/9 in the left eye, and intraocular pressure was within normal parameters. Iris neovascularisation and a swollen right optic disc were found on slit lamp biomicroscopy and fundoscopy. Brain imaging was requested, and confirmed the absence of metastases. A diagnosis of ocular ischaemic syndrome21 was suggested, but after discussion with the oncology specialist, a possible inflammatory aetiology was considered.
The patient was treated with 40 mg oral prednisolone daily, 0.1% dexamethasone eye drops and 1% mydrilate drops. She responded well to treatment, and was gradually weaned off steroids, and her vision recovered. Her liver function normalised and her performance status improved sufficiently for a return to normal activities of daily living. Subsequent staging compueterised tomography (CT) images indicated a partial response to CPIs. Six months later, despite the patient remaining well and asymptomatic, surveillance imaging identified disease recurrence in previously involved body sites with four new brain metastases. She was re-challenged with ipilimumab + nivolumab. No new IrAEs occurred, but after the second cycle, she was admitted to hospital with seizures due to haemorrhage into the brain metastases and died 10 weeks later, 11 months after starting CPIs for metastatic disease.
Ocular symptom management algorithm
Based on our own experience, review of the literature and international guidelines, we generated a management algorithm designed for multidisciplinary teams to use in clinical practice (Figure 2).
Figure 2. Management algorithm for patients treated with CPIs who present with ocular symptoms.
CPI, checkpoint inhibitor; FAF, fundus autofluorescence; FFA, fundus fluorescein angiography; ICG, indocyanine angiography; OCT, optical coherence tomography.
Patient symptoms and signs are classified according to international common toxicity criteria (CTCAE version 5.0)23 and management is determined by the severity of the condition. The international CTCAE grades classify the severity of ocular conditions from 1 (mild) to 4 (severe, with sight-threatening consequences). Anterior uveitis is graded in correspondence with the number of cells seen on slit lamp examination of the anterior chamber, as defined by the standardisation of uveitis nomenclature.12 Thus, grade 1 uveitis corresponds to a ‘trace’ of cells (1–5 cells in a 1 mm × 1 mm slit beam), and grade 3 uveitis corresponds to ‘3+’ (26–50 cells per field). Posterior uveitis is graded 3. In addition, a visual acuity of 20/200 (6/60 in European terminology) or less, meeting criteria for blindness in the affected eye, is graded as 4.
The ophthalmological assessments of patients with visual disturbance include visual acuity, colour vision and intraocular pressure measurement. A relative afferent pupillary defect can be tested for by carrying out the swinging flashlight test before dilating drops are instilled into the eyes. Our algorithm includes a pathway for specialist ophthalmic investigations used to diagnose uveitis, which may include FFA and indocyanine angiography (ICG), fundus autofluorescence (FAF) and OCT, depending on the individual case.
In the absence of intermediate or posterior signs, invasive dye-based angiography tests would not normally be indicated, but can be used to exclude retinal vasculitis and leakage (FFA) or undiagnosed choroiditis (ICG) in challenging cases. This can be valuable in both the diagnosis and monitoring of inflammatory eye disease.24 Non-invasive FAF imaging is used to map metabolic activity in the retinal photoreceptor and pigment epithelial layers, and can be useful in identifying inflammatory processes occurring in the outer retina.25 OCT scanning provides high resolution images of the retina in cross-section and has transformed modern ophthalmological practice.
In contrast to recommendations in current international guidelines, we have used clinical evidence to justify avoiding the discontinuation of CPIs as much as possible. The algorithm aims to emphasise the need for close liaison between oncologist and specialist ophthalmologist from the point of recognition to resolution of ocular symptoms, as well as the benefit of a multidisciplinary approach involving good communication between the specialties to balance the need for cancer control alongside patient safety and vision preservation.
Discussion
This report of eight patients experiencing ocular IrAEs associated with CPI treatment is one of the largest series published to date. Anterior uveitis was the most common ocular IrAE that we identified, occurring in five of our eight cases. The onset of uveitis is reported mainly to occur within 2 months of starting CPIs.7,13,26 This was generally the case in our cohort, with a median time to onset of 5 weeks (range 1–7 weeks). The exception was a single patient who developed anterior uveitis 2 years after completing 2 years of nivolumab treatment. It is noteworthy that he had other ocular IrAEs while on treatment that did not lead to CPI discontinuation, while his anterior uveitis was difficult to control. It is well recognised that some IrAEs (including ocular IrAEs)13 can occur months and years after stopping CPIs, and this case is a reminder to consider the need for ongoing follow-up, even in patients apparently entering long-term remission after completing treatment.
Ocular IrAEs may occur as the only IrAE, or in association with multiple body system IrAEs. In our series, their occurrence influenced the decision to interrupt CPI treatment in all seven patients who discontinued treatment early: uveitis was the primary reason for discontinuation in two (29%) patients, but contributed to the decision to stop treatment in the remaining five patients, all of whom experienced multiple IrAEs.
A literature review of 33 cases of uveitis secondary to CPIs10 concluded that one-third of patients experienced anterior uveitis alone, one-third had anterior uveitis plus posterior segment changes including macular oedema, retinal detachment, vitritis or papillitis, and one-third had panuveitis. A very recent larger review of 126 cases of CPI-associated uveitis was broadly consistent, noting that 35% of panuveitis cases occurred as part of a Vogt–Koyanagi–Harada (VKH)-like syndrome.27–30 VKH disease is a multisystem disease affecting melanin-containing tissues, which is thought to be autoimmune in origin. The most significant ocular manifestation is bilateral diffuse panuveitis with exudative retinal detachment, often accompanied by a variable spectrum of symptoms involving the skin, nervous system and inner ear.
Recognition of the different presentations of the subtypes of uveitis is clearly important, as this influences whether topical steroids alone can be used for treatment, sparing patients the need for systemic steroids which may adversely affect the outcome of anti-cancer treatment.7 As in our own series, most published series describe initial intervention with topical and/or oral corticosteroids. Although outcomes are generally good, with complete resolution of inflammation in most cases, some cases are recalcitrant, warranting alternative immunomodulatory agents, while peri-ocular or intravitreal steroids22 have been employed as steroid-sparing strategies.
Prompt recognition of ocular and visual symptoms by oncologists and referral to ophthalmology specialists is necessary to ensure rapid investigation, diagnosis and sight-preserving treatment, as well as to inform multidisciplinary team opinion concerning ongoing treatment with CPIs. This can be challenging, because the ocular symptoms experienced may not directly correlate with the severity of inflammation identified.14 Even so, in most of the case series published to date, the overwhelming majority of patients experiencing ocular irAEs have had their CPIs discontinued,12,13 and uncertainty exists whether this line of action may impact overall treatment outcomes.
Perhaps because of its low incidence relative to other IrAEs, the ESMO guidelines5 offer very little advice on how to manage ocular IrAEs. The American Society of Clinical Oncology (ASCO) guidelines,6 on the other hand, are far more extensive and recommend referral to ophthalmology services for new onset visual symptoms, while they also recognise that symptoms may not always correlate with severity. The guidelines make use of the CTCAE grading system for ocular IrAEs and include management recommendations on whether to withhold, or discontinue, immunotherapy. While these constitute a welcome framework, they may also prove unnecessarily restrictive.
The ASCO guidelines recommend that for grade 1 ocular IrAEs, CPIs can be continued, for grade 2 events CPIs should be withheld and for grades 3 and 4 events they should be permanently discontinued. Ocular IrAEs, while not usually life threatening, may be life changing, so urgent intervention aimed at avoiding permanent loss of eyesight is certainly warranted. However, it is important to note that even severe deterioration in visual acuity can sometimes be reversible. For example, significant visual impairment associated with macular oedema may recover following prompt treatment with oral or intravitreal steroids. In adherence to ASCO guidance, loss of visual acuity may result in an adverse event grading of 3 or 4, which we consider could unnecessarily lead to permanent cessation of immunotherapy.
In some patients who resume CPIs after treatment for IrAEs, relapse with the same symptoms has been observed.9,13 We argue that permanent discontinuation of immunotherapy may not always be justified in these circumstances. In our own series, one patient experienced significant bilateral loss of vision associated with an ocular IrAE after two cycles of CPI with ipilimumab + nivolumab, but did not experience further ocular symptoms on retreatment several months later. Moreover, a severe or acute drop in visual acuity may be due to other pathologies unrelated to CPI (for example, incidental retinal detachment, which has a lifetime risk in normal individuals of one in 300).31 On the other hand, a patient could have apparently mild visual impairment but severe intra-ocular inflammation.
We recommend early referral to an ophthalmology specialist on recognition of ocular symptoms to diagnose the possible ocular IrAE and accurately grade its severity. We further recommend that both eye treatment and the ongoing use of CPIs are discussed on an individual case basis within a multidisciplinary team of oncologists and ophthalmologists, keeping the option open for retreatment in situations in which the possible benefits outweigh the risks, assuming appropriate patient counselling and support.
Most cases of uveitis associated with CPI, including the majority of our cases, are mild and would be categorised as CTCAE grade 2. These cases do not require cessation of CPI and neither should they require systemic steroids, in general. The outcomes from topical treatment are mainly good, with either a limited course, or sometimes ongoing topical steroids. If systemic steroids are used, the ASCO guidelines recommend that CPIs are withheld until the patient is either off all steroids or is receiving a daily dose of 10 mg oral prednisolone (or equivalent) or less. As far as possible, the aim should be to treat ocular IrAEs with local options in order to avoid systemic steroids and cessation of CPI therapy. Aside from concerns regarding their impact on CPI efficacy, long-term steroid use is associated with many well-known harmful effects.
The goal of avoiding the interruption of CPI therapy is best achieved by taking a multidisciplinary approach, with close liaison between ophthalmology and oncology teams, remembering that patients may have a high degree of anxiety about stopping potentially life-saving anti-cancer therapy. In our cohort, five patients stopped CPIs due to ocular IrAEs, despite being categorised as grade 2, which does not necessarily mandate permanent discontinuation. Three of these patients were treated solely with topical steroids, which suggests a low threat to vision, and which would not normally interfere with CPIs. In cases where topical steroids are not sufficient, intravitreal or periocular steroids should be considered to enable patients to remain on CPIs.
It is possible that patients diagnosed with melanoma may be at increased risk of developing uveitis due to the presence of melanin in the retinal pigment epithelium. An immune-mediated response to melanin-producing cells in the eye may occur both in patients on treatment and in those who develop an immunological reaction to their cancer independent of treatment. In our series, MAR was the most likely diagnosis in one of two patients reporting ocular toxicities that were not due to uveitis, based on symptoms described and investigations performed. The pathology is thought to be due to shared neuroectodermal lineage of melanocytes and retinal cells. Conversely, uveitis is not unique to patients with a diagnosis of melanoma. Patients at increased risk of uveitis may include those with other immune-related side effects and those predisposed to autoimmune disease or with a significant family history.32
Four of our patients, of whom two had other IrAEs, responded very well to retreatment with CPIs, highlighting a key unanswered question concerning whether the occurrence of IrAEs can predict a therapeutic response.32,33 Several studies have reported increased progression-free and overall survival in patients who experienced IrAEs with CPIs compared to those who did not.34,35 To date, it remains unclear whether the development of uveitis or other specific IrAEs is associated with better outcomes from treatment with CPIs,34,36 although it is quite plausible that an observed inflammatory response within the eye or elsewhere might reflect an enhanced immune response against cancer. The number of patients in our study is insufficient to answer this question, but further study is warranted and, if proved, this could be reassuring for patients who have previously stopped immunotherapy while being treated for inflammatory side effects.
In conclusion, ocular IrAEs are relatively uncommon IrAEs associated with CPIs, but can be dramatic and may lead to permanent visual loss. Prompt recognition in oncology clinics and early referral to an ophthalmologist is essential. Patients with confirmed ocular inflammation require close monitoring in the eye clinic and ongoing liaison with their oncologist regarding optimal treatment and the use of corticosteroids. The option of intraocular steroid implants should be considered as an alternative to systemic steroids when IrAEs do not resolve with topical steroids alone, with the potential benefit of being able to continue on CPIs.
In conjunction with our ocular IrAE management algorithm (Figure 2), we propose the following basic steps to follow when seeing immunotherapy patients with ocular symptoms in the clinic:
document the symptoms and signs and their severity
escalate by referral to an ophthalmologist; consider urgency of referral and the need to interrupt CPI therapy depending on symptom severity
obtain an ophthalmological diagnosis
take a multidisciplinary approach to managing the ocular symptoms and the need or otherwise to restart CPIs, based on risk/benefit considerations.
The authors would like to thank the patients and their families for allowing us to share their case studies. Thanks also to the CUHFT research governance and audit teams for their assistance in the conduct of this study.
Conflict of interest: The authors declare that there is no conflict of interest.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Philippa Corrie
https://orcid.org/0000-0003-4875-7021 | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY-NC | 33633802 | 19,074,441 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm.
Ocular immune-related adverse events (IrAEs) associated with use of checkpoint inhibitors (CPIs) in cancer therapeutics are relatively rare, occurring in approximately 1% of treated patients. Recognition and early intervention are essential because the degree of tissue damage may be disproportionate to the symptoms, and lack of appropriate treatment risks permanent loss of vision. International guidelines on managing ocular IrAEs provide limited advice only. Importantly, local interventions can be effective and may avoid the need for systemic corticosteroids, thereby permitting the continuation of CPIs. We present a single institution case series of eight affected patients managed by our multidisciplinary team. Consistent with previously published series and case reports, we identified anterior uveitis as the most common ocular IrAE associated with CPIs requiring intervention. Based on our experience, as well as published guidance, we generated a simple algorithm to assist clinicians efficiently manage patients developing ocular symptoms during treatment with CPIs. In addition, we make recommendations for optimising treatment of uveitis and address implications for ongoing CPI therapy.
Background
Immunotherapy with checkpoint inhibitors (CPIs) has transformed the treatment of a wide range of malignancies.1,2 These drugs work by enabling the host immune system to eliminate malignant cells, recognisable through the expression of neoantigens. The CPIs currently in clinical use are antibodies which target the cytotoxic T-lymphocyte antigen-4 receptor (anti-CTLA-4), the programmed death-1 receptor (anti-PD-1) and its ligand (anti-PD-L1). The CTLA-4 receptor downregulates T-cell activation, whereas the PD-1 receptor inhibits T-cell proliferation, cytokine release, and cytotoxicity. Blocking their function can enhance T-cell response and allow immune-mediated tumour killing.
CPIs generate side effects termed immune-related adverse events (IrAEs), which stem from their mechanism of action, being predominantly autoimmune in nature and having the potential to affect any body organ. IrAEs range from being mild to life-threatening, or life-changing in some instances.3 Since their first introduction into clinical practice in 2011 as treatment for metastatic melanoma, the use of anti-CTLA-4 and anti-PD-L1 antibodies has expanded to include multiple cancer types including lung and urological cancers as well as lymphomas, with new treatment indications being added frequently. Their increasing use has resulted in greater awareness of both common and rarely seen IrAEs, ranging from mild presentations to severe reactions requiring prompt intervention.4
Optimal management of IrAEs is still in its infancy, with limited evidence to inform international guidelines which have been generated to assist clinical practice.5,6 The mainstay of treatment for what appear to be inflammatory conditions is immunosuppression with corticosteroids, prompting concerns about their effect on CPI efficacy.7 Moreover, the long-term effects on cancer survivors of high dose steroids, sometimes administered for protracted periods of time, have yet to be fully understood. The European Society of Medical Oncology (ESMO) clinical practice guidelines5 provide helpful algorithms for managing the more commonly occurring IrAEs, but consensus advice on managing less common IrAEs, such as those affecting the eyes, is also needed to minimise any negative impact of anti-cancer interventions.
Ocular IrAEs occur with an estimated prevalence of 1–3% of all treated patients.8,9 While the spectrum of severity is broad, they are highly significant as they can threaten vision. Reports of ocular IrAEs associated with CPIs are limited to small, single-digit case series and individual case reports, which principally report patients experiencing varying degrees of uveitis.8,10–13
Uveitis is a term used to describe inflammation of the uvea, the middle layer of the eye comprising the iris, ciliary body and choroid. It is classified as anterior, intermediate, posterior, or panuveitis, according to the predominant site of inflammation within the eye.14 Anterior uveitis is characterised by an infiltrate of white blood cells in the anterior chamber of the eye; intermediate uveitis is associated with inflammation in the vitreous gel, resulting in visual blurring, haze and floaters; posterior uveitis is characterised by retinal and/or choroidal inflammation.15,16 Symptoms of uveitis include pain, blurred vision and red eye. Involvement of the posterior segment can produce symptoms of floaters, flickering and shimmering lights (photopsias), as well as blind spots.
Anterior uveitis, whether acute or chronic, can often be managed with topical steroid drops alone. Severe uveitis of any subtype may lead to macular oedema, with accumulation of fluid at the most sensitive part of the retina, causing visual distortion and blurring. Severe ocular inflammation requires prompt intervention to avoid permanent loss of vision, and may require periocular or intravitreal steroid injections. More severe cases require systemic steroids, including oral, or pulsed intravenous methylprednisolone. Recalcitrant, chronic inflammatory eye diseases can be managed with secondary non-corticosteroid immunomodulatory therapeutic agents, including anti-metabolites like mycophenolate mofetil and methotrexate, or biological drugs like adalimumab.17 Common complications of uveitis and its treatment include cataract, glaucoma and choroidal neovascularisation. While most reports suggest a good response to therapy with complete resolution of inflammation, a minority of patients may develop permanent visual loss.
Other less common ocular IrAEs include ocular myasthenia, optic neuritis and auto-immune retinopathy. Dry eyes are described by up to one in four treated patients, but this is a common condition that is often not reported in clinical trials and is frequently undertreated, even in clinical practice.8,9 The risk of ocular IrAEs associated with CPIs was recently quantified using disproportionality analysis; odds ratios for uveitis ranged from 4.6 to 10.8, while that of any ocular IrAE was 2.5 compared with reported events associated with all other drugs.18
Uncertainties about optimal management of ocular IrAEs persist, such as when to interrupt or discontinue potentially life-saving CPI therapy and whether systemic steroids can influence the efficacy of CPIs. We report our experience of managing ocular IrAEs in a cohort of cancer patients receiving CPIs in a single institution and make management recommendations in a novel treatment algorithm.
Methods
We reviewed the electronic patient records of patients treated with CPIs from January to December 2019, and identified all cases referred to the ophthalmology service. The clinical characteristics, treatment and course of IrAEs over time were recorded. Details of their CPI treatment, other non-ocular irAEs, and disease response (based on routine radiological imaging and applying RECIST 1.1 response criteria) were also recorded. Survival was measured from the date of first CPI infusion until data cut-off, on 17 March, 2020.
Based on our case series and information contained in published international guidelines,5,6 we generated a simple assessment and treatment algorithm for use in routine clinical practice to guide the multidisciplinary team managing ocular symptoms and uveitis; the most common ocular IrAE reported.
This project was registered as a health service evaluation at Cambridge University Hospitals NHS Foundation Trust (CUHFT). The CUHFT research governance lead confirmed that, under the UK Policy Framework for Health and Social Care Research 2017, this project would not be classified or managed as research within the National Health Service and therefore did not require ethical review by a research ethics committee. Written informed consent to publish was obtained from the surviving case study patient.
Results
Patient characteristics
We identified eight patients (three women and five men, aged between 39 and 81 years) who developed ocular IrAEs after starting CPIs (Table 1). Seven patients were treated for advanced cancer; four for metastatic melanoma, two metastatic renal-cell carcinoma and one advanced ovarian carcinoma. One melanoma patient received CPI as an adjuvant therapy, after resection of regional lymph node disease. None had a previous history of uveitis. One patient had a history of glaucoma. Five patients received combination anti-CTLA-4 plus anti-PD-1 antibodies (ipilimumab + nivolumab), two patients received a single agent anti-PD-1 antibody (one pembrolizumab, one nivolumab) and one patient received anti-PD-1 antibody (nivolumab) in combination with a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor (rucaparib). Seven patients had their treatment discontinued early due to treatment-related adverse events; their treatment duration ranged from 3 to 9 weeks. The median number of adverse events contributing to treatment discontinuation was three (range 1–3). One patient completed 2 years of planned anti-PD-1 antibody therapy.
Table 1. Patient characteristics of patients experiencing ocular IrAEs associated with CPI treatment.
Patient case CPI regimen Duration of CPI therapy Reason for discontinuation AEs leading to discontinuation Best response to CPI Survival outcome
Melanoma-1
Metastatic
50-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Ocular IrAE Ocular
Skin
Fatigue Partial response Alive 16 months+
Kidney-1
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 3 weeks Multiple IrAE Ocular
Skin
Liver Stable disease Alive 15 months+
Kidney-2
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 4 weeks Multiple IrAEs Ocular
Liver
Arthritis Partial response Alive 16 months+
Ovarian
Metastatic
40-yo woman Nivolumab + rucaparib 8 weeks Multiple IrAE Ocular
Liver
Neutropaenia* Partial response Alive 10 months+
Melanoma-2
Resected stage III
74-yo woman Pembrolizumab
200 mg IV q3w 3 weeks Ocular IrAE Ocular Recurrence Treated with ipilimumab on recurrence; aborted after 6 weeks due to colitis.
Alive with stable disease:
14 months+
Melanoma-3
Metastatic
56-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Multiple IrAEs Ocular
Lung Partial response Alive 22 months+
Melanoma-4
Metastatic
40-yo woman Ipilimumab
1 mg/kg+ nivolumab 3 mg/kg 6 weeks Multiple IrAEs Ocular
Liver Partial response Rechallenged with 2 further cycles of ipilimumab+nivolumab on disease progression without significant IrAEs; progressive brain metastases.
Died after 11 months
Melanoma-5
Metastatic
81-yo man Nivolumab 240 mg 2 years Completed planned treatment – Near complete response Alive 5 years+
* Likely due to PARP inhibitor, not CPI.
AEs, adverse events; CPI, checkpoint inhibitor; IrEAs, immune-related adverse events; yo, year-old; PARP, poly-adenosine diphosphate ribose polymerase.
Ocular IrAE characteristics
The median time to the onset of ocular IrAE was 5 weeks from starting CPIs, although one patient developed symptoms after 18 months of treatment (Table 2). In all seven patients who discontinued CPIs early, ocular IrAE contributed to the decision to discontinue therapy. One patient with pre-existing glaucoma experienced ocular IrAE as the only IrAE, occurring after her first dose of pembrolizumab, and this led to treatment discontinuation. Four patients were diagnosed with anterior uveitis, one had intermediate uveitis, one had melanoma-associated retinopathy (MAR)19,20 and one had suspected ocular ischaemic syndrome.21 All patients had bilateral eye involvement. There were no hospitalisations associated with ocular IrAEs.
Table 2. Characteristics of ocular IrAEs experienced and their treatment.
Patient case Presenting symptoms Ocular IrAE Worst
CTCAE
grade Time to onset/resolution of ocular IrAE Worst visual acuity Visual acuity on resolution Local treatment Systemic steroids (starting dose) Outcome of ocular IrAE
Melanoma 1 Bilateral blurred vision, painful eyes Anterior uveitis 2 3 weeks/8 weeks R 6/19
L Normal R Normal
L Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Kidney 1 Bilateral blurred vision, painful eyes, headache Anterior uveitis
High IO pressures 2 5 weeks/11 weeks (uveitis)
6 months
(IO pressures) R 6/9.5
L 6/7.5 R Normal
L Normal Dexamethasone 0.1% drops
Timolol
Latanprost None Complete resolution
Kidney 2 Bilateral painful red eyes, light sensitivity Anterior uveitis
Left disc swelling 2 5 weeks/8 weeks Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Ovarian Bilateral blurred vision. Painful to focus Anterior uveitis 2 5 weeks/8 months Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Melanoma 2 Deterioration in vision Intermediate
uveitis 3 1 week/10 weeks R 6/9
L Normal R 6/9
L Normal None 40 mg prednisolone Resolved on 10 mg prednisolone; following 2 cycles of ipilimumab,
received IV steroids and infliximab for enteritis
Melanoma 3 Flashing lights, visual aura Melanoma associated retinopathy 4 3 weeks/18 months R 6/18 R 6/5 Anti-VEGF injections
Intra-ocular dexamethasone 50 mg prednisolone Permanent loss of vision; macular scarring
Melanoma 4 Rapid onset loss of vision in both eyes Suspected ocular ischaemic syndrome 4 7 weeks/4 weeks R 6/15
L 6/9 R Normal
L Normal Dexamethasone 0.1% drops
Mydrilate 1% drops 40 mg prednisolone Complete resolution
Melanoma 5 Red, eyes
Loss of vision in left eye
Blurred vision Conjunctivitis
Left retinal detachment*
Anterior uveitis 2
2 18 months
21 months
4 years/10 months R 6/12
L 6/7.5 R 6/12
L 6/7.5 Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Quiescent
* Association of retinal detachment as an IrAE could not be confirmed.
CTCAE, common toxicity criteria; IO, intra-ocular; IrEA, immune-related adverse event; IV, intravenous; L, left; R, right; VEGF, vascular endothelial growth factor.
The patient completing 2 years of nivolumab experienced ocular IrAEs both during and after completing CPI treatment. As the symptoms were manageable and no other IrAEs occurred, his planned treatment was not interrupted. He experienced conjunctivitis and left retinal detachment during treatment, both of which were managed successfully. Two years after completing CPIs, he developed bilateral anterior uveitis.
Treatment of ocular IrAEs
All five patients who developed anterior uveitis were treated with topical steroids only. The three other ocular conditions (intermediate uveitis, MAR and suspected ocular ischaemic syndrome) were treated with oral corticosteroids. No patients received intravenous steroids or other immunosuppressive agents to treat their ocular IrAEs. One patient diagnosed with MAR received intravitreal anti-vascular endothelial growth factor injections to treat a juxtafoveal choroidal neovascular membrane, as well as intra-ocular steroid implants to treat chronic photopsia in his only remaining eye.
The median ocular IrAE treatment duration was 11 weeks (range 8 weeks–10 months) with topical steroids and 10 weeks (range 4 weeks–6 months) with oral steroids. Two patients with anterior uveitis had rapid, complete resolution of their symptoms by 8 and 11 weeks. One patient had persistently raised intra-ocular pressures for approximately 6 months. Two patients had a protracted course of inflammatory eye disease, with recurrent episodes lasting 8 and 10 months, respectively. Of two patients re-challenged with CPIs at a later date, (one with ipilimumab, one with ipilimumab + nivolumab), neither had recurrence of ocular IrAEs.
Oncological response to CPIs
Overall, six out of the eight treated patients experienced a partial or near complete response to CPI therapy and seven remain alive and well at data cut-off. One melanoma patient whose adjuvant pembrolizumab treatment was aborted due to uveitis had disease recurrence documented 10 weeks after her first CPI administration, then received ipilimumab, which was aborted after teo cycles due to severe colitis, but her disease has remained stable since that time (15 months at data cut-off). A second melanoma patient who progressed on completing adjuvant pembrolizumab initially responded to ipilimumab + nivolumab, but died of metastatic disease 19 months after her first CPI administration.
Non-uveitis case studies
Case 1: (‘Melanoma 3’ in Tables 1 and 2)
A 56-year-old man received treatment with ipilimumab + nivolumab for metastatic uveal melanoma, having had exenteration of his left eye 4 years previously. Three weeks after his first CPI administration he complained of severe flashing lights in his remaining eye, and he was referred urgently for an ophthalmological assessment.
On slit lamp biomicroscopy, pale lesions were noted in the fundus, and these were presumed to be benign. He continued immunotherapy, but after 9 weeks (three cycles of CPI), he developed moderately severe pneumonitis which was initially treated with 50 mg oral prednisolone daily and CPI therapy was permanently discontinued. The pneumonitis resolved over 12 weeks and he was gradually weaned off steroids. While tapering his steroids, he noticed that his vision was deteriorating and a visual field defect was detected on formal testing.
Optical coherence tomography (OCT) scanning indicated a choroidal lesion next to the fovea, suggesting a possible neovascular membrane (Figure 1a), which could cause visual loss. This suspicion was confirmed by the presence of early leakage during fundus fluorescein angiography (FFA) (Figure 1b). The choroidal neovascular membrane was treated with a series of intravitreal anti-vascular endothelial growth factor (ranibizumab) injections, until it was deemed to be inactive.
Figure 1. Non-uveitis case study. (a) Optical coherence tomography scan showing a choroidal lesion next to the fovea, possibly representing a neovascular membrane. (b) Fundus fluorescein angiography demonstrating early hyperfluorescence of the juxtafoveal lesion, supporting a diagnosis of choroidal neovascularisation. (c) Pseudocolour image of the fundus showing the dexamethasone 0.7 mg steroid implant.
Electrodiagnostic testing subsequently revealed widespread post-phototransduction cone and rod dysfunction, compatible with MAR. His symptoms partially improved on restarting oral steroids (10 mg prednisolone daily), pointing to an inflammatory cause of his visual symptoms. On the basis of this evidence, he was offered short-acting and long-acting intravitreal steroid implants,22 (dexamethasone 0.7 mg and fluocinolone acetonide, respectively, Figure 1c) to avoid chronic side effects of long-term systemic steroids. At the time of data cut-off, the patient remained disease free, with relatively minor persistent visual impairment.
Case 2: (‘Melanoma 4’ in Tables 1 and 2)
A 40-year-old woman received adjuvant pembrolizumab for stage IIID BRAF wild type melanoma, which was well tolerated, without any IrAEs. After 11 months of treatment, she complained of generalised musculoskeletal pains and fatigue. Restaging scans identified widespread metastases including to liver and bone. She was commenced on ipilimumab + nivolumab. After 6 weeks (post cycle 2), her overall condition deteriorated, with severe fatigue and deterioration in liver function and performance status, although her serum lactate dehydrogenase dropped markedly from 1956 to 498 IU/L during the same time period. Her third cycle of ipilimumab + nivolumab was deferred.
One week later, she presented to the emergency department complaining of sudden onset bilateral loss of vision, worse in the right eye. Visual acuity was 6/15 in the right eye and 6/9 in the left eye, and intraocular pressure was within normal parameters. Iris neovascularisation and a swollen right optic disc were found on slit lamp biomicroscopy and fundoscopy. Brain imaging was requested, and confirmed the absence of metastases. A diagnosis of ocular ischaemic syndrome21 was suggested, but after discussion with the oncology specialist, a possible inflammatory aetiology was considered.
The patient was treated with 40 mg oral prednisolone daily, 0.1% dexamethasone eye drops and 1% mydrilate drops. She responded well to treatment, and was gradually weaned off steroids, and her vision recovered. Her liver function normalised and her performance status improved sufficiently for a return to normal activities of daily living. Subsequent staging compueterised tomography (CT) images indicated a partial response to CPIs. Six months later, despite the patient remaining well and asymptomatic, surveillance imaging identified disease recurrence in previously involved body sites with four new brain metastases. She was re-challenged with ipilimumab + nivolumab. No new IrAEs occurred, but after the second cycle, she was admitted to hospital with seizures due to haemorrhage into the brain metastases and died 10 weeks later, 11 months after starting CPIs for metastatic disease.
Ocular symptom management algorithm
Based on our own experience, review of the literature and international guidelines, we generated a management algorithm designed for multidisciplinary teams to use in clinical practice (Figure 2).
Figure 2. Management algorithm for patients treated with CPIs who present with ocular symptoms.
CPI, checkpoint inhibitor; FAF, fundus autofluorescence; FFA, fundus fluorescein angiography; ICG, indocyanine angiography; OCT, optical coherence tomography.
Patient symptoms and signs are classified according to international common toxicity criteria (CTCAE version 5.0)23 and management is determined by the severity of the condition. The international CTCAE grades classify the severity of ocular conditions from 1 (mild) to 4 (severe, with sight-threatening consequences). Anterior uveitis is graded in correspondence with the number of cells seen on slit lamp examination of the anterior chamber, as defined by the standardisation of uveitis nomenclature.12 Thus, grade 1 uveitis corresponds to a ‘trace’ of cells (1–5 cells in a 1 mm × 1 mm slit beam), and grade 3 uveitis corresponds to ‘3+’ (26–50 cells per field). Posterior uveitis is graded 3. In addition, a visual acuity of 20/200 (6/60 in European terminology) or less, meeting criteria for blindness in the affected eye, is graded as 4.
The ophthalmological assessments of patients with visual disturbance include visual acuity, colour vision and intraocular pressure measurement. A relative afferent pupillary defect can be tested for by carrying out the swinging flashlight test before dilating drops are instilled into the eyes. Our algorithm includes a pathway for specialist ophthalmic investigations used to diagnose uveitis, which may include FFA and indocyanine angiography (ICG), fundus autofluorescence (FAF) and OCT, depending on the individual case.
In the absence of intermediate or posterior signs, invasive dye-based angiography tests would not normally be indicated, but can be used to exclude retinal vasculitis and leakage (FFA) or undiagnosed choroiditis (ICG) in challenging cases. This can be valuable in both the diagnosis and monitoring of inflammatory eye disease.24 Non-invasive FAF imaging is used to map metabolic activity in the retinal photoreceptor and pigment epithelial layers, and can be useful in identifying inflammatory processes occurring in the outer retina.25 OCT scanning provides high resolution images of the retina in cross-section and has transformed modern ophthalmological practice.
In contrast to recommendations in current international guidelines, we have used clinical evidence to justify avoiding the discontinuation of CPIs as much as possible. The algorithm aims to emphasise the need for close liaison between oncologist and specialist ophthalmologist from the point of recognition to resolution of ocular symptoms, as well as the benefit of a multidisciplinary approach involving good communication between the specialties to balance the need for cancer control alongside patient safety and vision preservation.
Discussion
This report of eight patients experiencing ocular IrAEs associated with CPI treatment is one of the largest series published to date. Anterior uveitis was the most common ocular IrAE that we identified, occurring in five of our eight cases. The onset of uveitis is reported mainly to occur within 2 months of starting CPIs.7,13,26 This was generally the case in our cohort, with a median time to onset of 5 weeks (range 1–7 weeks). The exception was a single patient who developed anterior uveitis 2 years after completing 2 years of nivolumab treatment. It is noteworthy that he had other ocular IrAEs while on treatment that did not lead to CPI discontinuation, while his anterior uveitis was difficult to control. It is well recognised that some IrAEs (including ocular IrAEs)13 can occur months and years after stopping CPIs, and this case is a reminder to consider the need for ongoing follow-up, even in patients apparently entering long-term remission after completing treatment.
Ocular IrAEs may occur as the only IrAE, or in association with multiple body system IrAEs. In our series, their occurrence influenced the decision to interrupt CPI treatment in all seven patients who discontinued treatment early: uveitis was the primary reason for discontinuation in two (29%) patients, but contributed to the decision to stop treatment in the remaining five patients, all of whom experienced multiple IrAEs.
A literature review of 33 cases of uveitis secondary to CPIs10 concluded that one-third of patients experienced anterior uveitis alone, one-third had anterior uveitis plus posterior segment changes including macular oedema, retinal detachment, vitritis or papillitis, and one-third had panuveitis. A very recent larger review of 126 cases of CPI-associated uveitis was broadly consistent, noting that 35% of panuveitis cases occurred as part of a Vogt–Koyanagi–Harada (VKH)-like syndrome.27–30 VKH disease is a multisystem disease affecting melanin-containing tissues, which is thought to be autoimmune in origin. The most significant ocular manifestation is bilateral diffuse panuveitis with exudative retinal detachment, often accompanied by a variable spectrum of symptoms involving the skin, nervous system and inner ear.
Recognition of the different presentations of the subtypes of uveitis is clearly important, as this influences whether topical steroids alone can be used for treatment, sparing patients the need for systemic steroids which may adversely affect the outcome of anti-cancer treatment.7 As in our own series, most published series describe initial intervention with topical and/or oral corticosteroids. Although outcomes are generally good, with complete resolution of inflammation in most cases, some cases are recalcitrant, warranting alternative immunomodulatory agents, while peri-ocular or intravitreal steroids22 have been employed as steroid-sparing strategies.
Prompt recognition of ocular and visual symptoms by oncologists and referral to ophthalmology specialists is necessary to ensure rapid investigation, diagnosis and sight-preserving treatment, as well as to inform multidisciplinary team opinion concerning ongoing treatment with CPIs. This can be challenging, because the ocular symptoms experienced may not directly correlate with the severity of inflammation identified.14 Even so, in most of the case series published to date, the overwhelming majority of patients experiencing ocular irAEs have had their CPIs discontinued,12,13 and uncertainty exists whether this line of action may impact overall treatment outcomes.
Perhaps because of its low incidence relative to other IrAEs, the ESMO guidelines5 offer very little advice on how to manage ocular IrAEs. The American Society of Clinical Oncology (ASCO) guidelines,6 on the other hand, are far more extensive and recommend referral to ophthalmology services for new onset visual symptoms, while they also recognise that symptoms may not always correlate with severity. The guidelines make use of the CTCAE grading system for ocular IrAEs and include management recommendations on whether to withhold, or discontinue, immunotherapy. While these constitute a welcome framework, they may also prove unnecessarily restrictive.
The ASCO guidelines recommend that for grade 1 ocular IrAEs, CPIs can be continued, for grade 2 events CPIs should be withheld and for grades 3 and 4 events they should be permanently discontinued. Ocular IrAEs, while not usually life threatening, may be life changing, so urgent intervention aimed at avoiding permanent loss of eyesight is certainly warranted. However, it is important to note that even severe deterioration in visual acuity can sometimes be reversible. For example, significant visual impairment associated with macular oedema may recover following prompt treatment with oral or intravitreal steroids. In adherence to ASCO guidance, loss of visual acuity may result in an adverse event grading of 3 or 4, which we consider could unnecessarily lead to permanent cessation of immunotherapy.
In some patients who resume CPIs after treatment for IrAEs, relapse with the same symptoms has been observed.9,13 We argue that permanent discontinuation of immunotherapy may not always be justified in these circumstances. In our own series, one patient experienced significant bilateral loss of vision associated with an ocular IrAE after two cycles of CPI with ipilimumab + nivolumab, but did not experience further ocular symptoms on retreatment several months later. Moreover, a severe or acute drop in visual acuity may be due to other pathologies unrelated to CPI (for example, incidental retinal detachment, which has a lifetime risk in normal individuals of one in 300).31 On the other hand, a patient could have apparently mild visual impairment but severe intra-ocular inflammation.
We recommend early referral to an ophthalmology specialist on recognition of ocular symptoms to diagnose the possible ocular IrAE and accurately grade its severity. We further recommend that both eye treatment and the ongoing use of CPIs are discussed on an individual case basis within a multidisciplinary team of oncologists and ophthalmologists, keeping the option open for retreatment in situations in which the possible benefits outweigh the risks, assuming appropriate patient counselling and support.
Most cases of uveitis associated with CPI, including the majority of our cases, are mild and would be categorised as CTCAE grade 2. These cases do not require cessation of CPI and neither should they require systemic steroids, in general. The outcomes from topical treatment are mainly good, with either a limited course, or sometimes ongoing topical steroids. If systemic steroids are used, the ASCO guidelines recommend that CPIs are withheld until the patient is either off all steroids or is receiving a daily dose of 10 mg oral prednisolone (or equivalent) or less. As far as possible, the aim should be to treat ocular IrAEs with local options in order to avoid systemic steroids and cessation of CPI therapy. Aside from concerns regarding their impact on CPI efficacy, long-term steroid use is associated with many well-known harmful effects.
The goal of avoiding the interruption of CPI therapy is best achieved by taking a multidisciplinary approach, with close liaison between ophthalmology and oncology teams, remembering that patients may have a high degree of anxiety about stopping potentially life-saving anti-cancer therapy. In our cohort, five patients stopped CPIs due to ocular IrAEs, despite being categorised as grade 2, which does not necessarily mandate permanent discontinuation. Three of these patients were treated solely with topical steroids, which suggests a low threat to vision, and which would not normally interfere with CPIs. In cases where topical steroids are not sufficient, intravitreal or periocular steroids should be considered to enable patients to remain on CPIs.
It is possible that patients diagnosed with melanoma may be at increased risk of developing uveitis due to the presence of melanin in the retinal pigment epithelium. An immune-mediated response to melanin-producing cells in the eye may occur both in patients on treatment and in those who develop an immunological reaction to their cancer independent of treatment. In our series, MAR was the most likely diagnosis in one of two patients reporting ocular toxicities that were not due to uveitis, based on symptoms described and investigations performed. The pathology is thought to be due to shared neuroectodermal lineage of melanocytes and retinal cells. Conversely, uveitis is not unique to patients with a diagnosis of melanoma. Patients at increased risk of uveitis may include those with other immune-related side effects and those predisposed to autoimmune disease or with a significant family history.32
Four of our patients, of whom two had other IrAEs, responded very well to retreatment with CPIs, highlighting a key unanswered question concerning whether the occurrence of IrAEs can predict a therapeutic response.32,33 Several studies have reported increased progression-free and overall survival in patients who experienced IrAEs with CPIs compared to those who did not.34,35 To date, it remains unclear whether the development of uveitis or other specific IrAEs is associated with better outcomes from treatment with CPIs,34,36 although it is quite plausible that an observed inflammatory response within the eye or elsewhere might reflect an enhanced immune response against cancer. The number of patients in our study is insufficient to answer this question, but further study is warranted and, if proved, this could be reassuring for patients who have previously stopped immunotherapy while being treated for inflammatory side effects.
In conclusion, ocular IrAEs are relatively uncommon IrAEs associated with CPIs, but can be dramatic and may lead to permanent visual loss. Prompt recognition in oncology clinics and early referral to an ophthalmologist is essential. Patients with confirmed ocular inflammation require close monitoring in the eye clinic and ongoing liaison with their oncologist regarding optimal treatment and the use of corticosteroids. The option of intraocular steroid implants should be considered as an alternative to systemic steroids when IrAEs do not resolve with topical steroids alone, with the potential benefit of being able to continue on CPIs.
In conjunction with our ocular IrAE management algorithm (Figure 2), we propose the following basic steps to follow when seeing immunotherapy patients with ocular symptoms in the clinic:
document the symptoms and signs and their severity
escalate by referral to an ophthalmologist; consider urgency of referral and the need to interrupt CPI therapy depending on symptom severity
obtain an ophthalmological diagnosis
take a multidisciplinary approach to managing the ocular symptoms and the need or otherwise to restart CPIs, based on risk/benefit considerations.
The authors would like to thank the patients and their families for allowing us to share their case studies. Thanks also to the CUHFT research governance and audit teams for their assistance in the conduct of this study.
Conflict of interest: The authors declare that there is no conflict of interest.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Philippa Corrie
https://orcid.org/0000-0003-4875-7021 | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY-NC | 33633802 | 19,074,441 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonitis'. | Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm.
Ocular immune-related adverse events (IrAEs) associated with use of checkpoint inhibitors (CPIs) in cancer therapeutics are relatively rare, occurring in approximately 1% of treated patients. Recognition and early intervention are essential because the degree of tissue damage may be disproportionate to the symptoms, and lack of appropriate treatment risks permanent loss of vision. International guidelines on managing ocular IrAEs provide limited advice only. Importantly, local interventions can be effective and may avoid the need for systemic corticosteroids, thereby permitting the continuation of CPIs. We present a single institution case series of eight affected patients managed by our multidisciplinary team. Consistent with previously published series and case reports, we identified anterior uveitis as the most common ocular IrAE associated with CPIs requiring intervention. Based on our experience, as well as published guidance, we generated a simple algorithm to assist clinicians efficiently manage patients developing ocular symptoms during treatment with CPIs. In addition, we make recommendations for optimising treatment of uveitis and address implications for ongoing CPI therapy.
Background
Immunotherapy with checkpoint inhibitors (CPIs) has transformed the treatment of a wide range of malignancies.1,2 These drugs work by enabling the host immune system to eliminate malignant cells, recognisable through the expression of neoantigens. The CPIs currently in clinical use are antibodies which target the cytotoxic T-lymphocyte antigen-4 receptor (anti-CTLA-4), the programmed death-1 receptor (anti-PD-1) and its ligand (anti-PD-L1). The CTLA-4 receptor downregulates T-cell activation, whereas the PD-1 receptor inhibits T-cell proliferation, cytokine release, and cytotoxicity. Blocking their function can enhance T-cell response and allow immune-mediated tumour killing.
CPIs generate side effects termed immune-related adverse events (IrAEs), which stem from their mechanism of action, being predominantly autoimmune in nature and having the potential to affect any body organ. IrAEs range from being mild to life-threatening, or life-changing in some instances.3 Since their first introduction into clinical practice in 2011 as treatment for metastatic melanoma, the use of anti-CTLA-4 and anti-PD-L1 antibodies has expanded to include multiple cancer types including lung and urological cancers as well as lymphomas, with new treatment indications being added frequently. Their increasing use has resulted in greater awareness of both common and rarely seen IrAEs, ranging from mild presentations to severe reactions requiring prompt intervention.4
Optimal management of IrAEs is still in its infancy, with limited evidence to inform international guidelines which have been generated to assist clinical practice.5,6 The mainstay of treatment for what appear to be inflammatory conditions is immunosuppression with corticosteroids, prompting concerns about their effect on CPI efficacy.7 Moreover, the long-term effects on cancer survivors of high dose steroids, sometimes administered for protracted periods of time, have yet to be fully understood. The European Society of Medical Oncology (ESMO) clinical practice guidelines5 provide helpful algorithms for managing the more commonly occurring IrAEs, but consensus advice on managing less common IrAEs, such as those affecting the eyes, is also needed to minimise any negative impact of anti-cancer interventions.
Ocular IrAEs occur with an estimated prevalence of 1–3% of all treated patients.8,9 While the spectrum of severity is broad, they are highly significant as they can threaten vision. Reports of ocular IrAEs associated with CPIs are limited to small, single-digit case series and individual case reports, which principally report patients experiencing varying degrees of uveitis.8,10–13
Uveitis is a term used to describe inflammation of the uvea, the middle layer of the eye comprising the iris, ciliary body and choroid. It is classified as anterior, intermediate, posterior, or panuveitis, according to the predominant site of inflammation within the eye.14 Anterior uveitis is characterised by an infiltrate of white blood cells in the anterior chamber of the eye; intermediate uveitis is associated with inflammation in the vitreous gel, resulting in visual blurring, haze and floaters; posterior uveitis is characterised by retinal and/or choroidal inflammation.15,16 Symptoms of uveitis include pain, blurred vision and red eye. Involvement of the posterior segment can produce symptoms of floaters, flickering and shimmering lights (photopsias), as well as blind spots.
Anterior uveitis, whether acute or chronic, can often be managed with topical steroid drops alone. Severe uveitis of any subtype may lead to macular oedema, with accumulation of fluid at the most sensitive part of the retina, causing visual distortion and blurring. Severe ocular inflammation requires prompt intervention to avoid permanent loss of vision, and may require periocular or intravitreal steroid injections. More severe cases require systemic steroids, including oral, or pulsed intravenous methylprednisolone. Recalcitrant, chronic inflammatory eye diseases can be managed with secondary non-corticosteroid immunomodulatory therapeutic agents, including anti-metabolites like mycophenolate mofetil and methotrexate, or biological drugs like adalimumab.17 Common complications of uveitis and its treatment include cataract, glaucoma and choroidal neovascularisation. While most reports suggest a good response to therapy with complete resolution of inflammation, a minority of patients may develop permanent visual loss.
Other less common ocular IrAEs include ocular myasthenia, optic neuritis and auto-immune retinopathy. Dry eyes are described by up to one in four treated patients, but this is a common condition that is often not reported in clinical trials and is frequently undertreated, even in clinical practice.8,9 The risk of ocular IrAEs associated with CPIs was recently quantified using disproportionality analysis; odds ratios for uveitis ranged from 4.6 to 10.8, while that of any ocular IrAE was 2.5 compared with reported events associated with all other drugs.18
Uncertainties about optimal management of ocular IrAEs persist, such as when to interrupt or discontinue potentially life-saving CPI therapy and whether systemic steroids can influence the efficacy of CPIs. We report our experience of managing ocular IrAEs in a cohort of cancer patients receiving CPIs in a single institution and make management recommendations in a novel treatment algorithm.
Methods
We reviewed the electronic patient records of patients treated with CPIs from January to December 2019, and identified all cases referred to the ophthalmology service. The clinical characteristics, treatment and course of IrAEs over time were recorded. Details of their CPI treatment, other non-ocular irAEs, and disease response (based on routine radiological imaging and applying RECIST 1.1 response criteria) were also recorded. Survival was measured from the date of first CPI infusion until data cut-off, on 17 March, 2020.
Based on our case series and information contained in published international guidelines,5,6 we generated a simple assessment and treatment algorithm for use in routine clinical practice to guide the multidisciplinary team managing ocular symptoms and uveitis; the most common ocular IrAE reported.
This project was registered as a health service evaluation at Cambridge University Hospitals NHS Foundation Trust (CUHFT). The CUHFT research governance lead confirmed that, under the UK Policy Framework for Health and Social Care Research 2017, this project would not be classified or managed as research within the National Health Service and therefore did not require ethical review by a research ethics committee. Written informed consent to publish was obtained from the surviving case study patient.
Results
Patient characteristics
We identified eight patients (three women and five men, aged between 39 and 81 years) who developed ocular IrAEs after starting CPIs (Table 1). Seven patients were treated for advanced cancer; four for metastatic melanoma, two metastatic renal-cell carcinoma and one advanced ovarian carcinoma. One melanoma patient received CPI as an adjuvant therapy, after resection of regional lymph node disease. None had a previous history of uveitis. One patient had a history of glaucoma. Five patients received combination anti-CTLA-4 plus anti-PD-1 antibodies (ipilimumab + nivolumab), two patients received a single agent anti-PD-1 antibody (one pembrolizumab, one nivolumab) and one patient received anti-PD-1 antibody (nivolumab) in combination with a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor (rucaparib). Seven patients had their treatment discontinued early due to treatment-related adverse events; their treatment duration ranged from 3 to 9 weeks. The median number of adverse events contributing to treatment discontinuation was three (range 1–3). One patient completed 2 years of planned anti-PD-1 antibody therapy.
Table 1. Patient characteristics of patients experiencing ocular IrAEs associated with CPI treatment.
Patient case CPI regimen Duration of CPI therapy Reason for discontinuation AEs leading to discontinuation Best response to CPI Survival outcome
Melanoma-1
Metastatic
50-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Ocular IrAE Ocular
Skin
Fatigue Partial response Alive 16 months+
Kidney-1
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 3 weeks Multiple IrAE Ocular
Skin
Liver Stable disease Alive 15 months+
Kidney-2
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 4 weeks Multiple IrAEs Ocular
Liver
Arthritis Partial response Alive 16 months+
Ovarian
Metastatic
40-yo woman Nivolumab + rucaparib 8 weeks Multiple IrAE Ocular
Liver
Neutropaenia* Partial response Alive 10 months+
Melanoma-2
Resected stage III
74-yo woman Pembrolizumab
200 mg IV q3w 3 weeks Ocular IrAE Ocular Recurrence Treated with ipilimumab on recurrence; aborted after 6 weeks due to colitis.
Alive with stable disease:
14 months+
Melanoma-3
Metastatic
56-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Multiple IrAEs Ocular
Lung Partial response Alive 22 months+
Melanoma-4
Metastatic
40-yo woman Ipilimumab
1 mg/kg+ nivolumab 3 mg/kg 6 weeks Multiple IrAEs Ocular
Liver Partial response Rechallenged with 2 further cycles of ipilimumab+nivolumab on disease progression without significant IrAEs; progressive brain metastases.
Died after 11 months
Melanoma-5
Metastatic
81-yo man Nivolumab 240 mg 2 years Completed planned treatment – Near complete response Alive 5 years+
* Likely due to PARP inhibitor, not CPI.
AEs, adverse events; CPI, checkpoint inhibitor; IrEAs, immune-related adverse events; yo, year-old; PARP, poly-adenosine diphosphate ribose polymerase.
Ocular IrAE characteristics
The median time to the onset of ocular IrAE was 5 weeks from starting CPIs, although one patient developed symptoms after 18 months of treatment (Table 2). In all seven patients who discontinued CPIs early, ocular IrAE contributed to the decision to discontinue therapy. One patient with pre-existing glaucoma experienced ocular IrAE as the only IrAE, occurring after her first dose of pembrolizumab, and this led to treatment discontinuation. Four patients were diagnosed with anterior uveitis, one had intermediate uveitis, one had melanoma-associated retinopathy (MAR)19,20 and one had suspected ocular ischaemic syndrome.21 All patients had bilateral eye involvement. There were no hospitalisations associated with ocular IrAEs.
Table 2. Characteristics of ocular IrAEs experienced and their treatment.
Patient case Presenting symptoms Ocular IrAE Worst
CTCAE
grade Time to onset/resolution of ocular IrAE Worst visual acuity Visual acuity on resolution Local treatment Systemic steroids (starting dose) Outcome of ocular IrAE
Melanoma 1 Bilateral blurred vision, painful eyes Anterior uveitis 2 3 weeks/8 weeks R 6/19
L Normal R Normal
L Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Kidney 1 Bilateral blurred vision, painful eyes, headache Anterior uveitis
High IO pressures 2 5 weeks/11 weeks (uveitis)
6 months
(IO pressures) R 6/9.5
L 6/7.5 R Normal
L Normal Dexamethasone 0.1% drops
Timolol
Latanprost None Complete resolution
Kidney 2 Bilateral painful red eyes, light sensitivity Anterior uveitis
Left disc swelling 2 5 weeks/8 weeks Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Ovarian Bilateral blurred vision. Painful to focus Anterior uveitis 2 5 weeks/8 months Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Melanoma 2 Deterioration in vision Intermediate
uveitis 3 1 week/10 weeks R 6/9
L Normal R 6/9
L Normal None 40 mg prednisolone Resolved on 10 mg prednisolone; following 2 cycles of ipilimumab,
received IV steroids and infliximab for enteritis
Melanoma 3 Flashing lights, visual aura Melanoma associated retinopathy 4 3 weeks/18 months R 6/18 R 6/5 Anti-VEGF injections
Intra-ocular dexamethasone 50 mg prednisolone Permanent loss of vision; macular scarring
Melanoma 4 Rapid onset loss of vision in both eyes Suspected ocular ischaemic syndrome 4 7 weeks/4 weeks R 6/15
L 6/9 R Normal
L Normal Dexamethasone 0.1% drops
Mydrilate 1% drops 40 mg prednisolone Complete resolution
Melanoma 5 Red, eyes
Loss of vision in left eye
Blurred vision Conjunctivitis
Left retinal detachment*
Anterior uveitis 2
2 18 months
21 months
4 years/10 months R 6/12
L 6/7.5 R 6/12
L 6/7.5 Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Quiescent
* Association of retinal detachment as an IrAE could not be confirmed.
CTCAE, common toxicity criteria; IO, intra-ocular; IrEA, immune-related adverse event; IV, intravenous; L, left; R, right; VEGF, vascular endothelial growth factor.
The patient completing 2 years of nivolumab experienced ocular IrAEs both during and after completing CPI treatment. As the symptoms were manageable and no other IrAEs occurred, his planned treatment was not interrupted. He experienced conjunctivitis and left retinal detachment during treatment, both of which were managed successfully. Two years after completing CPIs, he developed bilateral anterior uveitis.
Treatment of ocular IrAEs
All five patients who developed anterior uveitis were treated with topical steroids only. The three other ocular conditions (intermediate uveitis, MAR and suspected ocular ischaemic syndrome) were treated with oral corticosteroids. No patients received intravenous steroids or other immunosuppressive agents to treat their ocular IrAEs. One patient diagnosed with MAR received intravitreal anti-vascular endothelial growth factor injections to treat a juxtafoveal choroidal neovascular membrane, as well as intra-ocular steroid implants to treat chronic photopsia in his only remaining eye.
The median ocular IrAE treatment duration was 11 weeks (range 8 weeks–10 months) with topical steroids and 10 weeks (range 4 weeks–6 months) with oral steroids. Two patients with anterior uveitis had rapid, complete resolution of their symptoms by 8 and 11 weeks. One patient had persistently raised intra-ocular pressures for approximately 6 months. Two patients had a protracted course of inflammatory eye disease, with recurrent episodes lasting 8 and 10 months, respectively. Of two patients re-challenged with CPIs at a later date, (one with ipilimumab, one with ipilimumab + nivolumab), neither had recurrence of ocular IrAEs.
Oncological response to CPIs
Overall, six out of the eight treated patients experienced a partial or near complete response to CPI therapy and seven remain alive and well at data cut-off. One melanoma patient whose adjuvant pembrolizumab treatment was aborted due to uveitis had disease recurrence documented 10 weeks after her first CPI administration, then received ipilimumab, which was aborted after teo cycles due to severe colitis, but her disease has remained stable since that time (15 months at data cut-off). A second melanoma patient who progressed on completing adjuvant pembrolizumab initially responded to ipilimumab + nivolumab, but died of metastatic disease 19 months after her first CPI administration.
Non-uveitis case studies
Case 1: (‘Melanoma 3’ in Tables 1 and 2)
A 56-year-old man received treatment with ipilimumab + nivolumab for metastatic uveal melanoma, having had exenteration of his left eye 4 years previously. Three weeks after his first CPI administration he complained of severe flashing lights in his remaining eye, and he was referred urgently for an ophthalmological assessment.
On slit lamp biomicroscopy, pale lesions were noted in the fundus, and these were presumed to be benign. He continued immunotherapy, but after 9 weeks (three cycles of CPI), he developed moderately severe pneumonitis which was initially treated with 50 mg oral prednisolone daily and CPI therapy was permanently discontinued. The pneumonitis resolved over 12 weeks and he was gradually weaned off steroids. While tapering his steroids, he noticed that his vision was deteriorating and a visual field defect was detected on formal testing.
Optical coherence tomography (OCT) scanning indicated a choroidal lesion next to the fovea, suggesting a possible neovascular membrane (Figure 1a), which could cause visual loss. This suspicion was confirmed by the presence of early leakage during fundus fluorescein angiography (FFA) (Figure 1b). The choroidal neovascular membrane was treated with a series of intravitreal anti-vascular endothelial growth factor (ranibizumab) injections, until it was deemed to be inactive.
Figure 1. Non-uveitis case study. (a) Optical coherence tomography scan showing a choroidal lesion next to the fovea, possibly representing a neovascular membrane. (b) Fundus fluorescein angiography demonstrating early hyperfluorescence of the juxtafoveal lesion, supporting a diagnosis of choroidal neovascularisation. (c) Pseudocolour image of the fundus showing the dexamethasone 0.7 mg steroid implant.
Electrodiagnostic testing subsequently revealed widespread post-phototransduction cone and rod dysfunction, compatible with MAR. His symptoms partially improved on restarting oral steroids (10 mg prednisolone daily), pointing to an inflammatory cause of his visual symptoms. On the basis of this evidence, he was offered short-acting and long-acting intravitreal steroid implants,22 (dexamethasone 0.7 mg and fluocinolone acetonide, respectively, Figure 1c) to avoid chronic side effects of long-term systemic steroids. At the time of data cut-off, the patient remained disease free, with relatively minor persistent visual impairment.
Case 2: (‘Melanoma 4’ in Tables 1 and 2)
A 40-year-old woman received adjuvant pembrolizumab for stage IIID BRAF wild type melanoma, which was well tolerated, without any IrAEs. After 11 months of treatment, she complained of generalised musculoskeletal pains and fatigue. Restaging scans identified widespread metastases including to liver and bone. She was commenced on ipilimumab + nivolumab. After 6 weeks (post cycle 2), her overall condition deteriorated, with severe fatigue and deterioration in liver function and performance status, although her serum lactate dehydrogenase dropped markedly from 1956 to 498 IU/L during the same time period. Her third cycle of ipilimumab + nivolumab was deferred.
One week later, she presented to the emergency department complaining of sudden onset bilateral loss of vision, worse in the right eye. Visual acuity was 6/15 in the right eye and 6/9 in the left eye, and intraocular pressure was within normal parameters. Iris neovascularisation and a swollen right optic disc were found on slit lamp biomicroscopy and fundoscopy. Brain imaging was requested, and confirmed the absence of metastases. A diagnosis of ocular ischaemic syndrome21 was suggested, but after discussion with the oncology specialist, a possible inflammatory aetiology was considered.
The patient was treated with 40 mg oral prednisolone daily, 0.1% dexamethasone eye drops and 1% mydrilate drops. She responded well to treatment, and was gradually weaned off steroids, and her vision recovered. Her liver function normalised and her performance status improved sufficiently for a return to normal activities of daily living. Subsequent staging compueterised tomography (CT) images indicated a partial response to CPIs. Six months later, despite the patient remaining well and asymptomatic, surveillance imaging identified disease recurrence in previously involved body sites with four new brain metastases. She was re-challenged with ipilimumab + nivolumab. No new IrAEs occurred, but after the second cycle, she was admitted to hospital with seizures due to haemorrhage into the brain metastases and died 10 weeks later, 11 months after starting CPIs for metastatic disease.
Ocular symptom management algorithm
Based on our own experience, review of the literature and international guidelines, we generated a management algorithm designed for multidisciplinary teams to use in clinical practice (Figure 2).
Figure 2. Management algorithm for patients treated with CPIs who present with ocular symptoms.
CPI, checkpoint inhibitor; FAF, fundus autofluorescence; FFA, fundus fluorescein angiography; ICG, indocyanine angiography; OCT, optical coherence tomography.
Patient symptoms and signs are classified according to international common toxicity criteria (CTCAE version 5.0)23 and management is determined by the severity of the condition. The international CTCAE grades classify the severity of ocular conditions from 1 (mild) to 4 (severe, with sight-threatening consequences). Anterior uveitis is graded in correspondence with the number of cells seen on slit lamp examination of the anterior chamber, as defined by the standardisation of uveitis nomenclature.12 Thus, grade 1 uveitis corresponds to a ‘trace’ of cells (1–5 cells in a 1 mm × 1 mm slit beam), and grade 3 uveitis corresponds to ‘3+’ (26–50 cells per field). Posterior uveitis is graded 3. In addition, a visual acuity of 20/200 (6/60 in European terminology) or less, meeting criteria for blindness in the affected eye, is graded as 4.
The ophthalmological assessments of patients with visual disturbance include visual acuity, colour vision and intraocular pressure measurement. A relative afferent pupillary defect can be tested for by carrying out the swinging flashlight test before dilating drops are instilled into the eyes. Our algorithm includes a pathway for specialist ophthalmic investigations used to diagnose uveitis, which may include FFA and indocyanine angiography (ICG), fundus autofluorescence (FAF) and OCT, depending on the individual case.
In the absence of intermediate or posterior signs, invasive dye-based angiography tests would not normally be indicated, but can be used to exclude retinal vasculitis and leakage (FFA) or undiagnosed choroiditis (ICG) in challenging cases. This can be valuable in both the diagnosis and monitoring of inflammatory eye disease.24 Non-invasive FAF imaging is used to map metabolic activity in the retinal photoreceptor and pigment epithelial layers, and can be useful in identifying inflammatory processes occurring in the outer retina.25 OCT scanning provides high resolution images of the retina in cross-section and has transformed modern ophthalmological practice.
In contrast to recommendations in current international guidelines, we have used clinical evidence to justify avoiding the discontinuation of CPIs as much as possible. The algorithm aims to emphasise the need for close liaison between oncologist and specialist ophthalmologist from the point of recognition to resolution of ocular symptoms, as well as the benefit of a multidisciplinary approach involving good communication between the specialties to balance the need for cancer control alongside patient safety and vision preservation.
Discussion
This report of eight patients experiencing ocular IrAEs associated with CPI treatment is one of the largest series published to date. Anterior uveitis was the most common ocular IrAE that we identified, occurring in five of our eight cases. The onset of uveitis is reported mainly to occur within 2 months of starting CPIs.7,13,26 This was generally the case in our cohort, with a median time to onset of 5 weeks (range 1–7 weeks). The exception was a single patient who developed anterior uveitis 2 years after completing 2 years of nivolumab treatment. It is noteworthy that he had other ocular IrAEs while on treatment that did not lead to CPI discontinuation, while his anterior uveitis was difficult to control. It is well recognised that some IrAEs (including ocular IrAEs)13 can occur months and years after stopping CPIs, and this case is a reminder to consider the need for ongoing follow-up, even in patients apparently entering long-term remission after completing treatment.
Ocular IrAEs may occur as the only IrAE, or in association with multiple body system IrAEs. In our series, their occurrence influenced the decision to interrupt CPI treatment in all seven patients who discontinued treatment early: uveitis was the primary reason for discontinuation in two (29%) patients, but contributed to the decision to stop treatment in the remaining five patients, all of whom experienced multiple IrAEs.
A literature review of 33 cases of uveitis secondary to CPIs10 concluded that one-third of patients experienced anterior uveitis alone, one-third had anterior uveitis plus posterior segment changes including macular oedema, retinal detachment, vitritis or papillitis, and one-third had panuveitis. A very recent larger review of 126 cases of CPI-associated uveitis was broadly consistent, noting that 35% of panuveitis cases occurred as part of a Vogt–Koyanagi–Harada (VKH)-like syndrome.27–30 VKH disease is a multisystem disease affecting melanin-containing tissues, which is thought to be autoimmune in origin. The most significant ocular manifestation is bilateral diffuse panuveitis with exudative retinal detachment, often accompanied by a variable spectrum of symptoms involving the skin, nervous system and inner ear.
Recognition of the different presentations of the subtypes of uveitis is clearly important, as this influences whether topical steroids alone can be used for treatment, sparing patients the need for systemic steroids which may adversely affect the outcome of anti-cancer treatment.7 As in our own series, most published series describe initial intervention with topical and/or oral corticosteroids. Although outcomes are generally good, with complete resolution of inflammation in most cases, some cases are recalcitrant, warranting alternative immunomodulatory agents, while peri-ocular or intravitreal steroids22 have been employed as steroid-sparing strategies.
Prompt recognition of ocular and visual symptoms by oncologists and referral to ophthalmology specialists is necessary to ensure rapid investigation, diagnosis and sight-preserving treatment, as well as to inform multidisciplinary team opinion concerning ongoing treatment with CPIs. This can be challenging, because the ocular symptoms experienced may not directly correlate with the severity of inflammation identified.14 Even so, in most of the case series published to date, the overwhelming majority of patients experiencing ocular irAEs have had their CPIs discontinued,12,13 and uncertainty exists whether this line of action may impact overall treatment outcomes.
Perhaps because of its low incidence relative to other IrAEs, the ESMO guidelines5 offer very little advice on how to manage ocular IrAEs. The American Society of Clinical Oncology (ASCO) guidelines,6 on the other hand, are far more extensive and recommend referral to ophthalmology services for new onset visual symptoms, while they also recognise that symptoms may not always correlate with severity. The guidelines make use of the CTCAE grading system for ocular IrAEs and include management recommendations on whether to withhold, or discontinue, immunotherapy. While these constitute a welcome framework, they may also prove unnecessarily restrictive.
The ASCO guidelines recommend that for grade 1 ocular IrAEs, CPIs can be continued, for grade 2 events CPIs should be withheld and for grades 3 and 4 events they should be permanently discontinued. Ocular IrAEs, while not usually life threatening, may be life changing, so urgent intervention aimed at avoiding permanent loss of eyesight is certainly warranted. However, it is important to note that even severe deterioration in visual acuity can sometimes be reversible. For example, significant visual impairment associated with macular oedema may recover following prompt treatment with oral or intravitreal steroids. In adherence to ASCO guidance, loss of visual acuity may result in an adverse event grading of 3 or 4, which we consider could unnecessarily lead to permanent cessation of immunotherapy.
In some patients who resume CPIs after treatment for IrAEs, relapse with the same symptoms has been observed.9,13 We argue that permanent discontinuation of immunotherapy may not always be justified in these circumstances. In our own series, one patient experienced significant bilateral loss of vision associated with an ocular IrAE after two cycles of CPI with ipilimumab + nivolumab, but did not experience further ocular symptoms on retreatment several months later. Moreover, a severe or acute drop in visual acuity may be due to other pathologies unrelated to CPI (for example, incidental retinal detachment, which has a lifetime risk in normal individuals of one in 300).31 On the other hand, a patient could have apparently mild visual impairment but severe intra-ocular inflammation.
We recommend early referral to an ophthalmology specialist on recognition of ocular symptoms to diagnose the possible ocular IrAE and accurately grade its severity. We further recommend that both eye treatment and the ongoing use of CPIs are discussed on an individual case basis within a multidisciplinary team of oncologists and ophthalmologists, keeping the option open for retreatment in situations in which the possible benefits outweigh the risks, assuming appropriate patient counselling and support.
Most cases of uveitis associated with CPI, including the majority of our cases, are mild and would be categorised as CTCAE grade 2. These cases do not require cessation of CPI and neither should they require systemic steroids, in general. The outcomes from topical treatment are mainly good, with either a limited course, or sometimes ongoing topical steroids. If systemic steroids are used, the ASCO guidelines recommend that CPIs are withheld until the patient is either off all steroids or is receiving a daily dose of 10 mg oral prednisolone (or equivalent) or less. As far as possible, the aim should be to treat ocular IrAEs with local options in order to avoid systemic steroids and cessation of CPI therapy. Aside from concerns regarding their impact on CPI efficacy, long-term steroid use is associated with many well-known harmful effects.
The goal of avoiding the interruption of CPI therapy is best achieved by taking a multidisciplinary approach, with close liaison between ophthalmology and oncology teams, remembering that patients may have a high degree of anxiety about stopping potentially life-saving anti-cancer therapy. In our cohort, five patients stopped CPIs due to ocular IrAEs, despite being categorised as grade 2, which does not necessarily mandate permanent discontinuation. Three of these patients were treated solely with topical steroids, which suggests a low threat to vision, and which would not normally interfere with CPIs. In cases where topical steroids are not sufficient, intravitreal or periocular steroids should be considered to enable patients to remain on CPIs.
It is possible that patients diagnosed with melanoma may be at increased risk of developing uveitis due to the presence of melanin in the retinal pigment epithelium. An immune-mediated response to melanin-producing cells in the eye may occur both in patients on treatment and in those who develop an immunological reaction to their cancer independent of treatment. In our series, MAR was the most likely diagnosis in one of two patients reporting ocular toxicities that were not due to uveitis, based on symptoms described and investigations performed. The pathology is thought to be due to shared neuroectodermal lineage of melanocytes and retinal cells. Conversely, uveitis is not unique to patients with a diagnosis of melanoma. Patients at increased risk of uveitis may include those with other immune-related side effects and those predisposed to autoimmune disease or with a significant family history.32
Four of our patients, of whom two had other IrAEs, responded very well to retreatment with CPIs, highlighting a key unanswered question concerning whether the occurrence of IrAEs can predict a therapeutic response.32,33 Several studies have reported increased progression-free and overall survival in patients who experienced IrAEs with CPIs compared to those who did not.34,35 To date, it remains unclear whether the development of uveitis or other specific IrAEs is associated with better outcomes from treatment with CPIs,34,36 although it is quite plausible that an observed inflammatory response within the eye or elsewhere might reflect an enhanced immune response against cancer. The number of patients in our study is insufficient to answer this question, but further study is warranted and, if proved, this could be reassuring for patients who have previously stopped immunotherapy while being treated for inflammatory side effects.
In conclusion, ocular IrAEs are relatively uncommon IrAEs associated with CPIs, but can be dramatic and may lead to permanent visual loss. Prompt recognition in oncology clinics and early referral to an ophthalmologist is essential. Patients with confirmed ocular inflammation require close monitoring in the eye clinic and ongoing liaison with their oncologist regarding optimal treatment and the use of corticosteroids. The option of intraocular steroid implants should be considered as an alternative to systemic steroids when IrAEs do not resolve with topical steroids alone, with the potential benefit of being able to continue on CPIs.
In conjunction with our ocular IrAE management algorithm (Figure 2), we propose the following basic steps to follow when seeing immunotherapy patients with ocular symptoms in the clinic:
document the symptoms and signs and their severity
escalate by referral to an ophthalmologist; consider urgency of referral and the need to interrupt CPI therapy depending on symptom severity
obtain an ophthalmological diagnosis
take a multidisciplinary approach to managing the ocular symptoms and the need or otherwise to restart CPIs, based on risk/benefit considerations.
The authors would like to thank the patients and their families for allowing us to share their case studies. Thanks also to the CUHFT research governance and audit teams for their assistance in the conduct of this study.
Conflict of interest: The authors declare that there is no conflict of interest.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Philippa Corrie
https://orcid.org/0000-0003-4875-7021 | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY-NC | 33633802 | 19,078,861 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Retinal melanoma'. | Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm.
Ocular immune-related adverse events (IrAEs) associated with use of checkpoint inhibitors (CPIs) in cancer therapeutics are relatively rare, occurring in approximately 1% of treated patients. Recognition and early intervention are essential because the degree of tissue damage may be disproportionate to the symptoms, and lack of appropriate treatment risks permanent loss of vision. International guidelines on managing ocular IrAEs provide limited advice only. Importantly, local interventions can be effective and may avoid the need for systemic corticosteroids, thereby permitting the continuation of CPIs. We present a single institution case series of eight affected patients managed by our multidisciplinary team. Consistent with previously published series and case reports, we identified anterior uveitis as the most common ocular IrAE associated with CPIs requiring intervention. Based on our experience, as well as published guidance, we generated a simple algorithm to assist clinicians efficiently manage patients developing ocular symptoms during treatment with CPIs. In addition, we make recommendations for optimising treatment of uveitis and address implications for ongoing CPI therapy.
Background
Immunotherapy with checkpoint inhibitors (CPIs) has transformed the treatment of a wide range of malignancies.1,2 These drugs work by enabling the host immune system to eliminate malignant cells, recognisable through the expression of neoantigens. The CPIs currently in clinical use are antibodies which target the cytotoxic T-lymphocyte antigen-4 receptor (anti-CTLA-4), the programmed death-1 receptor (anti-PD-1) and its ligand (anti-PD-L1). The CTLA-4 receptor downregulates T-cell activation, whereas the PD-1 receptor inhibits T-cell proliferation, cytokine release, and cytotoxicity. Blocking their function can enhance T-cell response and allow immune-mediated tumour killing.
CPIs generate side effects termed immune-related adverse events (IrAEs), which stem from their mechanism of action, being predominantly autoimmune in nature and having the potential to affect any body organ. IrAEs range from being mild to life-threatening, or life-changing in some instances.3 Since their first introduction into clinical practice in 2011 as treatment for metastatic melanoma, the use of anti-CTLA-4 and anti-PD-L1 antibodies has expanded to include multiple cancer types including lung and urological cancers as well as lymphomas, with new treatment indications being added frequently. Their increasing use has resulted in greater awareness of both common and rarely seen IrAEs, ranging from mild presentations to severe reactions requiring prompt intervention.4
Optimal management of IrAEs is still in its infancy, with limited evidence to inform international guidelines which have been generated to assist clinical practice.5,6 The mainstay of treatment for what appear to be inflammatory conditions is immunosuppression with corticosteroids, prompting concerns about their effect on CPI efficacy.7 Moreover, the long-term effects on cancer survivors of high dose steroids, sometimes administered for protracted periods of time, have yet to be fully understood. The European Society of Medical Oncology (ESMO) clinical practice guidelines5 provide helpful algorithms for managing the more commonly occurring IrAEs, but consensus advice on managing less common IrAEs, such as those affecting the eyes, is also needed to minimise any negative impact of anti-cancer interventions.
Ocular IrAEs occur with an estimated prevalence of 1–3% of all treated patients.8,9 While the spectrum of severity is broad, they are highly significant as they can threaten vision. Reports of ocular IrAEs associated with CPIs are limited to small, single-digit case series and individual case reports, which principally report patients experiencing varying degrees of uveitis.8,10–13
Uveitis is a term used to describe inflammation of the uvea, the middle layer of the eye comprising the iris, ciliary body and choroid. It is classified as anterior, intermediate, posterior, or panuveitis, according to the predominant site of inflammation within the eye.14 Anterior uveitis is characterised by an infiltrate of white blood cells in the anterior chamber of the eye; intermediate uveitis is associated with inflammation in the vitreous gel, resulting in visual blurring, haze and floaters; posterior uveitis is characterised by retinal and/or choroidal inflammation.15,16 Symptoms of uveitis include pain, blurred vision and red eye. Involvement of the posterior segment can produce symptoms of floaters, flickering and shimmering lights (photopsias), as well as blind spots.
Anterior uveitis, whether acute or chronic, can often be managed with topical steroid drops alone. Severe uveitis of any subtype may lead to macular oedema, with accumulation of fluid at the most sensitive part of the retina, causing visual distortion and blurring. Severe ocular inflammation requires prompt intervention to avoid permanent loss of vision, and may require periocular or intravitreal steroid injections. More severe cases require systemic steroids, including oral, or pulsed intravenous methylprednisolone. Recalcitrant, chronic inflammatory eye diseases can be managed with secondary non-corticosteroid immunomodulatory therapeutic agents, including anti-metabolites like mycophenolate mofetil and methotrexate, or biological drugs like adalimumab.17 Common complications of uveitis and its treatment include cataract, glaucoma and choroidal neovascularisation. While most reports suggest a good response to therapy with complete resolution of inflammation, a minority of patients may develop permanent visual loss.
Other less common ocular IrAEs include ocular myasthenia, optic neuritis and auto-immune retinopathy. Dry eyes are described by up to one in four treated patients, but this is a common condition that is often not reported in clinical trials and is frequently undertreated, even in clinical practice.8,9 The risk of ocular IrAEs associated with CPIs was recently quantified using disproportionality analysis; odds ratios for uveitis ranged from 4.6 to 10.8, while that of any ocular IrAE was 2.5 compared with reported events associated with all other drugs.18
Uncertainties about optimal management of ocular IrAEs persist, such as when to interrupt or discontinue potentially life-saving CPI therapy and whether systemic steroids can influence the efficacy of CPIs. We report our experience of managing ocular IrAEs in a cohort of cancer patients receiving CPIs in a single institution and make management recommendations in a novel treatment algorithm.
Methods
We reviewed the electronic patient records of patients treated with CPIs from January to December 2019, and identified all cases referred to the ophthalmology service. The clinical characteristics, treatment and course of IrAEs over time were recorded. Details of their CPI treatment, other non-ocular irAEs, and disease response (based on routine radiological imaging and applying RECIST 1.1 response criteria) were also recorded. Survival was measured from the date of first CPI infusion until data cut-off, on 17 March, 2020.
Based on our case series and information contained in published international guidelines,5,6 we generated a simple assessment and treatment algorithm for use in routine clinical practice to guide the multidisciplinary team managing ocular symptoms and uveitis; the most common ocular IrAE reported.
This project was registered as a health service evaluation at Cambridge University Hospitals NHS Foundation Trust (CUHFT). The CUHFT research governance lead confirmed that, under the UK Policy Framework for Health and Social Care Research 2017, this project would not be classified or managed as research within the National Health Service and therefore did not require ethical review by a research ethics committee. Written informed consent to publish was obtained from the surviving case study patient.
Results
Patient characteristics
We identified eight patients (three women and five men, aged between 39 and 81 years) who developed ocular IrAEs after starting CPIs (Table 1). Seven patients were treated for advanced cancer; four for metastatic melanoma, two metastatic renal-cell carcinoma and one advanced ovarian carcinoma. One melanoma patient received CPI as an adjuvant therapy, after resection of regional lymph node disease. None had a previous history of uveitis. One patient had a history of glaucoma. Five patients received combination anti-CTLA-4 plus anti-PD-1 antibodies (ipilimumab + nivolumab), two patients received a single agent anti-PD-1 antibody (one pembrolizumab, one nivolumab) and one patient received anti-PD-1 antibody (nivolumab) in combination with a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor (rucaparib). Seven patients had their treatment discontinued early due to treatment-related adverse events; their treatment duration ranged from 3 to 9 weeks. The median number of adverse events contributing to treatment discontinuation was three (range 1–3). One patient completed 2 years of planned anti-PD-1 antibody therapy.
Table 1. Patient characteristics of patients experiencing ocular IrAEs associated with CPI treatment.
Patient case CPI regimen Duration of CPI therapy Reason for discontinuation AEs leading to discontinuation Best response to CPI Survival outcome
Melanoma-1
Metastatic
50-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Ocular IrAE Ocular
Skin
Fatigue Partial response Alive 16 months+
Kidney-1
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 3 weeks Multiple IrAE Ocular
Skin
Liver Stable disease Alive 15 months+
Kidney-2
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 4 weeks Multiple IrAEs Ocular
Liver
Arthritis Partial response Alive 16 months+
Ovarian
Metastatic
40-yo woman Nivolumab + rucaparib 8 weeks Multiple IrAE Ocular
Liver
Neutropaenia* Partial response Alive 10 months+
Melanoma-2
Resected stage III
74-yo woman Pembrolizumab
200 mg IV q3w 3 weeks Ocular IrAE Ocular Recurrence Treated with ipilimumab on recurrence; aborted after 6 weeks due to colitis.
Alive with stable disease:
14 months+
Melanoma-3
Metastatic
56-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Multiple IrAEs Ocular
Lung Partial response Alive 22 months+
Melanoma-4
Metastatic
40-yo woman Ipilimumab
1 mg/kg+ nivolumab 3 mg/kg 6 weeks Multiple IrAEs Ocular
Liver Partial response Rechallenged with 2 further cycles of ipilimumab+nivolumab on disease progression without significant IrAEs; progressive brain metastases.
Died after 11 months
Melanoma-5
Metastatic
81-yo man Nivolumab 240 mg 2 years Completed planned treatment – Near complete response Alive 5 years+
* Likely due to PARP inhibitor, not CPI.
AEs, adverse events; CPI, checkpoint inhibitor; IrEAs, immune-related adverse events; yo, year-old; PARP, poly-adenosine diphosphate ribose polymerase.
Ocular IrAE characteristics
The median time to the onset of ocular IrAE was 5 weeks from starting CPIs, although one patient developed symptoms after 18 months of treatment (Table 2). In all seven patients who discontinued CPIs early, ocular IrAE contributed to the decision to discontinue therapy. One patient with pre-existing glaucoma experienced ocular IrAE as the only IrAE, occurring after her first dose of pembrolizumab, and this led to treatment discontinuation. Four patients were diagnosed with anterior uveitis, one had intermediate uveitis, one had melanoma-associated retinopathy (MAR)19,20 and one had suspected ocular ischaemic syndrome.21 All patients had bilateral eye involvement. There were no hospitalisations associated with ocular IrAEs.
Table 2. Characteristics of ocular IrAEs experienced and their treatment.
Patient case Presenting symptoms Ocular IrAE Worst
CTCAE
grade Time to onset/resolution of ocular IrAE Worst visual acuity Visual acuity on resolution Local treatment Systemic steroids (starting dose) Outcome of ocular IrAE
Melanoma 1 Bilateral blurred vision, painful eyes Anterior uveitis 2 3 weeks/8 weeks R 6/19
L Normal R Normal
L Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Kidney 1 Bilateral blurred vision, painful eyes, headache Anterior uveitis
High IO pressures 2 5 weeks/11 weeks (uveitis)
6 months
(IO pressures) R 6/9.5
L 6/7.5 R Normal
L Normal Dexamethasone 0.1% drops
Timolol
Latanprost None Complete resolution
Kidney 2 Bilateral painful red eyes, light sensitivity Anterior uveitis
Left disc swelling 2 5 weeks/8 weeks Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Ovarian Bilateral blurred vision. Painful to focus Anterior uveitis 2 5 weeks/8 months Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Melanoma 2 Deterioration in vision Intermediate
uveitis 3 1 week/10 weeks R 6/9
L Normal R 6/9
L Normal None 40 mg prednisolone Resolved on 10 mg prednisolone; following 2 cycles of ipilimumab,
received IV steroids and infliximab for enteritis
Melanoma 3 Flashing lights, visual aura Melanoma associated retinopathy 4 3 weeks/18 months R 6/18 R 6/5 Anti-VEGF injections
Intra-ocular dexamethasone 50 mg prednisolone Permanent loss of vision; macular scarring
Melanoma 4 Rapid onset loss of vision in both eyes Suspected ocular ischaemic syndrome 4 7 weeks/4 weeks R 6/15
L 6/9 R Normal
L Normal Dexamethasone 0.1% drops
Mydrilate 1% drops 40 mg prednisolone Complete resolution
Melanoma 5 Red, eyes
Loss of vision in left eye
Blurred vision Conjunctivitis
Left retinal detachment*
Anterior uveitis 2
2 18 months
21 months
4 years/10 months R 6/12
L 6/7.5 R 6/12
L 6/7.5 Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Quiescent
* Association of retinal detachment as an IrAE could not be confirmed.
CTCAE, common toxicity criteria; IO, intra-ocular; IrEA, immune-related adverse event; IV, intravenous; L, left; R, right; VEGF, vascular endothelial growth factor.
The patient completing 2 years of nivolumab experienced ocular IrAEs both during and after completing CPI treatment. As the symptoms were manageable and no other IrAEs occurred, his planned treatment was not interrupted. He experienced conjunctivitis and left retinal detachment during treatment, both of which were managed successfully. Two years after completing CPIs, he developed bilateral anterior uveitis.
Treatment of ocular IrAEs
All five patients who developed anterior uveitis were treated with topical steroids only. The three other ocular conditions (intermediate uveitis, MAR and suspected ocular ischaemic syndrome) were treated with oral corticosteroids. No patients received intravenous steroids or other immunosuppressive agents to treat their ocular IrAEs. One patient diagnosed with MAR received intravitreal anti-vascular endothelial growth factor injections to treat a juxtafoveal choroidal neovascular membrane, as well as intra-ocular steroid implants to treat chronic photopsia in his only remaining eye.
The median ocular IrAE treatment duration was 11 weeks (range 8 weeks–10 months) with topical steroids and 10 weeks (range 4 weeks–6 months) with oral steroids. Two patients with anterior uveitis had rapid, complete resolution of their symptoms by 8 and 11 weeks. One patient had persistently raised intra-ocular pressures for approximately 6 months. Two patients had a protracted course of inflammatory eye disease, with recurrent episodes lasting 8 and 10 months, respectively. Of two patients re-challenged with CPIs at a later date, (one with ipilimumab, one with ipilimumab + nivolumab), neither had recurrence of ocular IrAEs.
Oncological response to CPIs
Overall, six out of the eight treated patients experienced a partial or near complete response to CPI therapy and seven remain alive and well at data cut-off. One melanoma patient whose adjuvant pembrolizumab treatment was aborted due to uveitis had disease recurrence documented 10 weeks after her first CPI administration, then received ipilimumab, which was aborted after teo cycles due to severe colitis, but her disease has remained stable since that time (15 months at data cut-off). A second melanoma patient who progressed on completing adjuvant pembrolizumab initially responded to ipilimumab + nivolumab, but died of metastatic disease 19 months after her first CPI administration.
Non-uveitis case studies
Case 1: (‘Melanoma 3’ in Tables 1 and 2)
A 56-year-old man received treatment with ipilimumab + nivolumab for metastatic uveal melanoma, having had exenteration of his left eye 4 years previously. Three weeks after his first CPI administration he complained of severe flashing lights in his remaining eye, and he was referred urgently for an ophthalmological assessment.
On slit lamp biomicroscopy, pale lesions were noted in the fundus, and these were presumed to be benign. He continued immunotherapy, but after 9 weeks (three cycles of CPI), he developed moderately severe pneumonitis which was initially treated with 50 mg oral prednisolone daily and CPI therapy was permanently discontinued. The pneumonitis resolved over 12 weeks and he was gradually weaned off steroids. While tapering his steroids, he noticed that his vision was deteriorating and a visual field defect was detected on formal testing.
Optical coherence tomography (OCT) scanning indicated a choroidal lesion next to the fovea, suggesting a possible neovascular membrane (Figure 1a), which could cause visual loss. This suspicion was confirmed by the presence of early leakage during fundus fluorescein angiography (FFA) (Figure 1b). The choroidal neovascular membrane was treated with a series of intravitreal anti-vascular endothelial growth factor (ranibizumab) injections, until it was deemed to be inactive.
Figure 1. Non-uveitis case study. (a) Optical coherence tomography scan showing a choroidal lesion next to the fovea, possibly representing a neovascular membrane. (b) Fundus fluorescein angiography demonstrating early hyperfluorescence of the juxtafoveal lesion, supporting a diagnosis of choroidal neovascularisation. (c) Pseudocolour image of the fundus showing the dexamethasone 0.7 mg steroid implant.
Electrodiagnostic testing subsequently revealed widespread post-phototransduction cone and rod dysfunction, compatible with MAR. His symptoms partially improved on restarting oral steroids (10 mg prednisolone daily), pointing to an inflammatory cause of his visual symptoms. On the basis of this evidence, he was offered short-acting and long-acting intravitreal steroid implants,22 (dexamethasone 0.7 mg and fluocinolone acetonide, respectively, Figure 1c) to avoid chronic side effects of long-term systemic steroids. At the time of data cut-off, the patient remained disease free, with relatively minor persistent visual impairment.
Case 2: (‘Melanoma 4’ in Tables 1 and 2)
A 40-year-old woman received adjuvant pembrolizumab for stage IIID BRAF wild type melanoma, which was well tolerated, without any IrAEs. After 11 months of treatment, she complained of generalised musculoskeletal pains and fatigue. Restaging scans identified widespread metastases including to liver and bone. She was commenced on ipilimumab + nivolumab. After 6 weeks (post cycle 2), her overall condition deteriorated, with severe fatigue and deterioration in liver function and performance status, although her serum lactate dehydrogenase dropped markedly from 1956 to 498 IU/L during the same time period. Her third cycle of ipilimumab + nivolumab was deferred.
One week later, she presented to the emergency department complaining of sudden onset bilateral loss of vision, worse in the right eye. Visual acuity was 6/15 in the right eye and 6/9 in the left eye, and intraocular pressure was within normal parameters. Iris neovascularisation and a swollen right optic disc were found on slit lamp biomicroscopy and fundoscopy. Brain imaging was requested, and confirmed the absence of metastases. A diagnosis of ocular ischaemic syndrome21 was suggested, but after discussion with the oncology specialist, a possible inflammatory aetiology was considered.
The patient was treated with 40 mg oral prednisolone daily, 0.1% dexamethasone eye drops and 1% mydrilate drops. She responded well to treatment, and was gradually weaned off steroids, and her vision recovered. Her liver function normalised and her performance status improved sufficiently for a return to normal activities of daily living. Subsequent staging compueterised tomography (CT) images indicated a partial response to CPIs. Six months later, despite the patient remaining well and asymptomatic, surveillance imaging identified disease recurrence in previously involved body sites with four new brain metastases. She was re-challenged with ipilimumab + nivolumab. No new IrAEs occurred, but after the second cycle, she was admitted to hospital with seizures due to haemorrhage into the brain metastases and died 10 weeks later, 11 months after starting CPIs for metastatic disease.
Ocular symptom management algorithm
Based on our own experience, review of the literature and international guidelines, we generated a management algorithm designed for multidisciplinary teams to use in clinical practice (Figure 2).
Figure 2. Management algorithm for patients treated with CPIs who present with ocular symptoms.
CPI, checkpoint inhibitor; FAF, fundus autofluorescence; FFA, fundus fluorescein angiography; ICG, indocyanine angiography; OCT, optical coherence tomography.
Patient symptoms and signs are classified according to international common toxicity criteria (CTCAE version 5.0)23 and management is determined by the severity of the condition. The international CTCAE grades classify the severity of ocular conditions from 1 (mild) to 4 (severe, with sight-threatening consequences). Anterior uveitis is graded in correspondence with the number of cells seen on slit lamp examination of the anterior chamber, as defined by the standardisation of uveitis nomenclature.12 Thus, grade 1 uveitis corresponds to a ‘trace’ of cells (1–5 cells in a 1 mm × 1 mm slit beam), and grade 3 uveitis corresponds to ‘3+’ (26–50 cells per field). Posterior uveitis is graded 3. In addition, a visual acuity of 20/200 (6/60 in European terminology) or less, meeting criteria for blindness in the affected eye, is graded as 4.
The ophthalmological assessments of patients with visual disturbance include visual acuity, colour vision and intraocular pressure measurement. A relative afferent pupillary defect can be tested for by carrying out the swinging flashlight test before dilating drops are instilled into the eyes. Our algorithm includes a pathway for specialist ophthalmic investigations used to diagnose uveitis, which may include FFA and indocyanine angiography (ICG), fundus autofluorescence (FAF) and OCT, depending on the individual case.
In the absence of intermediate or posterior signs, invasive dye-based angiography tests would not normally be indicated, but can be used to exclude retinal vasculitis and leakage (FFA) or undiagnosed choroiditis (ICG) in challenging cases. This can be valuable in both the diagnosis and monitoring of inflammatory eye disease.24 Non-invasive FAF imaging is used to map metabolic activity in the retinal photoreceptor and pigment epithelial layers, and can be useful in identifying inflammatory processes occurring in the outer retina.25 OCT scanning provides high resolution images of the retina in cross-section and has transformed modern ophthalmological practice.
In contrast to recommendations in current international guidelines, we have used clinical evidence to justify avoiding the discontinuation of CPIs as much as possible. The algorithm aims to emphasise the need for close liaison between oncologist and specialist ophthalmologist from the point of recognition to resolution of ocular symptoms, as well as the benefit of a multidisciplinary approach involving good communication between the specialties to balance the need for cancer control alongside patient safety and vision preservation.
Discussion
This report of eight patients experiencing ocular IrAEs associated with CPI treatment is one of the largest series published to date. Anterior uveitis was the most common ocular IrAE that we identified, occurring in five of our eight cases. The onset of uveitis is reported mainly to occur within 2 months of starting CPIs.7,13,26 This was generally the case in our cohort, with a median time to onset of 5 weeks (range 1–7 weeks). The exception was a single patient who developed anterior uveitis 2 years after completing 2 years of nivolumab treatment. It is noteworthy that he had other ocular IrAEs while on treatment that did not lead to CPI discontinuation, while his anterior uveitis was difficult to control. It is well recognised that some IrAEs (including ocular IrAEs)13 can occur months and years after stopping CPIs, and this case is a reminder to consider the need for ongoing follow-up, even in patients apparently entering long-term remission after completing treatment.
Ocular IrAEs may occur as the only IrAE, or in association with multiple body system IrAEs. In our series, their occurrence influenced the decision to interrupt CPI treatment in all seven patients who discontinued treatment early: uveitis was the primary reason for discontinuation in two (29%) patients, but contributed to the decision to stop treatment in the remaining five patients, all of whom experienced multiple IrAEs.
A literature review of 33 cases of uveitis secondary to CPIs10 concluded that one-third of patients experienced anterior uveitis alone, one-third had anterior uveitis plus posterior segment changes including macular oedema, retinal detachment, vitritis or papillitis, and one-third had panuveitis. A very recent larger review of 126 cases of CPI-associated uveitis was broadly consistent, noting that 35% of panuveitis cases occurred as part of a Vogt–Koyanagi–Harada (VKH)-like syndrome.27–30 VKH disease is a multisystem disease affecting melanin-containing tissues, which is thought to be autoimmune in origin. The most significant ocular manifestation is bilateral diffuse panuveitis with exudative retinal detachment, often accompanied by a variable spectrum of symptoms involving the skin, nervous system and inner ear.
Recognition of the different presentations of the subtypes of uveitis is clearly important, as this influences whether topical steroids alone can be used for treatment, sparing patients the need for systemic steroids which may adversely affect the outcome of anti-cancer treatment.7 As in our own series, most published series describe initial intervention with topical and/or oral corticosteroids. Although outcomes are generally good, with complete resolution of inflammation in most cases, some cases are recalcitrant, warranting alternative immunomodulatory agents, while peri-ocular or intravitreal steroids22 have been employed as steroid-sparing strategies.
Prompt recognition of ocular and visual symptoms by oncologists and referral to ophthalmology specialists is necessary to ensure rapid investigation, diagnosis and sight-preserving treatment, as well as to inform multidisciplinary team opinion concerning ongoing treatment with CPIs. This can be challenging, because the ocular symptoms experienced may not directly correlate with the severity of inflammation identified.14 Even so, in most of the case series published to date, the overwhelming majority of patients experiencing ocular irAEs have had their CPIs discontinued,12,13 and uncertainty exists whether this line of action may impact overall treatment outcomes.
Perhaps because of its low incidence relative to other IrAEs, the ESMO guidelines5 offer very little advice on how to manage ocular IrAEs. The American Society of Clinical Oncology (ASCO) guidelines,6 on the other hand, are far more extensive and recommend referral to ophthalmology services for new onset visual symptoms, while they also recognise that symptoms may not always correlate with severity. The guidelines make use of the CTCAE grading system for ocular IrAEs and include management recommendations on whether to withhold, or discontinue, immunotherapy. While these constitute a welcome framework, they may also prove unnecessarily restrictive.
The ASCO guidelines recommend that for grade 1 ocular IrAEs, CPIs can be continued, for grade 2 events CPIs should be withheld and for grades 3 and 4 events they should be permanently discontinued. Ocular IrAEs, while not usually life threatening, may be life changing, so urgent intervention aimed at avoiding permanent loss of eyesight is certainly warranted. However, it is important to note that even severe deterioration in visual acuity can sometimes be reversible. For example, significant visual impairment associated with macular oedema may recover following prompt treatment with oral or intravitreal steroids. In adherence to ASCO guidance, loss of visual acuity may result in an adverse event grading of 3 or 4, which we consider could unnecessarily lead to permanent cessation of immunotherapy.
In some patients who resume CPIs after treatment for IrAEs, relapse with the same symptoms has been observed.9,13 We argue that permanent discontinuation of immunotherapy may not always be justified in these circumstances. In our own series, one patient experienced significant bilateral loss of vision associated with an ocular IrAE after two cycles of CPI with ipilimumab + nivolumab, but did not experience further ocular symptoms on retreatment several months later. Moreover, a severe or acute drop in visual acuity may be due to other pathologies unrelated to CPI (for example, incidental retinal detachment, which has a lifetime risk in normal individuals of one in 300).31 On the other hand, a patient could have apparently mild visual impairment but severe intra-ocular inflammation.
We recommend early referral to an ophthalmology specialist on recognition of ocular symptoms to diagnose the possible ocular IrAE and accurately grade its severity. We further recommend that both eye treatment and the ongoing use of CPIs are discussed on an individual case basis within a multidisciplinary team of oncologists and ophthalmologists, keeping the option open for retreatment in situations in which the possible benefits outweigh the risks, assuming appropriate patient counselling and support.
Most cases of uveitis associated with CPI, including the majority of our cases, are mild and would be categorised as CTCAE grade 2. These cases do not require cessation of CPI and neither should they require systemic steroids, in general. The outcomes from topical treatment are mainly good, with either a limited course, or sometimes ongoing topical steroids. If systemic steroids are used, the ASCO guidelines recommend that CPIs are withheld until the patient is either off all steroids or is receiving a daily dose of 10 mg oral prednisolone (or equivalent) or less. As far as possible, the aim should be to treat ocular IrAEs with local options in order to avoid systemic steroids and cessation of CPI therapy. Aside from concerns regarding their impact on CPI efficacy, long-term steroid use is associated with many well-known harmful effects.
The goal of avoiding the interruption of CPI therapy is best achieved by taking a multidisciplinary approach, with close liaison between ophthalmology and oncology teams, remembering that patients may have a high degree of anxiety about stopping potentially life-saving anti-cancer therapy. In our cohort, five patients stopped CPIs due to ocular IrAEs, despite being categorised as grade 2, which does not necessarily mandate permanent discontinuation. Three of these patients were treated solely with topical steroids, which suggests a low threat to vision, and which would not normally interfere with CPIs. In cases where topical steroids are not sufficient, intravitreal or periocular steroids should be considered to enable patients to remain on CPIs.
It is possible that patients diagnosed with melanoma may be at increased risk of developing uveitis due to the presence of melanin in the retinal pigment epithelium. An immune-mediated response to melanin-producing cells in the eye may occur both in patients on treatment and in those who develop an immunological reaction to their cancer independent of treatment. In our series, MAR was the most likely diagnosis in one of two patients reporting ocular toxicities that were not due to uveitis, based on symptoms described and investigations performed. The pathology is thought to be due to shared neuroectodermal lineage of melanocytes and retinal cells. Conversely, uveitis is not unique to patients with a diagnosis of melanoma. Patients at increased risk of uveitis may include those with other immune-related side effects and those predisposed to autoimmune disease or with a significant family history.32
Four of our patients, of whom two had other IrAEs, responded very well to retreatment with CPIs, highlighting a key unanswered question concerning whether the occurrence of IrAEs can predict a therapeutic response.32,33 Several studies have reported increased progression-free and overall survival in patients who experienced IrAEs with CPIs compared to those who did not.34,35 To date, it remains unclear whether the development of uveitis or other specific IrAEs is associated with better outcomes from treatment with CPIs,34,36 although it is quite plausible that an observed inflammatory response within the eye or elsewhere might reflect an enhanced immune response against cancer. The number of patients in our study is insufficient to answer this question, but further study is warranted and, if proved, this could be reassuring for patients who have previously stopped immunotherapy while being treated for inflammatory side effects.
In conclusion, ocular IrAEs are relatively uncommon IrAEs associated with CPIs, but can be dramatic and may lead to permanent visual loss. Prompt recognition in oncology clinics and early referral to an ophthalmologist is essential. Patients with confirmed ocular inflammation require close monitoring in the eye clinic and ongoing liaison with their oncologist regarding optimal treatment and the use of corticosteroids. The option of intraocular steroid implants should be considered as an alternative to systemic steroids when IrAEs do not resolve with topical steroids alone, with the potential benefit of being able to continue on CPIs.
In conjunction with our ocular IrAE management algorithm (Figure 2), we propose the following basic steps to follow when seeing immunotherapy patients with ocular symptoms in the clinic:
document the symptoms and signs and their severity
escalate by referral to an ophthalmologist; consider urgency of referral and the need to interrupt CPI therapy depending on symptom severity
obtain an ophthalmological diagnosis
take a multidisciplinary approach to managing the ocular symptoms and the need or otherwise to restart CPIs, based on risk/benefit considerations.
The authors would like to thank the patients and their families for allowing us to share their case studies. Thanks also to the CUHFT research governance and audit teams for their assistance in the conduct of this study.
Conflict of interest: The authors declare that there is no conflict of interest.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Philippa Corrie
https://orcid.org/0000-0003-4875-7021 | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY-NC | 33633802 | 19,078,861 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Skin disorder'. | Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm.
Ocular immune-related adverse events (IrAEs) associated with use of checkpoint inhibitors (CPIs) in cancer therapeutics are relatively rare, occurring in approximately 1% of treated patients. Recognition and early intervention are essential because the degree of tissue damage may be disproportionate to the symptoms, and lack of appropriate treatment risks permanent loss of vision. International guidelines on managing ocular IrAEs provide limited advice only. Importantly, local interventions can be effective and may avoid the need for systemic corticosteroids, thereby permitting the continuation of CPIs. We present a single institution case series of eight affected patients managed by our multidisciplinary team. Consistent with previously published series and case reports, we identified anterior uveitis as the most common ocular IrAE associated with CPIs requiring intervention. Based on our experience, as well as published guidance, we generated a simple algorithm to assist clinicians efficiently manage patients developing ocular symptoms during treatment with CPIs. In addition, we make recommendations for optimising treatment of uveitis and address implications for ongoing CPI therapy.
Background
Immunotherapy with checkpoint inhibitors (CPIs) has transformed the treatment of a wide range of malignancies.1,2 These drugs work by enabling the host immune system to eliminate malignant cells, recognisable through the expression of neoantigens. The CPIs currently in clinical use are antibodies which target the cytotoxic T-lymphocyte antigen-4 receptor (anti-CTLA-4), the programmed death-1 receptor (anti-PD-1) and its ligand (anti-PD-L1). The CTLA-4 receptor downregulates T-cell activation, whereas the PD-1 receptor inhibits T-cell proliferation, cytokine release, and cytotoxicity. Blocking their function can enhance T-cell response and allow immune-mediated tumour killing.
CPIs generate side effects termed immune-related adverse events (IrAEs), which stem from their mechanism of action, being predominantly autoimmune in nature and having the potential to affect any body organ. IrAEs range from being mild to life-threatening, or life-changing in some instances.3 Since their first introduction into clinical practice in 2011 as treatment for metastatic melanoma, the use of anti-CTLA-4 and anti-PD-L1 antibodies has expanded to include multiple cancer types including lung and urological cancers as well as lymphomas, with new treatment indications being added frequently. Their increasing use has resulted in greater awareness of both common and rarely seen IrAEs, ranging from mild presentations to severe reactions requiring prompt intervention.4
Optimal management of IrAEs is still in its infancy, with limited evidence to inform international guidelines which have been generated to assist clinical practice.5,6 The mainstay of treatment for what appear to be inflammatory conditions is immunosuppression with corticosteroids, prompting concerns about their effect on CPI efficacy.7 Moreover, the long-term effects on cancer survivors of high dose steroids, sometimes administered for protracted periods of time, have yet to be fully understood. The European Society of Medical Oncology (ESMO) clinical practice guidelines5 provide helpful algorithms for managing the more commonly occurring IrAEs, but consensus advice on managing less common IrAEs, such as those affecting the eyes, is also needed to minimise any negative impact of anti-cancer interventions.
Ocular IrAEs occur with an estimated prevalence of 1–3% of all treated patients.8,9 While the spectrum of severity is broad, they are highly significant as they can threaten vision. Reports of ocular IrAEs associated with CPIs are limited to small, single-digit case series and individual case reports, which principally report patients experiencing varying degrees of uveitis.8,10–13
Uveitis is a term used to describe inflammation of the uvea, the middle layer of the eye comprising the iris, ciliary body and choroid. It is classified as anterior, intermediate, posterior, or panuveitis, according to the predominant site of inflammation within the eye.14 Anterior uveitis is characterised by an infiltrate of white blood cells in the anterior chamber of the eye; intermediate uveitis is associated with inflammation in the vitreous gel, resulting in visual blurring, haze and floaters; posterior uveitis is characterised by retinal and/or choroidal inflammation.15,16 Symptoms of uveitis include pain, blurred vision and red eye. Involvement of the posterior segment can produce symptoms of floaters, flickering and shimmering lights (photopsias), as well as blind spots.
Anterior uveitis, whether acute or chronic, can often be managed with topical steroid drops alone. Severe uveitis of any subtype may lead to macular oedema, with accumulation of fluid at the most sensitive part of the retina, causing visual distortion and blurring. Severe ocular inflammation requires prompt intervention to avoid permanent loss of vision, and may require periocular or intravitreal steroid injections. More severe cases require systemic steroids, including oral, or pulsed intravenous methylprednisolone. Recalcitrant, chronic inflammatory eye diseases can be managed with secondary non-corticosteroid immunomodulatory therapeutic agents, including anti-metabolites like mycophenolate mofetil and methotrexate, or biological drugs like adalimumab.17 Common complications of uveitis and its treatment include cataract, glaucoma and choroidal neovascularisation. While most reports suggest a good response to therapy with complete resolution of inflammation, a minority of patients may develop permanent visual loss.
Other less common ocular IrAEs include ocular myasthenia, optic neuritis and auto-immune retinopathy. Dry eyes are described by up to one in four treated patients, but this is a common condition that is often not reported in clinical trials and is frequently undertreated, even in clinical practice.8,9 The risk of ocular IrAEs associated with CPIs was recently quantified using disproportionality analysis; odds ratios for uveitis ranged from 4.6 to 10.8, while that of any ocular IrAE was 2.5 compared with reported events associated with all other drugs.18
Uncertainties about optimal management of ocular IrAEs persist, such as when to interrupt or discontinue potentially life-saving CPI therapy and whether systemic steroids can influence the efficacy of CPIs. We report our experience of managing ocular IrAEs in a cohort of cancer patients receiving CPIs in a single institution and make management recommendations in a novel treatment algorithm.
Methods
We reviewed the electronic patient records of patients treated with CPIs from January to December 2019, and identified all cases referred to the ophthalmology service. The clinical characteristics, treatment and course of IrAEs over time were recorded. Details of their CPI treatment, other non-ocular irAEs, and disease response (based on routine radiological imaging and applying RECIST 1.1 response criteria) were also recorded. Survival was measured from the date of first CPI infusion until data cut-off, on 17 March, 2020.
Based on our case series and information contained in published international guidelines,5,6 we generated a simple assessment and treatment algorithm for use in routine clinical practice to guide the multidisciplinary team managing ocular symptoms and uveitis; the most common ocular IrAE reported.
This project was registered as a health service evaluation at Cambridge University Hospitals NHS Foundation Trust (CUHFT). The CUHFT research governance lead confirmed that, under the UK Policy Framework for Health and Social Care Research 2017, this project would not be classified or managed as research within the National Health Service and therefore did not require ethical review by a research ethics committee. Written informed consent to publish was obtained from the surviving case study patient.
Results
Patient characteristics
We identified eight patients (three women and five men, aged between 39 and 81 years) who developed ocular IrAEs after starting CPIs (Table 1). Seven patients were treated for advanced cancer; four for metastatic melanoma, two metastatic renal-cell carcinoma and one advanced ovarian carcinoma. One melanoma patient received CPI as an adjuvant therapy, after resection of regional lymph node disease. None had a previous history of uveitis. One patient had a history of glaucoma. Five patients received combination anti-CTLA-4 plus anti-PD-1 antibodies (ipilimumab + nivolumab), two patients received a single agent anti-PD-1 antibody (one pembrolizumab, one nivolumab) and one patient received anti-PD-1 antibody (nivolumab) in combination with a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor (rucaparib). Seven patients had their treatment discontinued early due to treatment-related adverse events; their treatment duration ranged from 3 to 9 weeks. The median number of adverse events contributing to treatment discontinuation was three (range 1–3). One patient completed 2 years of planned anti-PD-1 antibody therapy.
Table 1. Patient characteristics of patients experiencing ocular IrAEs associated with CPI treatment.
Patient case CPI regimen Duration of CPI therapy Reason for discontinuation AEs leading to discontinuation Best response to CPI Survival outcome
Melanoma-1
Metastatic
50-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Ocular IrAE Ocular
Skin
Fatigue Partial response Alive 16 months+
Kidney-1
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 3 weeks Multiple IrAE Ocular
Skin
Liver Stable disease Alive 15 months+
Kidney-2
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 4 weeks Multiple IrAEs Ocular
Liver
Arthritis Partial response Alive 16 months+
Ovarian
Metastatic
40-yo woman Nivolumab + rucaparib 8 weeks Multiple IrAE Ocular
Liver
Neutropaenia* Partial response Alive 10 months+
Melanoma-2
Resected stage III
74-yo woman Pembrolizumab
200 mg IV q3w 3 weeks Ocular IrAE Ocular Recurrence Treated with ipilimumab on recurrence; aborted after 6 weeks due to colitis.
Alive with stable disease:
14 months+
Melanoma-3
Metastatic
56-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Multiple IrAEs Ocular
Lung Partial response Alive 22 months+
Melanoma-4
Metastatic
40-yo woman Ipilimumab
1 mg/kg+ nivolumab 3 mg/kg 6 weeks Multiple IrAEs Ocular
Liver Partial response Rechallenged with 2 further cycles of ipilimumab+nivolumab on disease progression without significant IrAEs; progressive brain metastases.
Died after 11 months
Melanoma-5
Metastatic
81-yo man Nivolumab 240 mg 2 years Completed planned treatment – Near complete response Alive 5 years+
* Likely due to PARP inhibitor, not CPI.
AEs, adverse events; CPI, checkpoint inhibitor; IrEAs, immune-related adverse events; yo, year-old; PARP, poly-adenosine diphosphate ribose polymerase.
Ocular IrAE characteristics
The median time to the onset of ocular IrAE was 5 weeks from starting CPIs, although one patient developed symptoms after 18 months of treatment (Table 2). In all seven patients who discontinued CPIs early, ocular IrAE contributed to the decision to discontinue therapy. One patient with pre-existing glaucoma experienced ocular IrAE as the only IrAE, occurring after her first dose of pembrolizumab, and this led to treatment discontinuation. Four patients were diagnosed with anterior uveitis, one had intermediate uveitis, one had melanoma-associated retinopathy (MAR)19,20 and one had suspected ocular ischaemic syndrome.21 All patients had bilateral eye involvement. There were no hospitalisations associated with ocular IrAEs.
Table 2. Characteristics of ocular IrAEs experienced and their treatment.
Patient case Presenting symptoms Ocular IrAE Worst
CTCAE
grade Time to onset/resolution of ocular IrAE Worst visual acuity Visual acuity on resolution Local treatment Systemic steroids (starting dose) Outcome of ocular IrAE
Melanoma 1 Bilateral blurred vision, painful eyes Anterior uveitis 2 3 weeks/8 weeks R 6/19
L Normal R Normal
L Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Kidney 1 Bilateral blurred vision, painful eyes, headache Anterior uveitis
High IO pressures 2 5 weeks/11 weeks (uveitis)
6 months
(IO pressures) R 6/9.5
L 6/7.5 R Normal
L Normal Dexamethasone 0.1% drops
Timolol
Latanprost None Complete resolution
Kidney 2 Bilateral painful red eyes, light sensitivity Anterior uveitis
Left disc swelling 2 5 weeks/8 weeks Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Ovarian Bilateral blurred vision. Painful to focus Anterior uveitis 2 5 weeks/8 months Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Melanoma 2 Deterioration in vision Intermediate
uveitis 3 1 week/10 weeks R 6/9
L Normal R 6/9
L Normal None 40 mg prednisolone Resolved on 10 mg prednisolone; following 2 cycles of ipilimumab,
received IV steroids and infliximab for enteritis
Melanoma 3 Flashing lights, visual aura Melanoma associated retinopathy 4 3 weeks/18 months R 6/18 R 6/5 Anti-VEGF injections
Intra-ocular dexamethasone 50 mg prednisolone Permanent loss of vision; macular scarring
Melanoma 4 Rapid onset loss of vision in both eyes Suspected ocular ischaemic syndrome 4 7 weeks/4 weeks R 6/15
L 6/9 R Normal
L Normal Dexamethasone 0.1% drops
Mydrilate 1% drops 40 mg prednisolone Complete resolution
Melanoma 5 Red, eyes
Loss of vision in left eye
Blurred vision Conjunctivitis
Left retinal detachment*
Anterior uveitis 2
2 18 months
21 months
4 years/10 months R 6/12
L 6/7.5 R 6/12
L 6/7.5 Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Quiescent
* Association of retinal detachment as an IrAE could not be confirmed.
CTCAE, common toxicity criteria; IO, intra-ocular; IrEA, immune-related adverse event; IV, intravenous; L, left; R, right; VEGF, vascular endothelial growth factor.
The patient completing 2 years of nivolumab experienced ocular IrAEs both during and after completing CPI treatment. As the symptoms were manageable and no other IrAEs occurred, his planned treatment was not interrupted. He experienced conjunctivitis and left retinal detachment during treatment, both of which were managed successfully. Two years after completing CPIs, he developed bilateral anterior uveitis.
Treatment of ocular IrAEs
All five patients who developed anterior uveitis were treated with topical steroids only. The three other ocular conditions (intermediate uveitis, MAR and suspected ocular ischaemic syndrome) were treated with oral corticosteroids. No patients received intravenous steroids or other immunosuppressive agents to treat their ocular IrAEs. One patient diagnosed with MAR received intravitreal anti-vascular endothelial growth factor injections to treat a juxtafoveal choroidal neovascular membrane, as well as intra-ocular steroid implants to treat chronic photopsia in his only remaining eye.
The median ocular IrAE treatment duration was 11 weeks (range 8 weeks–10 months) with topical steroids and 10 weeks (range 4 weeks–6 months) with oral steroids. Two patients with anterior uveitis had rapid, complete resolution of their symptoms by 8 and 11 weeks. One patient had persistently raised intra-ocular pressures for approximately 6 months. Two patients had a protracted course of inflammatory eye disease, with recurrent episodes lasting 8 and 10 months, respectively. Of two patients re-challenged with CPIs at a later date, (one with ipilimumab, one with ipilimumab + nivolumab), neither had recurrence of ocular IrAEs.
Oncological response to CPIs
Overall, six out of the eight treated patients experienced a partial or near complete response to CPI therapy and seven remain alive and well at data cut-off. One melanoma patient whose adjuvant pembrolizumab treatment was aborted due to uveitis had disease recurrence documented 10 weeks after her first CPI administration, then received ipilimumab, which was aborted after teo cycles due to severe colitis, but her disease has remained stable since that time (15 months at data cut-off). A second melanoma patient who progressed on completing adjuvant pembrolizumab initially responded to ipilimumab + nivolumab, but died of metastatic disease 19 months after her first CPI administration.
Non-uveitis case studies
Case 1: (‘Melanoma 3’ in Tables 1 and 2)
A 56-year-old man received treatment with ipilimumab + nivolumab for metastatic uveal melanoma, having had exenteration of his left eye 4 years previously. Three weeks after his first CPI administration he complained of severe flashing lights in his remaining eye, and he was referred urgently for an ophthalmological assessment.
On slit lamp biomicroscopy, pale lesions were noted in the fundus, and these were presumed to be benign. He continued immunotherapy, but after 9 weeks (three cycles of CPI), he developed moderately severe pneumonitis which was initially treated with 50 mg oral prednisolone daily and CPI therapy was permanently discontinued. The pneumonitis resolved over 12 weeks and he was gradually weaned off steroids. While tapering his steroids, he noticed that his vision was deteriorating and a visual field defect was detected on formal testing.
Optical coherence tomography (OCT) scanning indicated a choroidal lesion next to the fovea, suggesting a possible neovascular membrane (Figure 1a), which could cause visual loss. This suspicion was confirmed by the presence of early leakage during fundus fluorescein angiography (FFA) (Figure 1b). The choroidal neovascular membrane was treated with a series of intravitreal anti-vascular endothelial growth factor (ranibizumab) injections, until it was deemed to be inactive.
Figure 1. Non-uveitis case study. (a) Optical coherence tomography scan showing a choroidal lesion next to the fovea, possibly representing a neovascular membrane. (b) Fundus fluorescein angiography demonstrating early hyperfluorescence of the juxtafoveal lesion, supporting a diagnosis of choroidal neovascularisation. (c) Pseudocolour image of the fundus showing the dexamethasone 0.7 mg steroid implant.
Electrodiagnostic testing subsequently revealed widespread post-phototransduction cone and rod dysfunction, compatible with MAR. His symptoms partially improved on restarting oral steroids (10 mg prednisolone daily), pointing to an inflammatory cause of his visual symptoms. On the basis of this evidence, he was offered short-acting and long-acting intravitreal steroid implants,22 (dexamethasone 0.7 mg and fluocinolone acetonide, respectively, Figure 1c) to avoid chronic side effects of long-term systemic steroids. At the time of data cut-off, the patient remained disease free, with relatively minor persistent visual impairment.
Case 2: (‘Melanoma 4’ in Tables 1 and 2)
A 40-year-old woman received adjuvant pembrolizumab for stage IIID BRAF wild type melanoma, which was well tolerated, without any IrAEs. After 11 months of treatment, she complained of generalised musculoskeletal pains and fatigue. Restaging scans identified widespread metastases including to liver and bone. She was commenced on ipilimumab + nivolumab. After 6 weeks (post cycle 2), her overall condition deteriorated, with severe fatigue and deterioration in liver function and performance status, although her serum lactate dehydrogenase dropped markedly from 1956 to 498 IU/L during the same time period. Her third cycle of ipilimumab + nivolumab was deferred.
One week later, she presented to the emergency department complaining of sudden onset bilateral loss of vision, worse in the right eye. Visual acuity was 6/15 in the right eye and 6/9 in the left eye, and intraocular pressure was within normal parameters. Iris neovascularisation and a swollen right optic disc were found on slit lamp biomicroscopy and fundoscopy. Brain imaging was requested, and confirmed the absence of metastases. A diagnosis of ocular ischaemic syndrome21 was suggested, but after discussion with the oncology specialist, a possible inflammatory aetiology was considered.
The patient was treated with 40 mg oral prednisolone daily, 0.1% dexamethasone eye drops and 1% mydrilate drops. She responded well to treatment, and was gradually weaned off steroids, and her vision recovered. Her liver function normalised and her performance status improved sufficiently for a return to normal activities of daily living. Subsequent staging compueterised tomography (CT) images indicated a partial response to CPIs. Six months later, despite the patient remaining well and asymptomatic, surveillance imaging identified disease recurrence in previously involved body sites with four new brain metastases. She was re-challenged with ipilimumab + nivolumab. No new IrAEs occurred, but after the second cycle, she was admitted to hospital with seizures due to haemorrhage into the brain metastases and died 10 weeks later, 11 months after starting CPIs for metastatic disease.
Ocular symptom management algorithm
Based on our own experience, review of the literature and international guidelines, we generated a management algorithm designed for multidisciplinary teams to use in clinical practice (Figure 2).
Figure 2. Management algorithm for patients treated with CPIs who present with ocular symptoms.
CPI, checkpoint inhibitor; FAF, fundus autofluorescence; FFA, fundus fluorescein angiography; ICG, indocyanine angiography; OCT, optical coherence tomography.
Patient symptoms and signs are classified according to international common toxicity criteria (CTCAE version 5.0)23 and management is determined by the severity of the condition. The international CTCAE grades classify the severity of ocular conditions from 1 (mild) to 4 (severe, with sight-threatening consequences). Anterior uveitis is graded in correspondence with the number of cells seen on slit lamp examination of the anterior chamber, as defined by the standardisation of uveitis nomenclature.12 Thus, grade 1 uveitis corresponds to a ‘trace’ of cells (1–5 cells in a 1 mm × 1 mm slit beam), and grade 3 uveitis corresponds to ‘3+’ (26–50 cells per field). Posterior uveitis is graded 3. In addition, a visual acuity of 20/200 (6/60 in European terminology) or less, meeting criteria for blindness in the affected eye, is graded as 4.
The ophthalmological assessments of patients with visual disturbance include visual acuity, colour vision and intraocular pressure measurement. A relative afferent pupillary defect can be tested for by carrying out the swinging flashlight test before dilating drops are instilled into the eyes. Our algorithm includes a pathway for specialist ophthalmic investigations used to diagnose uveitis, which may include FFA and indocyanine angiography (ICG), fundus autofluorescence (FAF) and OCT, depending on the individual case.
In the absence of intermediate or posterior signs, invasive dye-based angiography tests would not normally be indicated, but can be used to exclude retinal vasculitis and leakage (FFA) or undiagnosed choroiditis (ICG) in challenging cases. This can be valuable in both the diagnosis and monitoring of inflammatory eye disease.24 Non-invasive FAF imaging is used to map metabolic activity in the retinal photoreceptor and pigment epithelial layers, and can be useful in identifying inflammatory processes occurring in the outer retina.25 OCT scanning provides high resolution images of the retina in cross-section and has transformed modern ophthalmological practice.
In contrast to recommendations in current international guidelines, we have used clinical evidence to justify avoiding the discontinuation of CPIs as much as possible. The algorithm aims to emphasise the need for close liaison between oncologist and specialist ophthalmologist from the point of recognition to resolution of ocular symptoms, as well as the benefit of a multidisciplinary approach involving good communication between the specialties to balance the need for cancer control alongside patient safety and vision preservation.
Discussion
This report of eight patients experiencing ocular IrAEs associated with CPI treatment is one of the largest series published to date. Anterior uveitis was the most common ocular IrAE that we identified, occurring in five of our eight cases. The onset of uveitis is reported mainly to occur within 2 months of starting CPIs.7,13,26 This was generally the case in our cohort, with a median time to onset of 5 weeks (range 1–7 weeks). The exception was a single patient who developed anterior uveitis 2 years after completing 2 years of nivolumab treatment. It is noteworthy that he had other ocular IrAEs while on treatment that did not lead to CPI discontinuation, while his anterior uveitis was difficult to control. It is well recognised that some IrAEs (including ocular IrAEs)13 can occur months and years after stopping CPIs, and this case is a reminder to consider the need for ongoing follow-up, even in patients apparently entering long-term remission after completing treatment.
Ocular IrAEs may occur as the only IrAE, or in association with multiple body system IrAEs. In our series, their occurrence influenced the decision to interrupt CPI treatment in all seven patients who discontinued treatment early: uveitis was the primary reason for discontinuation in two (29%) patients, but contributed to the decision to stop treatment in the remaining five patients, all of whom experienced multiple IrAEs.
A literature review of 33 cases of uveitis secondary to CPIs10 concluded that one-third of patients experienced anterior uveitis alone, one-third had anterior uveitis plus posterior segment changes including macular oedema, retinal detachment, vitritis or papillitis, and one-third had panuveitis. A very recent larger review of 126 cases of CPI-associated uveitis was broadly consistent, noting that 35% of panuveitis cases occurred as part of a Vogt–Koyanagi–Harada (VKH)-like syndrome.27–30 VKH disease is a multisystem disease affecting melanin-containing tissues, which is thought to be autoimmune in origin. The most significant ocular manifestation is bilateral diffuse panuveitis with exudative retinal detachment, often accompanied by a variable spectrum of symptoms involving the skin, nervous system and inner ear.
Recognition of the different presentations of the subtypes of uveitis is clearly important, as this influences whether topical steroids alone can be used for treatment, sparing patients the need for systemic steroids which may adversely affect the outcome of anti-cancer treatment.7 As in our own series, most published series describe initial intervention with topical and/or oral corticosteroids. Although outcomes are generally good, with complete resolution of inflammation in most cases, some cases are recalcitrant, warranting alternative immunomodulatory agents, while peri-ocular or intravitreal steroids22 have been employed as steroid-sparing strategies.
Prompt recognition of ocular and visual symptoms by oncologists and referral to ophthalmology specialists is necessary to ensure rapid investigation, diagnosis and sight-preserving treatment, as well as to inform multidisciplinary team opinion concerning ongoing treatment with CPIs. This can be challenging, because the ocular symptoms experienced may not directly correlate with the severity of inflammation identified.14 Even so, in most of the case series published to date, the overwhelming majority of patients experiencing ocular irAEs have had their CPIs discontinued,12,13 and uncertainty exists whether this line of action may impact overall treatment outcomes.
Perhaps because of its low incidence relative to other IrAEs, the ESMO guidelines5 offer very little advice on how to manage ocular IrAEs. The American Society of Clinical Oncology (ASCO) guidelines,6 on the other hand, are far more extensive and recommend referral to ophthalmology services for new onset visual symptoms, while they also recognise that symptoms may not always correlate with severity. The guidelines make use of the CTCAE grading system for ocular IrAEs and include management recommendations on whether to withhold, or discontinue, immunotherapy. While these constitute a welcome framework, they may also prove unnecessarily restrictive.
The ASCO guidelines recommend that for grade 1 ocular IrAEs, CPIs can be continued, for grade 2 events CPIs should be withheld and for grades 3 and 4 events they should be permanently discontinued. Ocular IrAEs, while not usually life threatening, may be life changing, so urgent intervention aimed at avoiding permanent loss of eyesight is certainly warranted. However, it is important to note that even severe deterioration in visual acuity can sometimes be reversible. For example, significant visual impairment associated with macular oedema may recover following prompt treatment with oral or intravitreal steroids. In adherence to ASCO guidance, loss of visual acuity may result in an adverse event grading of 3 or 4, which we consider could unnecessarily lead to permanent cessation of immunotherapy.
In some patients who resume CPIs after treatment for IrAEs, relapse with the same symptoms has been observed.9,13 We argue that permanent discontinuation of immunotherapy may not always be justified in these circumstances. In our own series, one patient experienced significant bilateral loss of vision associated with an ocular IrAE after two cycles of CPI with ipilimumab + nivolumab, but did not experience further ocular symptoms on retreatment several months later. Moreover, a severe or acute drop in visual acuity may be due to other pathologies unrelated to CPI (for example, incidental retinal detachment, which has a lifetime risk in normal individuals of one in 300).31 On the other hand, a patient could have apparently mild visual impairment but severe intra-ocular inflammation.
We recommend early referral to an ophthalmology specialist on recognition of ocular symptoms to diagnose the possible ocular IrAE and accurately grade its severity. We further recommend that both eye treatment and the ongoing use of CPIs are discussed on an individual case basis within a multidisciplinary team of oncologists and ophthalmologists, keeping the option open for retreatment in situations in which the possible benefits outweigh the risks, assuming appropriate patient counselling and support.
Most cases of uveitis associated with CPI, including the majority of our cases, are mild and would be categorised as CTCAE grade 2. These cases do not require cessation of CPI and neither should they require systemic steroids, in general. The outcomes from topical treatment are mainly good, with either a limited course, or sometimes ongoing topical steroids. If systemic steroids are used, the ASCO guidelines recommend that CPIs are withheld until the patient is either off all steroids or is receiving a daily dose of 10 mg oral prednisolone (or equivalent) or less. As far as possible, the aim should be to treat ocular IrAEs with local options in order to avoid systemic steroids and cessation of CPI therapy. Aside from concerns regarding their impact on CPI efficacy, long-term steroid use is associated with many well-known harmful effects.
The goal of avoiding the interruption of CPI therapy is best achieved by taking a multidisciplinary approach, with close liaison between ophthalmology and oncology teams, remembering that patients may have a high degree of anxiety about stopping potentially life-saving anti-cancer therapy. In our cohort, five patients stopped CPIs due to ocular IrAEs, despite being categorised as grade 2, which does not necessarily mandate permanent discontinuation. Three of these patients were treated solely with topical steroids, which suggests a low threat to vision, and which would not normally interfere with CPIs. In cases where topical steroids are not sufficient, intravitreal or periocular steroids should be considered to enable patients to remain on CPIs.
It is possible that patients diagnosed with melanoma may be at increased risk of developing uveitis due to the presence of melanin in the retinal pigment epithelium. An immune-mediated response to melanin-producing cells in the eye may occur both in patients on treatment and in those who develop an immunological reaction to their cancer independent of treatment. In our series, MAR was the most likely diagnosis in one of two patients reporting ocular toxicities that were not due to uveitis, based on symptoms described and investigations performed. The pathology is thought to be due to shared neuroectodermal lineage of melanocytes and retinal cells. Conversely, uveitis is not unique to patients with a diagnosis of melanoma. Patients at increased risk of uveitis may include those with other immune-related side effects and those predisposed to autoimmune disease or with a significant family history.32
Four of our patients, of whom two had other IrAEs, responded very well to retreatment with CPIs, highlighting a key unanswered question concerning whether the occurrence of IrAEs can predict a therapeutic response.32,33 Several studies have reported increased progression-free and overall survival in patients who experienced IrAEs with CPIs compared to those who did not.34,35 To date, it remains unclear whether the development of uveitis or other specific IrAEs is associated with better outcomes from treatment with CPIs,34,36 although it is quite plausible that an observed inflammatory response within the eye or elsewhere might reflect an enhanced immune response against cancer. The number of patients in our study is insufficient to answer this question, but further study is warranted and, if proved, this could be reassuring for patients who have previously stopped immunotherapy while being treated for inflammatory side effects.
In conclusion, ocular IrAEs are relatively uncommon IrAEs associated with CPIs, but can be dramatic and may lead to permanent visual loss. Prompt recognition in oncology clinics and early referral to an ophthalmologist is essential. Patients with confirmed ocular inflammation require close monitoring in the eye clinic and ongoing liaison with their oncologist regarding optimal treatment and the use of corticosteroids. The option of intraocular steroid implants should be considered as an alternative to systemic steroids when IrAEs do not resolve with topical steroids alone, with the potential benefit of being able to continue on CPIs.
In conjunction with our ocular IrAE management algorithm (Figure 2), we propose the following basic steps to follow when seeing immunotherapy patients with ocular symptoms in the clinic:
document the symptoms and signs and their severity
escalate by referral to an ophthalmologist; consider urgency of referral and the need to interrupt CPI therapy depending on symptom severity
obtain an ophthalmological diagnosis
take a multidisciplinary approach to managing the ocular symptoms and the need or otherwise to restart CPIs, based on risk/benefit considerations.
The authors would like to thank the patients and their families for allowing us to share their case studies. Thanks also to the CUHFT research governance and audit teams for their assistance in the conduct of this study.
Conflict of interest: The authors declare that there is no conflict of interest.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Philippa Corrie
https://orcid.org/0000-0003-4875-7021 | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY-NC | 33633802 | 19,074,013 | 2021 |
What was the outcome of reaction 'Conjunctivitis'? | Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm.
Ocular immune-related adverse events (IrAEs) associated with use of checkpoint inhibitors (CPIs) in cancer therapeutics are relatively rare, occurring in approximately 1% of treated patients. Recognition and early intervention are essential because the degree of tissue damage may be disproportionate to the symptoms, and lack of appropriate treatment risks permanent loss of vision. International guidelines on managing ocular IrAEs provide limited advice only. Importantly, local interventions can be effective and may avoid the need for systemic corticosteroids, thereby permitting the continuation of CPIs. We present a single institution case series of eight affected patients managed by our multidisciplinary team. Consistent with previously published series and case reports, we identified anterior uveitis as the most common ocular IrAE associated with CPIs requiring intervention. Based on our experience, as well as published guidance, we generated a simple algorithm to assist clinicians efficiently manage patients developing ocular symptoms during treatment with CPIs. In addition, we make recommendations for optimising treatment of uveitis and address implications for ongoing CPI therapy.
Background
Immunotherapy with checkpoint inhibitors (CPIs) has transformed the treatment of a wide range of malignancies.1,2 These drugs work by enabling the host immune system to eliminate malignant cells, recognisable through the expression of neoantigens. The CPIs currently in clinical use are antibodies which target the cytotoxic T-lymphocyte antigen-4 receptor (anti-CTLA-4), the programmed death-1 receptor (anti-PD-1) and its ligand (anti-PD-L1). The CTLA-4 receptor downregulates T-cell activation, whereas the PD-1 receptor inhibits T-cell proliferation, cytokine release, and cytotoxicity. Blocking their function can enhance T-cell response and allow immune-mediated tumour killing.
CPIs generate side effects termed immune-related adverse events (IrAEs), which stem from their mechanism of action, being predominantly autoimmune in nature and having the potential to affect any body organ. IrAEs range from being mild to life-threatening, or life-changing in some instances.3 Since their first introduction into clinical practice in 2011 as treatment for metastatic melanoma, the use of anti-CTLA-4 and anti-PD-L1 antibodies has expanded to include multiple cancer types including lung and urological cancers as well as lymphomas, with new treatment indications being added frequently. Their increasing use has resulted in greater awareness of both common and rarely seen IrAEs, ranging from mild presentations to severe reactions requiring prompt intervention.4
Optimal management of IrAEs is still in its infancy, with limited evidence to inform international guidelines which have been generated to assist clinical practice.5,6 The mainstay of treatment for what appear to be inflammatory conditions is immunosuppression with corticosteroids, prompting concerns about their effect on CPI efficacy.7 Moreover, the long-term effects on cancer survivors of high dose steroids, sometimes administered for protracted periods of time, have yet to be fully understood. The European Society of Medical Oncology (ESMO) clinical practice guidelines5 provide helpful algorithms for managing the more commonly occurring IrAEs, but consensus advice on managing less common IrAEs, such as those affecting the eyes, is also needed to minimise any negative impact of anti-cancer interventions.
Ocular IrAEs occur with an estimated prevalence of 1–3% of all treated patients.8,9 While the spectrum of severity is broad, they are highly significant as they can threaten vision. Reports of ocular IrAEs associated with CPIs are limited to small, single-digit case series and individual case reports, which principally report patients experiencing varying degrees of uveitis.8,10–13
Uveitis is a term used to describe inflammation of the uvea, the middle layer of the eye comprising the iris, ciliary body and choroid. It is classified as anterior, intermediate, posterior, or panuveitis, according to the predominant site of inflammation within the eye.14 Anterior uveitis is characterised by an infiltrate of white blood cells in the anterior chamber of the eye; intermediate uveitis is associated with inflammation in the vitreous gel, resulting in visual blurring, haze and floaters; posterior uveitis is characterised by retinal and/or choroidal inflammation.15,16 Symptoms of uveitis include pain, blurred vision and red eye. Involvement of the posterior segment can produce symptoms of floaters, flickering and shimmering lights (photopsias), as well as blind spots.
Anterior uveitis, whether acute or chronic, can often be managed with topical steroid drops alone. Severe uveitis of any subtype may lead to macular oedema, with accumulation of fluid at the most sensitive part of the retina, causing visual distortion and blurring. Severe ocular inflammation requires prompt intervention to avoid permanent loss of vision, and may require periocular or intravitreal steroid injections. More severe cases require systemic steroids, including oral, or pulsed intravenous methylprednisolone. Recalcitrant, chronic inflammatory eye diseases can be managed with secondary non-corticosteroid immunomodulatory therapeutic agents, including anti-metabolites like mycophenolate mofetil and methotrexate, or biological drugs like adalimumab.17 Common complications of uveitis and its treatment include cataract, glaucoma and choroidal neovascularisation. While most reports suggest a good response to therapy with complete resolution of inflammation, a minority of patients may develop permanent visual loss.
Other less common ocular IrAEs include ocular myasthenia, optic neuritis and auto-immune retinopathy. Dry eyes are described by up to one in four treated patients, but this is a common condition that is often not reported in clinical trials and is frequently undertreated, even in clinical practice.8,9 The risk of ocular IrAEs associated with CPIs was recently quantified using disproportionality analysis; odds ratios for uveitis ranged from 4.6 to 10.8, while that of any ocular IrAE was 2.5 compared with reported events associated with all other drugs.18
Uncertainties about optimal management of ocular IrAEs persist, such as when to interrupt or discontinue potentially life-saving CPI therapy and whether systemic steroids can influence the efficacy of CPIs. We report our experience of managing ocular IrAEs in a cohort of cancer patients receiving CPIs in a single institution and make management recommendations in a novel treatment algorithm.
Methods
We reviewed the electronic patient records of patients treated with CPIs from January to December 2019, and identified all cases referred to the ophthalmology service. The clinical characteristics, treatment and course of IrAEs over time were recorded. Details of their CPI treatment, other non-ocular irAEs, and disease response (based on routine radiological imaging and applying RECIST 1.1 response criteria) were also recorded. Survival was measured from the date of first CPI infusion until data cut-off, on 17 March, 2020.
Based on our case series and information contained in published international guidelines,5,6 we generated a simple assessment and treatment algorithm for use in routine clinical practice to guide the multidisciplinary team managing ocular symptoms and uveitis; the most common ocular IrAE reported.
This project was registered as a health service evaluation at Cambridge University Hospitals NHS Foundation Trust (CUHFT). The CUHFT research governance lead confirmed that, under the UK Policy Framework for Health and Social Care Research 2017, this project would not be classified or managed as research within the National Health Service and therefore did not require ethical review by a research ethics committee. Written informed consent to publish was obtained from the surviving case study patient.
Results
Patient characteristics
We identified eight patients (three women and five men, aged between 39 and 81 years) who developed ocular IrAEs after starting CPIs (Table 1). Seven patients were treated for advanced cancer; four for metastatic melanoma, two metastatic renal-cell carcinoma and one advanced ovarian carcinoma. One melanoma patient received CPI as an adjuvant therapy, after resection of regional lymph node disease. None had a previous history of uveitis. One patient had a history of glaucoma. Five patients received combination anti-CTLA-4 plus anti-PD-1 antibodies (ipilimumab + nivolumab), two patients received a single agent anti-PD-1 antibody (one pembrolizumab, one nivolumab) and one patient received anti-PD-1 antibody (nivolumab) in combination with a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor (rucaparib). Seven patients had their treatment discontinued early due to treatment-related adverse events; their treatment duration ranged from 3 to 9 weeks. The median number of adverse events contributing to treatment discontinuation was three (range 1–3). One patient completed 2 years of planned anti-PD-1 antibody therapy.
Table 1. Patient characteristics of patients experiencing ocular IrAEs associated with CPI treatment.
Patient case CPI regimen Duration of CPI therapy Reason for discontinuation AEs leading to discontinuation Best response to CPI Survival outcome
Melanoma-1
Metastatic
50-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Ocular IrAE Ocular
Skin
Fatigue Partial response Alive 16 months+
Kidney-1
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 3 weeks Multiple IrAE Ocular
Skin
Liver Stable disease Alive 15 months+
Kidney-2
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 4 weeks Multiple IrAEs Ocular
Liver
Arthritis Partial response Alive 16 months+
Ovarian
Metastatic
40-yo woman Nivolumab + rucaparib 8 weeks Multiple IrAE Ocular
Liver
Neutropaenia* Partial response Alive 10 months+
Melanoma-2
Resected stage III
74-yo woman Pembrolizumab
200 mg IV q3w 3 weeks Ocular IrAE Ocular Recurrence Treated with ipilimumab on recurrence; aborted after 6 weeks due to colitis.
Alive with stable disease:
14 months+
Melanoma-3
Metastatic
56-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Multiple IrAEs Ocular
Lung Partial response Alive 22 months+
Melanoma-4
Metastatic
40-yo woman Ipilimumab
1 mg/kg+ nivolumab 3 mg/kg 6 weeks Multiple IrAEs Ocular
Liver Partial response Rechallenged with 2 further cycles of ipilimumab+nivolumab on disease progression without significant IrAEs; progressive brain metastases.
Died after 11 months
Melanoma-5
Metastatic
81-yo man Nivolumab 240 mg 2 years Completed planned treatment – Near complete response Alive 5 years+
* Likely due to PARP inhibitor, not CPI.
AEs, adverse events; CPI, checkpoint inhibitor; IrEAs, immune-related adverse events; yo, year-old; PARP, poly-adenosine diphosphate ribose polymerase.
Ocular IrAE characteristics
The median time to the onset of ocular IrAE was 5 weeks from starting CPIs, although one patient developed symptoms after 18 months of treatment (Table 2). In all seven patients who discontinued CPIs early, ocular IrAE contributed to the decision to discontinue therapy. One patient with pre-existing glaucoma experienced ocular IrAE as the only IrAE, occurring after her first dose of pembrolizumab, and this led to treatment discontinuation. Four patients were diagnosed with anterior uveitis, one had intermediate uveitis, one had melanoma-associated retinopathy (MAR)19,20 and one had suspected ocular ischaemic syndrome.21 All patients had bilateral eye involvement. There were no hospitalisations associated with ocular IrAEs.
Table 2. Characteristics of ocular IrAEs experienced and their treatment.
Patient case Presenting symptoms Ocular IrAE Worst
CTCAE
grade Time to onset/resolution of ocular IrAE Worst visual acuity Visual acuity on resolution Local treatment Systemic steroids (starting dose) Outcome of ocular IrAE
Melanoma 1 Bilateral blurred vision, painful eyes Anterior uveitis 2 3 weeks/8 weeks R 6/19
L Normal R Normal
L Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Kidney 1 Bilateral blurred vision, painful eyes, headache Anterior uveitis
High IO pressures 2 5 weeks/11 weeks (uveitis)
6 months
(IO pressures) R 6/9.5
L 6/7.5 R Normal
L Normal Dexamethasone 0.1% drops
Timolol
Latanprost None Complete resolution
Kidney 2 Bilateral painful red eyes, light sensitivity Anterior uveitis
Left disc swelling 2 5 weeks/8 weeks Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Ovarian Bilateral blurred vision. Painful to focus Anterior uveitis 2 5 weeks/8 months Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Melanoma 2 Deterioration in vision Intermediate
uveitis 3 1 week/10 weeks R 6/9
L Normal R 6/9
L Normal None 40 mg prednisolone Resolved on 10 mg prednisolone; following 2 cycles of ipilimumab,
received IV steroids and infliximab for enteritis
Melanoma 3 Flashing lights, visual aura Melanoma associated retinopathy 4 3 weeks/18 months R 6/18 R 6/5 Anti-VEGF injections
Intra-ocular dexamethasone 50 mg prednisolone Permanent loss of vision; macular scarring
Melanoma 4 Rapid onset loss of vision in both eyes Suspected ocular ischaemic syndrome 4 7 weeks/4 weeks R 6/15
L 6/9 R Normal
L Normal Dexamethasone 0.1% drops
Mydrilate 1% drops 40 mg prednisolone Complete resolution
Melanoma 5 Red, eyes
Loss of vision in left eye
Blurred vision Conjunctivitis
Left retinal detachment*
Anterior uveitis 2
2 18 months
21 months
4 years/10 months R 6/12
L 6/7.5 R 6/12
L 6/7.5 Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Quiescent
* Association of retinal detachment as an IrAE could not be confirmed.
CTCAE, common toxicity criteria; IO, intra-ocular; IrEA, immune-related adverse event; IV, intravenous; L, left; R, right; VEGF, vascular endothelial growth factor.
The patient completing 2 years of nivolumab experienced ocular IrAEs both during and after completing CPI treatment. As the symptoms were manageable and no other IrAEs occurred, his planned treatment was not interrupted. He experienced conjunctivitis and left retinal detachment during treatment, both of which were managed successfully. Two years after completing CPIs, he developed bilateral anterior uveitis.
Treatment of ocular IrAEs
All five patients who developed anterior uveitis were treated with topical steroids only. The three other ocular conditions (intermediate uveitis, MAR and suspected ocular ischaemic syndrome) were treated with oral corticosteroids. No patients received intravenous steroids or other immunosuppressive agents to treat their ocular IrAEs. One patient diagnosed with MAR received intravitreal anti-vascular endothelial growth factor injections to treat a juxtafoveal choroidal neovascular membrane, as well as intra-ocular steroid implants to treat chronic photopsia in his only remaining eye.
The median ocular IrAE treatment duration was 11 weeks (range 8 weeks–10 months) with topical steroids and 10 weeks (range 4 weeks–6 months) with oral steroids. Two patients with anterior uveitis had rapid, complete resolution of their symptoms by 8 and 11 weeks. One patient had persistently raised intra-ocular pressures for approximately 6 months. Two patients had a protracted course of inflammatory eye disease, with recurrent episodes lasting 8 and 10 months, respectively. Of two patients re-challenged with CPIs at a later date, (one with ipilimumab, one with ipilimumab + nivolumab), neither had recurrence of ocular IrAEs.
Oncological response to CPIs
Overall, six out of the eight treated patients experienced a partial or near complete response to CPI therapy and seven remain alive and well at data cut-off. One melanoma patient whose adjuvant pembrolizumab treatment was aborted due to uveitis had disease recurrence documented 10 weeks after her first CPI administration, then received ipilimumab, which was aborted after teo cycles due to severe colitis, but her disease has remained stable since that time (15 months at data cut-off). A second melanoma patient who progressed on completing adjuvant pembrolizumab initially responded to ipilimumab + nivolumab, but died of metastatic disease 19 months after her first CPI administration.
Non-uveitis case studies
Case 1: (‘Melanoma 3’ in Tables 1 and 2)
A 56-year-old man received treatment with ipilimumab + nivolumab for metastatic uveal melanoma, having had exenteration of his left eye 4 years previously. Three weeks after his first CPI administration he complained of severe flashing lights in his remaining eye, and he was referred urgently for an ophthalmological assessment.
On slit lamp biomicroscopy, pale lesions were noted in the fundus, and these were presumed to be benign. He continued immunotherapy, but after 9 weeks (three cycles of CPI), he developed moderately severe pneumonitis which was initially treated with 50 mg oral prednisolone daily and CPI therapy was permanently discontinued. The pneumonitis resolved over 12 weeks and he was gradually weaned off steroids. While tapering his steroids, he noticed that his vision was deteriorating and a visual field defect was detected on formal testing.
Optical coherence tomography (OCT) scanning indicated a choroidal lesion next to the fovea, suggesting a possible neovascular membrane (Figure 1a), which could cause visual loss. This suspicion was confirmed by the presence of early leakage during fundus fluorescein angiography (FFA) (Figure 1b). The choroidal neovascular membrane was treated with a series of intravitreal anti-vascular endothelial growth factor (ranibizumab) injections, until it was deemed to be inactive.
Figure 1. Non-uveitis case study. (a) Optical coherence tomography scan showing a choroidal lesion next to the fovea, possibly representing a neovascular membrane. (b) Fundus fluorescein angiography demonstrating early hyperfluorescence of the juxtafoveal lesion, supporting a diagnosis of choroidal neovascularisation. (c) Pseudocolour image of the fundus showing the dexamethasone 0.7 mg steroid implant.
Electrodiagnostic testing subsequently revealed widespread post-phototransduction cone and rod dysfunction, compatible with MAR. His symptoms partially improved on restarting oral steroids (10 mg prednisolone daily), pointing to an inflammatory cause of his visual symptoms. On the basis of this evidence, he was offered short-acting and long-acting intravitreal steroid implants,22 (dexamethasone 0.7 mg and fluocinolone acetonide, respectively, Figure 1c) to avoid chronic side effects of long-term systemic steroids. At the time of data cut-off, the patient remained disease free, with relatively minor persistent visual impairment.
Case 2: (‘Melanoma 4’ in Tables 1 and 2)
A 40-year-old woman received adjuvant pembrolizumab for stage IIID BRAF wild type melanoma, which was well tolerated, without any IrAEs. After 11 months of treatment, she complained of generalised musculoskeletal pains and fatigue. Restaging scans identified widespread metastases including to liver and bone. She was commenced on ipilimumab + nivolumab. After 6 weeks (post cycle 2), her overall condition deteriorated, with severe fatigue and deterioration in liver function and performance status, although her serum lactate dehydrogenase dropped markedly from 1956 to 498 IU/L during the same time period. Her third cycle of ipilimumab + nivolumab was deferred.
One week later, she presented to the emergency department complaining of sudden onset bilateral loss of vision, worse in the right eye. Visual acuity was 6/15 in the right eye and 6/9 in the left eye, and intraocular pressure was within normal parameters. Iris neovascularisation and a swollen right optic disc were found on slit lamp biomicroscopy and fundoscopy. Brain imaging was requested, and confirmed the absence of metastases. A diagnosis of ocular ischaemic syndrome21 was suggested, but after discussion with the oncology specialist, a possible inflammatory aetiology was considered.
The patient was treated with 40 mg oral prednisolone daily, 0.1% dexamethasone eye drops and 1% mydrilate drops. She responded well to treatment, and was gradually weaned off steroids, and her vision recovered. Her liver function normalised and her performance status improved sufficiently for a return to normal activities of daily living. Subsequent staging compueterised tomography (CT) images indicated a partial response to CPIs. Six months later, despite the patient remaining well and asymptomatic, surveillance imaging identified disease recurrence in previously involved body sites with four new brain metastases. She was re-challenged with ipilimumab + nivolumab. No new IrAEs occurred, but after the second cycle, she was admitted to hospital with seizures due to haemorrhage into the brain metastases and died 10 weeks later, 11 months after starting CPIs for metastatic disease.
Ocular symptom management algorithm
Based on our own experience, review of the literature and international guidelines, we generated a management algorithm designed for multidisciplinary teams to use in clinical practice (Figure 2).
Figure 2. Management algorithm for patients treated with CPIs who present with ocular symptoms.
CPI, checkpoint inhibitor; FAF, fundus autofluorescence; FFA, fundus fluorescein angiography; ICG, indocyanine angiography; OCT, optical coherence tomography.
Patient symptoms and signs are classified according to international common toxicity criteria (CTCAE version 5.0)23 and management is determined by the severity of the condition. The international CTCAE grades classify the severity of ocular conditions from 1 (mild) to 4 (severe, with sight-threatening consequences). Anterior uveitis is graded in correspondence with the number of cells seen on slit lamp examination of the anterior chamber, as defined by the standardisation of uveitis nomenclature.12 Thus, grade 1 uveitis corresponds to a ‘trace’ of cells (1–5 cells in a 1 mm × 1 mm slit beam), and grade 3 uveitis corresponds to ‘3+’ (26–50 cells per field). Posterior uveitis is graded 3. In addition, a visual acuity of 20/200 (6/60 in European terminology) or less, meeting criteria for blindness in the affected eye, is graded as 4.
The ophthalmological assessments of patients with visual disturbance include visual acuity, colour vision and intraocular pressure measurement. A relative afferent pupillary defect can be tested for by carrying out the swinging flashlight test before dilating drops are instilled into the eyes. Our algorithm includes a pathway for specialist ophthalmic investigations used to diagnose uveitis, which may include FFA and indocyanine angiography (ICG), fundus autofluorescence (FAF) and OCT, depending on the individual case.
In the absence of intermediate or posterior signs, invasive dye-based angiography tests would not normally be indicated, but can be used to exclude retinal vasculitis and leakage (FFA) or undiagnosed choroiditis (ICG) in challenging cases. This can be valuable in both the diagnosis and monitoring of inflammatory eye disease.24 Non-invasive FAF imaging is used to map metabolic activity in the retinal photoreceptor and pigment epithelial layers, and can be useful in identifying inflammatory processes occurring in the outer retina.25 OCT scanning provides high resolution images of the retina in cross-section and has transformed modern ophthalmological practice.
In contrast to recommendations in current international guidelines, we have used clinical evidence to justify avoiding the discontinuation of CPIs as much as possible. The algorithm aims to emphasise the need for close liaison between oncologist and specialist ophthalmologist from the point of recognition to resolution of ocular symptoms, as well as the benefit of a multidisciplinary approach involving good communication between the specialties to balance the need for cancer control alongside patient safety and vision preservation.
Discussion
This report of eight patients experiencing ocular IrAEs associated with CPI treatment is one of the largest series published to date. Anterior uveitis was the most common ocular IrAE that we identified, occurring in five of our eight cases. The onset of uveitis is reported mainly to occur within 2 months of starting CPIs.7,13,26 This was generally the case in our cohort, with a median time to onset of 5 weeks (range 1–7 weeks). The exception was a single patient who developed anterior uveitis 2 years after completing 2 years of nivolumab treatment. It is noteworthy that he had other ocular IrAEs while on treatment that did not lead to CPI discontinuation, while his anterior uveitis was difficult to control. It is well recognised that some IrAEs (including ocular IrAEs)13 can occur months and years after stopping CPIs, and this case is a reminder to consider the need for ongoing follow-up, even in patients apparently entering long-term remission after completing treatment.
Ocular IrAEs may occur as the only IrAE, or in association with multiple body system IrAEs. In our series, their occurrence influenced the decision to interrupt CPI treatment in all seven patients who discontinued treatment early: uveitis was the primary reason for discontinuation in two (29%) patients, but contributed to the decision to stop treatment in the remaining five patients, all of whom experienced multiple IrAEs.
A literature review of 33 cases of uveitis secondary to CPIs10 concluded that one-third of patients experienced anterior uveitis alone, one-third had anterior uveitis plus posterior segment changes including macular oedema, retinal detachment, vitritis or papillitis, and one-third had panuveitis. A very recent larger review of 126 cases of CPI-associated uveitis was broadly consistent, noting that 35% of panuveitis cases occurred as part of a Vogt–Koyanagi–Harada (VKH)-like syndrome.27–30 VKH disease is a multisystem disease affecting melanin-containing tissues, which is thought to be autoimmune in origin. The most significant ocular manifestation is bilateral diffuse panuveitis with exudative retinal detachment, often accompanied by a variable spectrum of symptoms involving the skin, nervous system and inner ear.
Recognition of the different presentations of the subtypes of uveitis is clearly important, as this influences whether topical steroids alone can be used for treatment, sparing patients the need for systemic steroids which may adversely affect the outcome of anti-cancer treatment.7 As in our own series, most published series describe initial intervention with topical and/or oral corticosteroids. Although outcomes are generally good, with complete resolution of inflammation in most cases, some cases are recalcitrant, warranting alternative immunomodulatory agents, while peri-ocular or intravitreal steroids22 have been employed as steroid-sparing strategies.
Prompt recognition of ocular and visual symptoms by oncologists and referral to ophthalmology specialists is necessary to ensure rapid investigation, diagnosis and sight-preserving treatment, as well as to inform multidisciplinary team opinion concerning ongoing treatment with CPIs. This can be challenging, because the ocular symptoms experienced may not directly correlate with the severity of inflammation identified.14 Even so, in most of the case series published to date, the overwhelming majority of patients experiencing ocular irAEs have had their CPIs discontinued,12,13 and uncertainty exists whether this line of action may impact overall treatment outcomes.
Perhaps because of its low incidence relative to other IrAEs, the ESMO guidelines5 offer very little advice on how to manage ocular IrAEs. The American Society of Clinical Oncology (ASCO) guidelines,6 on the other hand, are far more extensive and recommend referral to ophthalmology services for new onset visual symptoms, while they also recognise that symptoms may not always correlate with severity. The guidelines make use of the CTCAE grading system for ocular IrAEs and include management recommendations on whether to withhold, or discontinue, immunotherapy. While these constitute a welcome framework, they may also prove unnecessarily restrictive.
The ASCO guidelines recommend that for grade 1 ocular IrAEs, CPIs can be continued, for grade 2 events CPIs should be withheld and for grades 3 and 4 events they should be permanently discontinued. Ocular IrAEs, while not usually life threatening, may be life changing, so urgent intervention aimed at avoiding permanent loss of eyesight is certainly warranted. However, it is important to note that even severe deterioration in visual acuity can sometimes be reversible. For example, significant visual impairment associated with macular oedema may recover following prompt treatment with oral or intravitreal steroids. In adherence to ASCO guidance, loss of visual acuity may result in an adverse event grading of 3 or 4, which we consider could unnecessarily lead to permanent cessation of immunotherapy.
In some patients who resume CPIs after treatment for IrAEs, relapse with the same symptoms has been observed.9,13 We argue that permanent discontinuation of immunotherapy may not always be justified in these circumstances. In our own series, one patient experienced significant bilateral loss of vision associated with an ocular IrAE after two cycles of CPI with ipilimumab + nivolumab, but did not experience further ocular symptoms on retreatment several months later. Moreover, a severe or acute drop in visual acuity may be due to other pathologies unrelated to CPI (for example, incidental retinal detachment, which has a lifetime risk in normal individuals of one in 300).31 On the other hand, a patient could have apparently mild visual impairment but severe intra-ocular inflammation.
We recommend early referral to an ophthalmology specialist on recognition of ocular symptoms to diagnose the possible ocular IrAE and accurately grade its severity. We further recommend that both eye treatment and the ongoing use of CPIs are discussed on an individual case basis within a multidisciplinary team of oncologists and ophthalmologists, keeping the option open for retreatment in situations in which the possible benefits outweigh the risks, assuming appropriate patient counselling and support.
Most cases of uveitis associated with CPI, including the majority of our cases, are mild and would be categorised as CTCAE grade 2. These cases do not require cessation of CPI and neither should they require systemic steroids, in general. The outcomes from topical treatment are mainly good, with either a limited course, or sometimes ongoing topical steroids. If systemic steroids are used, the ASCO guidelines recommend that CPIs are withheld until the patient is either off all steroids or is receiving a daily dose of 10 mg oral prednisolone (or equivalent) or less. As far as possible, the aim should be to treat ocular IrAEs with local options in order to avoid systemic steroids and cessation of CPI therapy. Aside from concerns regarding their impact on CPI efficacy, long-term steroid use is associated with many well-known harmful effects.
The goal of avoiding the interruption of CPI therapy is best achieved by taking a multidisciplinary approach, with close liaison between ophthalmology and oncology teams, remembering that patients may have a high degree of anxiety about stopping potentially life-saving anti-cancer therapy. In our cohort, five patients stopped CPIs due to ocular IrAEs, despite being categorised as grade 2, which does not necessarily mandate permanent discontinuation. Three of these patients were treated solely with topical steroids, which suggests a low threat to vision, and which would not normally interfere with CPIs. In cases where topical steroids are not sufficient, intravitreal or periocular steroids should be considered to enable patients to remain on CPIs.
It is possible that patients diagnosed with melanoma may be at increased risk of developing uveitis due to the presence of melanin in the retinal pigment epithelium. An immune-mediated response to melanin-producing cells in the eye may occur both in patients on treatment and in those who develop an immunological reaction to their cancer independent of treatment. In our series, MAR was the most likely diagnosis in one of two patients reporting ocular toxicities that were not due to uveitis, based on symptoms described and investigations performed. The pathology is thought to be due to shared neuroectodermal lineage of melanocytes and retinal cells. Conversely, uveitis is not unique to patients with a diagnosis of melanoma. Patients at increased risk of uveitis may include those with other immune-related side effects and those predisposed to autoimmune disease or with a significant family history.32
Four of our patients, of whom two had other IrAEs, responded very well to retreatment with CPIs, highlighting a key unanswered question concerning whether the occurrence of IrAEs can predict a therapeutic response.32,33 Several studies have reported increased progression-free and overall survival in patients who experienced IrAEs with CPIs compared to those who did not.34,35 To date, it remains unclear whether the development of uveitis or other specific IrAEs is associated with better outcomes from treatment with CPIs,34,36 although it is quite plausible that an observed inflammatory response within the eye or elsewhere might reflect an enhanced immune response against cancer. The number of patients in our study is insufficient to answer this question, but further study is warranted and, if proved, this could be reassuring for patients who have previously stopped immunotherapy while being treated for inflammatory side effects.
In conclusion, ocular IrAEs are relatively uncommon IrAEs associated with CPIs, but can be dramatic and may lead to permanent visual loss. Prompt recognition in oncology clinics and early referral to an ophthalmologist is essential. Patients with confirmed ocular inflammation require close monitoring in the eye clinic and ongoing liaison with their oncologist regarding optimal treatment and the use of corticosteroids. The option of intraocular steroid implants should be considered as an alternative to systemic steroids when IrAEs do not resolve with topical steroids alone, with the potential benefit of being able to continue on CPIs.
In conjunction with our ocular IrAE management algorithm (Figure 2), we propose the following basic steps to follow when seeing immunotherapy patients with ocular symptoms in the clinic:
document the symptoms and signs and their severity
escalate by referral to an ophthalmologist; consider urgency of referral and the need to interrupt CPI therapy depending on symptom severity
obtain an ophthalmological diagnosis
take a multidisciplinary approach to managing the ocular symptoms and the need or otherwise to restart CPIs, based on risk/benefit considerations.
The authors would like to thank the patients and their families for allowing us to share their case studies. Thanks also to the CUHFT research governance and audit teams for their assistance in the conduct of this study.
Conflict of interest: The authors declare that there is no conflict of interest.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Philippa Corrie
https://orcid.org/0000-0003-4875-7021 | Not recovered | ReactionOutcome | CC BY-NC | 33633802 | 19,074,234 | 2021 |
What was the outcome of reaction 'Ocular ischaemic syndrome'? | Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm.
Ocular immune-related adverse events (IrAEs) associated with use of checkpoint inhibitors (CPIs) in cancer therapeutics are relatively rare, occurring in approximately 1% of treated patients. Recognition and early intervention are essential because the degree of tissue damage may be disproportionate to the symptoms, and lack of appropriate treatment risks permanent loss of vision. International guidelines on managing ocular IrAEs provide limited advice only. Importantly, local interventions can be effective and may avoid the need for systemic corticosteroids, thereby permitting the continuation of CPIs. We present a single institution case series of eight affected patients managed by our multidisciplinary team. Consistent with previously published series and case reports, we identified anterior uveitis as the most common ocular IrAE associated with CPIs requiring intervention. Based on our experience, as well as published guidance, we generated a simple algorithm to assist clinicians efficiently manage patients developing ocular symptoms during treatment with CPIs. In addition, we make recommendations for optimising treatment of uveitis and address implications for ongoing CPI therapy.
Background
Immunotherapy with checkpoint inhibitors (CPIs) has transformed the treatment of a wide range of malignancies.1,2 These drugs work by enabling the host immune system to eliminate malignant cells, recognisable through the expression of neoantigens. The CPIs currently in clinical use are antibodies which target the cytotoxic T-lymphocyte antigen-4 receptor (anti-CTLA-4), the programmed death-1 receptor (anti-PD-1) and its ligand (anti-PD-L1). The CTLA-4 receptor downregulates T-cell activation, whereas the PD-1 receptor inhibits T-cell proliferation, cytokine release, and cytotoxicity. Blocking their function can enhance T-cell response and allow immune-mediated tumour killing.
CPIs generate side effects termed immune-related adverse events (IrAEs), which stem from their mechanism of action, being predominantly autoimmune in nature and having the potential to affect any body organ. IrAEs range from being mild to life-threatening, or life-changing in some instances.3 Since their first introduction into clinical practice in 2011 as treatment for metastatic melanoma, the use of anti-CTLA-4 and anti-PD-L1 antibodies has expanded to include multiple cancer types including lung and urological cancers as well as lymphomas, with new treatment indications being added frequently. Their increasing use has resulted in greater awareness of both common and rarely seen IrAEs, ranging from mild presentations to severe reactions requiring prompt intervention.4
Optimal management of IrAEs is still in its infancy, with limited evidence to inform international guidelines which have been generated to assist clinical practice.5,6 The mainstay of treatment for what appear to be inflammatory conditions is immunosuppression with corticosteroids, prompting concerns about their effect on CPI efficacy.7 Moreover, the long-term effects on cancer survivors of high dose steroids, sometimes administered for protracted periods of time, have yet to be fully understood. The European Society of Medical Oncology (ESMO) clinical practice guidelines5 provide helpful algorithms for managing the more commonly occurring IrAEs, but consensus advice on managing less common IrAEs, such as those affecting the eyes, is also needed to minimise any negative impact of anti-cancer interventions.
Ocular IrAEs occur with an estimated prevalence of 1–3% of all treated patients.8,9 While the spectrum of severity is broad, they are highly significant as they can threaten vision. Reports of ocular IrAEs associated with CPIs are limited to small, single-digit case series and individual case reports, which principally report patients experiencing varying degrees of uveitis.8,10–13
Uveitis is a term used to describe inflammation of the uvea, the middle layer of the eye comprising the iris, ciliary body and choroid. It is classified as anterior, intermediate, posterior, or panuveitis, according to the predominant site of inflammation within the eye.14 Anterior uveitis is characterised by an infiltrate of white blood cells in the anterior chamber of the eye; intermediate uveitis is associated with inflammation in the vitreous gel, resulting in visual blurring, haze and floaters; posterior uveitis is characterised by retinal and/or choroidal inflammation.15,16 Symptoms of uveitis include pain, blurred vision and red eye. Involvement of the posterior segment can produce symptoms of floaters, flickering and shimmering lights (photopsias), as well as blind spots.
Anterior uveitis, whether acute or chronic, can often be managed with topical steroid drops alone. Severe uveitis of any subtype may lead to macular oedema, with accumulation of fluid at the most sensitive part of the retina, causing visual distortion and blurring. Severe ocular inflammation requires prompt intervention to avoid permanent loss of vision, and may require periocular or intravitreal steroid injections. More severe cases require systemic steroids, including oral, or pulsed intravenous methylprednisolone. Recalcitrant, chronic inflammatory eye diseases can be managed with secondary non-corticosteroid immunomodulatory therapeutic agents, including anti-metabolites like mycophenolate mofetil and methotrexate, or biological drugs like adalimumab.17 Common complications of uveitis and its treatment include cataract, glaucoma and choroidal neovascularisation. While most reports suggest a good response to therapy with complete resolution of inflammation, a minority of patients may develop permanent visual loss.
Other less common ocular IrAEs include ocular myasthenia, optic neuritis and auto-immune retinopathy. Dry eyes are described by up to one in four treated patients, but this is a common condition that is often not reported in clinical trials and is frequently undertreated, even in clinical practice.8,9 The risk of ocular IrAEs associated with CPIs was recently quantified using disproportionality analysis; odds ratios for uveitis ranged from 4.6 to 10.8, while that of any ocular IrAE was 2.5 compared with reported events associated with all other drugs.18
Uncertainties about optimal management of ocular IrAEs persist, such as when to interrupt or discontinue potentially life-saving CPI therapy and whether systemic steroids can influence the efficacy of CPIs. We report our experience of managing ocular IrAEs in a cohort of cancer patients receiving CPIs in a single institution and make management recommendations in a novel treatment algorithm.
Methods
We reviewed the electronic patient records of patients treated with CPIs from January to December 2019, and identified all cases referred to the ophthalmology service. The clinical characteristics, treatment and course of IrAEs over time were recorded. Details of their CPI treatment, other non-ocular irAEs, and disease response (based on routine radiological imaging and applying RECIST 1.1 response criteria) were also recorded. Survival was measured from the date of first CPI infusion until data cut-off, on 17 March, 2020.
Based on our case series and information contained in published international guidelines,5,6 we generated a simple assessment and treatment algorithm for use in routine clinical practice to guide the multidisciplinary team managing ocular symptoms and uveitis; the most common ocular IrAE reported.
This project was registered as a health service evaluation at Cambridge University Hospitals NHS Foundation Trust (CUHFT). The CUHFT research governance lead confirmed that, under the UK Policy Framework for Health and Social Care Research 2017, this project would not be classified or managed as research within the National Health Service and therefore did not require ethical review by a research ethics committee. Written informed consent to publish was obtained from the surviving case study patient.
Results
Patient characteristics
We identified eight patients (three women and five men, aged between 39 and 81 years) who developed ocular IrAEs after starting CPIs (Table 1). Seven patients were treated for advanced cancer; four for metastatic melanoma, two metastatic renal-cell carcinoma and one advanced ovarian carcinoma. One melanoma patient received CPI as an adjuvant therapy, after resection of regional lymph node disease. None had a previous history of uveitis. One patient had a history of glaucoma. Five patients received combination anti-CTLA-4 plus anti-PD-1 antibodies (ipilimumab + nivolumab), two patients received a single agent anti-PD-1 antibody (one pembrolizumab, one nivolumab) and one patient received anti-PD-1 antibody (nivolumab) in combination with a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor (rucaparib). Seven patients had their treatment discontinued early due to treatment-related adverse events; their treatment duration ranged from 3 to 9 weeks. The median number of adverse events contributing to treatment discontinuation was three (range 1–3). One patient completed 2 years of planned anti-PD-1 antibody therapy.
Table 1. Patient characteristics of patients experiencing ocular IrAEs associated with CPI treatment.
Patient case CPI regimen Duration of CPI therapy Reason for discontinuation AEs leading to discontinuation Best response to CPI Survival outcome
Melanoma-1
Metastatic
50-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Ocular IrAE Ocular
Skin
Fatigue Partial response Alive 16 months+
Kidney-1
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 3 weeks Multiple IrAE Ocular
Skin
Liver Stable disease Alive 15 months+
Kidney-2
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 4 weeks Multiple IrAEs Ocular
Liver
Arthritis Partial response Alive 16 months+
Ovarian
Metastatic
40-yo woman Nivolumab + rucaparib 8 weeks Multiple IrAE Ocular
Liver
Neutropaenia* Partial response Alive 10 months+
Melanoma-2
Resected stage III
74-yo woman Pembrolizumab
200 mg IV q3w 3 weeks Ocular IrAE Ocular Recurrence Treated with ipilimumab on recurrence; aborted after 6 weeks due to colitis.
Alive with stable disease:
14 months+
Melanoma-3
Metastatic
56-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Multiple IrAEs Ocular
Lung Partial response Alive 22 months+
Melanoma-4
Metastatic
40-yo woman Ipilimumab
1 mg/kg+ nivolumab 3 mg/kg 6 weeks Multiple IrAEs Ocular
Liver Partial response Rechallenged with 2 further cycles of ipilimumab+nivolumab on disease progression without significant IrAEs; progressive brain metastases.
Died after 11 months
Melanoma-5
Metastatic
81-yo man Nivolumab 240 mg 2 years Completed planned treatment – Near complete response Alive 5 years+
* Likely due to PARP inhibitor, not CPI.
AEs, adverse events; CPI, checkpoint inhibitor; IrEAs, immune-related adverse events; yo, year-old; PARP, poly-adenosine diphosphate ribose polymerase.
Ocular IrAE characteristics
The median time to the onset of ocular IrAE was 5 weeks from starting CPIs, although one patient developed symptoms after 18 months of treatment (Table 2). In all seven patients who discontinued CPIs early, ocular IrAE contributed to the decision to discontinue therapy. One patient with pre-existing glaucoma experienced ocular IrAE as the only IrAE, occurring after her first dose of pembrolizumab, and this led to treatment discontinuation. Four patients were diagnosed with anterior uveitis, one had intermediate uveitis, one had melanoma-associated retinopathy (MAR)19,20 and one had suspected ocular ischaemic syndrome.21 All patients had bilateral eye involvement. There were no hospitalisations associated with ocular IrAEs.
Table 2. Characteristics of ocular IrAEs experienced and their treatment.
Patient case Presenting symptoms Ocular IrAE Worst
CTCAE
grade Time to onset/resolution of ocular IrAE Worst visual acuity Visual acuity on resolution Local treatment Systemic steroids (starting dose) Outcome of ocular IrAE
Melanoma 1 Bilateral blurred vision, painful eyes Anterior uveitis 2 3 weeks/8 weeks R 6/19
L Normal R Normal
L Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Kidney 1 Bilateral blurred vision, painful eyes, headache Anterior uveitis
High IO pressures 2 5 weeks/11 weeks (uveitis)
6 months
(IO pressures) R 6/9.5
L 6/7.5 R Normal
L Normal Dexamethasone 0.1% drops
Timolol
Latanprost None Complete resolution
Kidney 2 Bilateral painful red eyes, light sensitivity Anterior uveitis
Left disc swelling 2 5 weeks/8 weeks Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Ovarian Bilateral blurred vision. Painful to focus Anterior uveitis 2 5 weeks/8 months Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Melanoma 2 Deterioration in vision Intermediate
uveitis 3 1 week/10 weeks R 6/9
L Normal R 6/9
L Normal None 40 mg prednisolone Resolved on 10 mg prednisolone; following 2 cycles of ipilimumab,
received IV steroids and infliximab for enteritis
Melanoma 3 Flashing lights, visual aura Melanoma associated retinopathy 4 3 weeks/18 months R 6/18 R 6/5 Anti-VEGF injections
Intra-ocular dexamethasone 50 mg prednisolone Permanent loss of vision; macular scarring
Melanoma 4 Rapid onset loss of vision in both eyes Suspected ocular ischaemic syndrome 4 7 weeks/4 weeks R 6/15
L 6/9 R Normal
L Normal Dexamethasone 0.1% drops
Mydrilate 1% drops 40 mg prednisolone Complete resolution
Melanoma 5 Red, eyes
Loss of vision in left eye
Blurred vision Conjunctivitis
Left retinal detachment*
Anterior uveitis 2
2 18 months
21 months
4 years/10 months R 6/12
L 6/7.5 R 6/12
L 6/7.5 Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Quiescent
* Association of retinal detachment as an IrAE could not be confirmed.
CTCAE, common toxicity criteria; IO, intra-ocular; IrEA, immune-related adverse event; IV, intravenous; L, left; R, right; VEGF, vascular endothelial growth factor.
The patient completing 2 years of nivolumab experienced ocular IrAEs both during and after completing CPI treatment. As the symptoms were manageable and no other IrAEs occurred, his planned treatment was not interrupted. He experienced conjunctivitis and left retinal detachment during treatment, both of which were managed successfully. Two years after completing CPIs, he developed bilateral anterior uveitis.
Treatment of ocular IrAEs
All five patients who developed anterior uveitis were treated with topical steroids only. The three other ocular conditions (intermediate uveitis, MAR and suspected ocular ischaemic syndrome) were treated with oral corticosteroids. No patients received intravenous steroids or other immunosuppressive agents to treat their ocular IrAEs. One patient diagnosed with MAR received intravitreal anti-vascular endothelial growth factor injections to treat a juxtafoveal choroidal neovascular membrane, as well as intra-ocular steroid implants to treat chronic photopsia in his only remaining eye.
The median ocular IrAE treatment duration was 11 weeks (range 8 weeks–10 months) with topical steroids and 10 weeks (range 4 weeks–6 months) with oral steroids. Two patients with anterior uveitis had rapid, complete resolution of their symptoms by 8 and 11 weeks. One patient had persistently raised intra-ocular pressures for approximately 6 months. Two patients had a protracted course of inflammatory eye disease, with recurrent episodes lasting 8 and 10 months, respectively. Of two patients re-challenged with CPIs at a later date, (one with ipilimumab, one with ipilimumab + nivolumab), neither had recurrence of ocular IrAEs.
Oncological response to CPIs
Overall, six out of the eight treated patients experienced a partial or near complete response to CPI therapy and seven remain alive and well at data cut-off. One melanoma patient whose adjuvant pembrolizumab treatment was aborted due to uveitis had disease recurrence documented 10 weeks after her first CPI administration, then received ipilimumab, which was aborted after teo cycles due to severe colitis, but her disease has remained stable since that time (15 months at data cut-off). A second melanoma patient who progressed on completing adjuvant pembrolizumab initially responded to ipilimumab + nivolumab, but died of metastatic disease 19 months after her first CPI administration.
Non-uveitis case studies
Case 1: (‘Melanoma 3’ in Tables 1 and 2)
A 56-year-old man received treatment with ipilimumab + nivolumab for metastatic uveal melanoma, having had exenteration of his left eye 4 years previously. Three weeks after his first CPI administration he complained of severe flashing lights in his remaining eye, and he was referred urgently for an ophthalmological assessment.
On slit lamp biomicroscopy, pale lesions were noted in the fundus, and these were presumed to be benign. He continued immunotherapy, but after 9 weeks (three cycles of CPI), he developed moderately severe pneumonitis which was initially treated with 50 mg oral prednisolone daily and CPI therapy was permanently discontinued. The pneumonitis resolved over 12 weeks and he was gradually weaned off steroids. While tapering his steroids, he noticed that his vision was deteriorating and a visual field defect was detected on formal testing.
Optical coherence tomography (OCT) scanning indicated a choroidal lesion next to the fovea, suggesting a possible neovascular membrane (Figure 1a), which could cause visual loss. This suspicion was confirmed by the presence of early leakage during fundus fluorescein angiography (FFA) (Figure 1b). The choroidal neovascular membrane was treated with a series of intravitreal anti-vascular endothelial growth factor (ranibizumab) injections, until it was deemed to be inactive.
Figure 1. Non-uveitis case study. (a) Optical coherence tomography scan showing a choroidal lesion next to the fovea, possibly representing a neovascular membrane. (b) Fundus fluorescein angiography demonstrating early hyperfluorescence of the juxtafoveal lesion, supporting a diagnosis of choroidal neovascularisation. (c) Pseudocolour image of the fundus showing the dexamethasone 0.7 mg steroid implant.
Electrodiagnostic testing subsequently revealed widespread post-phototransduction cone and rod dysfunction, compatible with MAR. His symptoms partially improved on restarting oral steroids (10 mg prednisolone daily), pointing to an inflammatory cause of his visual symptoms. On the basis of this evidence, he was offered short-acting and long-acting intravitreal steroid implants,22 (dexamethasone 0.7 mg and fluocinolone acetonide, respectively, Figure 1c) to avoid chronic side effects of long-term systemic steroids. At the time of data cut-off, the patient remained disease free, with relatively minor persistent visual impairment.
Case 2: (‘Melanoma 4’ in Tables 1 and 2)
A 40-year-old woman received adjuvant pembrolizumab for stage IIID BRAF wild type melanoma, which was well tolerated, without any IrAEs. After 11 months of treatment, she complained of generalised musculoskeletal pains and fatigue. Restaging scans identified widespread metastases including to liver and bone. She was commenced on ipilimumab + nivolumab. After 6 weeks (post cycle 2), her overall condition deteriorated, with severe fatigue and deterioration in liver function and performance status, although her serum lactate dehydrogenase dropped markedly from 1956 to 498 IU/L during the same time period. Her third cycle of ipilimumab + nivolumab was deferred.
One week later, she presented to the emergency department complaining of sudden onset bilateral loss of vision, worse in the right eye. Visual acuity was 6/15 in the right eye and 6/9 in the left eye, and intraocular pressure was within normal parameters. Iris neovascularisation and a swollen right optic disc were found on slit lamp biomicroscopy and fundoscopy. Brain imaging was requested, and confirmed the absence of metastases. A diagnosis of ocular ischaemic syndrome21 was suggested, but after discussion with the oncology specialist, a possible inflammatory aetiology was considered.
The patient was treated with 40 mg oral prednisolone daily, 0.1% dexamethasone eye drops and 1% mydrilate drops. She responded well to treatment, and was gradually weaned off steroids, and her vision recovered. Her liver function normalised and her performance status improved sufficiently for a return to normal activities of daily living. Subsequent staging compueterised tomography (CT) images indicated a partial response to CPIs. Six months later, despite the patient remaining well and asymptomatic, surveillance imaging identified disease recurrence in previously involved body sites with four new brain metastases. She was re-challenged with ipilimumab + nivolumab. No new IrAEs occurred, but after the second cycle, she was admitted to hospital with seizures due to haemorrhage into the brain metastases and died 10 weeks later, 11 months after starting CPIs for metastatic disease.
Ocular symptom management algorithm
Based on our own experience, review of the literature and international guidelines, we generated a management algorithm designed for multidisciplinary teams to use in clinical practice (Figure 2).
Figure 2. Management algorithm for patients treated with CPIs who present with ocular symptoms.
CPI, checkpoint inhibitor; FAF, fundus autofluorescence; FFA, fundus fluorescein angiography; ICG, indocyanine angiography; OCT, optical coherence tomography.
Patient symptoms and signs are classified according to international common toxicity criteria (CTCAE version 5.0)23 and management is determined by the severity of the condition. The international CTCAE grades classify the severity of ocular conditions from 1 (mild) to 4 (severe, with sight-threatening consequences). Anterior uveitis is graded in correspondence with the number of cells seen on slit lamp examination of the anterior chamber, as defined by the standardisation of uveitis nomenclature.12 Thus, grade 1 uveitis corresponds to a ‘trace’ of cells (1–5 cells in a 1 mm × 1 mm slit beam), and grade 3 uveitis corresponds to ‘3+’ (26–50 cells per field). Posterior uveitis is graded 3. In addition, a visual acuity of 20/200 (6/60 in European terminology) or less, meeting criteria for blindness in the affected eye, is graded as 4.
The ophthalmological assessments of patients with visual disturbance include visual acuity, colour vision and intraocular pressure measurement. A relative afferent pupillary defect can be tested for by carrying out the swinging flashlight test before dilating drops are instilled into the eyes. Our algorithm includes a pathway for specialist ophthalmic investigations used to diagnose uveitis, which may include FFA and indocyanine angiography (ICG), fundus autofluorescence (FAF) and OCT, depending on the individual case.
In the absence of intermediate or posterior signs, invasive dye-based angiography tests would not normally be indicated, but can be used to exclude retinal vasculitis and leakage (FFA) or undiagnosed choroiditis (ICG) in challenging cases. This can be valuable in both the diagnosis and monitoring of inflammatory eye disease.24 Non-invasive FAF imaging is used to map metabolic activity in the retinal photoreceptor and pigment epithelial layers, and can be useful in identifying inflammatory processes occurring in the outer retina.25 OCT scanning provides high resolution images of the retina in cross-section and has transformed modern ophthalmological practice.
In contrast to recommendations in current international guidelines, we have used clinical evidence to justify avoiding the discontinuation of CPIs as much as possible. The algorithm aims to emphasise the need for close liaison between oncologist and specialist ophthalmologist from the point of recognition to resolution of ocular symptoms, as well as the benefit of a multidisciplinary approach involving good communication between the specialties to balance the need for cancer control alongside patient safety and vision preservation.
Discussion
This report of eight patients experiencing ocular IrAEs associated with CPI treatment is one of the largest series published to date. Anterior uveitis was the most common ocular IrAE that we identified, occurring in five of our eight cases. The onset of uveitis is reported mainly to occur within 2 months of starting CPIs.7,13,26 This was generally the case in our cohort, with a median time to onset of 5 weeks (range 1–7 weeks). The exception was a single patient who developed anterior uveitis 2 years after completing 2 years of nivolumab treatment. It is noteworthy that he had other ocular IrAEs while on treatment that did not lead to CPI discontinuation, while his anterior uveitis was difficult to control. It is well recognised that some IrAEs (including ocular IrAEs)13 can occur months and years after stopping CPIs, and this case is a reminder to consider the need for ongoing follow-up, even in patients apparently entering long-term remission after completing treatment.
Ocular IrAEs may occur as the only IrAE, or in association with multiple body system IrAEs. In our series, their occurrence influenced the decision to interrupt CPI treatment in all seven patients who discontinued treatment early: uveitis was the primary reason for discontinuation in two (29%) patients, but contributed to the decision to stop treatment in the remaining five patients, all of whom experienced multiple IrAEs.
A literature review of 33 cases of uveitis secondary to CPIs10 concluded that one-third of patients experienced anterior uveitis alone, one-third had anterior uveitis plus posterior segment changes including macular oedema, retinal detachment, vitritis or papillitis, and one-third had panuveitis. A very recent larger review of 126 cases of CPI-associated uveitis was broadly consistent, noting that 35% of panuveitis cases occurred as part of a Vogt–Koyanagi–Harada (VKH)-like syndrome.27–30 VKH disease is a multisystem disease affecting melanin-containing tissues, which is thought to be autoimmune in origin. The most significant ocular manifestation is bilateral diffuse panuveitis with exudative retinal detachment, often accompanied by a variable spectrum of symptoms involving the skin, nervous system and inner ear.
Recognition of the different presentations of the subtypes of uveitis is clearly important, as this influences whether topical steroids alone can be used for treatment, sparing patients the need for systemic steroids which may adversely affect the outcome of anti-cancer treatment.7 As in our own series, most published series describe initial intervention with topical and/or oral corticosteroids. Although outcomes are generally good, with complete resolution of inflammation in most cases, some cases are recalcitrant, warranting alternative immunomodulatory agents, while peri-ocular or intravitreal steroids22 have been employed as steroid-sparing strategies.
Prompt recognition of ocular and visual symptoms by oncologists and referral to ophthalmology specialists is necessary to ensure rapid investigation, diagnosis and sight-preserving treatment, as well as to inform multidisciplinary team opinion concerning ongoing treatment with CPIs. This can be challenging, because the ocular symptoms experienced may not directly correlate with the severity of inflammation identified.14 Even so, in most of the case series published to date, the overwhelming majority of patients experiencing ocular irAEs have had their CPIs discontinued,12,13 and uncertainty exists whether this line of action may impact overall treatment outcomes.
Perhaps because of its low incidence relative to other IrAEs, the ESMO guidelines5 offer very little advice on how to manage ocular IrAEs. The American Society of Clinical Oncology (ASCO) guidelines,6 on the other hand, are far more extensive and recommend referral to ophthalmology services for new onset visual symptoms, while they also recognise that symptoms may not always correlate with severity. The guidelines make use of the CTCAE grading system for ocular IrAEs and include management recommendations on whether to withhold, or discontinue, immunotherapy. While these constitute a welcome framework, they may also prove unnecessarily restrictive.
The ASCO guidelines recommend that for grade 1 ocular IrAEs, CPIs can be continued, for grade 2 events CPIs should be withheld and for grades 3 and 4 events they should be permanently discontinued. Ocular IrAEs, while not usually life threatening, may be life changing, so urgent intervention aimed at avoiding permanent loss of eyesight is certainly warranted. However, it is important to note that even severe deterioration in visual acuity can sometimes be reversible. For example, significant visual impairment associated with macular oedema may recover following prompt treatment with oral or intravitreal steroids. In adherence to ASCO guidance, loss of visual acuity may result in an adverse event grading of 3 or 4, which we consider could unnecessarily lead to permanent cessation of immunotherapy.
In some patients who resume CPIs after treatment for IrAEs, relapse with the same symptoms has been observed.9,13 We argue that permanent discontinuation of immunotherapy may not always be justified in these circumstances. In our own series, one patient experienced significant bilateral loss of vision associated with an ocular IrAE after two cycles of CPI with ipilimumab + nivolumab, but did not experience further ocular symptoms on retreatment several months later. Moreover, a severe or acute drop in visual acuity may be due to other pathologies unrelated to CPI (for example, incidental retinal detachment, which has a lifetime risk in normal individuals of one in 300).31 On the other hand, a patient could have apparently mild visual impairment but severe intra-ocular inflammation.
We recommend early referral to an ophthalmology specialist on recognition of ocular symptoms to diagnose the possible ocular IrAE and accurately grade its severity. We further recommend that both eye treatment and the ongoing use of CPIs are discussed on an individual case basis within a multidisciplinary team of oncologists and ophthalmologists, keeping the option open for retreatment in situations in which the possible benefits outweigh the risks, assuming appropriate patient counselling and support.
Most cases of uveitis associated with CPI, including the majority of our cases, are mild and would be categorised as CTCAE grade 2. These cases do not require cessation of CPI and neither should they require systemic steroids, in general. The outcomes from topical treatment are mainly good, with either a limited course, or sometimes ongoing topical steroids. If systemic steroids are used, the ASCO guidelines recommend that CPIs are withheld until the patient is either off all steroids or is receiving a daily dose of 10 mg oral prednisolone (or equivalent) or less. As far as possible, the aim should be to treat ocular IrAEs with local options in order to avoid systemic steroids and cessation of CPI therapy. Aside from concerns regarding their impact on CPI efficacy, long-term steroid use is associated with many well-known harmful effects.
The goal of avoiding the interruption of CPI therapy is best achieved by taking a multidisciplinary approach, with close liaison between ophthalmology and oncology teams, remembering that patients may have a high degree of anxiety about stopping potentially life-saving anti-cancer therapy. In our cohort, five patients stopped CPIs due to ocular IrAEs, despite being categorised as grade 2, which does not necessarily mandate permanent discontinuation. Three of these patients were treated solely with topical steroids, which suggests a low threat to vision, and which would not normally interfere with CPIs. In cases where topical steroids are not sufficient, intravitreal or periocular steroids should be considered to enable patients to remain on CPIs.
It is possible that patients diagnosed with melanoma may be at increased risk of developing uveitis due to the presence of melanin in the retinal pigment epithelium. An immune-mediated response to melanin-producing cells in the eye may occur both in patients on treatment and in those who develop an immunological reaction to their cancer independent of treatment. In our series, MAR was the most likely diagnosis in one of two patients reporting ocular toxicities that were not due to uveitis, based on symptoms described and investigations performed. The pathology is thought to be due to shared neuroectodermal lineage of melanocytes and retinal cells. Conversely, uveitis is not unique to patients with a diagnosis of melanoma. Patients at increased risk of uveitis may include those with other immune-related side effects and those predisposed to autoimmune disease or with a significant family history.32
Four of our patients, of whom two had other IrAEs, responded very well to retreatment with CPIs, highlighting a key unanswered question concerning whether the occurrence of IrAEs can predict a therapeutic response.32,33 Several studies have reported increased progression-free and overall survival in patients who experienced IrAEs with CPIs compared to those who did not.34,35 To date, it remains unclear whether the development of uveitis or other specific IrAEs is associated with better outcomes from treatment with CPIs,34,36 although it is quite plausible that an observed inflammatory response within the eye or elsewhere might reflect an enhanced immune response against cancer. The number of patients in our study is insufficient to answer this question, but further study is warranted and, if proved, this could be reassuring for patients who have previously stopped immunotherapy while being treated for inflammatory side effects.
In conclusion, ocular IrAEs are relatively uncommon IrAEs associated with CPIs, but can be dramatic and may lead to permanent visual loss. Prompt recognition in oncology clinics and early referral to an ophthalmologist is essential. Patients with confirmed ocular inflammation require close monitoring in the eye clinic and ongoing liaison with their oncologist regarding optimal treatment and the use of corticosteroids. The option of intraocular steroid implants should be considered as an alternative to systemic steroids when IrAEs do not resolve with topical steroids alone, with the potential benefit of being able to continue on CPIs.
In conjunction with our ocular IrAE management algorithm (Figure 2), we propose the following basic steps to follow when seeing immunotherapy patients with ocular symptoms in the clinic:
document the symptoms and signs and their severity
escalate by referral to an ophthalmologist; consider urgency of referral and the need to interrupt CPI therapy depending on symptom severity
obtain an ophthalmological diagnosis
take a multidisciplinary approach to managing the ocular symptoms and the need or otherwise to restart CPIs, based on risk/benefit considerations.
The authors would like to thank the patients and their families for allowing us to share their case studies. Thanks also to the CUHFT research governance and audit teams for their assistance in the conduct of this study.
Conflict of interest: The authors declare that there is no conflict of interest.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Philippa Corrie
https://orcid.org/0000-0003-4875-7021 | Recovered | ReactionOutcome | CC BY-NC | 33633802 | 19,074,441 | 2021 |
What was the outcome of reaction 'Retinal melanoma'? | Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm.
Ocular immune-related adverse events (IrAEs) associated with use of checkpoint inhibitors (CPIs) in cancer therapeutics are relatively rare, occurring in approximately 1% of treated patients. Recognition and early intervention are essential because the degree of tissue damage may be disproportionate to the symptoms, and lack of appropriate treatment risks permanent loss of vision. International guidelines on managing ocular IrAEs provide limited advice only. Importantly, local interventions can be effective and may avoid the need for systemic corticosteroids, thereby permitting the continuation of CPIs. We present a single institution case series of eight affected patients managed by our multidisciplinary team. Consistent with previously published series and case reports, we identified anterior uveitis as the most common ocular IrAE associated with CPIs requiring intervention. Based on our experience, as well as published guidance, we generated a simple algorithm to assist clinicians efficiently manage patients developing ocular symptoms during treatment with CPIs. In addition, we make recommendations for optimising treatment of uveitis and address implications for ongoing CPI therapy.
Background
Immunotherapy with checkpoint inhibitors (CPIs) has transformed the treatment of a wide range of malignancies.1,2 These drugs work by enabling the host immune system to eliminate malignant cells, recognisable through the expression of neoantigens. The CPIs currently in clinical use are antibodies which target the cytotoxic T-lymphocyte antigen-4 receptor (anti-CTLA-4), the programmed death-1 receptor (anti-PD-1) and its ligand (anti-PD-L1). The CTLA-4 receptor downregulates T-cell activation, whereas the PD-1 receptor inhibits T-cell proliferation, cytokine release, and cytotoxicity. Blocking their function can enhance T-cell response and allow immune-mediated tumour killing.
CPIs generate side effects termed immune-related adverse events (IrAEs), which stem from their mechanism of action, being predominantly autoimmune in nature and having the potential to affect any body organ. IrAEs range from being mild to life-threatening, or life-changing in some instances.3 Since their first introduction into clinical practice in 2011 as treatment for metastatic melanoma, the use of anti-CTLA-4 and anti-PD-L1 antibodies has expanded to include multiple cancer types including lung and urological cancers as well as lymphomas, with new treatment indications being added frequently. Their increasing use has resulted in greater awareness of both common and rarely seen IrAEs, ranging from mild presentations to severe reactions requiring prompt intervention.4
Optimal management of IrAEs is still in its infancy, with limited evidence to inform international guidelines which have been generated to assist clinical practice.5,6 The mainstay of treatment for what appear to be inflammatory conditions is immunosuppression with corticosteroids, prompting concerns about their effect on CPI efficacy.7 Moreover, the long-term effects on cancer survivors of high dose steroids, sometimes administered for protracted periods of time, have yet to be fully understood. The European Society of Medical Oncology (ESMO) clinical practice guidelines5 provide helpful algorithms for managing the more commonly occurring IrAEs, but consensus advice on managing less common IrAEs, such as those affecting the eyes, is also needed to minimise any negative impact of anti-cancer interventions.
Ocular IrAEs occur with an estimated prevalence of 1–3% of all treated patients.8,9 While the spectrum of severity is broad, they are highly significant as they can threaten vision. Reports of ocular IrAEs associated with CPIs are limited to small, single-digit case series and individual case reports, which principally report patients experiencing varying degrees of uveitis.8,10–13
Uveitis is a term used to describe inflammation of the uvea, the middle layer of the eye comprising the iris, ciliary body and choroid. It is classified as anterior, intermediate, posterior, or panuveitis, according to the predominant site of inflammation within the eye.14 Anterior uveitis is characterised by an infiltrate of white blood cells in the anterior chamber of the eye; intermediate uveitis is associated with inflammation in the vitreous gel, resulting in visual blurring, haze and floaters; posterior uveitis is characterised by retinal and/or choroidal inflammation.15,16 Symptoms of uveitis include pain, blurred vision and red eye. Involvement of the posterior segment can produce symptoms of floaters, flickering and shimmering lights (photopsias), as well as blind spots.
Anterior uveitis, whether acute or chronic, can often be managed with topical steroid drops alone. Severe uveitis of any subtype may lead to macular oedema, with accumulation of fluid at the most sensitive part of the retina, causing visual distortion and blurring. Severe ocular inflammation requires prompt intervention to avoid permanent loss of vision, and may require periocular or intravitreal steroid injections. More severe cases require systemic steroids, including oral, or pulsed intravenous methylprednisolone. Recalcitrant, chronic inflammatory eye diseases can be managed with secondary non-corticosteroid immunomodulatory therapeutic agents, including anti-metabolites like mycophenolate mofetil and methotrexate, or biological drugs like adalimumab.17 Common complications of uveitis and its treatment include cataract, glaucoma and choroidal neovascularisation. While most reports suggest a good response to therapy with complete resolution of inflammation, a minority of patients may develop permanent visual loss.
Other less common ocular IrAEs include ocular myasthenia, optic neuritis and auto-immune retinopathy. Dry eyes are described by up to one in four treated patients, but this is a common condition that is often not reported in clinical trials and is frequently undertreated, even in clinical practice.8,9 The risk of ocular IrAEs associated with CPIs was recently quantified using disproportionality analysis; odds ratios for uveitis ranged from 4.6 to 10.8, while that of any ocular IrAE was 2.5 compared with reported events associated with all other drugs.18
Uncertainties about optimal management of ocular IrAEs persist, such as when to interrupt or discontinue potentially life-saving CPI therapy and whether systemic steroids can influence the efficacy of CPIs. We report our experience of managing ocular IrAEs in a cohort of cancer patients receiving CPIs in a single institution and make management recommendations in a novel treatment algorithm.
Methods
We reviewed the electronic patient records of patients treated with CPIs from January to December 2019, and identified all cases referred to the ophthalmology service. The clinical characteristics, treatment and course of IrAEs over time were recorded. Details of their CPI treatment, other non-ocular irAEs, and disease response (based on routine radiological imaging and applying RECIST 1.1 response criteria) were also recorded. Survival was measured from the date of first CPI infusion until data cut-off, on 17 March, 2020.
Based on our case series and information contained in published international guidelines,5,6 we generated a simple assessment and treatment algorithm for use in routine clinical practice to guide the multidisciplinary team managing ocular symptoms and uveitis; the most common ocular IrAE reported.
This project was registered as a health service evaluation at Cambridge University Hospitals NHS Foundation Trust (CUHFT). The CUHFT research governance lead confirmed that, under the UK Policy Framework for Health and Social Care Research 2017, this project would not be classified or managed as research within the National Health Service and therefore did not require ethical review by a research ethics committee. Written informed consent to publish was obtained from the surviving case study patient.
Results
Patient characteristics
We identified eight patients (three women and five men, aged between 39 and 81 years) who developed ocular IrAEs after starting CPIs (Table 1). Seven patients were treated for advanced cancer; four for metastatic melanoma, two metastatic renal-cell carcinoma and one advanced ovarian carcinoma. One melanoma patient received CPI as an adjuvant therapy, after resection of regional lymph node disease. None had a previous history of uveitis. One patient had a history of glaucoma. Five patients received combination anti-CTLA-4 plus anti-PD-1 antibodies (ipilimumab + nivolumab), two patients received a single agent anti-PD-1 antibody (one pembrolizumab, one nivolumab) and one patient received anti-PD-1 antibody (nivolumab) in combination with a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor (rucaparib). Seven patients had their treatment discontinued early due to treatment-related adverse events; their treatment duration ranged from 3 to 9 weeks. The median number of adverse events contributing to treatment discontinuation was three (range 1–3). One patient completed 2 years of planned anti-PD-1 antibody therapy.
Table 1. Patient characteristics of patients experiencing ocular IrAEs associated with CPI treatment.
Patient case CPI regimen Duration of CPI therapy Reason for discontinuation AEs leading to discontinuation Best response to CPI Survival outcome
Melanoma-1
Metastatic
50-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Ocular IrAE Ocular
Skin
Fatigue Partial response Alive 16 months+
Kidney-1
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 3 weeks Multiple IrAE Ocular
Skin
Liver Stable disease Alive 15 months+
Kidney-2
Metastatic
53-yo man Ipilimumab 1 mg/kg + nivolumab 3 mg/kg 4 weeks Multiple IrAEs Ocular
Liver
Arthritis Partial response Alive 16 months+
Ovarian
Metastatic
40-yo woman Nivolumab + rucaparib 8 weeks Multiple IrAE Ocular
Liver
Neutropaenia* Partial response Alive 10 months+
Melanoma-2
Resected stage III
74-yo woman Pembrolizumab
200 mg IV q3w 3 weeks Ocular IrAE Ocular Recurrence Treated with ipilimumab on recurrence; aborted after 6 weeks due to colitis.
Alive with stable disease:
14 months+
Melanoma-3
Metastatic
56-yo man Ipilimumab 3 mg/kg + nivolumab 1 mg/kg 9 weeks Multiple IrAEs Ocular
Lung Partial response Alive 22 months+
Melanoma-4
Metastatic
40-yo woman Ipilimumab
1 mg/kg+ nivolumab 3 mg/kg 6 weeks Multiple IrAEs Ocular
Liver Partial response Rechallenged with 2 further cycles of ipilimumab+nivolumab on disease progression without significant IrAEs; progressive brain metastases.
Died after 11 months
Melanoma-5
Metastatic
81-yo man Nivolumab 240 mg 2 years Completed planned treatment – Near complete response Alive 5 years+
* Likely due to PARP inhibitor, not CPI.
AEs, adverse events; CPI, checkpoint inhibitor; IrEAs, immune-related adverse events; yo, year-old; PARP, poly-adenosine diphosphate ribose polymerase.
Ocular IrAE characteristics
The median time to the onset of ocular IrAE was 5 weeks from starting CPIs, although one patient developed symptoms after 18 months of treatment (Table 2). In all seven patients who discontinued CPIs early, ocular IrAE contributed to the decision to discontinue therapy. One patient with pre-existing glaucoma experienced ocular IrAE as the only IrAE, occurring after her first dose of pembrolizumab, and this led to treatment discontinuation. Four patients were diagnosed with anterior uveitis, one had intermediate uveitis, one had melanoma-associated retinopathy (MAR)19,20 and one had suspected ocular ischaemic syndrome.21 All patients had bilateral eye involvement. There were no hospitalisations associated with ocular IrAEs.
Table 2. Characteristics of ocular IrAEs experienced and their treatment.
Patient case Presenting symptoms Ocular IrAE Worst
CTCAE
grade Time to onset/resolution of ocular IrAE Worst visual acuity Visual acuity on resolution Local treatment Systemic steroids (starting dose) Outcome of ocular IrAE
Melanoma 1 Bilateral blurred vision, painful eyes Anterior uveitis 2 3 weeks/8 weeks R 6/19
L Normal R Normal
L Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Kidney 1 Bilateral blurred vision, painful eyes, headache Anterior uveitis
High IO pressures 2 5 weeks/11 weeks (uveitis)
6 months
(IO pressures) R 6/9.5
L 6/7.5 R Normal
L Normal Dexamethasone 0.1% drops
Timolol
Latanprost None Complete resolution
Kidney 2 Bilateral painful red eyes, light sensitivity Anterior uveitis
Left disc swelling 2 5 weeks/8 weeks Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Ovarian Bilateral blurred vision. Painful to focus Anterior uveitis 2 5 weeks/8 months Normal Normal Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Complete resolution
Melanoma 2 Deterioration in vision Intermediate
uveitis 3 1 week/10 weeks R 6/9
L Normal R 6/9
L Normal None 40 mg prednisolone Resolved on 10 mg prednisolone; following 2 cycles of ipilimumab,
received IV steroids and infliximab for enteritis
Melanoma 3 Flashing lights, visual aura Melanoma associated retinopathy 4 3 weeks/18 months R 6/18 R 6/5 Anti-VEGF injections
Intra-ocular dexamethasone 50 mg prednisolone Permanent loss of vision; macular scarring
Melanoma 4 Rapid onset loss of vision in both eyes Suspected ocular ischaemic syndrome 4 7 weeks/4 weeks R 6/15
L 6/9 R Normal
L Normal Dexamethasone 0.1% drops
Mydrilate 1% drops 40 mg prednisolone Complete resolution
Melanoma 5 Red, eyes
Loss of vision in left eye
Blurred vision Conjunctivitis
Left retinal detachment*
Anterior uveitis 2
2 18 months
21 months
4 years/10 months R 6/12
L 6/7.5 R 6/12
L 6/7.5 Dexamethasone 0.1% drops
Cyclopentolate 1% drops None Quiescent
* Association of retinal detachment as an IrAE could not be confirmed.
CTCAE, common toxicity criteria; IO, intra-ocular; IrEA, immune-related adverse event; IV, intravenous; L, left; R, right; VEGF, vascular endothelial growth factor.
The patient completing 2 years of nivolumab experienced ocular IrAEs both during and after completing CPI treatment. As the symptoms were manageable and no other IrAEs occurred, his planned treatment was not interrupted. He experienced conjunctivitis and left retinal detachment during treatment, both of which were managed successfully. Two years after completing CPIs, he developed bilateral anterior uveitis.
Treatment of ocular IrAEs
All five patients who developed anterior uveitis were treated with topical steroids only. The three other ocular conditions (intermediate uveitis, MAR and suspected ocular ischaemic syndrome) were treated with oral corticosteroids. No patients received intravenous steroids or other immunosuppressive agents to treat their ocular IrAEs. One patient diagnosed with MAR received intravitreal anti-vascular endothelial growth factor injections to treat a juxtafoveal choroidal neovascular membrane, as well as intra-ocular steroid implants to treat chronic photopsia in his only remaining eye.
The median ocular IrAE treatment duration was 11 weeks (range 8 weeks–10 months) with topical steroids and 10 weeks (range 4 weeks–6 months) with oral steroids. Two patients with anterior uveitis had rapid, complete resolution of their symptoms by 8 and 11 weeks. One patient had persistently raised intra-ocular pressures for approximately 6 months. Two patients had a protracted course of inflammatory eye disease, with recurrent episodes lasting 8 and 10 months, respectively. Of two patients re-challenged with CPIs at a later date, (one with ipilimumab, one with ipilimumab + nivolumab), neither had recurrence of ocular IrAEs.
Oncological response to CPIs
Overall, six out of the eight treated patients experienced a partial or near complete response to CPI therapy and seven remain alive and well at data cut-off. One melanoma patient whose adjuvant pembrolizumab treatment was aborted due to uveitis had disease recurrence documented 10 weeks after her first CPI administration, then received ipilimumab, which was aborted after teo cycles due to severe colitis, but her disease has remained stable since that time (15 months at data cut-off). A second melanoma patient who progressed on completing adjuvant pembrolizumab initially responded to ipilimumab + nivolumab, but died of metastatic disease 19 months after her first CPI administration.
Non-uveitis case studies
Case 1: (‘Melanoma 3’ in Tables 1 and 2)
A 56-year-old man received treatment with ipilimumab + nivolumab for metastatic uveal melanoma, having had exenteration of his left eye 4 years previously. Three weeks after his first CPI administration he complained of severe flashing lights in his remaining eye, and he was referred urgently for an ophthalmological assessment.
On slit lamp biomicroscopy, pale lesions were noted in the fundus, and these were presumed to be benign. He continued immunotherapy, but after 9 weeks (three cycles of CPI), he developed moderately severe pneumonitis which was initially treated with 50 mg oral prednisolone daily and CPI therapy was permanently discontinued. The pneumonitis resolved over 12 weeks and he was gradually weaned off steroids. While tapering his steroids, he noticed that his vision was deteriorating and a visual field defect was detected on formal testing.
Optical coherence tomography (OCT) scanning indicated a choroidal lesion next to the fovea, suggesting a possible neovascular membrane (Figure 1a), which could cause visual loss. This suspicion was confirmed by the presence of early leakage during fundus fluorescein angiography (FFA) (Figure 1b). The choroidal neovascular membrane was treated with a series of intravitreal anti-vascular endothelial growth factor (ranibizumab) injections, until it was deemed to be inactive.
Figure 1. Non-uveitis case study. (a) Optical coherence tomography scan showing a choroidal lesion next to the fovea, possibly representing a neovascular membrane. (b) Fundus fluorescein angiography demonstrating early hyperfluorescence of the juxtafoveal lesion, supporting a diagnosis of choroidal neovascularisation. (c) Pseudocolour image of the fundus showing the dexamethasone 0.7 mg steroid implant.
Electrodiagnostic testing subsequently revealed widespread post-phototransduction cone and rod dysfunction, compatible with MAR. His symptoms partially improved on restarting oral steroids (10 mg prednisolone daily), pointing to an inflammatory cause of his visual symptoms. On the basis of this evidence, he was offered short-acting and long-acting intravitreal steroid implants,22 (dexamethasone 0.7 mg and fluocinolone acetonide, respectively, Figure 1c) to avoid chronic side effects of long-term systemic steroids. At the time of data cut-off, the patient remained disease free, with relatively minor persistent visual impairment.
Case 2: (‘Melanoma 4’ in Tables 1 and 2)
A 40-year-old woman received adjuvant pembrolizumab for stage IIID BRAF wild type melanoma, which was well tolerated, without any IrAEs. After 11 months of treatment, she complained of generalised musculoskeletal pains and fatigue. Restaging scans identified widespread metastases including to liver and bone. She was commenced on ipilimumab + nivolumab. After 6 weeks (post cycle 2), her overall condition deteriorated, with severe fatigue and deterioration in liver function and performance status, although her serum lactate dehydrogenase dropped markedly from 1956 to 498 IU/L during the same time period. Her third cycle of ipilimumab + nivolumab was deferred.
One week later, she presented to the emergency department complaining of sudden onset bilateral loss of vision, worse in the right eye. Visual acuity was 6/15 in the right eye and 6/9 in the left eye, and intraocular pressure was within normal parameters. Iris neovascularisation and a swollen right optic disc were found on slit lamp biomicroscopy and fundoscopy. Brain imaging was requested, and confirmed the absence of metastases. A diagnosis of ocular ischaemic syndrome21 was suggested, but after discussion with the oncology specialist, a possible inflammatory aetiology was considered.
The patient was treated with 40 mg oral prednisolone daily, 0.1% dexamethasone eye drops and 1% mydrilate drops. She responded well to treatment, and was gradually weaned off steroids, and her vision recovered. Her liver function normalised and her performance status improved sufficiently for a return to normal activities of daily living. Subsequent staging compueterised tomography (CT) images indicated a partial response to CPIs. Six months later, despite the patient remaining well and asymptomatic, surveillance imaging identified disease recurrence in previously involved body sites with four new brain metastases. She was re-challenged with ipilimumab + nivolumab. No new IrAEs occurred, but after the second cycle, she was admitted to hospital with seizures due to haemorrhage into the brain metastases and died 10 weeks later, 11 months after starting CPIs for metastatic disease.
Ocular symptom management algorithm
Based on our own experience, review of the literature and international guidelines, we generated a management algorithm designed for multidisciplinary teams to use in clinical practice (Figure 2).
Figure 2. Management algorithm for patients treated with CPIs who present with ocular symptoms.
CPI, checkpoint inhibitor; FAF, fundus autofluorescence; FFA, fundus fluorescein angiography; ICG, indocyanine angiography; OCT, optical coherence tomography.
Patient symptoms and signs are classified according to international common toxicity criteria (CTCAE version 5.0)23 and management is determined by the severity of the condition. The international CTCAE grades classify the severity of ocular conditions from 1 (mild) to 4 (severe, with sight-threatening consequences). Anterior uveitis is graded in correspondence with the number of cells seen on slit lamp examination of the anterior chamber, as defined by the standardisation of uveitis nomenclature.12 Thus, grade 1 uveitis corresponds to a ‘trace’ of cells (1–5 cells in a 1 mm × 1 mm slit beam), and grade 3 uveitis corresponds to ‘3+’ (26–50 cells per field). Posterior uveitis is graded 3. In addition, a visual acuity of 20/200 (6/60 in European terminology) or less, meeting criteria for blindness in the affected eye, is graded as 4.
The ophthalmological assessments of patients with visual disturbance include visual acuity, colour vision and intraocular pressure measurement. A relative afferent pupillary defect can be tested for by carrying out the swinging flashlight test before dilating drops are instilled into the eyes. Our algorithm includes a pathway for specialist ophthalmic investigations used to diagnose uveitis, which may include FFA and indocyanine angiography (ICG), fundus autofluorescence (FAF) and OCT, depending on the individual case.
In the absence of intermediate or posterior signs, invasive dye-based angiography tests would not normally be indicated, but can be used to exclude retinal vasculitis and leakage (FFA) or undiagnosed choroiditis (ICG) in challenging cases. This can be valuable in both the diagnosis and monitoring of inflammatory eye disease.24 Non-invasive FAF imaging is used to map metabolic activity in the retinal photoreceptor and pigment epithelial layers, and can be useful in identifying inflammatory processes occurring in the outer retina.25 OCT scanning provides high resolution images of the retina in cross-section and has transformed modern ophthalmological practice.
In contrast to recommendations in current international guidelines, we have used clinical evidence to justify avoiding the discontinuation of CPIs as much as possible. The algorithm aims to emphasise the need for close liaison between oncologist and specialist ophthalmologist from the point of recognition to resolution of ocular symptoms, as well as the benefit of a multidisciplinary approach involving good communication between the specialties to balance the need for cancer control alongside patient safety and vision preservation.
Discussion
This report of eight patients experiencing ocular IrAEs associated with CPI treatment is one of the largest series published to date. Anterior uveitis was the most common ocular IrAE that we identified, occurring in five of our eight cases. The onset of uveitis is reported mainly to occur within 2 months of starting CPIs.7,13,26 This was generally the case in our cohort, with a median time to onset of 5 weeks (range 1–7 weeks). The exception was a single patient who developed anterior uveitis 2 years after completing 2 years of nivolumab treatment. It is noteworthy that he had other ocular IrAEs while on treatment that did not lead to CPI discontinuation, while his anterior uveitis was difficult to control. It is well recognised that some IrAEs (including ocular IrAEs)13 can occur months and years after stopping CPIs, and this case is a reminder to consider the need for ongoing follow-up, even in patients apparently entering long-term remission after completing treatment.
Ocular IrAEs may occur as the only IrAE, or in association with multiple body system IrAEs. In our series, their occurrence influenced the decision to interrupt CPI treatment in all seven patients who discontinued treatment early: uveitis was the primary reason for discontinuation in two (29%) patients, but contributed to the decision to stop treatment in the remaining five patients, all of whom experienced multiple IrAEs.
A literature review of 33 cases of uveitis secondary to CPIs10 concluded that one-third of patients experienced anterior uveitis alone, one-third had anterior uveitis plus posterior segment changes including macular oedema, retinal detachment, vitritis or papillitis, and one-third had panuveitis. A very recent larger review of 126 cases of CPI-associated uveitis was broadly consistent, noting that 35% of panuveitis cases occurred as part of a Vogt–Koyanagi–Harada (VKH)-like syndrome.27–30 VKH disease is a multisystem disease affecting melanin-containing tissues, which is thought to be autoimmune in origin. The most significant ocular manifestation is bilateral diffuse panuveitis with exudative retinal detachment, often accompanied by a variable spectrum of symptoms involving the skin, nervous system and inner ear.
Recognition of the different presentations of the subtypes of uveitis is clearly important, as this influences whether topical steroids alone can be used for treatment, sparing patients the need for systemic steroids which may adversely affect the outcome of anti-cancer treatment.7 As in our own series, most published series describe initial intervention with topical and/or oral corticosteroids. Although outcomes are generally good, with complete resolution of inflammation in most cases, some cases are recalcitrant, warranting alternative immunomodulatory agents, while peri-ocular or intravitreal steroids22 have been employed as steroid-sparing strategies.
Prompt recognition of ocular and visual symptoms by oncologists and referral to ophthalmology specialists is necessary to ensure rapid investigation, diagnosis and sight-preserving treatment, as well as to inform multidisciplinary team opinion concerning ongoing treatment with CPIs. This can be challenging, because the ocular symptoms experienced may not directly correlate with the severity of inflammation identified.14 Even so, in most of the case series published to date, the overwhelming majority of patients experiencing ocular irAEs have had their CPIs discontinued,12,13 and uncertainty exists whether this line of action may impact overall treatment outcomes.
Perhaps because of its low incidence relative to other IrAEs, the ESMO guidelines5 offer very little advice on how to manage ocular IrAEs. The American Society of Clinical Oncology (ASCO) guidelines,6 on the other hand, are far more extensive and recommend referral to ophthalmology services for new onset visual symptoms, while they also recognise that symptoms may not always correlate with severity. The guidelines make use of the CTCAE grading system for ocular IrAEs and include management recommendations on whether to withhold, or discontinue, immunotherapy. While these constitute a welcome framework, they may also prove unnecessarily restrictive.
The ASCO guidelines recommend that for grade 1 ocular IrAEs, CPIs can be continued, for grade 2 events CPIs should be withheld and for grades 3 and 4 events they should be permanently discontinued. Ocular IrAEs, while not usually life threatening, may be life changing, so urgent intervention aimed at avoiding permanent loss of eyesight is certainly warranted. However, it is important to note that even severe deterioration in visual acuity can sometimes be reversible. For example, significant visual impairment associated with macular oedema may recover following prompt treatment with oral or intravitreal steroids. In adherence to ASCO guidance, loss of visual acuity may result in an adverse event grading of 3 or 4, which we consider could unnecessarily lead to permanent cessation of immunotherapy.
In some patients who resume CPIs after treatment for IrAEs, relapse with the same symptoms has been observed.9,13 We argue that permanent discontinuation of immunotherapy may not always be justified in these circumstances. In our own series, one patient experienced significant bilateral loss of vision associated with an ocular IrAE after two cycles of CPI with ipilimumab + nivolumab, but did not experience further ocular symptoms on retreatment several months later. Moreover, a severe or acute drop in visual acuity may be due to other pathologies unrelated to CPI (for example, incidental retinal detachment, which has a lifetime risk in normal individuals of one in 300).31 On the other hand, a patient could have apparently mild visual impairment but severe intra-ocular inflammation.
We recommend early referral to an ophthalmology specialist on recognition of ocular symptoms to diagnose the possible ocular IrAE and accurately grade its severity. We further recommend that both eye treatment and the ongoing use of CPIs are discussed on an individual case basis within a multidisciplinary team of oncologists and ophthalmologists, keeping the option open for retreatment in situations in which the possible benefits outweigh the risks, assuming appropriate patient counselling and support.
Most cases of uveitis associated with CPI, including the majority of our cases, are mild and would be categorised as CTCAE grade 2. These cases do not require cessation of CPI and neither should they require systemic steroids, in general. The outcomes from topical treatment are mainly good, with either a limited course, or sometimes ongoing topical steroids. If systemic steroids are used, the ASCO guidelines recommend that CPIs are withheld until the patient is either off all steroids or is receiving a daily dose of 10 mg oral prednisolone (or equivalent) or less. As far as possible, the aim should be to treat ocular IrAEs with local options in order to avoid systemic steroids and cessation of CPI therapy. Aside from concerns regarding their impact on CPI efficacy, long-term steroid use is associated with many well-known harmful effects.
The goal of avoiding the interruption of CPI therapy is best achieved by taking a multidisciplinary approach, with close liaison between ophthalmology and oncology teams, remembering that patients may have a high degree of anxiety about stopping potentially life-saving anti-cancer therapy. In our cohort, five patients stopped CPIs due to ocular IrAEs, despite being categorised as grade 2, which does not necessarily mandate permanent discontinuation. Three of these patients were treated solely with topical steroids, which suggests a low threat to vision, and which would not normally interfere with CPIs. In cases where topical steroids are not sufficient, intravitreal or periocular steroids should be considered to enable patients to remain on CPIs.
It is possible that patients diagnosed with melanoma may be at increased risk of developing uveitis due to the presence of melanin in the retinal pigment epithelium. An immune-mediated response to melanin-producing cells in the eye may occur both in patients on treatment and in those who develop an immunological reaction to their cancer independent of treatment. In our series, MAR was the most likely diagnosis in one of two patients reporting ocular toxicities that were not due to uveitis, based on symptoms described and investigations performed. The pathology is thought to be due to shared neuroectodermal lineage of melanocytes and retinal cells. Conversely, uveitis is not unique to patients with a diagnosis of melanoma. Patients at increased risk of uveitis may include those with other immune-related side effects and those predisposed to autoimmune disease or with a significant family history.32
Four of our patients, of whom two had other IrAEs, responded very well to retreatment with CPIs, highlighting a key unanswered question concerning whether the occurrence of IrAEs can predict a therapeutic response.32,33 Several studies have reported increased progression-free and overall survival in patients who experienced IrAEs with CPIs compared to those who did not.34,35 To date, it remains unclear whether the development of uveitis or other specific IrAEs is associated with better outcomes from treatment with CPIs,34,36 although it is quite plausible that an observed inflammatory response within the eye or elsewhere might reflect an enhanced immune response against cancer. The number of patients in our study is insufficient to answer this question, but further study is warranted and, if proved, this could be reassuring for patients who have previously stopped immunotherapy while being treated for inflammatory side effects.
In conclusion, ocular IrAEs are relatively uncommon IrAEs associated with CPIs, but can be dramatic and may lead to permanent visual loss. Prompt recognition in oncology clinics and early referral to an ophthalmologist is essential. Patients with confirmed ocular inflammation require close monitoring in the eye clinic and ongoing liaison with their oncologist regarding optimal treatment and the use of corticosteroids. The option of intraocular steroid implants should be considered as an alternative to systemic steroids when IrAEs do not resolve with topical steroids alone, with the potential benefit of being able to continue on CPIs.
In conjunction with our ocular IrAE management algorithm (Figure 2), we propose the following basic steps to follow when seeing immunotherapy patients with ocular symptoms in the clinic:
document the symptoms and signs and their severity
escalate by referral to an ophthalmologist; consider urgency of referral and the need to interrupt CPI therapy depending on symptom severity
obtain an ophthalmological diagnosis
take a multidisciplinary approach to managing the ocular symptoms and the need or otherwise to restart CPIs, based on risk/benefit considerations.
The authors would like to thank the patients and their families for allowing us to share their case studies. Thanks also to the CUHFT research governance and audit teams for their assistance in the conduct of this study.
Conflict of interest: The authors declare that there is no conflict of interest.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Philippa Corrie
https://orcid.org/0000-0003-4875-7021 | Not recovered | ReactionOutcome | CC BY-NC | 33633802 | 19,078,861 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Twelve Drummers Drumming… With Dystonia.
Reports of drummers' dystonia are rare, particularly compared to the literature on dystonia in string, piano and brass players. Several cases of drummers' dystonia have been included in large series of multiple instrumentalists, but there are few reports comprised exclusively of drummers with musicians' dystonia. We present here a series of 12 drummers with task-specific, focal dystonia affecting their upper limbs while drumming and spanning multiple playing techniques and musical styles.
We conducted a retrospective chart review of drummers with dystonia seen at academic Movement Disorders centers.
All 12 patients were male, and the majority eventually developed spread of dystonia to tasks other than drumming. Ten of the 12 had dystonia affecting their fingers, while 8/12 had dystonia affecting the wrist. Only 1/12 had involvement proximal to the wrist. Pharmacologic interventions were largely ineffective; 3 had some benefit from botulinum toxin injections, but this was limited by problematic weakness in one drummer.
The phenomenology in our series is concordant with prior reported cases, demonstrating frequent wrist involvement, though we also found that a greater proportion of patients had dystonia affecting the fingers. It could be hypothesized that different drumming techniques or musical styles modulate the relative risk of dystonic involvement of the different anatomical regions of the upper limb.
Drummers' dystonia is one of the least common forms of musicians' dystonia, though this may reflect fewer numbers of these instrumentalists. We present the largest series of drummers' dystonia and review previously published cases. Our cohort, representing diverse drumming styles, showed frequent involvement of dystonia in the wrists and fingers.
Introduction
Musicians’ dystonia is a particularly disabling form of occupational, task-specific focal hand dystonia and can be a career-ending disorder for professional musicians. It typically presents as a sustained twisting, tremor, or loss of coordination while playing an instrument. Musicians’ dystonia is estimated to affect 1% of professional musicians, but can affect amateurs and students as well [1]. The region of the body that is most commonly affected varies by instrument type but is often localized to the area of the body or limb producing the most rapid and highly skilled movements. This is reflected in more frequent involvement of the left hand in bowed string players, right hand in keyboard players, and embouchure in brass players [2].
Although drummers’ dystonia has been previously reported, it is relatively rare in the literature, particularly in comparison to reports in other types of musicians. Several cases affecting drummers have been included in large series of multiple instrumentalists, but there are few reports comprised exclusively of drummers. Out of all instrumentalists seen in performing arts clinics for focal dystonia, as reported in 4 large case series, only 1–5% were percussionists [3456]. Drummers’ dystonia has been reported most frequently to affect the upper limbs, but recent case reports describe lower limb dystonia in drummers using pedals [789]. The largest published series of drummers’ dystonia to date included 6 drummers [6]. Here, we present a series of 12 drummers with focal hand dystonia seen in Movement Disorders clinics at academic medical centers and describe the clinical features of the drummers, the phenomenology of their dystonia, and compare with prior reports in the literature.
Methods
This study was a retrospective chart review of drummers’ dystonia seen at academic medical centers (Columbia University Medical Center/Mount Sinai Health System [S.J.F.], Rush University Medical Center [J.G.G., I.O.B.], University of Maryland Medical Center [S.G.R.], University of California, San Francisco [I.O.B.]). The variables ascertained from the patient charts and videos were established a priori by the investigators. These variables included the age at which drumming was first started, instruments and musical styles played, age at development of dystonic symptoms, phenomenological features of dystonia, exacerbating and ameliorating factors, events prior to development of dystonic symptoms, and interventions tried. Descriptive statistics were used to describe the demographic and clinical features of the drummers in the cohort.
Results
Description of cohort (TABLE 1)
Table 1 Clinical characteristics of drummers with dystonia from multiple cohorts.
COHORT SEX RACE (CURRENT SERIES ONLY) AGE AT ONSET, YEARS AGE AT PRESENTATION/EVALUATION, YEARS SIDE AFFECTED DOMINANT HAND INSTRUMENTS (MUSICAL STYLE) PHENOMENOLOGY WITH INSTRUMENT TREMOR REPORTED SPREAD TO OTHER TASKS BENEFICIAL INTERVENTIONS
Current series, No. 1 [Video, Case 1] M Caucasian 23 27 Left Unknown Drum, Xylophone Ext 2, 3, 4, 5 Yes Yes – typing None (trial ofcarbidopa/levodopa without benefit, unknown dose)
Current series, No. 2 [Video, Case 2] M Caucasian 41 44 Right Right Drum set (Pop) Flex 2, 3, 4, 5; wrist ulnar deviation No Yes – Golfing, brushing teeth, holding knife None (lorazepam without benefit, unknown dose; referred for botulinum toxin injections but lost to follow up and results unknown)
Current series, No. 3 [Video, Case 3] M Caucasian 43 45 Right Unknown Indian tabla, classical percussion Flex 2 No No External sensory trick with tape and orthopedic finger splint
Current series, No. 4 [Video, Case 4] M Caucasian 22 25 Left Right Classical Percussion Irregular tremor at wrist; Flex 3, 4, 5 (PIP/DIP); Wrist Flex, radial deviation Yes No Declined botulinum toxin injections or other treatment trials.
Current series, No. 5 M Caucasian 53 54 Left Right Drums (jazz, rock) Wrist Flex and ulnar deviation Yes Yes – putting on glasses, drinking from cup None (multiple treatments tried including carbidopa/levodopa 600 mg daily, clonazepam, trihexyphenidyl 30 mg/daily, Botulinum toxin A injections, with EMG guidance – mild benefit, but limited by weakness: 25 units to each of left FCU, left pronator quadratus, left ECU; occupational therapy, limb immobilization)
Current series, No. 6 M Caucasian 19 20 Both Right Drums (multiple genres) Right: Flex 4, 5 (PIP); Left: Flex 4, 5 (PIP), wrist Ext and ulnar deviation No No Good benefit with botulinum toxin A injections using EMG guidance – Right side: FCU 20 units, FDS 25 units. Left side: FCR 15 units, FCU 20 units, EDC 15 units. (Carbidopa/levodopa 450 mg daily with no benefit)
Current series, No. 7 M Caucasian 33 42 Right Right Drums, xylophone, vibraphone (multiple genres) Ext 2, abduction of 5; loosened thumb grip; tightness in forearm and wrist No No Trihexyphenidyl 24 mg daily, modest benefit. Botulinum toxin A injections, with EMG guidance, 60–70% improvement: Right EPL 7.5 units; Right EIP 7.5 units; Right ECR 10 units
Current series, No. 8 M Unknown 39 42 Right Right Indian tabla Wrist ulnar deviation No No Referred for botulinum toxin injections, but lost to follow up and results unknown
Current series, No. 9 M Unknown 31 34 Left Right Classical percussion Ext 4, 5 (at MCP), wrist Ext and radial deviation No Yes – holding stick between hands None (Clonazepam, uncertain dose; trihexyphenidyl 6 mg daily without benefit; referred for botulinum toxin injections, but results unknown)
Current series, No. 10 M Unknown 45 52 Left Right African-Cuban and African-Caribbean drumming Ext 2, 3, 4 (at PIP, DIP); Flex 2, 3, 4 (at MCP); wrist Flex, shoulder elevation Yes Yes – handling fork, newspaper None (Received 2 cycles of botulinum toxin injections elsewhere without benefit; unknown injection pattern)
Current series, No. 11 M Unknown 39 48 Left Unknown Timpani (Classical) Ext 3, 4, 5 (at PIP); Flex 3, 4, 5 (at MCP); abduction of digits; wrist ulnar deviation No No Diazepam with modest benefit – unknown dose.
Current series, No. 12 M Caucasian 34 38 Right Right Snare drum (Multiple genres) Flex 2, 3, 4, tremor when writing Yes Yes – writing, brushing teeth Propranolol LA 60 mg daily modest benefit; carbidopa/levodopa 250 mg daily without benefit.
Lederman 2004 [6] M 34 35 Right Left Drum set (Jazz/Rock) Right forearm supination, wrist Flex No Yes – in opposite hand Trihexyphenidyl (modest)
Lederman 2004 M 21 22 Right Left Classical Percussion Right forearm tightening, thumb slides off drumstick No No None
Lederman 2004 M 36 39 Right Right Drum set (Country Music) Right wrist Flex, thumb abduction/extension No Yes None
Lederman 2004 M 22 23 Left Right Unspecified – Master’s Degree performance program Left forearm supination and tremor Yes No None
Lederman 2004 F 42 52 Both (Left > Right) Right Classical Percussion (Snare drum most affected; also xylophone and other mallet instruments) Left wrist Ext, tremor; mild right side tremor Yes Unknown Low dose propranolol; softer mallets; quit snare drum
Lederman 2004 M 51 53 Left Right Drum set (Jazz) Left wrist Flex and ulnar deviation No Yes Limb immobilization trial (unknown long term improvement)
Ragothaman 2004 [11] M 31 32 Right Unknown Tabla Ext 1, Flex 2, 3, 4, 5, forearm pronation, wrist ulnar deviation No No Botulinum toxin injections (onabotulinumtoxinA)
Ragothaman 2004 M 45 47 Both (R > L) Unknown Tabla Right: wrist Flex and ulnar deviation; Left finger flexion No No Botulinum toxin injections (onabotulinumtoxinA – minimal improvement)
Brandfonbrener 1995 [17] F ? 19 Left Right Unspecified Left Flex 3, Ext 4, 5 No Unknown
Brandfonbrener 1995 M 32 Left Right Unspecified Left Flex 3, loss of control of 4th/5th digits No Unknown
Brandfonbrener 1995 F 25 Right Right Unspecified Right Ext 3, 4, 5 No Unknown
Sussman 2015 [18] Unknown Unknown Left Unknown Unknown Left wrist flexion, shoulder abduction No
Conti 2008 [19] M 22 Left Right Drums Tremor Yes Unknown
Rosset-Llobet 2012 [9] M 23 23 Left leg Unknown Drum set (Jazz) Toe extension, left toe, ankle, knee tension No No Sensory Motor Retraining
Rosset-Llobet 2012 M 20 22 Both legs Unknown Drum set (Rock) Toe flexion, heel elevation No No Modified practice routines
Lee 2014 [8] M 26 28 Right leg Unknown Drum set (Heavy Metal) Thigh tightness; coactivation of hamstring and quadriceps on EMG No No IncobotulinumtoxinA – slight effect
Katz 2013 [7] M 45 75 Right leg Unknown Drum set Plantar flexion No Yes AFO; botulinum toxin; Functional Electrical Stimulation of peroneal nerve
Asahi 2018 [20] M 22 37 Right hand and foot Left Drum set Reported difficulty with control of fine movements in foot; right forearm tightness No Yes – writing Improvement with left Vo thalamotomy
Schirinzi 2018 [21] M 46 49 Left hand Right Unknown Loss of dexterity in left hand; wrist flexion and internal rotation of forearm No Yes Slight benefit with levodopa (<20%); greater benefit with trihexyphenidyl (6 mg daily) and botulinum toxin injections.
Song 2020 [22] M 59 59 Left arm Unknown Janggu (traditional Korean drum) Left arm and wrist flexion No Yes, in other tasks involving flexion of left arm Partial benefit with botulinum toxin injections
Abbreviations: DIP (distal interphalangeal); Ext (Extension); F (female); Flex (Flexion); M (male); MCP (metacarpophalangeal); PIP (proximal interphalangeal).
Upper extremity digits represented by numbers 1 (thumb) to 5.
All 12 patients with drummers’ dystonia were male. Mean age of dystonia onset was 35.2 ± 10 years, spanning a range of 19 to 53 years. The mean time from symptom onset to diagnosis was 4.1 ± 2.78 years. Nearly all drummers experienced marked professional impairment. Two patients changed careers from musical performance to non-performance focuses, including music education and composition. Information regarding style of music played was obtained in 9 drummers: three were primarily classical percussionists, two played traditional Indian tabla, one played jazz and rock, one played pop, one played African-Cuban and African-Caribbean drums, and two played multiple styles. Information regarding age at which the instrument was first started was available for 7 drummers, with a mean age of 11.8 ± 6.7 years, and a range of 2.5–24 years. Only one drummer, who had a father with writer’s cramp, reported a family history of dystonia. None of the patients in our cohort had genetic testing for variants in dystonia associated genes.
Clinical features
Only upper limbs were involved in our cohort of drummers: six had left upper limb involvement, five had right upper limb involvement, and one had bilateral involvement. Wrist involvement alone was reported in two patients, and isolated finger involvement in four. Six patients had combined finger and wrist dystonia during drumming. Only one drummer had involvement of any arm region proximal to the wrist, with involuntary shoulder elevation in conjunction with wrist and finger posturing. The pattern of involuntary finger movements was divided between flexion in some drummers and extension in others, though two had a pattern of combined distal finger extension and proximal flexion at the metacarpophalangeal joints. One of the drummers experienced irregular tremor in the left upper extremity when playing with very slow strokes; tremor consisted of irregular flexion/extension movements of the wrist at times intermixed with forearm pronation/supination. Four drummers experienced tremor in their affected hand when engaged in tasks other than drumming.
Four drummers identified specific musical patterns or settings in which the dystonia was most intrusive or severe. For one drummer, this included a single roll, as opposed to double roll strokes. Another patient, a classical Indian tabla player, found that the strokes involving his right index finger were the most difficult to execute, but was able to continue to play passages using the wrist without difficulty. Another patient who also played Indian tabla, but played other styles as well, experienced no dystonia when using mallets, but developed marked dystonic flexion of the right index finger when playing tabla and striking the drum directly with his hand. One drummer found that his dystonia, consisting of thumb, index, and middle finger flexion, was most severe when playing soft passages or when playing the snare drum in particular (Table 1, No. 12).
A sensory trick was identified by four of the drummers. One had improvement of dystonic ulnar deviation of the wrist when he rested his right forearm on his right knee or when someone else applied moderate pressure to his right arm. One found that using heavier drum sticks with thinner grips was helpful, while another noted the opposite, with improvement in drumming with thicker drum sticks. The fourth had marked improvement in dystonic flexion of his right index finger by bringing his thumb next to the finger; he also experienced improvement by taping the dystonic finger and from wearing an orthopedic finger splint, and this became his main therapeutic approach to improve the dystonia while drumming. Several patients modified their technique to improve their playing. These modifications included altering the angle of upper limb approach to the drum, changing the angle of drums, or using compensatory postures (e.g., adduction of the left elbow in one drummer so it was closer to his trunk and supination of the forearm in another drummer). Half the drummers (6/12) eventually had spread of dystonia to activities other than drumming. The non-musical tasks that were affected included typing, putting on glasses, drinking from a cup, golfing, manipulating cutlery, writing, and brushing teeth. The other half retained task specificity, with occurrence of dystonic movements triggered exclusively by drumming.
Only one patient identified a definite physical change or medical issue prior to dystonia onset, undergoing a C4–6 cervical fusion four months prior to developing dystonia. Another had EMG findings of chronic denervation/reinnervation in FCU and FDP III/IV on the side of dystonia, suggesting the presence of an ulnar neuropathy. However, he had no detectable weakness in the affected hand or arm, no sensory changes, and had not experienced clinical symptoms suggestive of ulnar neuropathy. Another drummer noted the prior use of a very heavy instrument strapped to his left shoulder, the side on which he developed dystonia, although this was not clearly linked temporally to dystonia symptom onset.
Interventions
Nearly all drummers had tried a number of interventions in hopes of symptom improvement; most treatment interventions tried were pharmacological. Three patients had trials of carbidopa/levodopa without benefit; one of these three also tried trihexyphenidyl but stopped due to dry mouth. Two other patients tried trihexyphenidyl with one experiencing only mild benefit, and one with no benefit. Four patients tried benzodiazepines, which produced mixed results; diazepam gave some improvement in one patient, but lorazepam gave no benefit to another and clonazepam no clear benefit to two others. One drummer tried baclofen without improvement. One patient reported modest improvement in tremor that accompanied the dystonic posturing with the use of propranolol long-acting 60 mg/day. Seven patients received botulinum toxin injections; others were offered a trial of injections but declined or had injections performed but were lost to follow up. Of those receiving injections, one was noted to have good benefit, one reported 60–70% improvement, another had mild improvement in symptoms but experienced problematic weakness, and one had no benefit. Three patients had botulinum toxin injections performed by other practitioners and information regarding effectiveness of these injections was not available. Other intervention trials included limb immobilization in one drummer, which led to transient weakness and no benefit. Another patient tried physical therapy, massage, and stretching without benefit in addition to several alternative treatments, including laser treatment and magnetic therapy, which were all ineffective.
Selected Cases and Videos
Case 1. (Table 1. No. 1; Video segment 1)
Video 1 Clinical features of drummers’ dystonia in cases 1–4.
A 27-year-old professional musician was evaluated for hand dystonia that developed 4 years previously. Dystonia while playing his drums and xylophone consisted of extension of left 2nd–5th digits. With his left hand outstretched when not playing, he had mild ulnar deviation of the left hand and mild tremor. He also had dystonia when typing on a small keyboard. A trial of carbidopa/levodopa resulted in no improvement. He was able to remain professionally involved in music, but not as a performer.
Case 2. (Table 1. No. 2; Video segment 2)
A 44-year-old professional drummer of popular music developed dystonia at age 41. While playing, his right wrist would have involuntary ulnar deviation followed by flexion of all fingers resulting in a curled position. He became unable to move his wrist with involuntary contraction of flexor carpi ulnaris and was then unable to drum with his right hand. He experienced spread of the dystonia to other tasks, including golfing, brushing his teeth, and holding a knife.
Case 3. (Table 1. No. 3; Video segment 3)
A 45-year-old percussionist and teacher first developed dystonia at age 43. He was trained in classical percussion, but in the prior 20 years played primarily Indian tabla. He first developed dystonia during a period of intensive tabla playing in India, in which he played 8–10 hours daily. The dystonic pattern was of involuntary flexion of the right index finger and would occur whenever he used the finger in tabla playing or with other percussive techniques in which the finger was primarily involved. In contrast, he experienced no abnormal postures when using a mallet. Faster passages would reliably trigger the dystonia. He had a clear sensory trick, in which approximating the right thumb to the index finger would dramatically improve the dystonia. In addition to this classic sensory trick, he also identified an external sensory trick in which an orthopedic finger splint or application of tape to the distal affected finger significantly reduced the unwanted postures.
Case 4. (Table 1. No. 4; Video segment 4)
A 25-year-old classical percussionist was evaluated for progressive difficulty controlling the left wrist and fingers while drumming, first evident at age 22. Two years into his symptoms, he developed intermittent, irregular tremor of the left hand while playing, brought on when flexing the wrist. He additionally experienced involuntary dystonic flexion of left 3rd–5th digits at the distal and proximal interphalangeal joints while drumming. He had significant difficulty controlling wrist flexion and extension during strokes and had the sense that the wrist was flexing involuntarily with radial deviation. He finished a Master’s degree in performance, but was unable to continue his performance career because of the dystonia.
Discussion
This largest series of drummers’ dystonia reported highlights the clinical features of this relatively uncommon type of musicians’ dystonia, the results of attempted treatments, and outcomes in 12 patients. These cases span diverse musical styles and techniques of drumming and broaden the spectrum of described phenomenology in drummers’ dystonia. All drummers in our series were male and there was frequent involvement of proximal fingers and the wrist. Only one patient had dystonia proximal to the wrist, consisting of shoulder elevation while playing. The majority had eventual spread of dystonia to tasks other than drumming, and most therapeutic interventions did not yield satisfactory results with several musicians abandoning their performance careers.
There is one previously published series of drummers’ dystonia describing a cohort of 6 percussionists that, similar to our series, was almost exclusively male (5/6) [6]. Median age of onset was 34 years. All but one drummer had predominant or exclusive involvement of the non-dominant arm. The pattern of dystonia was wrist flexion in four, wrist extension in one, and forearm supination in three. Two drummers had jerking or tremor of the hand or arm. Two had involvement of a thumb, but none had involvement of other digits. One patient was able to continue playing by giving up the snare drum and concentrating on percussion instruments using mallets rather than sticks. Three patients tried botulinum toxin injections, but none had lasting benefit and no more than two treatment sessions were administered in each case. One drummer reported significant benefit from trihexyphenidyl taken before each performance. Another patient reported benefit from a trial of limb-immobilization which had been started just prior to the report, but long-term outcomes for this intervention were not available.
Concordant with results of the above study, we also found frequent involvement of the wrist, seen in 8/12 drummers. This propensity for wrist involvement in drummers’ dystonia may reflect the relative frequency and importance of wrist movements in drumming technique [10]. A study evaluating muscle activation in drummers highlighted the centrality of wrist movements in these instrumentalists. Drummers studied noticed that muscle groups producing movement at the wrist were the most important for high-speed movements in their playing, and this was confirmed by objective evaluation [10].
In contrast to the report by Lederman, we found involvement of fingers in nearly all patients in our cohort (10/12). As drumming involves heterogeneous techniques, it is possible that drummers in our cohort utilized techniques or played styles that involve finger movements more than those in the Lederman cohort. At least three patients in our series played styles (i.e., tabla and Cuban-African drumming) that emphasize striking drums directly with the hand more than those that rely on use of a stick or mallet. A similar pattern of dystonia, with wrist and proximal finger involvement, was seen in 2 tabla players with dystonia in a previous report [11]. However, in addition to the tabla and African-Cuban drummers in our cohort, six other players had dystonia involving fingers while playing in styles that generally utilize a stick or mallet. Thus, this dystonic finger pattern does not appear to be exclusive to drummers that strike the drum directly with their hands.
Another notable feature in our cohort was the eventual spread of dystonia to tasks other than drumming in half the patients (6/12). This is similar to the cohort reported by Lederman showing spread to other tasks in 3 of 6 drummers and underscores the importance of inquiring about spread to non-musical tasks and the impact on activities of daily living in musicians’ dystonia patients. The commonality of spread to other activities in the present and prior cohorts is significant as it emphasizes the potential disability over and above occupational impairment, a risk that appears high in this cohort.
The use of the lower extremities in drum-set is somewhat unique among instrumentalists (apart from certain keyboard and organ players,) and presents the potential risk of developing lower extremity dystonia. This has been elsewhere reported in jazz, rock, and heavy metal drummers [89], but was not seen in our cohort.
All patients in our series were male, though this may reflect gender selection of the instrument rather than a particular predilection to drummers’ dystonia in men. Male predominance of percussion players has been demonstrated in at least one survey of music students enrolled in German conservatories [12]. Similar findings in this country were observed in a survey administered to all professional symphony players who were members of the International Conference of Symphony and Opera Musicians (ICSOM). The survey documented 93 percussionists, of whom 81 (87%) were male [6]. While men do appear to be over-represented among drummers, the male predominance of our cohort may also reflect the higher incidence, in general, of musicians’ dystonia in men as compared to women, with a ratio as high as 4:1 in some studies [13]. It is difficult to draw conclusions about the relative risk of dystonia among drummers as compared to other instrumentalists. In one evaluation of instrumentalists from eight conservatories [14], 2.8% were percussionists. This percentage falls within the range of proportions of drummers with focal dystonia among all instrumentalists seen with focal dystonia in 4 large case series (1–5%) [3456]. These data may suggest that rates of drummers’ dystonia are proportional to drummers’ representation among musicians, but given limited data, more formal assessments and longitudinal follow up of drummers are needed to draw stronger conclusions.
In addition to presenting data from our series, Table 1 also includes 20 previously published cases of drummers’ dystonia from multiple sources, including upper and lower limb dystonia. Similar to our findings, the other drummers are mostly male, play a diversity of drumming styles and techniques, and have frequent involvement of the wrists and fingers. Only four drummers have been reported with lower limb dystonia, and the pattern is variable, including toe flexion, toe extension, plantar flexion/heel elevation, and more diffuse tension in the leg when playing.
The critical importance of reciprocal inhibition of antagonist muscle groups in accurate drumming was demonstrated in a study comparing electromyographic (EMG) activation patterns of healthy drummers and non-drummers in a rapid drumming task [15]. Healthy drummers showed less co-contraction of wrist flexors and extensors compared to non-drummers. In contrast, breakdown in reciprocal inhibition has been demonstrated in EMG studies of drummers with dystonia, though these studies examined lower extremity dystonia in particular [89]. A study of accuracy of timing in drummers with upper limb dystonia, however, showed increased variability in timing at fast tempos in dystonic drummers, highlighting the potentially severe impact of dystonia on the fidelity of performance [16].
Strengths of our study include a large cohort of drummers who were evaluated at specialty Movement Disorders clinics by experts in the field, the diversity of drummers and musical styles represented, and detailed clinical and videographic information available. We acknowledge that there are limitations with the study’s retrospective design and that not all information was available for all patients, including detailed evaluations of hours played daily, other details of musical training, and demographic details in some cases. Future prospective studies with clinical, videographic, and other quantitative information such as electrophysiology would be helpful in advancing our understanding of drummers’ dystonia. Additionally, there is a significant need for well-designed clinical trials evaluating the use of botulinum toxin in musicians’ hand dystonia in order to better guide treatment dosing, muscle selection, and injection technique, and to offer better evidence-based data to patients when considering treatment approaches.
Conclusions
Our large cohort involving drummers who played multiple styles with a variety of techniques showed a pattern of dystonia most commonly involving the wrist and proximal fingers and with a high risk of spread to other tasks. These results, taken in context with previously published reports, support the idea that the drumming style or pattern of movements commonly performed may modulate the risk of a particular region being affected by dystonia. Players that utilize finger movements more frequently as part of their playing have a high risk of finger involvement, though finger involvement was also noted in players utilizing sticks or mallets. Further research is needed in the underlying pathophysiology in order to identify potential environmental strategies to minimize the risk of developing dystonia or to design more effective treatments.
Ethics and Consent
Written informed consent was obtained from all participants for publication of their videos.
Funding Information
IOB: Advisory board: Biogen Inc., Boston Scientific, Accorda, Amneal Pharmaceuticals; Consultant: LEK Consulting, Ideo Inc., Humancraft.
SGR: Book royalties: Springer; Oxford; Interin: Data Safety Monitoring Board; UpToDate: reviewer; Best Doctors: Consultant.
JGG: Grant/research funding: Acadia, Michael J. Fox Foundation, Parkinson’s Foundation; Consultant: Worldwide Med; Honoraria: Medscape, Davis Phinney Foundation, International Parkinson and Movement Disorder Society, and Parkinson’s Foundation.
Competing Interests
The authors have no competing interests to declare. | CARBIDOPA\LEVODOPA | DrugsGivenReaction | CC BY | 33633869 | 19,141,165 | 2021-02-08 |
What was the administration route of drug 'CARBIDOPA\LEVODOPA'? | Twelve Drummers Drumming… With Dystonia.
Reports of drummers' dystonia are rare, particularly compared to the literature on dystonia in string, piano and brass players. Several cases of drummers' dystonia have been included in large series of multiple instrumentalists, but there are few reports comprised exclusively of drummers with musicians' dystonia. We present here a series of 12 drummers with task-specific, focal dystonia affecting their upper limbs while drumming and spanning multiple playing techniques and musical styles.
We conducted a retrospective chart review of drummers with dystonia seen at academic Movement Disorders centers.
All 12 patients were male, and the majority eventually developed spread of dystonia to tasks other than drumming. Ten of the 12 had dystonia affecting their fingers, while 8/12 had dystonia affecting the wrist. Only 1/12 had involvement proximal to the wrist. Pharmacologic interventions were largely ineffective; 3 had some benefit from botulinum toxin injections, but this was limited by problematic weakness in one drummer.
The phenomenology in our series is concordant with prior reported cases, demonstrating frequent wrist involvement, though we also found that a greater proportion of patients had dystonia affecting the fingers. It could be hypothesized that different drumming techniques or musical styles modulate the relative risk of dystonic involvement of the different anatomical regions of the upper limb.
Drummers' dystonia is one of the least common forms of musicians' dystonia, though this may reflect fewer numbers of these instrumentalists. We present the largest series of drummers' dystonia and review previously published cases. Our cohort, representing diverse drumming styles, showed frequent involvement of dystonia in the wrists and fingers.
Introduction
Musicians’ dystonia is a particularly disabling form of occupational, task-specific focal hand dystonia and can be a career-ending disorder for professional musicians. It typically presents as a sustained twisting, tremor, or loss of coordination while playing an instrument. Musicians’ dystonia is estimated to affect 1% of professional musicians, but can affect amateurs and students as well [1]. The region of the body that is most commonly affected varies by instrument type but is often localized to the area of the body or limb producing the most rapid and highly skilled movements. This is reflected in more frequent involvement of the left hand in bowed string players, right hand in keyboard players, and embouchure in brass players [2].
Although drummers’ dystonia has been previously reported, it is relatively rare in the literature, particularly in comparison to reports in other types of musicians. Several cases affecting drummers have been included in large series of multiple instrumentalists, but there are few reports comprised exclusively of drummers. Out of all instrumentalists seen in performing arts clinics for focal dystonia, as reported in 4 large case series, only 1–5% were percussionists [3456]. Drummers’ dystonia has been reported most frequently to affect the upper limbs, but recent case reports describe lower limb dystonia in drummers using pedals [789]. The largest published series of drummers’ dystonia to date included 6 drummers [6]. Here, we present a series of 12 drummers with focal hand dystonia seen in Movement Disorders clinics at academic medical centers and describe the clinical features of the drummers, the phenomenology of their dystonia, and compare with prior reports in the literature.
Methods
This study was a retrospective chart review of drummers’ dystonia seen at academic medical centers (Columbia University Medical Center/Mount Sinai Health System [S.J.F.], Rush University Medical Center [J.G.G., I.O.B.], University of Maryland Medical Center [S.G.R.], University of California, San Francisco [I.O.B.]). The variables ascertained from the patient charts and videos were established a priori by the investigators. These variables included the age at which drumming was first started, instruments and musical styles played, age at development of dystonic symptoms, phenomenological features of dystonia, exacerbating and ameliorating factors, events prior to development of dystonic symptoms, and interventions tried. Descriptive statistics were used to describe the demographic and clinical features of the drummers in the cohort.
Results
Description of cohort (TABLE 1)
Table 1 Clinical characteristics of drummers with dystonia from multiple cohorts.
COHORT SEX RACE (CURRENT SERIES ONLY) AGE AT ONSET, YEARS AGE AT PRESENTATION/EVALUATION, YEARS SIDE AFFECTED DOMINANT HAND INSTRUMENTS (MUSICAL STYLE) PHENOMENOLOGY WITH INSTRUMENT TREMOR REPORTED SPREAD TO OTHER TASKS BENEFICIAL INTERVENTIONS
Current series, No. 1 [Video, Case 1] M Caucasian 23 27 Left Unknown Drum, Xylophone Ext 2, 3, 4, 5 Yes Yes – typing None (trial ofcarbidopa/levodopa without benefit, unknown dose)
Current series, No. 2 [Video, Case 2] M Caucasian 41 44 Right Right Drum set (Pop) Flex 2, 3, 4, 5; wrist ulnar deviation No Yes – Golfing, brushing teeth, holding knife None (lorazepam without benefit, unknown dose; referred for botulinum toxin injections but lost to follow up and results unknown)
Current series, No. 3 [Video, Case 3] M Caucasian 43 45 Right Unknown Indian tabla, classical percussion Flex 2 No No External sensory trick with tape and orthopedic finger splint
Current series, No. 4 [Video, Case 4] M Caucasian 22 25 Left Right Classical Percussion Irregular tremor at wrist; Flex 3, 4, 5 (PIP/DIP); Wrist Flex, radial deviation Yes No Declined botulinum toxin injections or other treatment trials.
Current series, No. 5 M Caucasian 53 54 Left Right Drums (jazz, rock) Wrist Flex and ulnar deviation Yes Yes – putting on glasses, drinking from cup None (multiple treatments tried including carbidopa/levodopa 600 mg daily, clonazepam, trihexyphenidyl 30 mg/daily, Botulinum toxin A injections, with EMG guidance – mild benefit, but limited by weakness: 25 units to each of left FCU, left pronator quadratus, left ECU; occupational therapy, limb immobilization)
Current series, No. 6 M Caucasian 19 20 Both Right Drums (multiple genres) Right: Flex 4, 5 (PIP); Left: Flex 4, 5 (PIP), wrist Ext and ulnar deviation No No Good benefit with botulinum toxin A injections using EMG guidance – Right side: FCU 20 units, FDS 25 units. Left side: FCR 15 units, FCU 20 units, EDC 15 units. (Carbidopa/levodopa 450 mg daily with no benefit)
Current series, No. 7 M Caucasian 33 42 Right Right Drums, xylophone, vibraphone (multiple genres) Ext 2, abduction of 5; loosened thumb grip; tightness in forearm and wrist No No Trihexyphenidyl 24 mg daily, modest benefit. Botulinum toxin A injections, with EMG guidance, 60–70% improvement: Right EPL 7.5 units; Right EIP 7.5 units; Right ECR 10 units
Current series, No. 8 M Unknown 39 42 Right Right Indian tabla Wrist ulnar deviation No No Referred for botulinum toxin injections, but lost to follow up and results unknown
Current series, No. 9 M Unknown 31 34 Left Right Classical percussion Ext 4, 5 (at MCP), wrist Ext and radial deviation No Yes – holding stick between hands None (Clonazepam, uncertain dose; trihexyphenidyl 6 mg daily without benefit; referred for botulinum toxin injections, but results unknown)
Current series, No. 10 M Unknown 45 52 Left Right African-Cuban and African-Caribbean drumming Ext 2, 3, 4 (at PIP, DIP); Flex 2, 3, 4 (at MCP); wrist Flex, shoulder elevation Yes Yes – handling fork, newspaper None (Received 2 cycles of botulinum toxin injections elsewhere without benefit; unknown injection pattern)
Current series, No. 11 M Unknown 39 48 Left Unknown Timpani (Classical) Ext 3, 4, 5 (at PIP); Flex 3, 4, 5 (at MCP); abduction of digits; wrist ulnar deviation No No Diazepam with modest benefit – unknown dose.
Current series, No. 12 M Caucasian 34 38 Right Right Snare drum (Multiple genres) Flex 2, 3, 4, tremor when writing Yes Yes – writing, brushing teeth Propranolol LA 60 mg daily modest benefit; carbidopa/levodopa 250 mg daily without benefit.
Lederman 2004 [6] M 34 35 Right Left Drum set (Jazz/Rock) Right forearm supination, wrist Flex No Yes – in opposite hand Trihexyphenidyl (modest)
Lederman 2004 M 21 22 Right Left Classical Percussion Right forearm tightening, thumb slides off drumstick No No None
Lederman 2004 M 36 39 Right Right Drum set (Country Music) Right wrist Flex, thumb abduction/extension No Yes None
Lederman 2004 M 22 23 Left Right Unspecified – Master’s Degree performance program Left forearm supination and tremor Yes No None
Lederman 2004 F 42 52 Both (Left > Right) Right Classical Percussion (Snare drum most affected; also xylophone and other mallet instruments) Left wrist Ext, tremor; mild right side tremor Yes Unknown Low dose propranolol; softer mallets; quit snare drum
Lederman 2004 M 51 53 Left Right Drum set (Jazz) Left wrist Flex and ulnar deviation No Yes Limb immobilization trial (unknown long term improvement)
Ragothaman 2004 [11] M 31 32 Right Unknown Tabla Ext 1, Flex 2, 3, 4, 5, forearm pronation, wrist ulnar deviation No No Botulinum toxin injections (onabotulinumtoxinA)
Ragothaman 2004 M 45 47 Both (R > L) Unknown Tabla Right: wrist Flex and ulnar deviation; Left finger flexion No No Botulinum toxin injections (onabotulinumtoxinA – minimal improvement)
Brandfonbrener 1995 [17] F ? 19 Left Right Unspecified Left Flex 3, Ext 4, 5 No Unknown
Brandfonbrener 1995 M 32 Left Right Unspecified Left Flex 3, loss of control of 4th/5th digits No Unknown
Brandfonbrener 1995 F 25 Right Right Unspecified Right Ext 3, 4, 5 No Unknown
Sussman 2015 [18] Unknown Unknown Left Unknown Unknown Left wrist flexion, shoulder abduction No
Conti 2008 [19] M 22 Left Right Drums Tremor Yes Unknown
Rosset-Llobet 2012 [9] M 23 23 Left leg Unknown Drum set (Jazz) Toe extension, left toe, ankle, knee tension No No Sensory Motor Retraining
Rosset-Llobet 2012 M 20 22 Both legs Unknown Drum set (Rock) Toe flexion, heel elevation No No Modified practice routines
Lee 2014 [8] M 26 28 Right leg Unknown Drum set (Heavy Metal) Thigh tightness; coactivation of hamstring and quadriceps on EMG No No IncobotulinumtoxinA – slight effect
Katz 2013 [7] M 45 75 Right leg Unknown Drum set Plantar flexion No Yes AFO; botulinum toxin; Functional Electrical Stimulation of peroneal nerve
Asahi 2018 [20] M 22 37 Right hand and foot Left Drum set Reported difficulty with control of fine movements in foot; right forearm tightness No Yes – writing Improvement with left Vo thalamotomy
Schirinzi 2018 [21] M 46 49 Left hand Right Unknown Loss of dexterity in left hand; wrist flexion and internal rotation of forearm No Yes Slight benefit with levodopa (<20%); greater benefit with trihexyphenidyl (6 mg daily) and botulinum toxin injections.
Song 2020 [22] M 59 59 Left arm Unknown Janggu (traditional Korean drum) Left arm and wrist flexion No Yes, in other tasks involving flexion of left arm Partial benefit with botulinum toxin injections
Abbreviations: DIP (distal interphalangeal); Ext (Extension); F (female); Flex (Flexion); M (male); MCP (metacarpophalangeal); PIP (proximal interphalangeal).
Upper extremity digits represented by numbers 1 (thumb) to 5.
All 12 patients with drummers’ dystonia were male. Mean age of dystonia onset was 35.2 ± 10 years, spanning a range of 19 to 53 years. The mean time from symptom onset to diagnosis was 4.1 ± 2.78 years. Nearly all drummers experienced marked professional impairment. Two patients changed careers from musical performance to non-performance focuses, including music education and composition. Information regarding style of music played was obtained in 9 drummers: three were primarily classical percussionists, two played traditional Indian tabla, one played jazz and rock, one played pop, one played African-Cuban and African-Caribbean drums, and two played multiple styles. Information regarding age at which the instrument was first started was available for 7 drummers, with a mean age of 11.8 ± 6.7 years, and a range of 2.5–24 years. Only one drummer, who had a father with writer’s cramp, reported a family history of dystonia. None of the patients in our cohort had genetic testing for variants in dystonia associated genes.
Clinical features
Only upper limbs were involved in our cohort of drummers: six had left upper limb involvement, five had right upper limb involvement, and one had bilateral involvement. Wrist involvement alone was reported in two patients, and isolated finger involvement in four. Six patients had combined finger and wrist dystonia during drumming. Only one drummer had involvement of any arm region proximal to the wrist, with involuntary shoulder elevation in conjunction with wrist and finger posturing. The pattern of involuntary finger movements was divided between flexion in some drummers and extension in others, though two had a pattern of combined distal finger extension and proximal flexion at the metacarpophalangeal joints. One of the drummers experienced irregular tremor in the left upper extremity when playing with very slow strokes; tremor consisted of irregular flexion/extension movements of the wrist at times intermixed with forearm pronation/supination. Four drummers experienced tremor in their affected hand when engaged in tasks other than drumming.
Four drummers identified specific musical patterns or settings in which the dystonia was most intrusive or severe. For one drummer, this included a single roll, as opposed to double roll strokes. Another patient, a classical Indian tabla player, found that the strokes involving his right index finger were the most difficult to execute, but was able to continue to play passages using the wrist without difficulty. Another patient who also played Indian tabla, but played other styles as well, experienced no dystonia when using mallets, but developed marked dystonic flexion of the right index finger when playing tabla and striking the drum directly with his hand. One drummer found that his dystonia, consisting of thumb, index, and middle finger flexion, was most severe when playing soft passages or when playing the snare drum in particular (Table 1, No. 12).
A sensory trick was identified by four of the drummers. One had improvement of dystonic ulnar deviation of the wrist when he rested his right forearm on his right knee or when someone else applied moderate pressure to his right arm. One found that using heavier drum sticks with thinner grips was helpful, while another noted the opposite, with improvement in drumming with thicker drum sticks. The fourth had marked improvement in dystonic flexion of his right index finger by bringing his thumb next to the finger; he also experienced improvement by taping the dystonic finger and from wearing an orthopedic finger splint, and this became his main therapeutic approach to improve the dystonia while drumming. Several patients modified their technique to improve their playing. These modifications included altering the angle of upper limb approach to the drum, changing the angle of drums, or using compensatory postures (e.g., adduction of the left elbow in one drummer so it was closer to his trunk and supination of the forearm in another drummer). Half the drummers (6/12) eventually had spread of dystonia to activities other than drumming. The non-musical tasks that were affected included typing, putting on glasses, drinking from a cup, golfing, manipulating cutlery, writing, and brushing teeth. The other half retained task specificity, with occurrence of dystonic movements triggered exclusively by drumming.
Only one patient identified a definite physical change or medical issue prior to dystonia onset, undergoing a C4–6 cervical fusion four months prior to developing dystonia. Another had EMG findings of chronic denervation/reinnervation in FCU and FDP III/IV on the side of dystonia, suggesting the presence of an ulnar neuropathy. However, he had no detectable weakness in the affected hand or arm, no sensory changes, and had not experienced clinical symptoms suggestive of ulnar neuropathy. Another drummer noted the prior use of a very heavy instrument strapped to his left shoulder, the side on which he developed dystonia, although this was not clearly linked temporally to dystonia symptom onset.
Interventions
Nearly all drummers had tried a number of interventions in hopes of symptom improvement; most treatment interventions tried were pharmacological. Three patients had trials of carbidopa/levodopa without benefit; one of these three also tried trihexyphenidyl but stopped due to dry mouth. Two other patients tried trihexyphenidyl with one experiencing only mild benefit, and one with no benefit. Four patients tried benzodiazepines, which produced mixed results; diazepam gave some improvement in one patient, but lorazepam gave no benefit to another and clonazepam no clear benefit to two others. One drummer tried baclofen without improvement. One patient reported modest improvement in tremor that accompanied the dystonic posturing with the use of propranolol long-acting 60 mg/day. Seven patients received botulinum toxin injections; others were offered a trial of injections but declined or had injections performed but were lost to follow up. Of those receiving injections, one was noted to have good benefit, one reported 60–70% improvement, another had mild improvement in symptoms but experienced problematic weakness, and one had no benefit. Three patients had botulinum toxin injections performed by other practitioners and information regarding effectiveness of these injections was not available. Other intervention trials included limb immobilization in one drummer, which led to transient weakness and no benefit. Another patient tried physical therapy, massage, and stretching without benefit in addition to several alternative treatments, including laser treatment and magnetic therapy, which were all ineffective.
Selected Cases and Videos
Case 1. (Table 1. No. 1; Video segment 1)
Video 1 Clinical features of drummers’ dystonia in cases 1–4.
A 27-year-old professional musician was evaluated for hand dystonia that developed 4 years previously. Dystonia while playing his drums and xylophone consisted of extension of left 2nd–5th digits. With his left hand outstretched when not playing, he had mild ulnar deviation of the left hand and mild tremor. He also had dystonia when typing on a small keyboard. A trial of carbidopa/levodopa resulted in no improvement. He was able to remain professionally involved in music, but not as a performer.
Case 2. (Table 1. No. 2; Video segment 2)
A 44-year-old professional drummer of popular music developed dystonia at age 41. While playing, his right wrist would have involuntary ulnar deviation followed by flexion of all fingers resulting in a curled position. He became unable to move his wrist with involuntary contraction of flexor carpi ulnaris and was then unable to drum with his right hand. He experienced spread of the dystonia to other tasks, including golfing, brushing his teeth, and holding a knife.
Case 3. (Table 1. No. 3; Video segment 3)
A 45-year-old percussionist and teacher first developed dystonia at age 43. He was trained in classical percussion, but in the prior 20 years played primarily Indian tabla. He first developed dystonia during a period of intensive tabla playing in India, in which he played 8–10 hours daily. The dystonic pattern was of involuntary flexion of the right index finger and would occur whenever he used the finger in tabla playing or with other percussive techniques in which the finger was primarily involved. In contrast, he experienced no abnormal postures when using a mallet. Faster passages would reliably trigger the dystonia. He had a clear sensory trick, in which approximating the right thumb to the index finger would dramatically improve the dystonia. In addition to this classic sensory trick, he also identified an external sensory trick in which an orthopedic finger splint or application of tape to the distal affected finger significantly reduced the unwanted postures.
Case 4. (Table 1. No. 4; Video segment 4)
A 25-year-old classical percussionist was evaluated for progressive difficulty controlling the left wrist and fingers while drumming, first evident at age 22. Two years into his symptoms, he developed intermittent, irregular tremor of the left hand while playing, brought on when flexing the wrist. He additionally experienced involuntary dystonic flexion of left 3rd–5th digits at the distal and proximal interphalangeal joints while drumming. He had significant difficulty controlling wrist flexion and extension during strokes and had the sense that the wrist was flexing involuntarily with radial deviation. He finished a Master’s degree in performance, but was unable to continue his performance career because of the dystonia.
Discussion
This largest series of drummers’ dystonia reported highlights the clinical features of this relatively uncommon type of musicians’ dystonia, the results of attempted treatments, and outcomes in 12 patients. These cases span diverse musical styles and techniques of drumming and broaden the spectrum of described phenomenology in drummers’ dystonia. All drummers in our series were male and there was frequent involvement of proximal fingers and the wrist. Only one patient had dystonia proximal to the wrist, consisting of shoulder elevation while playing. The majority had eventual spread of dystonia to tasks other than drumming, and most therapeutic interventions did not yield satisfactory results with several musicians abandoning their performance careers.
There is one previously published series of drummers’ dystonia describing a cohort of 6 percussionists that, similar to our series, was almost exclusively male (5/6) [6]. Median age of onset was 34 years. All but one drummer had predominant or exclusive involvement of the non-dominant arm. The pattern of dystonia was wrist flexion in four, wrist extension in one, and forearm supination in three. Two drummers had jerking or tremor of the hand or arm. Two had involvement of a thumb, but none had involvement of other digits. One patient was able to continue playing by giving up the snare drum and concentrating on percussion instruments using mallets rather than sticks. Three patients tried botulinum toxin injections, but none had lasting benefit and no more than two treatment sessions were administered in each case. One drummer reported significant benefit from trihexyphenidyl taken before each performance. Another patient reported benefit from a trial of limb-immobilization which had been started just prior to the report, but long-term outcomes for this intervention were not available.
Concordant with results of the above study, we also found frequent involvement of the wrist, seen in 8/12 drummers. This propensity for wrist involvement in drummers’ dystonia may reflect the relative frequency and importance of wrist movements in drumming technique [10]. A study evaluating muscle activation in drummers highlighted the centrality of wrist movements in these instrumentalists. Drummers studied noticed that muscle groups producing movement at the wrist were the most important for high-speed movements in their playing, and this was confirmed by objective evaluation [10].
In contrast to the report by Lederman, we found involvement of fingers in nearly all patients in our cohort (10/12). As drumming involves heterogeneous techniques, it is possible that drummers in our cohort utilized techniques or played styles that involve finger movements more than those in the Lederman cohort. At least three patients in our series played styles (i.e., tabla and Cuban-African drumming) that emphasize striking drums directly with the hand more than those that rely on use of a stick or mallet. A similar pattern of dystonia, with wrist and proximal finger involvement, was seen in 2 tabla players with dystonia in a previous report [11]. However, in addition to the tabla and African-Cuban drummers in our cohort, six other players had dystonia involving fingers while playing in styles that generally utilize a stick or mallet. Thus, this dystonic finger pattern does not appear to be exclusive to drummers that strike the drum directly with their hands.
Another notable feature in our cohort was the eventual spread of dystonia to tasks other than drumming in half the patients (6/12). This is similar to the cohort reported by Lederman showing spread to other tasks in 3 of 6 drummers and underscores the importance of inquiring about spread to non-musical tasks and the impact on activities of daily living in musicians’ dystonia patients. The commonality of spread to other activities in the present and prior cohorts is significant as it emphasizes the potential disability over and above occupational impairment, a risk that appears high in this cohort.
The use of the lower extremities in drum-set is somewhat unique among instrumentalists (apart from certain keyboard and organ players,) and presents the potential risk of developing lower extremity dystonia. This has been elsewhere reported in jazz, rock, and heavy metal drummers [89], but was not seen in our cohort.
All patients in our series were male, though this may reflect gender selection of the instrument rather than a particular predilection to drummers’ dystonia in men. Male predominance of percussion players has been demonstrated in at least one survey of music students enrolled in German conservatories [12]. Similar findings in this country were observed in a survey administered to all professional symphony players who were members of the International Conference of Symphony and Opera Musicians (ICSOM). The survey documented 93 percussionists, of whom 81 (87%) were male [6]. While men do appear to be over-represented among drummers, the male predominance of our cohort may also reflect the higher incidence, in general, of musicians’ dystonia in men as compared to women, with a ratio as high as 4:1 in some studies [13]. It is difficult to draw conclusions about the relative risk of dystonia among drummers as compared to other instrumentalists. In one evaluation of instrumentalists from eight conservatories [14], 2.8% were percussionists. This percentage falls within the range of proportions of drummers with focal dystonia among all instrumentalists seen with focal dystonia in 4 large case series (1–5%) [3456]. These data may suggest that rates of drummers’ dystonia are proportional to drummers’ representation among musicians, but given limited data, more formal assessments and longitudinal follow up of drummers are needed to draw stronger conclusions.
In addition to presenting data from our series, Table 1 also includes 20 previously published cases of drummers’ dystonia from multiple sources, including upper and lower limb dystonia. Similar to our findings, the other drummers are mostly male, play a diversity of drumming styles and techniques, and have frequent involvement of the wrists and fingers. Only four drummers have been reported with lower limb dystonia, and the pattern is variable, including toe flexion, toe extension, plantar flexion/heel elevation, and more diffuse tension in the leg when playing.
The critical importance of reciprocal inhibition of antagonist muscle groups in accurate drumming was demonstrated in a study comparing electromyographic (EMG) activation patterns of healthy drummers and non-drummers in a rapid drumming task [15]. Healthy drummers showed less co-contraction of wrist flexors and extensors compared to non-drummers. In contrast, breakdown in reciprocal inhibition has been demonstrated in EMG studies of drummers with dystonia, though these studies examined lower extremity dystonia in particular [89]. A study of accuracy of timing in drummers with upper limb dystonia, however, showed increased variability in timing at fast tempos in dystonic drummers, highlighting the potentially severe impact of dystonia on the fidelity of performance [16].
Strengths of our study include a large cohort of drummers who were evaluated at specialty Movement Disorders clinics by experts in the field, the diversity of drummers and musical styles represented, and detailed clinical and videographic information available. We acknowledge that there are limitations with the study’s retrospective design and that not all information was available for all patients, including detailed evaluations of hours played daily, other details of musical training, and demographic details in some cases. Future prospective studies with clinical, videographic, and other quantitative information such as electrophysiology would be helpful in advancing our understanding of drummers’ dystonia. Additionally, there is a significant need for well-designed clinical trials evaluating the use of botulinum toxin in musicians’ hand dystonia in order to better guide treatment dosing, muscle selection, and injection technique, and to offer better evidence-based data to patients when considering treatment approaches.
Conclusions
Our large cohort involving drummers who played multiple styles with a variety of techniques showed a pattern of dystonia most commonly involving the wrist and proximal fingers and with a high risk of spread to other tasks. These results, taken in context with previously published reports, support the idea that the drumming style or pattern of movements commonly performed may modulate the risk of a particular region being affected by dystonia. Players that utilize finger movements more frequently as part of their playing have a high risk of finger involvement, though finger involvement was also noted in players utilizing sticks or mallets. Further research is needed in the underlying pathophysiology in order to identify potential environmental strategies to minimize the risk of developing dystonia or to design more effective treatments.
Ethics and Consent
Written informed consent was obtained from all participants for publication of their videos.
Funding Information
IOB: Advisory board: Biogen Inc., Boston Scientific, Accorda, Amneal Pharmaceuticals; Consultant: LEK Consulting, Ideo Inc., Humancraft.
SGR: Book royalties: Springer; Oxford; Interin: Data Safety Monitoring Board; UpToDate: reviewer; Best Doctors: Consultant.
JGG: Grant/research funding: Acadia, Michael J. Fox Foundation, Parkinson’s Foundation; Consultant: Worldwide Med; Honoraria: Medscape, Davis Phinney Foundation, International Parkinson and Movement Disorder Society, and Parkinson’s Foundation.
Competing Interests
The authors have no competing interests to declare. | Oral | DrugAdministrationRoute | CC BY | 33633869 | 19,141,165 | 2021-02-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blindness'. | An Uncommon Aflibercept Side Effect: Full Thickness Macular Hole Formation After Intravitreal Injections in Patients With Pre-existing Vitreomacular Traction.
Aflibercept is an intravitreally injected anti-vascular endothelial growth factor, commonly used in patients with several retinal pathologies, including neovascular age-related macular degeneration. We report a case series of three patients under treatment with an aflibercept regime for neovascular age-related macular degeneration, who were referred to vitreoretinal service between 2015-2016. In all cases, pre-existing vitreomacular traction was detected with an optical coherence tomography scan. All of them developed full-thickness macular hole after aflibercept intravitreal injections. The combined cataract and macular hole surgery was successful, with improvement in visual acuity. We suggest that dynamic alterations of the size of the pigment epithelium detachment resulting from intravitreal injections might intensify the pre-existing pathological adhesion of the vitreous-retinal interface and subsequently cause the formation of a full-thickness macular hole. Therefore, all practitioners treating patients with aflibercept intravitreal injections and pre-existing vitreomacular traction should be aware of the possible macular hole formation.
Introduction
Aflibercept is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF) - binding portions from the extracellular domains of human VEGF receptors one and two, which are fused to the fragment crystallizable (Fc) portion of the human immunoglobulin G1 (IgG1). A high volume of aflibercept intravitreal injections is performed for several retinal pathologies, including neovascular age-related macular degeneration. Adverse effects from aflibercept intravitreal injections, as per product information provided by manufacturers, do not include macular hole formation.
There have been reported only a few cases that associate intravitreal injections of anti-VEGF drugs with macular hole formation; only one case concerns aflibercept, without being mentioned whether pre-existing vitreomacular traction was present [1, 2]. This is the first report of full-thickness macular hole formation in patients with pre-existing vitreomacular traction.
Case presentation
Three patients with neovascular age-related macular degeneration, treated between 2015-2016, were included in the study. Optical coherence tomography (OCT) scan, SPECTRALIS HRA + OCT/Heidelberg Engineering (Franklin, MA, USA), was used to record both the vitreomacular traction and the full-thickness macular hole. Written informed consent was obtained from all patients. The research was approved by the Hellenic Data Protection Authority (Approval Number: 1808/ΓΝ/ΕΞ/75-2/01-02-2017) and followed the tenets of the Declaration of Helsinki.
Case 1
A 65-year-old female, presenting best corrected visual acuity 6/24 in her left eye, was diagnosed with neovascular age-related macular degeneration and vitreomacular traction. The regime for neovascular age-related macular degeneration included monthly intravitreal injections of aflibercept in the left eye for four months. Two weeks after the second injection, a stage-three full-thickness macular hole was detected (Figure 1), with visual acuity decreased to 6/60. Combined cataract and macular hole surgery was successful and the vision in the left eye improved to 6/24.
Figure 1 Fundus photographs from Case 1
a. Full-thickness macular hole after aflibercept intravitreal injection, indicated by arrow.
b. Full-thickness macular hole after aflibercept intravitreal injection, indicated by arrow, with the use of red-free light.
Case 2
A 76-year-old female visited the emergency eye department with a one-week history of visual distortion in her right eye. The patient had an unremarkable past ocular history and her best corrected visual acuity was 6/18 in the right eye. OCT scan revealed the presence of subretinal fluid, intraretinal fluid, small pigment epithelial detachment, and also vitreomacular traction (Figure 2a). The diagnosis was neovascular age-related macular degeneration, and treatment with intravitreal injections of aflibercept was initiated. A week after the first injection, the patient attended the emergency eye department with symptoms of flashes and floaters, and her best corrected visual acuity dropped to 6/36 in the right eye. The patient underwent clinical examination, including examination of the peripheral retina. No evidence of peripheral retinal pathology was detected that potentially could justify the patient's symptoms. The patient underwent another OCT that revealed a significant reduction of the intraretinal fluid and the subretinal fluid, but full-thickness macular hole formation (Figure 2b). The patient referred to the vitreoretinal service and intravitreal aflibercept treatment resumed. Two months after the referral, the patient underwent combined cataract surgery and macular hole repair. Six weeks postoperatively, the best corrected visual acuity improved to 6/18 with complete closure of the full-thickness macular hole formation (Figure 2c).
Figure 2 Optical coherence tomography (OCT) photographs from Case 2
a. Pre-injection OCT: Presence of subretinal fluid, intraretinal fluid, small pigment epithelial detachment, and also a small degree of vitreomacular traction.
b. Post-injection OCT: Significant reduction of subretinal fluid, intraretinal fluid but formation of full-thickness macular hole.
c. Post-cataract and macular hole surgery OCT: Complete closure of the full-thickness macular hole.
Case 3
A 74-year-old male was treated with monthly aflibercept intravitreal injections for four months on account of neovascular age-related macular degeneration in the right eye. Vitreomacular traction was observed at initial diagnosis and the best corrected visual acuity was 6/36 preoperatively. One week after the second injection, a stage-three full-thickness macular hole was diagnosed with best corrected visual acuity being reduced to 6/60. Combined cataract and macular hole surgery was successful. Consequently, the vision in the right eye was increased to 6/36.
Discussion
The posterior hyaloid interface, consisting of the posterior hyaloid membrane and the internal limiting membrane, has been implicated in a number of macular diseases. The posterior hyaloid membrane, which is a true basement membrane, consists of collagen IV. The internal limiting membrane consists of collagen types I and IV, proteoglycans, fibronectin, and laminin. It varies in thickness and composition. Firm vitreoretinal attachments are observed in areas with a thin internal limiting membrane as present at the vitreous base, optic disk, fovea, and over the major retinal blood vessels [3, 4].
The mechanism of idiopathic full-thickness macular hole, as proposed by Gass, includes focal tangential traction on the fovea, resulting from contraction of the pre-foveal vitreous cortex [5]. An OCT study of macular holes in 1999 by Gaudric et al. indicated that vitreous traction is possible oblique and therefore both tangential and anterior-posterior trans-vitreal traction have been implicated in idiopathic full-thickness macular hole development [6].
Researchers studying full-thickness macular hole formation after ranibizumab intravitreal injections in neovascular age-related macular degeneration have reported five cases with pre-existing pigment epithelial detachment and vitreomacular traction that treated with Lucentis®. In cases where fully thickness macular holes developed, there was no pattern as to when the hole developed after intravitreal injections began [1].
Querques et al. proposed that vitreoretinal traction may be a possible result of vitreous incarceration in the injection’s entry site, induced by intravitreal injection. Full-thickness macular hole formation may be caused by forces imposed on the retinal pigment epithelium and the retinal surface, due to contraction of the choroidal neovascular membrane [7].
Clemens et al. suggested that the structure of the vitreous gel is modified when chemical compounds are applied to the vitreous cavity. As a consequence, incomplete posterior vitreous detachment and vitreomacular traction are possible to appear, leading to macular hole formation [8].
Another hypothesis by Grigoropoulos et al. was that intravitreal injections probably increase the traction on the fovea by causing vitreous syneresis, globe deformation during needle insertion, and vitreous incarceration at the insertion spot. Focal sites of traction on the retinal surface may be created by incomplete posterior vitreous detachment induced during the intravitreal injection. In pre-existing vitreomacular traction, this may lead to a full-thickness macular hole [9].
Oshima et al. described a case of full-thickness macular hole development after three aflibercept intravitreal injections in a patient with neovascular age-related macular degeneration. In this specific case, a preexisting retinal pigment epithelium tear was detected, but no information about pre-existing vitreomacular traction is provided. The researchers suggested that the rolled retinal pigment epithelium flap associated with the subretinal fibrosis caused traction on the fovea during aflibercept treatment. This traction on the site of the fovea resulted in progression to a full-thickness macular hole [2].
In all three cases of the present study, pre-existing vitreomacular traction was detected in OCT. It is suggested that this pathological element may be a significant risk factor related to the pathophysiological mechanism of full-thickness macular hole formation. It is possible that elevation of the foveal retina and stretching of the photoreceptor layer by physical forces may occur due to subfoveal pigment epithelial detachment. As a result, the structural support of the fovea may be affected. This makes it more susceptible to vitreofoveal tractional forces, which can initiate a neurosensory retinal detachment and ultimately a full-thickness macular hole. Dynamic alterations of flattening and elevation of pigment epithelium detachment resulting from injections might intensify the pre-existing pathological adhesion of the vitreous-retinal interface and subsequently cause the formation of a full-thickness macular hole. Thus, it is proposed that full-thickness macular hole formation is more a mechanical phenomenon rather than an aftereffect of the anti-VEGF chemical structure itself.
This is the first report of full-thickness macular hole formation after aflibercept intravitreal injection in patients with neovascular age-related macular degeneration and pre-existing vitreomacular traction. All patients underwent successful macular hole surgery. Moreover, visual acuity improved significantly and stabilized after macular hole repair surgery in all patients.
Conclusions
Overall, full-thickness macular hole seems to be a potential complication of anti-VEGF intravitreal injections, aflibercept in our cases, in patients with vitreomacular traction, and this should be taken into consideration. Consequently, patients with age-related macular degeneration and pre-existing vitreomacular traction before initiation of treatment with anti-VEGF should be informed by their clinician about the risk of full-thickness macular hole formation.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study. Hellenic Data Protection Authority issued approval 1808/ΓΝ/ΕΞ/75-2/01-02-2017. The research was approved by the Hellenic Data Protection Authority (Approval Number: 1808/ΓΝ/ΕΞ/75-2/01-02-2017) and followed the tenets of the Declaration of Helsinki.
We wish to thank Professor Nikolaos Ziakas and Professor Ioannis T. Tsinopoulos for their mentoring and encouragement. Also, we wish to acknowledge the contribution of Mr Andrew C. Browning for his support as supervising consultant of age-related macular degeneration patients. | AFLIBERCEPT | DrugsGivenReaction | CC BY | 33633901 | 18,945,478 | 2021-01-23 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Macular hole'. | An Uncommon Aflibercept Side Effect: Full Thickness Macular Hole Formation After Intravitreal Injections in Patients With Pre-existing Vitreomacular Traction.
Aflibercept is an intravitreally injected anti-vascular endothelial growth factor, commonly used in patients with several retinal pathologies, including neovascular age-related macular degeneration. We report a case series of three patients under treatment with an aflibercept regime for neovascular age-related macular degeneration, who were referred to vitreoretinal service between 2015-2016. In all cases, pre-existing vitreomacular traction was detected with an optical coherence tomography scan. All of them developed full-thickness macular hole after aflibercept intravitreal injections. The combined cataract and macular hole surgery was successful, with improvement in visual acuity. We suggest that dynamic alterations of the size of the pigment epithelium detachment resulting from intravitreal injections might intensify the pre-existing pathological adhesion of the vitreous-retinal interface and subsequently cause the formation of a full-thickness macular hole. Therefore, all practitioners treating patients with aflibercept intravitreal injections and pre-existing vitreomacular traction should be aware of the possible macular hole formation.
Introduction
Aflibercept is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF) - binding portions from the extracellular domains of human VEGF receptors one and two, which are fused to the fragment crystallizable (Fc) portion of the human immunoglobulin G1 (IgG1). A high volume of aflibercept intravitreal injections is performed for several retinal pathologies, including neovascular age-related macular degeneration. Adverse effects from aflibercept intravitreal injections, as per product information provided by manufacturers, do not include macular hole formation.
There have been reported only a few cases that associate intravitreal injections of anti-VEGF drugs with macular hole formation; only one case concerns aflibercept, without being mentioned whether pre-existing vitreomacular traction was present [1, 2]. This is the first report of full-thickness macular hole formation in patients with pre-existing vitreomacular traction.
Case presentation
Three patients with neovascular age-related macular degeneration, treated between 2015-2016, were included in the study. Optical coherence tomography (OCT) scan, SPECTRALIS HRA + OCT/Heidelberg Engineering (Franklin, MA, USA), was used to record both the vitreomacular traction and the full-thickness macular hole. Written informed consent was obtained from all patients. The research was approved by the Hellenic Data Protection Authority (Approval Number: 1808/ΓΝ/ΕΞ/75-2/01-02-2017) and followed the tenets of the Declaration of Helsinki.
Case 1
A 65-year-old female, presenting best corrected visual acuity 6/24 in her left eye, was diagnosed with neovascular age-related macular degeneration and vitreomacular traction. The regime for neovascular age-related macular degeneration included monthly intravitreal injections of aflibercept in the left eye for four months. Two weeks after the second injection, a stage-three full-thickness macular hole was detected (Figure 1), with visual acuity decreased to 6/60. Combined cataract and macular hole surgery was successful and the vision in the left eye improved to 6/24.
Figure 1 Fundus photographs from Case 1
a. Full-thickness macular hole after aflibercept intravitreal injection, indicated by arrow.
b. Full-thickness macular hole after aflibercept intravitreal injection, indicated by arrow, with the use of red-free light.
Case 2
A 76-year-old female visited the emergency eye department with a one-week history of visual distortion in her right eye. The patient had an unremarkable past ocular history and her best corrected visual acuity was 6/18 in the right eye. OCT scan revealed the presence of subretinal fluid, intraretinal fluid, small pigment epithelial detachment, and also vitreomacular traction (Figure 2a). The diagnosis was neovascular age-related macular degeneration, and treatment with intravitreal injections of aflibercept was initiated. A week after the first injection, the patient attended the emergency eye department with symptoms of flashes and floaters, and her best corrected visual acuity dropped to 6/36 in the right eye. The patient underwent clinical examination, including examination of the peripheral retina. No evidence of peripheral retinal pathology was detected that potentially could justify the patient's symptoms. The patient underwent another OCT that revealed a significant reduction of the intraretinal fluid and the subretinal fluid, but full-thickness macular hole formation (Figure 2b). The patient referred to the vitreoretinal service and intravitreal aflibercept treatment resumed. Two months after the referral, the patient underwent combined cataract surgery and macular hole repair. Six weeks postoperatively, the best corrected visual acuity improved to 6/18 with complete closure of the full-thickness macular hole formation (Figure 2c).
Figure 2 Optical coherence tomography (OCT) photographs from Case 2
a. Pre-injection OCT: Presence of subretinal fluid, intraretinal fluid, small pigment epithelial detachment, and also a small degree of vitreomacular traction.
b. Post-injection OCT: Significant reduction of subretinal fluid, intraretinal fluid but formation of full-thickness macular hole.
c. Post-cataract and macular hole surgery OCT: Complete closure of the full-thickness macular hole.
Case 3
A 74-year-old male was treated with monthly aflibercept intravitreal injections for four months on account of neovascular age-related macular degeneration in the right eye. Vitreomacular traction was observed at initial diagnosis and the best corrected visual acuity was 6/36 preoperatively. One week after the second injection, a stage-three full-thickness macular hole was diagnosed with best corrected visual acuity being reduced to 6/60. Combined cataract and macular hole surgery was successful. Consequently, the vision in the right eye was increased to 6/36.
Discussion
The posterior hyaloid interface, consisting of the posterior hyaloid membrane and the internal limiting membrane, has been implicated in a number of macular diseases. The posterior hyaloid membrane, which is a true basement membrane, consists of collagen IV. The internal limiting membrane consists of collagen types I and IV, proteoglycans, fibronectin, and laminin. It varies in thickness and composition. Firm vitreoretinal attachments are observed in areas with a thin internal limiting membrane as present at the vitreous base, optic disk, fovea, and over the major retinal blood vessels [3, 4].
The mechanism of idiopathic full-thickness macular hole, as proposed by Gass, includes focal tangential traction on the fovea, resulting from contraction of the pre-foveal vitreous cortex [5]. An OCT study of macular holes in 1999 by Gaudric et al. indicated that vitreous traction is possible oblique and therefore both tangential and anterior-posterior trans-vitreal traction have been implicated in idiopathic full-thickness macular hole development [6].
Researchers studying full-thickness macular hole formation after ranibizumab intravitreal injections in neovascular age-related macular degeneration have reported five cases with pre-existing pigment epithelial detachment and vitreomacular traction that treated with Lucentis®. In cases where fully thickness macular holes developed, there was no pattern as to when the hole developed after intravitreal injections began [1].
Querques et al. proposed that vitreoretinal traction may be a possible result of vitreous incarceration in the injection’s entry site, induced by intravitreal injection. Full-thickness macular hole formation may be caused by forces imposed on the retinal pigment epithelium and the retinal surface, due to contraction of the choroidal neovascular membrane [7].
Clemens et al. suggested that the structure of the vitreous gel is modified when chemical compounds are applied to the vitreous cavity. As a consequence, incomplete posterior vitreous detachment and vitreomacular traction are possible to appear, leading to macular hole formation [8].
Another hypothesis by Grigoropoulos et al. was that intravitreal injections probably increase the traction on the fovea by causing vitreous syneresis, globe deformation during needle insertion, and vitreous incarceration at the insertion spot. Focal sites of traction on the retinal surface may be created by incomplete posterior vitreous detachment induced during the intravitreal injection. In pre-existing vitreomacular traction, this may lead to a full-thickness macular hole [9].
Oshima et al. described a case of full-thickness macular hole development after three aflibercept intravitreal injections in a patient with neovascular age-related macular degeneration. In this specific case, a preexisting retinal pigment epithelium tear was detected, but no information about pre-existing vitreomacular traction is provided. The researchers suggested that the rolled retinal pigment epithelium flap associated with the subretinal fibrosis caused traction on the fovea during aflibercept treatment. This traction on the site of the fovea resulted in progression to a full-thickness macular hole [2].
In all three cases of the present study, pre-existing vitreomacular traction was detected in OCT. It is suggested that this pathological element may be a significant risk factor related to the pathophysiological mechanism of full-thickness macular hole formation. It is possible that elevation of the foveal retina and stretching of the photoreceptor layer by physical forces may occur due to subfoveal pigment epithelial detachment. As a result, the structural support of the fovea may be affected. This makes it more susceptible to vitreofoveal tractional forces, which can initiate a neurosensory retinal detachment and ultimately a full-thickness macular hole. Dynamic alterations of flattening and elevation of pigment epithelium detachment resulting from injections might intensify the pre-existing pathological adhesion of the vitreous-retinal interface and subsequently cause the formation of a full-thickness macular hole. Thus, it is proposed that full-thickness macular hole formation is more a mechanical phenomenon rather than an aftereffect of the anti-VEGF chemical structure itself.
This is the first report of full-thickness macular hole formation after aflibercept intravitreal injection in patients with neovascular age-related macular degeneration and pre-existing vitreomacular traction. All patients underwent successful macular hole surgery. Moreover, visual acuity improved significantly and stabilized after macular hole repair surgery in all patients.
Conclusions
Overall, full-thickness macular hole seems to be a potential complication of anti-VEGF intravitreal injections, aflibercept in our cases, in patients with vitreomacular traction, and this should be taken into consideration. Consequently, patients with age-related macular degeneration and pre-existing vitreomacular traction before initiation of treatment with anti-VEGF should be informed by their clinician about the risk of full-thickness macular hole formation.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study. Hellenic Data Protection Authority issued approval 1808/ΓΝ/ΕΞ/75-2/01-02-2017. The research was approved by the Hellenic Data Protection Authority (Approval Number: 1808/ΓΝ/ΕΞ/75-2/01-02-2017) and followed the tenets of the Declaration of Helsinki.
We wish to thank Professor Nikolaos Ziakas and Professor Ioannis T. Tsinopoulos for their mentoring and encouragement. Also, we wish to acknowledge the contribution of Mr Andrew C. Browning for his support as supervising consultant of age-related macular degeneration patients. | AFLIBERCEPT | DrugsGivenReaction | CC BY | 33633901 | 18,945,478 | 2021-01-23 |
What was the administration route of drug 'AFLIBERCEPT'? | An Uncommon Aflibercept Side Effect: Full Thickness Macular Hole Formation After Intravitreal Injections in Patients With Pre-existing Vitreomacular Traction.
Aflibercept is an intravitreally injected anti-vascular endothelial growth factor, commonly used in patients with several retinal pathologies, including neovascular age-related macular degeneration. We report a case series of three patients under treatment with an aflibercept regime for neovascular age-related macular degeneration, who were referred to vitreoretinal service between 2015-2016. In all cases, pre-existing vitreomacular traction was detected with an optical coherence tomography scan. All of them developed full-thickness macular hole after aflibercept intravitreal injections. The combined cataract and macular hole surgery was successful, with improvement in visual acuity. We suggest that dynamic alterations of the size of the pigment epithelium detachment resulting from intravitreal injections might intensify the pre-existing pathological adhesion of the vitreous-retinal interface and subsequently cause the formation of a full-thickness macular hole. Therefore, all practitioners treating patients with aflibercept intravitreal injections and pre-existing vitreomacular traction should be aware of the possible macular hole formation.
Introduction
Aflibercept is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF) - binding portions from the extracellular domains of human VEGF receptors one and two, which are fused to the fragment crystallizable (Fc) portion of the human immunoglobulin G1 (IgG1). A high volume of aflibercept intravitreal injections is performed for several retinal pathologies, including neovascular age-related macular degeneration. Adverse effects from aflibercept intravitreal injections, as per product information provided by manufacturers, do not include macular hole formation.
There have been reported only a few cases that associate intravitreal injections of anti-VEGF drugs with macular hole formation; only one case concerns aflibercept, without being mentioned whether pre-existing vitreomacular traction was present [1, 2]. This is the first report of full-thickness macular hole formation in patients with pre-existing vitreomacular traction.
Case presentation
Three patients with neovascular age-related macular degeneration, treated between 2015-2016, were included in the study. Optical coherence tomography (OCT) scan, SPECTRALIS HRA + OCT/Heidelberg Engineering (Franklin, MA, USA), was used to record both the vitreomacular traction and the full-thickness macular hole. Written informed consent was obtained from all patients. The research was approved by the Hellenic Data Protection Authority (Approval Number: 1808/ΓΝ/ΕΞ/75-2/01-02-2017) and followed the tenets of the Declaration of Helsinki.
Case 1
A 65-year-old female, presenting best corrected visual acuity 6/24 in her left eye, was diagnosed with neovascular age-related macular degeneration and vitreomacular traction. The regime for neovascular age-related macular degeneration included monthly intravitreal injections of aflibercept in the left eye for four months. Two weeks after the second injection, a stage-three full-thickness macular hole was detected (Figure 1), with visual acuity decreased to 6/60. Combined cataract and macular hole surgery was successful and the vision in the left eye improved to 6/24.
Figure 1 Fundus photographs from Case 1
a. Full-thickness macular hole after aflibercept intravitreal injection, indicated by arrow.
b. Full-thickness macular hole after aflibercept intravitreal injection, indicated by arrow, with the use of red-free light.
Case 2
A 76-year-old female visited the emergency eye department with a one-week history of visual distortion in her right eye. The patient had an unremarkable past ocular history and her best corrected visual acuity was 6/18 in the right eye. OCT scan revealed the presence of subretinal fluid, intraretinal fluid, small pigment epithelial detachment, and also vitreomacular traction (Figure 2a). The diagnosis was neovascular age-related macular degeneration, and treatment with intravitreal injections of aflibercept was initiated. A week after the first injection, the patient attended the emergency eye department with symptoms of flashes and floaters, and her best corrected visual acuity dropped to 6/36 in the right eye. The patient underwent clinical examination, including examination of the peripheral retina. No evidence of peripheral retinal pathology was detected that potentially could justify the patient's symptoms. The patient underwent another OCT that revealed a significant reduction of the intraretinal fluid and the subretinal fluid, but full-thickness macular hole formation (Figure 2b). The patient referred to the vitreoretinal service and intravitreal aflibercept treatment resumed. Two months after the referral, the patient underwent combined cataract surgery and macular hole repair. Six weeks postoperatively, the best corrected visual acuity improved to 6/18 with complete closure of the full-thickness macular hole formation (Figure 2c).
Figure 2 Optical coherence tomography (OCT) photographs from Case 2
a. Pre-injection OCT: Presence of subretinal fluid, intraretinal fluid, small pigment epithelial detachment, and also a small degree of vitreomacular traction.
b. Post-injection OCT: Significant reduction of subretinal fluid, intraretinal fluid but formation of full-thickness macular hole.
c. Post-cataract and macular hole surgery OCT: Complete closure of the full-thickness macular hole.
Case 3
A 74-year-old male was treated with monthly aflibercept intravitreal injections for four months on account of neovascular age-related macular degeneration in the right eye. Vitreomacular traction was observed at initial diagnosis and the best corrected visual acuity was 6/36 preoperatively. One week after the second injection, a stage-three full-thickness macular hole was diagnosed with best corrected visual acuity being reduced to 6/60. Combined cataract and macular hole surgery was successful. Consequently, the vision in the right eye was increased to 6/36.
Discussion
The posterior hyaloid interface, consisting of the posterior hyaloid membrane and the internal limiting membrane, has been implicated in a number of macular diseases. The posterior hyaloid membrane, which is a true basement membrane, consists of collagen IV. The internal limiting membrane consists of collagen types I and IV, proteoglycans, fibronectin, and laminin. It varies in thickness and composition. Firm vitreoretinal attachments are observed in areas with a thin internal limiting membrane as present at the vitreous base, optic disk, fovea, and over the major retinal blood vessels [3, 4].
The mechanism of idiopathic full-thickness macular hole, as proposed by Gass, includes focal tangential traction on the fovea, resulting from contraction of the pre-foveal vitreous cortex [5]. An OCT study of macular holes in 1999 by Gaudric et al. indicated that vitreous traction is possible oblique and therefore both tangential and anterior-posterior trans-vitreal traction have been implicated in idiopathic full-thickness macular hole development [6].
Researchers studying full-thickness macular hole formation after ranibizumab intravitreal injections in neovascular age-related macular degeneration have reported five cases with pre-existing pigment epithelial detachment and vitreomacular traction that treated with Lucentis®. In cases where fully thickness macular holes developed, there was no pattern as to when the hole developed after intravitreal injections began [1].
Querques et al. proposed that vitreoretinal traction may be a possible result of vitreous incarceration in the injection’s entry site, induced by intravitreal injection. Full-thickness macular hole formation may be caused by forces imposed on the retinal pigment epithelium and the retinal surface, due to contraction of the choroidal neovascular membrane [7].
Clemens et al. suggested that the structure of the vitreous gel is modified when chemical compounds are applied to the vitreous cavity. As a consequence, incomplete posterior vitreous detachment and vitreomacular traction are possible to appear, leading to macular hole formation [8].
Another hypothesis by Grigoropoulos et al. was that intravitreal injections probably increase the traction on the fovea by causing vitreous syneresis, globe deformation during needle insertion, and vitreous incarceration at the insertion spot. Focal sites of traction on the retinal surface may be created by incomplete posterior vitreous detachment induced during the intravitreal injection. In pre-existing vitreomacular traction, this may lead to a full-thickness macular hole [9].
Oshima et al. described a case of full-thickness macular hole development after three aflibercept intravitreal injections in a patient with neovascular age-related macular degeneration. In this specific case, a preexisting retinal pigment epithelium tear was detected, but no information about pre-existing vitreomacular traction is provided. The researchers suggested that the rolled retinal pigment epithelium flap associated with the subretinal fibrosis caused traction on the fovea during aflibercept treatment. This traction on the site of the fovea resulted in progression to a full-thickness macular hole [2].
In all three cases of the present study, pre-existing vitreomacular traction was detected in OCT. It is suggested that this pathological element may be a significant risk factor related to the pathophysiological mechanism of full-thickness macular hole formation. It is possible that elevation of the foveal retina and stretching of the photoreceptor layer by physical forces may occur due to subfoveal pigment epithelial detachment. As a result, the structural support of the fovea may be affected. This makes it more susceptible to vitreofoveal tractional forces, which can initiate a neurosensory retinal detachment and ultimately a full-thickness macular hole. Dynamic alterations of flattening and elevation of pigment epithelium detachment resulting from injections might intensify the pre-existing pathological adhesion of the vitreous-retinal interface and subsequently cause the formation of a full-thickness macular hole. Thus, it is proposed that full-thickness macular hole formation is more a mechanical phenomenon rather than an aftereffect of the anti-VEGF chemical structure itself.
This is the first report of full-thickness macular hole formation after aflibercept intravitreal injection in patients with neovascular age-related macular degeneration and pre-existing vitreomacular traction. All patients underwent successful macular hole surgery. Moreover, visual acuity improved significantly and stabilized after macular hole repair surgery in all patients.
Conclusions
Overall, full-thickness macular hole seems to be a potential complication of anti-VEGF intravitreal injections, aflibercept in our cases, in patients with vitreomacular traction, and this should be taken into consideration. Consequently, patients with age-related macular degeneration and pre-existing vitreomacular traction before initiation of treatment with anti-VEGF should be informed by their clinician about the risk of full-thickness macular hole formation.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study. Hellenic Data Protection Authority issued approval 1808/ΓΝ/ΕΞ/75-2/01-02-2017. The research was approved by the Hellenic Data Protection Authority (Approval Number: 1808/ΓΝ/ΕΞ/75-2/01-02-2017) and followed the tenets of the Declaration of Helsinki.
We wish to thank Professor Nikolaos Ziakas and Professor Ioannis T. Tsinopoulos for their mentoring and encouragement. Also, we wish to acknowledge the contribution of Mr Andrew C. Browning for his support as supervising consultant of age-related macular degeneration patients. | Intraocular | DrugAdministrationRoute | CC BY | 33633901 | 18,945,478 | 2021-01-23 |
What was the outcome of reaction 'Blindness'? | An Uncommon Aflibercept Side Effect: Full Thickness Macular Hole Formation After Intravitreal Injections in Patients With Pre-existing Vitreomacular Traction.
Aflibercept is an intravitreally injected anti-vascular endothelial growth factor, commonly used in patients with several retinal pathologies, including neovascular age-related macular degeneration. We report a case series of three patients under treatment with an aflibercept regime for neovascular age-related macular degeneration, who were referred to vitreoretinal service between 2015-2016. In all cases, pre-existing vitreomacular traction was detected with an optical coherence tomography scan. All of them developed full-thickness macular hole after aflibercept intravitreal injections. The combined cataract and macular hole surgery was successful, with improvement in visual acuity. We suggest that dynamic alterations of the size of the pigment epithelium detachment resulting from intravitreal injections might intensify the pre-existing pathological adhesion of the vitreous-retinal interface and subsequently cause the formation of a full-thickness macular hole. Therefore, all practitioners treating patients with aflibercept intravitreal injections and pre-existing vitreomacular traction should be aware of the possible macular hole formation.
Introduction
Aflibercept is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF) - binding portions from the extracellular domains of human VEGF receptors one and two, which are fused to the fragment crystallizable (Fc) portion of the human immunoglobulin G1 (IgG1). A high volume of aflibercept intravitreal injections is performed for several retinal pathologies, including neovascular age-related macular degeneration. Adverse effects from aflibercept intravitreal injections, as per product information provided by manufacturers, do not include macular hole formation.
There have been reported only a few cases that associate intravitreal injections of anti-VEGF drugs with macular hole formation; only one case concerns aflibercept, without being mentioned whether pre-existing vitreomacular traction was present [1, 2]. This is the first report of full-thickness macular hole formation in patients with pre-existing vitreomacular traction.
Case presentation
Three patients with neovascular age-related macular degeneration, treated between 2015-2016, were included in the study. Optical coherence tomography (OCT) scan, SPECTRALIS HRA + OCT/Heidelberg Engineering (Franklin, MA, USA), was used to record both the vitreomacular traction and the full-thickness macular hole. Written informed consent was obtained from all patients. The research was approved by the Hellenic Data Protection Authority (Approval Number: 1808/ΓΝ/ΕΞ/75-2/01-02-2017) and followed the tenets of the Declaration of Helsinki.
Case 1
A 65-year-old female, presenting best corrected visual acuity 6/24 in her left eye, was diagnosed with neovascular age-related macular degeneration and vitreomacular traction. The regime for neovascular age-related macular degeneration included monthly intravitreal injections of aflibercept in the left eye for four months. Two weeks after the second injection, a stage-three full-thickness macular hole was detected (Figure 1), with visual acuity decreased to 6/60. Combined cataract and macular hole surgery was successful and the vision in the left eye improved to 6/24.
Figure 1 Fundus photographs from Case 1
a. Full-thickness macular hole after aflibercept intravitreal injection, indicated by arrow.
b. Full-thickness macular hole after aflibercept intravitreal injection, indicated by arrow, with the use of red-free light.
Case 2
A 76-year-old female visited the emergency eye department with a one-week history of visual distortion in her right eye. The patient had an unremarkable past ocular history and her best corrected visual acuity was 6/18 in the right eye. OCT scan revealed the presence of subretinal fluid, intraretinal fluid, small pigment epithelial detachment, and also vitreomacular traction (Figure 2a). The diagnosis was neovascular age-related macular degeneration, and treatment with intravitreal injections of aflibercept was initiated. A week after the first injection, the patient attended the emergency eye department with symptoms of flashes and floaters, and her best corrected visual acuity dropped to 6/36 in the right eye. The patient underwent clinical examination, including examination of the peripheral retina. No evidence of peripheral retinal pathology was detected that potentially could justify the patient's symptoms. The patient underwent another OCT that revealed a significant reduction of the intraretinal fluid and the subretinal fluid, but full-thickness macular hole formation (Figure 2b). The patient referred to the vitreoretinal service and intravitreal aflibercept treatment resumed. Two months after the referral, the patient underwent combined cataract surgery and macular hole repair. Six weeks postoperatively, the best corrected visual acuity improved to 6/18 with complete closure of the full-thickness macular hole formation (Figure 2c).
Figure 2 Optical coherence tomography (OCT) photographs from Case 2
a. Pre-injection OCT: Presence of subretinal fluid, intraretinal fluid, small pigment epithelial detachment, and also a small degree of vitreomacular traction.
b. Post-injection OCT: Significant reduction of subretinal fluid, intraretinal fluid but formation of full-thickness macular hole.
c. Post-cataract and macular hole surgery OCT: Complete closure of the full-thickness macular hole.
Case 3
A 74-year-old male was treated with monthly aflibercept intravitreal injections for four months on account of neovascular age-related macular degeneration in the right eye. Vitreomacular traction was observed at initial diagnosis and the best corrected visual acuity was 6/36 preoperatively. One week after the second injection, a stage-three full-thickness macular hole was diagnosed with best corrected visual acuity being reduced to 6/60. Combined cataract and macular hole surgery was successful. Consequently, the vision in the right eye was increased to 6/36.
Discussion
The posterior hyaloid interface, consisting of the posterior hyaloid membrane and the internal limiting membrane, has been implicated in a number of macular diseases. The posterior hyaloid membrane, which is a true basement membrane, consists of collagen IV. The internal limiting membrane consists of collagen types I and IV, proteoglycans, fibronectin, and laminin. It varies in thickness and composition. Firm vitreoretinal attachments are observed in areas with a thin internal limiting membrane as present at the vitreous base, optic disk, fovea, and over the major retinal blood vessels [3, 4].
The mechanism of idiopathic full-thickness macular hole, as proposed by Gass, includes focal tangential traction on the fovea, resulting from contraction of the pre-foveal vitreous cortex [5]. An OCT study of macular holes in 1999 by Gaudric et al. indicated that vitreous traction is possible oblique and therefore both tangential and anterior-posterior trans-vitreal traction have been implicated in idiopathic full-thickness macular hole development [6].
Researchers studying full-thickness macular hole formation after ranibizumab intravitreal injections in neovascular age-related macular degeneration have reported five cases with pre-existing pigment epithelial detachment and vitreomacular traction that treated with Lucentis®. In cases where fully thickness macular holes developed, there was no pattern as to when the hole developed after intravitreal injections began [1].
Querques et al. proposed that vitreoretinal traction may be a possible result of vitreous incarceration in the injection’s entry site, induced by intravitreal injection. Full-thickness macular hole formation may be caused by forces imposed on the retinal pigment epithelium and the retinal surface, due to contraction of the choroidal neovascular membrane [7].
Clemens et al. suggested that the structure of the vitreous gel is modified when chemical compounds are applied to the vitreous cavity. As a consequence, incomplete posterior vitreous detachment and vitreomacular traction are possible to appear, leading to macular hole formation [8].
Another hypothesis by Grigoropoulos et al. was that intravitreal injections probably increase the traction on the fovea by causing vitreous syneresis, globe deformation during needle insertion, and vitreous incarceration at the insertion spot. Focal sites of traction on the retinal surface may be created by incomplete posterior vitreous detachment induced during the intravitreal injection. In pre-existing vitreomacular traction, this may lead to a full-thickness macular hole [9].
Oshima et al. described a case of full-thickness macular hole development after three aflibercept intravitreal injections in a patient with neovascular age-related macular degeneration. In this specific case, a preexisting retinal pigment epithelium tear was detected, but no information about pre-existing vitreomacular traction is provided. The researchers suggested that the rolled retinal pigment epithelium flap associated with the subretinal fibrosis caused traction on the fovea during aflibercept treatment. This traction on the site of the fovea resulted in progression to a full-thickness macular hole [2].
In all three cases of the present study, pre-existing vitreomacular traction was detected in OCT. It is suggested that this pathological element may be a significant risk factor related to the pathophysiological mechanism of full-thickness macular hole formation. It is possible that elevation of the foveal retina and stretching of the photoreceptor layer by physical forces may occur due to subfoveal pigment epithelial detachment. As a result, the structural support of the fovea may be affected. This makes it more susceptible to vitreofoveal tractional forces, which can initiate a neurosensory retinal detachment and ultimately a full-thickness macular hole. Dynamic alterations of flattening and elevation of pigment epithelium detachment resulting from injections might intensify the pre-existing pathological adhesion of the vitreous-retinal interface and subsequently cause the formation of a full-thickness macular hole. Thus, it is proposed that full-thickness macular hole formation is more a mechanical phenomenon rather than an aftereffect of the anti-VEGF chemical structure itself.
This is the first report of full-thickness macular hole formation after aflibercept intravitreal injection in patients with neovascular age-related macular degeneration and pre-existing vitreomacular traction. All patients underwent successful macular hole surgery. Moreover, visual acuity improved significantly and stabilized after macular hole repair surgery in all patients.
Conclusions
Overall, full-thickness macular hole seems to be a potential complication of anti-VEGF intravitreal injections, aflibercept in our cases, in patients with vitreomacular traction, and this should be taken into consideration. Consequently, patients with age-related macular degeneration and pre-existing vitreomacular traction before initiation of treatment with anti-VEGF should be informed by their clinician about the risk of full-thickness macular hole formation.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study. Hellenic Data Protection Authority issued approval 1808/ΓΝ/ΕΞ/75-2/01-02-2017. The research was approved by the Hellenic Data Protection Authority (Approval Number: 1808/ΓΝ/ΕΞ/75-2/01-02-2017) and followed the tenets of the Declaration of Helsinki.
We wish to thank Professor Nikolaos Ziakas and Professor Ioannis T. Tsinopoulos for their mentoring and encouragement. Also, we wish to acknowledge the contribution of Mr Andrew C. Browning for his support as supervising consultant of age-related macular degeneration patients. | Recovering | ReactionOutcome | CC BY | 33633901 | 18,945,478 | 2021-01-23 |
What was the outcome of reaction 'Macular hole'? | An Uncommon Aflibercept Side Effect: Full Thickness Macular Hole Formation After Intravitreal Injections in Patients With Pre-existing Vitreomacular Traction.
Aflibercept is an intravitreally injected anti-vascular endothelial growth factor, commonly used in patients with several retinal pathologies, including neovascular age-related macular degeneration. We report a case series of three patients under treatment with an aflibercept regime for neovascular age-related macular degeneration, who were referred to vitreoretinal service between 2015-2016. In all cases, pre-existing vitreomacular traction was detected with an optical coherence tomography scan. All of them developed full-thickness macular hole after aflibercept intravitreal injections. The combined cataract and macular hole surgery was successful, with improvement in visual acuity. We suggest that dynamic alterations of the size of the pigment epithelium detachment resulting from intravitreal injections might intensify the pre-existing pathological adhesion of the vitreous-retinal interface and subsequently cause the formation of a full-thickness macular hole. Therefore, all practitioners treating patients with aflibercept intravitreal injections and pre-existing vitreomacular traction should be aware of the possible macular hole formation.
Introduction
Aflibercept is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF) - binding portions from the extracellular domains of human VEGF receptors one and two, which are fused to the fragment crystallizable (Fc) portion of the human immunoglobulin G1 (IgG1). A high volume of aflibercept intravitreal injections is performed for several retinal pathologies, including neovascular age-related macular degeneration. Adverse effects from aflibercept intravitreal injections, as per product information provided by manufacturers, do not include macular hole formation.
There have been reported only a few cases that associate intravitreal injections of anti-VEGF drugs with macular hole formation; only one case concerns aflibercept, without being mentioned whether pre-existing vitreomacular traction was present [1, 2]. This is the first report of full-thickness macular hole formation in patients with pre-existing vitreomacular traction.
Case presentation
Three patients with neovascular age-related macular degeneration, treated between 2015-2016, were included in the study. Optical coherence tomography (OCT) scan, SPECTRALIS HRA + OCT/Heidelberg Engineering (Franklin, MA, USA), was used to record both the vitreomacular traction and the full-thickness macular hole. Written informed consent was obtained from all patients. The research was approved by the Hellenic Data Protection Authority (Approval Number: 1808/ΓΝ/ΕΞ/75-2/01-02-2017) and followed the tenets of the Declaration of Helsinki.
Case 1
A 65-year-old female, presenting best corrected visual acuity 6/24 in her left eye, was diagnosed with neovascular age-related macular degeneration and vitreomacular traction. The regime for neovascular age-related macular degeneration included monthly intravitreal injections of aflibercept in the left eye for four months. Two weeks after the second injection, a stage-three full-thickness macular hole was detected (Figure 1), with visual acuity decreased to 6/60. Combined cataract and macular hole surgery was successful and the vision in the left eye improved to 6/24.
Figure 1 Fundus photographs from Case 1
a. Full-thickness macular hole after aflibercept intravitreal injection, indicated by arrow.
b. Full-thickness macular hole after aflibercept intravitreal injection, indicated by arrow, with the use of red-free light.
Case 2
A 76-year-old female visited the emergency eye department with a one-week history of visual distortion in her right eye. The patient had an unremarkable past ocular history and her best corrected visual acuity was 6/18 in the right eye. OCT scan revealed the presence of subretinal fluid, intraretinal fluid, small pigment epithelial detachment, and also vitreomacular traction (Figure 2a). The diagnosis was neovascular age-related macular degeneration, and treatment with intravitreal injections of aflibercept was initiated. A week after the first injection, the patient attended the emergency eye department with symptoms of flashes and floaters, and her best corrected visual acuity dropped to 6/36 in the right eye. The patient underwent clinical examination, including examination of the peripheral retina. No evidence of peripheral retinal pathology was detected that potentially could justify the patient's symptoms. The patient underwent another OCT that revealed a significant reduction of the intraretinal fluid and the subretinal fluid, but full-thickness macular hole formation (Figure 2b). The patient referred to the vitreoretinal service and intravitreal aflibercept treatment resumed. Two months after the referral, the patient underwent combined cataract surgery and macular hole repair. Six weeks postoperatively, the best corrected visual acuity improved to 6/18 with complete closure of the full-thickness macular hole formation (Figure 2c).
Figure 2 Optical coherence tomography (OCT) photographs from Case 2
a. Pre-injection OCT: Presence of subretinal fluid, intraretinal fluid, small pigment epithelial detachment, and also a small degree of vitreomacular traction.
b. Post-injection OCT: Significant reduction of subretinal fluid, intraretinal fluid but formation of full-thickness macular hole.
c. Post-cataract and macular hole surgery OCT: Complete closure of the full-thickness macular hole.
Case 3
A 74-year-old male was treated with monthly aflibercept intravitreal injections for four months on account of neovascular age-related macular degeneration in the right eye. Vitreomacular traction was observed at initial diagnosis and the best corrected visual acuity was 6/36 preoperatively. One week after the second injection, a stage-three full-thickness macular hole was diagnosed with best corrected visual acuity being reduced to 6/60. Combined cataract and macular hole surgery was successful. Consequently, the vision in the right eye was increased to 6/36.
Discussion
The posterior hyaloid interface, consisting of the posterior hyaloid membrane and the internal limiting membrane, has been implicated in a number of macular diseases. The posterior hyaloid membrane, which is a true basement membrane, consists of collagen IV. The internal limiting membrane consists of collagen types I and IV, proteoglycans, fibronectin, and laminin. It varies in thickness and composition. Firm vitreoretinal attachments are observed in areas with a thin internal limiting membrane as present at the vitreous base, optic disk, fovea, and over the major retinal blood vessels [3, 4].
The mechanism of idiopathic full-thickness macular hole, as proposed by Gass, includes focal tangential traction on the fovea, resulting from contraction of the pre-foveal vitreous cortex [5]. An OCT study of macular holes in 1999 by Gaudric et al. indicated that vitreous traction is possible oblique and therefore both tangential and anterior-posterior trans-vitreal traction have been implicated in idiopathic full-thickness macular hole development [6].
Researchers studying full-thickness macular hole formation after ranibizumab intravitreal injections in neovascular age-related macular degeneration have reported five cases with pre-existing pigment epithelial detachment and vitreomacular traction that treated with Lucentis®. In cases where fully thickness macular holes developed, there was no pattern as to when the hole developed after intravitreal injections began [1].
Querques et al. proposed that vitreoretinal traction may be a possible result of vitreous incarceration in the injection’s entry site, induced by intravitreal injection. Full-thickness macular hole formation may be caused by forces imposed on the retinal pigment epithelium and the retinal surface, due to contraction of the choroidal neovascular membrane [7].
Clemens et al. suggested that the structure of the vitreous gel is modified when chemical compounds are applied to the vitreous cavity. As a consequence, incomplete posterior vitreous detachment and vitreomacular traction are possible to appear, leading to macular hole formation [8].
Another hypothesis by Grigoropoulos et al. was that intravitreal injections probably increase the traction on the fovea by causing vitreous syneresis, globe deformation during needle insertion, and vitreous incarceration at the insertion spot. Focal sites of traction on the retinal surface may be created by incomplete posterior vitreous detachment induced during the intravitreal injection. In pre-existing vitreomacular traction, this may lead to a full-thickness macular hole [9].
Oshima et al. described a case of full-thickness macular hole development after three aflibercept intravitreal injections in a patient with neovascular age-related macular degeneration. In this specific case, a preexisting retinal pigment epithelium tear was detected, but no information about pre-existing vitreomacular traction is provided. The researchers suggested that the rolled retinal pigment epithelium flap associated with the subretinal fibrosis caused traction on the fovea during aflibercept treatment. This traction on the site of the fovea resulted in progression to a full-thickness macular hole [2].
In all three cases of the present study, pre-existing vitreomacular traction was detected in OCT. It is suggested that this pathological element may be a significant risk factor related to the pathophysiological mechanism of full-thickness macular hole formation. It is possible that elevation of the foveal retina and stretching of the photoreceptor layer by physical forces may occur due to subfoveal pigment epithelial detachment. As a result, the structural support of the fovea may be affected. This makes it more susceptible to vitreofoveal tractional forces, which can initiate a neurosensory retinal detachment and ultimately a full-thickness macular hole. Dynamic alterations of flattening and elevation of pigment epithelium detachment resulting from injections might intensify the pre-existing pathological adhesion of the vitreous-retinal interface and subsequently cause the formation of a full-thickness macular hole. Thus, it is proposed that full-thickness macular hole formation is more a mechanical phenomenon rather than an aftereffect of the anti-VEGF chemical structure itself.
This is the first report of full-thickness macular hole formation after aflibercept intravitreal injection in patients with neovascular age-related macular degeneration and pre-existing vitreomacular traction. All patients underwent successful macular hole surgery. Moreover, visual acuity improved significantly and stabilized after macular hole repair surgery in all patients.
Conclusions
Overall, full-thickness macular hole seems to be a potential complication of anti-VEGF intravitreal injections, aflibercept in our cases, in patients with vitreomacular traction, and this should be taken into consideration. Consequently, patients with age-related macular degeneration and pre-existing vitreomacular traction before initiation of treatment with anti-VEGF should be informed by their clinician about the risk of full-thickness macular hole formation.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study. Hellenic Data Protection Authority issued approval 1808/ΓΝ/ΕΞ/75-2/01-02-2017. The research was approved by the Hellenic Data Protection Authority (Approval Number: 1808/ΓΝ/ΕΞ/75-2/01-02-2017) and followed the tenets of the Declaration of Helsinki.
We wish to thank Professor Nikolaos Ziakas and Professor Ioannis T. Tsinopoulos for their mentoring and encouragement. Also, we wish to acknowledge the contribution of Mr Andrew C. Browning for his support as supervising consultant of age-related macular degeneration patients. | Recovered | ReactionOutcome | CC BY | 33633901 | 18,945,480 | 2021-01-23 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Depressed mood'. | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | ASPIRIN, ATORVASTATIN, CARVEDILOL, CLOPIDOGREL BISULFATE, DEUTETRABENAZINE, DOCUSATE, HYDRALAZINE HYDROCHLORIDE, LEVOTHYROXINE, NIFEDIPINE, QUETIAPINE | DrugsGivenReaction | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Overdose'. | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | ASPIRIN, ATORVASTATIN, CARVEDILOL, CLOPIDOGREL BISULFATE, DEUTETRABENAZINE, DOCUSATE, HYDRALAZINE HYDROCHLORIDE, LEVOTHYROXINE, NIFEDIPINE, QUETIAPINE | DrugsGivenReaction | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Somnolence'. | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | ASPIRIN, ATORVASTATIN, CARVEDILOL, CLOPIDOGREL BISULFATE, DEUTETRABENAZINE, DOCUSATE, HYDRALAZINE HYDROCHLORIDE, LEVOTHYROXINE, NIFEDIPINE, QUETIAPINE | DrugsGivenReaction | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the administration route of drug 'ASPIRIN'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the administration route of drug 'ATORVASTATIN'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the administration route of drug 'CARVEDILOL'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the administration route of drug 'CLOPIDOGREL BISULFATE'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the administration route of drug 'DEUTETRABENAZINE'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the administration route of drug 'DOCUSATE'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the administration route of drug 'HYDRALAZINE HYDROCHLORIDE'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the administration route of drug 'LEVOTHYROXINE'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the administration route of drug 'NIFEDIPINE'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the administration route of drug 'QUETIAPINE'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the dosage of drug 'ASPIRIN'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | 81 MILLIGRAM DAILY; | DrugDosageText | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the dosage of drug 'ATORVASTATIN'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | 40 MILLIGRAM DAILY; | DrugDosageText | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the dosage of drug 'CLOPIDOGREL BISULFATE'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | 75 MILLIGRAM DAILY; | DrugDosageText | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the dosage of drug 'DEUTETRABENAZINE'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | 12 MILLIGRAM DAILY; | DrugDosageText | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the dosage of drug 'LEVOTHYROXINE'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | 125 MICROGRAM DAILY; | DrugDosageText | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the dosage of drug 'NIFEDIPINE'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | 90 MILLIGRAM DAILY; | DrugDosageText | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
What was the dosage of drug 'QUETIAPINE'? | Benign Presentation Following Massive Deutetrabenazine Overdose.
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.
Introduction
Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.
Case presentation
A 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.
Her vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.
Table 1 Patient’s outpatient medications prior to overdose presentation
Mg: milligrams, mCg: microgram, Cap: capsule
Drug Dose
Aspirin 81 mg by mouth, daily
Atorvastatin 40 mg by mouth, daily
Carvedilol 12.5 mg by mouth, twice daily
Clopidogrel 75 mg by mouth, daily
Deutetrabenazine 12 mg by mouth, daily
Docusate One Cap 100 mg by mouth, twice daily
Hydralazine 75 mg by mouth, three times daily
Levothyroxine 125 mCg by mouth, daily
Nifedipine Tab 90 mg by mouth, daily
Quetiapine Tab 50 mg by mouth, before bed
Electrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.
The toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.
Discussion
Before the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].
DTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].
Although it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.
In this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].
The diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.
Conclusions
DTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | 50 MILLIGRAM DAILY; BEFORE BED | DrugDosageText | CC BY | 33633914 | 18,962,515 | 2021-01-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Glomerulonephritis membranous'. | Membranous nephropathy in a patient with coronavirus disease 2019 (COVID-19): A case report.
BACKGROUND
Though respiratory, immune, and coagulation systems are major targets of coronavirus disease 2019 (COVID-19), kidney dysfunction, presenting with acute kidney injury (AKI), is also common. Most AKI cases in COVID-19 manifest as acute tubular injury (ATI) in conjunction with multiorgan failure. While initial renal pathological findings were limited to acute tubular necrosis and collapsing glomerulopathy, a recent case series reported a larger spectrum of findings.
METHODS
Here, we report a case of membranous nephropathy (MN) in an 81-year-old Hispanic man with underlying chronic kidney disease (CKD) stage 3 who developed ATI in the setting of COVID-19. The patient was hospitalized for hypoxic respiratory failure in the setting of AKI stage 3 with serum creatinine 7.1 mg/dL 6 days after a positive-SARS-CoV-2 screening. He was found to have nephrotic range proteinuria, glycosuria (with normal serum glucose), anemia, and hypoalbuminemia. Kidney biopsy showed ATI and early MN. Workup for primary and secondary MN was unrevealing, and serum PLA2R antibody was negative. No viral particles were observed in podocytes.
CONCLUSIONS
Although the MN could be incidental, this observation raises the question of whether SARS-CoV-2 infection can trigger or worsen an underlying MN from an exaggerated immune response associated with COVID-19.
Introduction
Coronavirus disease 2019 (COVID-19), caused by a coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide since December 2019 [1].The principle feature of COVID-19 is viral pneumonia, leading to acute respiratory distress syndrome (ARDS) [2]. Similar to other coronaviruses, angiotensin-converting enzyme 2 (ACE2) may play a major role in the entry of SARS-CoV-2 to its target cells [3]. Besides the respiratory system, ACE2 is also highly expressed in the brush border of proximal tubular cells and, to a lesser extent, in glomerular podocytes [4]. Kidney involvement of COVID-19, mainly presents as acute kidney injury (AKI) [5], primarily due to acute tubular injury (ATI) in the setting of multiorgan failure. Clinically, the incidence of AKI in COVID-19 varies from 0.9 to 29% in hospitalized or critically ill patients at different centers [6, 7, 8] and is associated with worse outcomes [5, 9]. ATI and direct parenchymal infection of tubular epithelial cells and podocytes were reported in 26 postmortem examinations of patients with severe COVID-19 [10]. Proteinuria and hematuria are also common, occurring in 44 and 27%, respectively [5]. Kidney biopsy findings have been reported initially in four living COVID-19 cases, all of which showed collapsing glomerulopathy [11, 12, 13, 14]. Recently, two case series of kidney biopsy findings showed that ATI was the most common finding in COVID-19-associated kidney injury, but the series by Kudose et al. [15, 16] reported a wide spectrum of glomerular and tubular disease including minimal change disease and membranous glomerulopathy. Here, we report a case of membranous nephropathy (MN) diagnosed in the setting of AKI associated with COVID-19.
Case report
An 81-year-old Hispanic man presented to the emergency department complaining of progressive fatigue and shortness of breath 6 days after being diagnosed with COVID-19 (positive nasopharyngeal SARS-CoV-2 PCR). He reported myalgia, sore throat, intermittent dry cough, loss of smell and taste, poor appetite, and nausea without vomiting. He also had diarrhea and an episode of urinary incontinence. He denied fever or chills, chest pain, and headache. Because of hypoxemia requiring high-flow oxygen, the patient was admitted to the critical care unit.
Previous medical history includes prostate cancer treated with chemotherapy and androgen deprivation therapy in 2013, in remission with undetectable prostate-specific antigen (PSA) since 2014, prediabetes, hyperlipidemia, hypertension, chronic kidney disease (CKD) stage 3 (baseline creatinine 1.2 – 1.6 mg/dL) attributed to hypertension with prior urine analysis in 2017 showing proteinuria of 385 mg/day, aortic valve stenosis, and cervical radiculopathy. Home medications included olmesartan 20 mg twice daily and hydrochlorothiazide 12.5 mg daily. Notably, he had a history of non-steroidal anti-inflammatory drugs (NSAIDs) use, 400 – 800 mg of ibuprofen per day for chronic neck pain. He is a former smoker but quit in 2012 and did not have lung disease.
Initial vital signs: temperature 37.4 °C, blood pressure 166/69 mmHg, heart rate 68 beats per minute, respiratory rate 27 breaths per minute, and peripheral capillary oxygen saturation (SpO2) 95% on high-flow nasal cannula (50 L/min with FiO2 of 100%). Physical examination was notable for tachypnea with the remainder of physical examination unremarkable.
Table 1 and Table 2 show his laboratory results. Repeat SARS-CoV-2 PCR via nasopharyngeal swab was positive. He had evidence of AKI stage 3 with a serum creatinine of 7.1 mg/dL. Urinalysis demonstrated 3 – 10 red blood cells per high power field, nephrotic range proteinuria of 4.6 g per 24 hours, glycosuria, and tubular epithelial cells. He had anemia with hemoglobin of 10.3 g/dL, hypoalbuminemia of 1.7 g/dL, and multiple elevated inflammatory markers, including interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin. Kidney ultrasound revealed bilaterally increased parenchymal echogenicity consistent with CKD. Chest radiograph showed indistinct pulmonary vasculature bilaterally with bronchocentric ground glass, and bilateral patchy infiltrates, consistent with COVID-19 pneumonia. Lower extremities Doppler did not reveal deep vein thromboses, and transthoracic echocardiogram was normal.
He was enrolled in a randomized placebo-controlled clinical trial of lenzilumab (monoclonal antibody targeting GM-CSF) 600 mg for 3 doses, in addition to intravenous antibiotics for possible superimposed community-acquired pneumonia. He completed a steroid trial with 5 days of intravenous methylprednisolone. Due to increasing D-dimer to 100,000 ng/mL, low-intensity heparin infusion was initiated.
Over the first few hospitalization days, creatinine remained elevated at ~ 7 mg/dL. He did not require dialysis as he maintained excellent urine output. Serologic testing for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), tuberculosis, as well as C3, C4, anti-neutrophil cytoplasmic antibodies (ANCA), anti-glomerular basement membrane (GBM), and anti-phospholipase A2 receptors (PLA2R) were all negative. Anti-THSD7A was indeterminate due to high background. No serum monoclonal proteins were detected. Kidney biopsy was performed on hospital day 4.
On hospital day 7, the patient’s respiratory status worsened requiring intubation, mechanical ventilation, and initiation of vasopressors. Despite that, his AKI was slowly recovering and creatinine reached 3.7 mg/dL on hospital day 11. However, the shock state subsequently worsened, continuous dialysis was started but eventually the patient died on hospital day 16. Family declined an autopsy.
Kidney pathology findings
19 glomeruli were sampled for light microscopy, 8 of which were globally sclerotic and 1 was segmentally sclerotic. The glomeruli showed segmental mild mesangial hypercellularity and mesangial expansion, with thickening of their basement membranes (Figure 1A). No collapsing features, endocapillary hypercellularity, thrombi, necrosis, or crescents were seen. The tubulointerstitial compartment exhibited diffuse ATI, tubular protein reabsorption granules, mild tubular atrophy and interstitial fibrosis, and very mild mononuclear cell infiltrate without tubulitis. There was moderate arteriosclerosis and arteriolar hyalinosis.
Immunofluorescence studies were unable to be performed due to an inadequate sample. Immunohistochemistry staining for PLA2R was performed on sections prepared from the paraffin block and was negative.
In situ hybridization (ISH) staining for the presence of SARS-CoV-2 RNA was performed using RNAScope (ACD, Newark, CA, USA) and failed to show evidence of viral RNA in the kidney (methods in Supplemental Material).
Electron microscopy showed abundant small granular sub-epithelial electron-dense deposits without or associated with early basement membrane spike formation (Figure 1B). The glomerular basement membrane lamina densa was thickened. There was mild mesangial sclerosis with segmental mesangial electron-dense deposits, without sub-endothelial deposits. Abundant tubuloreticular inclusion bodies were seen in the endothelial cell cytoplasm (Figure 1C). Podocytes exhibited severe foot process effacement.
The pathological diagnosis was MN (stage 1 to early stage 2), diffuse ATI, mild mesangial sclerosing glomerulopathy (associated with hypertension, pre-diabetes, and smoking), and moderate arteriosclerosis and arteriolar hyalinosis.
Discussion
To our knowledge, MN diagnosed in a patient with COVID-19 has been reported in only 2 patients in one case series of 17 patients [16]. The finding of severe ATI in this case is not surprising as reported in recent series of COVID-19 patients [10, 15]. However, the finding of MN was unexpected.
MN, an inflammatory and autoimmune disease of the glomerulus, is one of the most common causes of nephrotic syndrome in adults. The etiology of ~ 75% of MN is unknown “primary”. Secondary MN can be secondary to infection, drugs, and malignancy [18]. Thus, the main question is whether the MN in this case is related to SARS-CoV-2 or not. This patient had a history of prostate cancer, but he was in remission for at least 6 years with normal PSA, so it is unlikely that his cancer was the underlying cause of the MN. NSAIDs can cause proteinuria and have been associated with minimal change disease as well as MN, but the patient did not have prior evidence of nephrotic syndrome despite being on NSAIDs for many years. The absence of detectable anti-PLA2R antibodies, the negative glomerular staining for PLA2R and the presence of mesangial deposits, as well as abundant tubuloreticular inclusions favor secondary MN over primary MN. The patient had mild proteinuria (385 mg/day) prior to COVID-19 which is likely due to underlying mild mesangial sclerosing glomerulopathy (associated with hypertension, prediabetes, and smoking). MN was mostly stage 1 favoring a recent development of disease temporally associated with COVID-19 over pre-existing MN.
The pathogenesis of MN involves formation and deposition of immune complexes in sub-epithelial sites [18]. The receptor for SARS-CoV-2, ACE2, is highly expressed on proximal tubular cells and glomerular podocytes [4]. In addition, TMPRSS2, an essential serine protease, is required for spike glycoprotein of SARS-CoV-2 priming after binding to ACE2, and thus activates membrane fusion facilitating to gain access to its target cells [19]. In kidneys, expression of TMPRSS2 is only detectable in the proximal tubule S3 segment [20]. An in vitro study showed that the administration of TMPRSS2 inhibitor, camostat mesylate, had a valuable treatment effect, blocking multiple SARS-CoV-2 entry routes [21]. In postmortem kidney samples, SARS-CoV-2 antigens and viral particles were detected in the tubular epithelium and podocytes [10, 17]. In the case of collapsing glomerulopathy associated with COVID-19 reported by Kissling et al. [13], the virus was seen in podocytes by electron microscopy. However, most recent biopsy series fail to show viral particles in kidney biopsies by immunohistochemistry staining or by electron microscopy arguing against a direct viral infection of the kidneys [15, 16]. Similarly, in this case we did not find evidence of viral particles in the kidneys. Rather than a direct toxic viral effect on the kidneys, the ATI is most likely cytokine mediated, although the NSAID, angiotensin receptor blocker, and diuretic exposures could also have contributed. Whether MN can be secondary to SARS-CoV-2 remains to be elucidated, but we speculate that it could result from an exaggerated immune response associated with COVID-19. In the passive Heymann nephritis model, sub-epithelial deposits with very early basement membrane reaction could be seen as early as 7 days after injection [22]. Therefore, we hypothesize that the development of MN deposits could possibly occur quickly after a viral infection, or alternatively the COVID-19-related immune response and the resulting high-grade proteinuria could unmask an underlying MN. If this is the case, the treatment of this patient’s MN is conservative and immunosuppressive therapy is not recommended.
Funding
None.
Conflict of interest
The authors declare no relevant financial interest.
Supplemental material
ISH methods
In situ hybridization was performed with RNAScope (ACD, Newark, CA) using probes directed against SARS-CoV-2 on formalin-fixed paraffin-embedded tissue sections cut at a thickness of 3 microns. 1A negative control (bacterial gene dapB) was also included to assess background signals as well as positive control probes to the housekeeping gene peptidylprolyl isomerase B (PPIB). The ISH sections were counterstained using periodic acid-Schiff. (Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012; 14: 22-29).
Table 1. Laboratory data.
Laboratory test 1 year before
admission Day 1 Day 4
(Kidney biopsy) Day 7 Reference
Arterial blood gas
pH 7.43 7.36 7.29 7.35 – 7.45
pCO2, mmHg 23 27 38 32 – 45
pO2, mmHg 137 68 72 83 – 108
HCO3
-, mmol/L 15 15 18 22 – 26
Complete blood count
WBC count, 109/L 11.2 15.0 15.1 3.4 – 9.6
Neutrophils, 109/L 10.35 1.56 – 6.45
Lymphocytes, 109/L 0.46 0.95 – 3.07
Erythrocytes, 1012/L 3.37 3.40 2.36 4.35 – 5.65
Hemoglobin, g/dL 11.3 11.4 7.9 13.2 – 16.6
Reticulocytes, % 2.12 0.6 – 2.71
Platelet count, 109/L 449 436 295 135 – 317
Serum biochemistry
Sodium, mmol/L 138 139 138 135 – 145
Potassium, mmol/L 5.4 4.5 4.1 3.6 – 5.2
Chloride, mmol/L 100 99 103 98 – 107
Bicarbonate, mmol/L 17 17 19 22 – 29
Anion gap 21 23 17 7 – 15
BUN, mg/dL 98 133 128 8 – 24
Creatinine, mg/dL 1.4 7.05 6.96 4.41 0.74 – 1.35
eGFR, mL/min/BSA 49 < 15 < 15 < 15 > 60
eGFR by cystatin C, mL/min/BSA 6 > 60
Calcium, total, mg/dL 8.9 8.3 8.1 8.8 – 10.2
Calcium, ionized, mg/dL 4.40 4.57 4.62 4.65 – 5.30
Glucose, mg/dL 127 165 145 70 – 140
Magnesium, mg/dL 3.8 2.9 1.7 – 2.3
Phosphorus, mg/dL 11.5 7.9 2.5 – 4.5
Total protein, g/dL 4.4 4.5 6.3 – 7.9
Albumin, g/dL 1.7 2.6 3.5 – 5.0
Hemoglobin A1C, % 5.9 4 – 5.6
Lactate, mmol/L 1.3 1.1 0.5 – 2.2
Liver function
ALT, U/L 45 36 11 7 – 55
AST, U/L 43 49 22 8 – 48
Bilirubin, total, mg/dL 0.6 < 0.2 0.5 < 1.2
Bilirubin, direct, mg/dL 0.3 < 0.2 0.4 0.0 – 0.3
Alkaline protease, U/L 155 70 40 – 129
Lipid/cardiac risk
Total cholesterol, mg/dL 241 226 < 200
HDL, mg/dL 38 34 ≥ 40
LDL, mg/dL 153 131 < 100
Triglycerides, mg/dL 248 304 < 150
Troponin T, ng/L 71 160 < 15
Troponin T-2h, ng/L 80 153 < 15
Troponin T-6h, ng/L 87 152 < 15
NT-pro BNP, pg/mL 220 5,030 5 – 131
Creatinine kinase, U/L 108 39 – 308
Coagulation
Antithrombin activity 91 80 – 130%
D-dimer, ng/mL 13,286 > 100,000 48,550 < 500
Fibrinogen, Clauss, mg/dL > 800 561 200 – 500
Coag factor II 101 92 75 – 145%
Coag factor V 132 110 70 – 165%
Coag factor VII 116 83 65 – 180%
Coag factor X 131 86 70 – 150%
C-reactive protein, mg/L > 400 173.3 142.1 < 8
Soluble fibrin monomer, mcg/mL > 1,100 36 ≤ 8
Plasminogen activity 98 75 – 140%
α-2 plasmin inhibitor 105 80 – 140%
Sedimentation rate, mm/h > 140 123 3 – 28
Ferritin, µg/L 1,122 1,813 911 24 – 336
Serology
HBs antigen Negative Negative
HBc total Ab Negative Negative
HCV Ab screen Negative Negative
HIV-1/-2 Ag and Ab Negative Negative
Complement C3, mg/dL 163 75 – 175
Complement C4, mg/dL 36 13 – 40
C-ANCA Negative Negative
p-ANCA Negative Negative
Anti-GBM, U < 0.2 < 1 (negative)
Anti-phospholipase A2 receptor (IF) Negative Negative
Anti-phospholipase A2 receptor (ELISA), RU/mL < 2 < 14
Interleukin 6, pg/mL 39.5 3.5 5.7 < 1.8
Monoclonal gammopathy screen
κ free light chain, mg/dL 15.5 0.33 – 1.94
λ free light chain, mg/dL 8.73 0.57 – 2.63
κ/λ ratio 1.78 0.26 – 1.65
Total protein, g/dL 5.3 6.3 – 7.9
Albumin, g/dL 1.4 3.4 – 4.7
α-1 globulin, g/dL 0.6 0.1 – 0.3
α 2-globulin, g/dL 1.5 0.6 – 1.0
β globulin, g/dL 1.0 0.7 – 1.2
γ globulin, g/dL 0.8 0.6 – 1.6
A/G ratio 0.36
M protein isotype Cannot rule out small monoclonal protein
Endocrine
TSH, mIU/L 1.1 0.2 0.3 – 4.2
T4 (thyroxine), ng/dL 1.3 0.9 – 1.7
PTH, pg/mL 231 15 – 65
Tumor/malignancy marker
Prostate specific Ag, ng/mL 0.21 0.15 ≤ 7.2
Table 2. Urinalysis data.
Laboratory test 3 years prior to admission On admission Day 2 Reference range
Source Midstream Catheter Catheter
Appearance Normal Normal Normal
Osmolality, mOsm/kg 372 339 150 – 1150
pH 5.2 5.5 4.5 – 8.0
Glucose, mg/dL 5 81 12 0 – 15
Protein, mg/dL 17 339 117 < 26
Protein/Osmolality, ratio 0.39 9.11 3.45 < 0.42
Predicted 24 h protein, mg 385 7,735 3,066
24-h urine protein, mg/24 h 4,662 < 229
Hemoglobin Negative Trace Moderate Negative
Red blood cell 3 – 10 < 3/HPF
Dysmorphic RBC (%) < 25 < 25
White blood cell 1 – 3 1 – 3 1 – 3/HPF
Casts, hyaline 1 – 3 Occasional
Casts, granular Occasional
Fat, free Occasional Occasional
Fat, in casts Occasional
Oval fat body Occasional
Renal epithelial cells 1 – 3 None seen/HPF
Ketones Negative Negative
Nitrite Negative Negative
Leukocyte Negative Negative
Figure 1. Renal pathologic findings in this COVID-19 patient. A: Glomerulus showing thickening of the glomerular basement membrane with mild mesangial sclerosis and hypercellularity (silver stain, × 400). B: Glomerular capillary loop showing abundant small sub-epithelial electron-dense deposits. The overlying podocytes show extensive foot process effacement (electron microscopy, × 11,000). C: Large glomerular endothelial tubuloreticular inclusion is shown. Tiny sub-epithelial electron-dense deposits are also evident (electron microscopy, × 30,000). | HYDROCHLOROTHIAZIDE, OLMESARTAN | DrugsGivenReaction | CC BY | 33633925 | 19,326,783 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoalbuminaemia'. | Membranous nephropathy in a patient with coronavirus disease 2019 (COVID-19): A case report.
BACKGROUND
Though respiratory, immune, and coagulation systems are major targets of coronavirus disease 2019 (COVID-19), kidney dysfunction, presenting with acute kidney injury (AKI), is also common. Most AKI cases in COVID-19 manifest as acute tubular injury (ATI) in conjunction with multiorgan failure. While initial renal pathological findings were limited to acute tubular necrosis and collapsing glomerulopathy, a recent case series reported a larger spectrum of findings.
METHODS
Here, we report a case of membranous nephropathy (MN) in an 81-year-old Hispanic man with underlying chronic kidney disease (CKD) stage 3 who developed ATI in the setting of COVID-19. The patient was hospitalized for hypoxic respiratory failure in the setting of AKI stage 3 with serum creatinine 7.1 mg/dL 6 days after a positive-SARS-CoV-2 screening. He was found to have nephrotic range proteinuria, glycosuria (with normal serum glucose), anemia, and hypoalbuminemia. Kidney biopsy showed ATI and early MN. Workup for primary and secondary MN was unrevealing, and serum PLA2R antibody was negative. No viral particles were observed in podocytes.
CONCLUSIONS
Although the MN could be incidental, this observation raises the question of whether SARS-CoV-2 infection can trigger or worsen an underlying MN from an exaggerated immune response associated with COVID-19.
Introduction
Coronavirus disease 2019 (COVID-19), caused by a coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide since December 2019 [1].The principle feature of COVID-19 is viral pneumonia, leading to acute respiratory distress syndrome (ARDS) [2]. Similar to other coronaviruses, angiotensin-converting enzyme 2 (ACE2) may play a major role in the entry of SARS-CoV-2 to its target cells [3]. Besides the respiratory system, ACE2 is also highly expressed in the brush border of proximal tubular cells and, to a lesser extent, in glomerular podocytes [4]. Kidney involvement of COVID-19, mainly presents as acute kidney injury (AKI) [5], primarily due to acute tubular injury (ATI) in the setting of multiorgan failure. Clinically, the incidence of AKI in COVID-19 varies from 0.9 to 29% in hospitalized or critically ill patients at different centers [6, 7, 8] and is associated with worse outcomes [5, 9]. ATI and direct parenchymal infection of tubular epithelial cells and podocytes were reported in 26 postmortem examinations of patients with severe COVID-19 [10]. Proteinuria and hematuria are also common, occurring in 44 and 27%, respectively [5]. Kidney biopsy findings have been reported initially in four living COVID-19 cases, all of which showed collapsing glomerulopathy [11, 12, 13, 14]. Recently, two case series of kidney biopsy findings showed that ATI was the most common finding in COVID-19-associated kidney injury, but the series by Kudose et al. [15, 16] reported a wide spectrum of glomerular and tubular disease including minimal change disease and membranous glomerulopathy. Here, we report a case of membranous nephropathy (MN) diagnosed in the setting of AKI associated with COVID-19.
Case report
An 81-year-old Hispanic man presented to the emergency department complaining of progressive fatigue and shortness of breath 6 days after being diagnosed with COVID-19 (positive nasopharyngeal SARS-CoV-2 PCR). He reported myalgia, sore throat, intermittent dry cough, loss of smell and taste, poor appetite, and nausea without vomiting. He also had diarrhea and an episode of urinary incontinence. He denied fever or chills, chest pain, and headache. Because of hypoxemia requiring high-flow oxygen, the patient was admitted to the critical care unit.
Previous medical history includes prostate cancer treated with chemotherapy and androgen deprivation therapy in 2013, in remission with undetectable prostate-specific antigen (PSA) since 2014, prediabetes, hyperlipidemia, hypertension, chronic kidney disease (CKD) stage 3 (baseline creatinine 1.2 – 1.6 mg/dL) attributed to hypertension with prior urine analysis in 2017 showing proteinuria of 385 mg/day, aortic valve stenosis, and cervical radiculopathy. Home medications included olmesartan 20 mg twice daily and hydrochlorothiazide 12.5 mg daily. Notably, he had a history of non-steroidal anti-inflammatory drugs (NSAIDs) use, 400 – 800 mg of ibuprofen per day for chronic neck pain. He is a former smoker but quit in 2012 and did not have lung disease.
Initial vital signs: temperature 37.4 °C, blood pressure 166/69 mmHg, heart rate 68 beats per minute, respiratory rate 27 breaths per minute, and peripheral capillary oxygen saturation (SpO2) 95% on high-flow nasal cannula (50 L/min with FiO2 of 100%). Physical examination was notable for tachypnea with the remainder of physical examination unremarkable.
Table 1 and Table 2 show his laboratory results. Repeat SARS-CoV-2 PCR via nasopharyngeal swab was positive. He had evidence of AKI stage 3 with a serum creatinine of 7.1 mg/dL. Urinalysis demonstrated 3 – 10 red blood cells per high power field, nephrotic range proteinuria of 4.6 g per 24 hours, glycosuria, and tubular epithelial cells. He had anemia with hemoglobin of 10.3 g/dL, hypoalbuminemia of 1.7 g/dL, and multiple elevated inflammatory markers, including interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin. Kidney ultrasound revealed bilaterally increased parenchymal echogenicity consistent with CKD. Chest radiograph showed indistinct pulmonary vasculature bilaterally with bronchocentric ground glass, and bilateral patchy infiltrates, consistent with COVID-19 pneumonia. Lower extremities Doppler did not reveal deep vein thromboses, and transthoracic echocardiogram was normal.
He was enrolled in a randomized placebo-controlled clinical trial of lenzilumab (monoclonal antibody targeting GM-CSF) 600 mg for 3 doses, in addition to intravenous antibiotics for possible superimposed community-acquired pneumonia. He completed a steroid trial with 5 days of intravenous methylprednisolone. Due to increasing D-dimer to 100,000 ng/mL, low-intensity heparin infusion was initiated.
Over the first few hospitalization days, creatinine remained elevated at ~ 7 mg/dL. He did not require dialysis as he maintained excellent urine output. Serologic testing for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), tuberculosis, as well as C3, C4, anti-neutrophil cytoplasmic antibodies (ANCA), anti-glomerular basement membrane (GBM), and anti-phospholipase A2 receptors (PLA2R) were all negative. Anti-THSD7A was indeterminate due to high background. No serum monoclonal proteins were detected. Kidney biopsy was performed on hospital day 4.
On hospital day 7, the patient’s respiratory status worsened requiring intubation, mechanical ventilation, and initiation of vasopressors. Despite that, his AKI was slowly recovering and creatinine reached 3.7 mg/dL on hospital day 11. However, the shock state subsequently worsened, continuous dialysis was started but eventually the patient died on hospital day 16. Family declined an autopsy.
Kidney pathology findings
19 glomeruli were sampled for light microscopy, 8 of which were globally sclerotic and 1 was segmentally sclerotic. The glomeruli showed segmental mild mesangial hypercellularity and mesangial expansion, with thickening of their basement membranes (Figure 1A). No collapsing features, endocapillary hypercellularity, thrombi, necrosis, or crescents were seen. The tubulointerstitial compartment exhibited diffuse ATI, tubular protein reabsorption granules, mild tubular atrophy and interstitial fibrosis, and very mild mononuclear cell infiltrate without tubulitis. There was moderate arteriosclerosis and arteriolar hyalinosis.
Immunofluorescence studies were unable to be performed due to an inadequate sample. Immunohistochemistry staining for PLA2R was performed on sections prepared from the paraffin block and was negative.
In situ hybridization (ISH) staining for the presence of SARS-CoV-2 RNA was performed using RNAScope (ACD, Newark, CA, USA) and failed to show evidence of viral RNA in the kidney (methods in Supplemental Material).
Electron microscopy showed abundant small granular sub-epithelial electron-dense deposits without or associated with early basement membrane spike formation (Figure 1B). The glomerular basement membrane lamina densa was thickened. There was mild mesangial sclerosis with segmental mesangial electron-dense deposits, without sub-endothelial deposits. Abundant tubuloreticular inclusion bodies were seen in the endothelial cell cytoplasm (Figure 1C). Podocytes exhibited severe foot process effacement.
The pathological diagnosis was MN (stage 1 to early stage 2), diffuse ATI, mild mesangial sclerosing glomerulopathy (associated with hypertension, pre-diabetes, and smoking), and moderate arteriosclerosis and arteriolar hyalinosis.
Discussion
To our knowledge, MN diagnosed in a patient with COVID-19 has been reported in only 2 patients in one case series of 17 patients [16]. The finding of severe ATI in this case is not surprising as reported in recent series of COVID-19 patients [10, 15]. However, the finding of MN was unexpected.
MN, an inflammatory and autoimmune disease of the glomerulus, is one of the most common causes of nephrotic syndrome in adults. The etiology of ~ 75% of MN is unknown “primary”. Secondary MN can be secondary to infection, drugs, and malignancy [18]. Thus, the main question is whether the MN in this case is related to SARS-CoV-2 or not. This patient had a history of prostate cancer, but he was in remission for at least 6 years with normal PSA, so it is unlikely that his cancer was the underlying cause of the MN. NSAIDs can cause proteinuria and have been associated with minimal change disease as well as MN, but the patient did not have prior evidence of nephrotic syndrome despite being on NSAIDs for many years. The absence of detectable anti-PLA2R antibodies, the negative glomerular staining for PLA2R and the presence of mesangial deposits, as well as abundant tubuloreticular inclusions favor secondary MN over primary MN. The patient had mild proteinuria (385 mg/day) prior to COVID-19 which is likely due to underlying mild mesangial sclerosing glomerulopathy (associated with hypertension, prediabetes, and smoking). MN was mostly stage 1 favoring a recent development of disease temporally associated with COVID-19 over pre-existing MN.
The pathogenesis of MN involves formation and deposition of immune complexes in sub-epithelial sites [18]. The receptor for SARS-CoV-2, ACE2, is highly expressed on proximal tubular cells and glomerular podocytes [4]. In addition, TMPRSS2, an essential serine protease, is required for spike glycoprotein of SARS-CoV-2 priming after binding to ACE2, and thus activates membrane fusion facilitating to gain access to its target cells [19]. In kidneys, expression of TMPRSS2 is only detectable in the proximal tubule S3 segment [20]. An in vitro study showed that the administration of TMPRSS2 inhibitor, camostat mesylate, had a valuable treatment effect, blocking multiple SARS-CoV-2 entry routes [21]. In postmortem kidney samples, SARS-CoV-2 antigens and viral particles were detected in the tubular epithelium and podocytes [10, 17]. In the case of collapsing glomerulopathy associated with COVID-19 reported by Kissling et al. [13], the virus was seen in podocytes by electron microscopy. However, most recent biopsy series fail to show viral particles in kidney biopsies by immunohistochemistry staining or by electron microscopy arguing against a direct viral infection of the kidneys [15, 16]. Similarly, in this case we did not find evidence of viral particles in the kidneys. Rather than a direct toxic viral effect on the kidneys, the ATI is most likely cytokine mediated, although the NSAID, angiotensin receptor blocker, and diuretic exposures could also have contributed. Whether MN can be secondary to SARS-CoV-2 remains to be elucidated, but we speculate that it could result from an exaggerated immune response associated with COVID-19. In the passive Heymann nephritis model, sub-epithelial deposits with very early basement membrane reaction could be seen as early as 7 days after injection [22]. Therefore, we hypothesize that the development of MN deposits could possibly occur quickly after a viral infection, or alternatively the COVID-19-related immune response and the resulting high-grade proteinuria could unmask an underlying MN. If this is the case, the treatment of this patient’s MN is conservative and immunosuppressive therapy is not recommended.
Funding
None.
Conflict of interest
The authors declare no relevant financial interest.
Supplemental material
ISH methods
In situ hybridization was performed with RNAScope (ACD, Newark, CA) using probes directed against SARS-CoV-2 on formalin-fixed paraffin-embedded tissue sections cut at a thickness of 3 microns. 1A negative control (bacterial gene dapB) was also included to assess background signals as well as positive control probes to the housekeeping gene peptidylprolyl isomerase B (PPIB). The ISH sections were counterstained using periodic acid-Schiff. (Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012; 14: 22-29).
Table 1. Laboratory data.
Laboratory test 1 year before
admission Day 1 Day 4
(Kidney biopsy) Day 7 Reference
Arterial blood gas
pH 7.43 7.36 7.29 7.35 – 7.45
pCO2, mmHg 23 27 38 32 – 45
pO2, mmHg 137 68 72 83 – 108
HCO3
-, mmol/L 15 15 18 22 – 26
Complete blood count
WBC count, 109/L 11.2 15.0 15.1 3.4 – 9.6
Neutrophils, 109/L 10.35 1.56 – 6.45
Lymphocytes, 109/L 0.46 0.95 – 3.07
Erythrocytes, 1012/L 3.37 3.40 2.36 4.35 – 5.65
Hemoglobin, g/dL 11.3 11.4 7.9 13.2 – 16.6
Reticulocytes, % 2.12 0.6 – 2.71
Platelet count, 109/L 449 436 295 135 – 317
Serum biochemistry
Sodium, mmol/L 138 139 138 135 – 145
Potassium, mmol/L 5.4 4.5 4.1 3.6 – 5.2
Chloride, mmol/L 100 99 103 98 – 107
Bicarbonate, mmol/L 17 17 19 22 – 29
Anion gap 21 23 17 7 – 15
BUN, mg/dL 98 133 128 8 – 24
Creatinine, mg/dL 1.4 7.05 6.96 4.41 0.74 – 1.35
eGFR, mL/min/BSA 49 < 15 < 15 < 15 > 60
eGFR by cystatin C, mL/min/BSA 6 > 60
Calcium, total, mg/dL 8.9 8.3 8.1 8.8 – 10.2
Calcium, ionized, mg/dL 4.40 4.57 4.62 4.65 – 5.30
Glucose, mg/dL 127 165 145 70 – 140
Magnesium, mg/dL 3.8 2.9 1.7 – 2.3
Phosphorus, mg/dL 11.5 7.9 2.5 – 4.5
Total protein, g/dL 4.4 4.5 6.3 – 7.9
Albumin, g/dL 1.7 2.6 3.5 – 5.0
Hemoglobin A1C, % 5.9 4 – 5.6
Lactate, mmol/L 1.3 1.1 0.5 – 2.2
Liver function
ALT, U/L 45 36 11 7 – 55
AST, U/L 43 49 22 8 – 48
Bilirubin, total, mg/dL 0.6 < 0.2 0.5 < 1.2
Bilirubin, direct, mg/dL 0.3 < 0.2 0.4 0.0 – 0.3
Alkaline protease, U/L 155 70 40 – 129
Lipid/cardiac risk
Total cholesterol, mg/dL 241 226 < 200
HDL, mg/dL 38 34 ≥ 40
LDL, mg/dL 153 131 < 100
Triglycerides, mg/dL 248 304 < 150
Troponin T, ng/L 71 160 < 15
Troponin T-2h, ng/L 80 153 < 15
Troponin T-6h, ng/L 87 152 < 15
NT-pro BNP, pg/mL 220 5,030 5 – 131
Creatinine kinase, U/L 108 39 – 308
Coagulation
Antithrombin activity 91 80 – 130%
D-dimer, ng/mL 13,286 > 100,000 48,550 < 500
Fibrinogen, Clauss, mg/dL > 800 561 200 – 500
Coag factor II 101 92 75 – 145%
Coag factor V 132 110 70 – 165%
Coag factor VII 116 83 65 – 180%
Coag factor X 131 86 70 – 150%
C-reactive protein, mg/L > 400 173.3 142.1 < 8
Soluble fibrin monomer, mcg/mL > 1,100 36 ≤ 8
Plasminogen activity 98 75 – 140%
α-2 plasmin inhibitor 105 80 – 140%
Sedimentation rate, mm/h > 140 123 3 – 28
Ferritin, µg/L 1,122 1,813 911 24 – 336
Serology
HBs antigen Negative Negative
HBc total Ab Negative Negative
HCV Ab screen Negative Negative
HIV-1/-2 Ag and Ab Negative Negative
Complement C3, mg/dL 163 75 – 175
Complement C4, mg/dL 36 13 – 40
C-ANCA Negative Negative
p-ANCA Negative Negative
Anti-GBM, U < 0.2 < 1 (negative)
Anti-phospholipase A2 receptor (IF) Negative Negative
Anti-phospholipase A2 receptor (ELISA), RU/mL < 2 < 14
Interleukin 6, pg/mL 39.5 3.5 5.7 < 1.8
Monoclonal gammopathy screen
κ free light chain, mg/dL 15.5 0.33 – 1.94
λ free light chain, mg/dL 8.73 0.57 – 2.63
κ/λ ratio 1.78 0.26 – 1.65
Total protein, g/dL 5.3 6.3 – 7.9
Albumin, g/dL 1.4 3.4 – 4.7
α-1 globulin, g/dL 0.6 0.1 – 0.3
α 2-globulin, g/dL 1.5 0.6 – 1.0
β globulin, g/dL 1.0 0.7 – 1.2
γ globulin, g/dL 0.8 0.6 – 1.6
A/G ratio 0.36
M protein isotype Cannot rule out small monoclonal protein
Endocrine
TSH, mIU/L 1.1 0.2 0.3 – 4.2
T4 (thyroxine), ng/dL 1.3 0.9 – 1.7
PTH, pg/mL 231 15 – 65
Tumor/malignancy marker
Prostate specific Ag, ng/mL 0.21 0.15 ≤ 7.2
Table 2. Urinalysis data.
Laboratory test 3 years prior to admission On admission Day 2 Reference range
Source Midstream Catheter Catheter
Appearance Normal Normal Normal
Osmolality, mOsm/kg 372 339 150 – 1150
pH 5.2 5.5 4.5 – 8.0
Glucose, mg/dL 5 81 12 0 – 15
Protein, mg/dL 17 339 117 < 26
Protein/Osmolality, ratio 0.39 9.11 3.45 < 0.42
Predicted 24 h protein, mg 385 7,735 3,066
24-h urine protein, mg/24 h 4,662 < 229
Hemoglobin Negative Trace Moderate Negative
Red blood cell 3 – 10 < 3/HPF
Dysmorphic RBC (%) < 25 < 25
White blood cell 1 – 3 1 – 3 1 – 3/HPF
Casts, hyaline 1 – 3 Occasional
Casts, granular Occasional
Fat, free Occasional Occasional
Fat, in casts Occasional
Oval fat body Occasional
Renal epithelial cells 1 – 3 None seen/HPF
Ketones Negative Negative
Nitrite Negative Negative
Leukocyte Negative Negative
Figure 1. Renal pathologic findings in this COVID-19 patient. A: Glomerulus showing thickening of the glomerular basement membrane with mild mesangial sclerosis and hypercellularity (silver stain, × 400). B: Glomerular capillary loop showing abundant small sub-epithelial electron-dense deposits. The overlying podocytes show extensive foot process effacement (electron microscopy, × 11,000). C: Large glomerular endothelial tubuloreticular inclusion is shown. Tiny sub-epithelial electron-dense deposits are also evident (electron microscopy, × 30,000). | HEPARIN SODIUM, HYDROCHLOROTHIAZIDE, IBUPROFEN, LENZILUMAB, METHYLPREDNISOLONE, OLMESARTAN | DrugsGivenReaction | CC BY | 33633925 | 19,483,859 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Membranous nephropathy in a patient with coronavirus disease 2019 (COVID-19): A case report.
BACKGROUND
Though respiratory, immune, and coagulation systems are major targets of coronavirus disease 2019 (COVID-19), kidney dysfunction, presenting with acute kidney injury (AKI), is also common. Most AKI cases in COVID-19 manifest as acute tubular injury (ATI) in conjunction with multiorgan failure. While initial renal pathological findings were limited to acute tubular necrosis and collapsing glomerulopathy, a recent case series reported a larger spectrum of findings.
METHODS
Here, we report a case of membranous nephropathy (MN) in an 81-year-old Hispanic man with underlying chronic kidney disease (CKD) stage 3 who developed ATI in the setting of COVID-19. The patient was hospitalized for hypoxic respiratory failure in the setting of AKI stage 3 with serum creatinine 7.1 mg/dL 6 days after a positive-SARS-CoV-2 screening. He was found to have nephrotic range proteinuria, glycosuria (with normal serum glucose), anemia, and hypoalbuminemia. Kidney biopsy showed ATI and early MN. Workup for primary and secondary MN was unrevealing, and serum PLA2R antibody was negative. No viral particles were observed in podocytes.
CONCLUSIONS
Although the MN could be incidental, this observation raises the question of whether SARS-CoV-2 infection can trigger or worsen an underlying MN from an exaggerated immune response associated with COVID-19.
Introduction
Coronavirus disease 2019 (COVID-19), caused by a coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide since December 2019 [1].The principle feature of COVID-19 is viral pneumonia, leading to acute respiratory distress syndrome (ARDS) [2]. Similar to other coronaviruses, angiotensin-converting enzyme 2 (ACE2) may play a major role in the entry of SARS-CoV-2 to its target cells [3]. Besides the respiratory system, ACE2 is also highly expressed in the brush border of proximal tubular cells and, to a lesser extent, in glomerular podocytes [4]. Kidney involvement of COVID-19, mainly presents as acute kidney injury (AKI) [5], primarily due to acute tubular injury (ATI) in the setting of multiorgan failure. Clinically, the incidence of AKI in COVID-19 varies from 0.9 to 29% in hospitalized or critically ill patients at different centers [6, 7, 8] and is associated with worse outcomes [5, 9]. ATI and direct parenchymal infection of tubular epithelial cells and podocytes were reported in 26 postmortem examinations of patients with severe COVID-19 [10]. Proteinuria and hematuria are also common, occurring in 44 and 27%, respectively [5]. Kidney biopsy findings have been reported initially in four living COVID-19 cases, all of which showed collapsing glomerulopathy [11, 12, 13, 14]. Recently, two case series of kidney biopsy findings showed that ATI was the most common finding in COVID-19-associated kidney injury, but the series by Kudose et al. [15, 16] reported a wide spectrum of glomerular and tubular disease including minimal change disease and membranous glomerulopathy. Here, we report a case of membranous nephropathy (MN) diagnosed in the setting of AKI associated with COVID-19.
Case report
An 81-year-old Hispanic man presented to the emergency department complaining of progressive fatigue and shortness of breath 6 days after being diagnosed with COVID-19 (positive nasopharyngeal SARS-CoV-2 PCR). He reported myalgia, sore throat, intermittent dry cough, loss of smell and taste, poor appetite, and nausea without vomiting. He also had diarrhea and an episode of urinary incontinence. He denied fever or chills, chest pain, and headache. Because of hypoxemia requiring high-flow oxygen, the patient was admitted to the critical care unit.
Previous medical history includes prostate cancer treated with chemotherapy and androgen deprivation therapy in 2013, in remission with undetectable prostate-specific antigen (PSA) since 2014, prediabetes, hyperlipidemia, hypertension, chronic kidney disease (CKD) stage 3 (baseline creatinine 1.2 – 1.6 mg/dL) attributed to hypertension with prior urine analysis in 2017 showing proteinuria of 385 mg/day, aortic valve stenosis, and cervical radiculopathy. Home medications included olmesartan 20 mg twice daily and hydrochlorothiazide 12.5 mg daily. Notably, he had a history of non-steroidal anti-inflammatory drugs (NSAIDs) use, 400 – 800 mg of ibuprofen per day for chronic neck pain. He is a former smoker but quit in 2012 and did not have lung disease.
Initial vital signs: temperature 37.4 °C, blood pressure 166/69 mmHg, heart rate 68 beats per minute, respiratory rate 27 breaths per minute, and peripheral capillary oxygen saturation (SpO2) 95% on high-flow nasal cannula (50 L/min with FiO2 of 100%). Physical examination was notable for tachypnea with the remainder of physical examination unremarkable.
Table 1 and Table 2 show his laboratory results. Repeat SARS-CoV-2 PCR via nasopharyngeal swab was positive. He had evidence of AKI stage 3 with a serum creatinine of 7.1 mg/dL. Urinalysis demonstrated 3 – 10 red blood cells per high power field, nephrotic range proteinuria of 4.6 g per 24 hours, glycosuria, and tubular epithelial cells. He had anemia with hemoglobin of 10.3 g/dL, hypoalbuminemia of 1.7 g/dL, and multiple elevated inflammatory markers, including interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin. Kidney ultrasound revealed bilaterally increased parenchymal echogenicity consistent with CKD. Chest radiograph showed indistinct pulmonary vasculature bilaterally with bronchocentric ground glass, and bilateral patchy infiltrates, consistent with COVID-19 pneumonia. Lower extremities Doppler did not reveal deep vein thromboses, and transthoracic echocardiogram was normal.
He was enrolled in a randomized placebo-controlled clinical trial of lenzilumab (monoclonal antibody targeting GM-CSF) 600 mg for 3 doses, in addition to intravenous antibiotics for possible superimposed community-acquired pneumonia. He completed a steroid trial with 5 days of intravenous methylprednisolone. Due to increasing D-dimer to 100,000 ng/mL, low-intensity heparin infusion was initiated.
Over the first few hospitalization days, creatinine remained elevated at ~ 7 mg/dL. He did not require dialysis as he maintained excellent urine output. Serologic testing for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), tuberculosis, as well as C3, C4, anti-neutrophil cytoplasmic antibodies (ANCA), anti-glomerular basement membrane (GBM), and anti-phospholipase A2 receptors (PLA2R) were all negative. Anti-THSD7A was indeterminate due to high background. No serum monoclonal proteins were detected. Kidney biopsy was performed on hospital day 4.
On hospital day 7, the patient’s respiratory status worsened requiring intubation, mechanical ventilation, and initiation of vasopressors. Despite that, his AKI was slowly recovering and creatinine reached 3.7 mg/dL on hospital day 11. However, the shock state subsequently worsened, continuous dialysis was started but eventually the patient died on hospital day 16. Family declined an autopsy.
Kidney pathology findings
19 glomeruli were sampled for light microscopy, 8 of which were globally sclerotic and 1 was segmentally sclerotic. The glomeruli showed segmental mild mesangial hypercellularity and mesangial expansion, with thickening of their basement membranes (Figure 1A). No collapsing features, endocapillary hypercellularity, thrombi, necrosis, or crescents were seen. The tubulointerstitial compartment exhibited diffuse ATI, tubular protein reabsorption granules, mild tubular atrophy and interstitial fibrosis, and very mild mononuclear cell infiltrate without tubulitis. There was moderate arteriosclerosis and arteriolar hyalinosis.
Immunofluorescence studies were unable to be performed due to an inadequate sample. Immunohistochemistry staining for PLA2R was performed on sections prepared from the paraffin block and was negative.
In situ hybridization (ISH) staining for the presence of SARS-CoV-2 RNA was performed using RNAScope (ACD, Newark, CA, USA) and failed to show evidence of viral RNA in the kidney (methods in Supplemental Material).
Electron microscopy showed abundant small granular sub-epithelial electron-dense deposits without or associated with early basement membrane spike formation (Figure 1B). The glomerular basement membrane lamina densa was thickened. There was mild mesangial sclerosis with segmental mesangial electron-dense deposits, without sub-endothelial deposits. Abundant tubuloreticular inclusion bodies were seen in the endothelial cell cytoplasm (Figure 1C). Podocytes exhibited severe foot process effacement.
The pathological diagnosis was MN (stage 1 to early stage 2), diffuse ATI, mild mesangial sclerosing glomerulopathy (associated with hypertension, pre-diabetes, and smoking), and moderate arteriosclerosis and arteriolar hyalinosis.
Discussion
To our knowledge, MN diagnosed in a patient with COVID-19 has been reported in only 2 patients in one case series of 17 patients [16]. The finding of severe ATI in this case is not surprising as reported in recent series of COVID-19 patients [10, 15]. However, the finding of MN was unexpected.
MN, an inflammatory and autoimmune disease of the glomerulus, is one of the most common causes of nephrotic syndrome in adults. The etiology of ~ 75% of MN is unknown “primary”. Secondary MN can be secondary to infection, drugs, and malignancy [18]. Thus, the main question is whether the MN in this case is related to SARS-CoV-2 or not. This patient had a history of prostate cancer, but he was in remission for at least 6 years with normal PSA, so it is unlikely that his cancer was the underlying cause of the MN. NSAIDs can cause proteinuria and have been associated with minimal change disease as well as MN, but the patient did not have prior evidence of nephrotic syndrome despite being on NSAIDs for many years. The absence of detectable anti-PLA2R antibodies, the negative glomerular staining for PLA2R and the presence of mesangial deposits, as well as abundant tubuloreticular inclusions favor secondary MN over primary MN. The patient had mild proteinuria (385 mg/day) prior to COVID-19 which is likely due to underlying mild mesangial sclerosing glomerulopathy (associated with hypertension, prediabetes, and smoking). MN was mostly stage 1 favoring a recent development of disease temporally associated with COVID-19 over pre-existing MN.
The pathogenesis of MN involves formation and deposition of immune complexes in sub-epithelial sites [18]. The receptor for SARS-CoV-2, ACE2, is highly expressed on proximal tubular cells and glomerular podocytes [4]. In addition, TMPRSS2, an essential serine protease, is required for spike glycoprotein of SARS-CoV-2 priming after binding to ACE2, and thus activates membrane fusion facilitating to gain access to its target cells [19]. In kidneys, expression of TMPRSS2 is only detectable in the proximal tubule S3 segment [20]. An in vitro study showed that the administration of TMPRSS2 inhibitor, camostat mesylate, had a valuable treatment effect, blocking multiple SARS-CoV-2 entry routes [21]. In postmortem kidney samples, SARS-CoV-2 antigens and viral particles were detected in the tubular epithelium and podocytes [10, 17]. In the case of collapsing glomerulopathy associated with COVID-19 reported by Kissling et al. [13], the virus was seen in podocytes by electron microscopy. However, most recent biopsy series fail to show viral particles in kidney biopsies by immunohistochemistry staining or by electron microscopy arguing against a direct viral infection of the kidneys [15, 16]. Similarly, in this case we did not find evidence of viral particles in the kidneys. Rather than a direct toxic viral effect on the kidneys, the ATI is most likely cytokine mediated, although the NSAID, angiotensin receptor blocker, and diuretic exposures could also have contributed. Whether MN can be secondary to SARS-CoV-2 remains to be elucidated, but we speculate that it could result from an exaggerated immune response associated with COVID-19. In the passive Heymann nephritis model, sub-epithelial deposits with very early basement membrane reaction could be seen as early as 7 days after injection [22]. Therefore, we hypothesize that the development of MN deposits could possibly occur quickly after a viral infection, or alternatively the COVID-19-related immune response and the resulting high-grade proteinuria could unmask an underlying MN. If this is the case, the treatment of this patient’s MN is conservative and immunosuppressive therapy is not recommended.
Funding
None.
Conflict of interest
The authors declare no relevant financial interest.
Supplemental material
ISH methods
In situ hybridization was performed with RNAScope (ACD, Newark, CA) using probes directed against SARS-CoV-2 on formalin-fixed paraffin-embedded tissue sections cut at a thickness of 3 microns. 1A negative control (bacterial gene dapB) was also included to assess background signals as well as positive control probes to the housekeeping gene peptidylprolyl isomerase B (PPIB). The ISH sections were counterstained using periodic acid-Schiff. (Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012; 14: 22-29).
Table 1. Laboratory data.
Laboratory test 1 year before
admission Day 1 Day 4
(Kidney biopsy) Day 7 Reference
Arterial blood gas
pH 7.43 7.36 7.29 7.35 – 7.45
pCO2, mmHg 23 27 38 32 – 45
pO2, mmHg 137 68 72 83 – 108
HCO3
-, mmol/L 15 15 18 22 – 26
Complete blood count
WBC count, 109/L 11.2 15.0 15.1 3.4 – 9.6
Neutrophils, 109/L 10.35 1.56 – 6.45
Lymphocytes, 109/L 0.46 0.95 – 3.07
Erythrocytes, 1012/L 3.37 3.40 2.36 4.35 – 5.65
Hemoglobin, g/dL 11.3 11.4 7.9 13.2 – 16.6
Reticulocytes, % 2.12 0.6 – 2.71
Platelet count, 109/L 449 436 295 135 – 317
Serum biochemistry
Sodium, mmol/L 138 139 138 135 – 145
Potassium, mmol/L 5.4 4.5 4.1 3.6 – 5.2
Chloride, mmol/L 100 99 103 98 – 107
Bicarbonate, mmol/L 17 17 19 22 – 29
Anion gap 21 23 17 7 – 15
BUN, mg/dL 98 133 128 8 – 24
Creatinine, mg/dL 1.4 7.05 6.96 4.41 0.74 – 1.35
eGFR, mL/min/BSA 49 < 15 < 15 < 15 > 60
eGFR by cystatin C, mL/min/BSA 6 > 60
Calcium, total, mg/dL 8.9 8.3 8.1 8.8 – 10.2
Calcium, ionized, mg/dL 4.40 4.57 4.62 4.65 – 5.30
Glucose, mg/dL 127 165 145 70 – 140
Magnesium, mg/dL 3.8 2.9 1.7 – 2.3
Phosphorus, mg/dL 11.5 7.9 2.5 – 4.5
Total protein, g/dL 4.4 4.5 6.3 – 7.9
Albumin, g/dL 1.7 2.6 3.5 – 5.0
Hemoglobin A1C, % 5.9 4 – 5.6
Lactate, mmol/L 1.3 1.1 0.5 – 2.2
Liver function
ALT, U/L 45 36 11 7 – 55
AST, U/L 43 49 22 8 – 48
Bilirubin, total, mg/dL 0.6 < 0.2 0.5 < 1.2
Bilirubin, direct, mg/dL 0.3 < 0.2 0.4 0.0 – 0.3
Alkaline protease, U/L 155 70 40 – 129
Lipid/cardiac risk
Total cholesterol, mg/dL 241 226 < 200
HDL, mg/dL 38 34 ≥ 40
LDL, mg/dL 153 131 < 100
Triglycerides, mg/dL 248 304 < 150
Troponin T, ng/L 71 160 < 15
Troponin T-2h, ng/L 80 153 < 15
Troponin T-6h, ng/L 87 152 < 15
NT-pro BNP, pg/mL 220 5,030 5 – 131
Creatinine kinase, U/L 108 39 – 308
Coagulation
Antithrombin activity 91 80 – 130%
D-dimer, ng/mL 13,286 > 100,000 48,550 < 500
Fibrinogen, Clauss, mg/dL > 800 561 200 – 500
Coag factor II 101 92 75 – 145%
Coag factor V 132 110 70 – 165%
Coag factor VII 116 83 65 – 180%
Coag factor X 131 86 70 – 150%
C-reactive protein, mg/L > 400 173.3 142.1 < 8
Soluble fibrin monomer, mcg/mL > 1,100 36 ≤ 8
Plasminogen activity 98 75 – 140%
α-2 plasmin inhibitor 105 80 – 140%
Sedimentation rate, mm/h > 140 123 3 – 28
Ferritin, µg/L 1,122 1,813 911 24 – 336
Serology
HBs antigen Negative Negative
HBc total Ab Negative Negative
HCV Ab screen Negative Negative
HIV-1/-2 Ag and Ab Negative Negative
Complement C3, mg/dL 163 75 – 175
Complement C4, mg/dL 36 13 – 40
C-ANCA Negative Negative
p-ANCA Negative Negative
Anti-GBM, U < 0.2 < 1 (negative)
Anti-phospholipase A2 receptor (IF) Negative Negative
Anti-phospholipase A2 receptor (ELISA), RU/mL < 2 < 14
Interleukin 6, pg/mL 39.5 3.5 5.7 < 1.8
Monoclonal gammopathy screen
κ free light chain, mg/dL 15.5 0.33 – 1.94
λ free light chain, mg/dL 8.73 0.57 – 2.63
κ/λ ratio 1.78 0.26 – 1.65
Total protein, g/dL 5.3 6.3 – 7.9
Albumin, g/dL 1.4 3.4 – 4.7
α-1 globulin, g/dL 0.6 0.1 – 0.3
α 2-globulin, g/dL 1.5 0.6 – 1.0
β globulin, g/dL 1.0 0.7 – 1.2
γ globulin, g/dL 0.8 0.6 – 1.6
A/G ratio 0.36
M protein isotype Cannot rule out small monoclonal protein
Endocrine
TSH, mIU/L 1.1 0.2 0.3 – 4.2
T4 (thyroxine), ng/dL 1.3 0.9 – 1.7
PTH, pg/mL 231 15 – 65
Tumor/malignancy marker
Prostate specific Ag, ng/mL 0.21 0.15 ≤ 7.2
Table 2. Urinalysis data.
Laboratory test 3 years prior to admission On admission Day 2 Reference range
Source Midstream Catheter Catheter
Appearance Normal Normal Normal
Osmolality, mOsm/kg 372 339 150 – 1150
pH 5.2 5.5 4.5 – 8.0
Glucose, mg/dL 5 81 12 0 – 15
Protein, mg/dL 17 339 117 < 26
Protein/Osmolality, ratio 0.39 9.11 3.45 < 0.42
Predicted 24 h protein, mg 385 7,735 3,066
24-h urine protein, mg/24 h 4,662 < 229
Hemoglobin Negative Trace Moderate Negative
Red blood cell 3 – 10 < 3/HPF
Dysmorphic RBC (%) < 25 < 25
White blood cell 1 – 3 1 – 3 1 – 3/HPF
Casts, hyaline 1 – 3 Occasional
Casts, granular Occasional
Fat, free Occasional Occasional
Fat, in casts Occasional
Oval fat body Occasional
Renal epithelial cells 1 – 3 None seen/HPF
Ketones Negative Negative
Nitrite Negative Negative
Leukocyte Negative Negative
Figure 1. Renal pathologic findings in this COVID-19 patient. A: Glomerulus showing thickening of the glomerular basement membrane with mild mesangial sclerosis and hypercellularity (silver stain, × 400). B: Glomerular capillary loop showing abundant small sub-epithelial electron-dense deposits. The overlying podocytes show extensive foot process effacement (electron microscopy, × 11,000). C: Large glomerular endothelial tubuloreticular inclusion is shown. Tiny sub-epithelial electron-dense deposits are also evident (electron microscopy, × 30,000). | HEPARIN SODIUM, HYDROCHLOROTHIAZIDE, IBUPROFEN, LENZILUMAB, METHYLPREDNISOLONE, OLMESARTAN | DrugsGivenReaction | CC BY | 33633925 | 19,483,859 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Proteinuria'. | Membranous nephropathy in a patient with coronavirus disease 2019 (COVID-19): A case report.
BACKGROUND
Though respiratory, immune, and coagulation systems are major targets of coronavirus disease 2019 (COVID-19), kidney dysfunction, presenting with acute kidney injury (AKI), is also common. Most AKI cases in COVID-19 manifest as acute tubular injury (ATI) in conjunction with multiorgan failure. While initial renal pathological findings were limited to acute tubular necrosis and collapsing glomerulopathy, a recent case series reported a larger spectrum of findings.
METHODS
Here, we report a case of membranous nephropathy (MN) in an 81-year-old Hispanic man with underlying chronic kidney disease (CKD) stage 3 who developed ATI in the setting of COVID-19. The patient was hospitalized for hypoxic respiratory failure in the setting of AKI stage 3 with serum creatinine 7.1 mg/dL 6 days after a positive-SARS-CoV-2 screening. He was found to have nephrotic range proteinuria, glycosuria (with normal serum glucose), anemia, and hypoalbuminemia. Kidney biopsy showed ATI and early MN. Workup for primary and secondary MN was unrevealing, and serum PLA2R antibody was negative. No viral particles were observed in podocytes.
CONCLUSIONS
Although the MN could be incidental, this observation raises the question of whether SARS-CoV-2 infection can trigger or worsen an underlying MN from an exaggerated immune response associated with COVID-19.
Introduction
Coronavirus disease 2019 (COVID-19), caused by a coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide since December 2019 [1].The principle feature of COVID-19 is viral pneumonia, leading to acute respiratory distress syndrome (ARDS) [2]. Similar to other coronaviruses, angiotensin-converting enzyme 2 (ACE2) may play a major role in the entry of SARS-CoV-2 to its target cells [3]. Besides the respiratory system, ACE2 is also highly expressed in the brush border of proximal tubular cells and, to a lesser extent, in glomerular podocytes [4]. Kidney involvement of COVID-19, mainly presents as acute kidney injury (AKI) [5], primarily due to acute tubular injury (ATI) in the setting of multiorgan failure. Clinically, the incidence of AKI in COVID-19 varies from 0.9 to 29% in hospitalized or critically ill patients at different centers [6, 7, 8] and is associated with worse outcomes [5, 9]. ATI and direct parenchymal infection of tubular epithelial cells and podocytes were reported in 26 postmortem examinations of patients with severe COVID-19 [10]. Proteinuria and hematuria are also common, occurring in 44 and 27%, respectively [5]. Kidney biopsy findings have been reported initially in four living COVID-19 cases, all of which showed collapsing glomerulopathy [11, 12, 13, 14]. Recently, two case series of kidney biopsy findings showed that ATI was the most common finding in COVID-19-associated kidney injury, but the series by Kudose et al. [15, 16] reported a wide spectrum of glomerular and tubular disease including minimal change disease and membranous glomerulopathy. Here, we report a case of membranous nephropathy (MN) diagnosed in the setting of AKI associated with COVID-19.
Case report
An 81-year-old Hispanic man presented to the emergency department complaining of progressive fatigue and shortness of breath 6 days after being diagnosed with COVID-19 (positive nasopharyngeal SARS-CoV-2 PCR). He reported myalgia, sore throat, intermittent dry cough, loss of smell and taste, poor appetite, and nausea without vomiting. He also had diarrhea and an episode of urinary incontinence. He denied fever or chills, chest pain, and headache. Because of hypoxemia requiring high-flow oxygen, the patient was admitted to the critical care unit.
Previous medical history includes prostate cancer treated with chemotherapy and androgen deprivation therapy in 2013, in remission with undetectable prostate-specific antigen (PSA) since 2014, prediabetes, hyperlipidemia, hypertension, chronic kidney disease (CKD) stage 3 (baseline creatinine 1.2 – 1.6 mg/dL) attributed to hypertension with prior urine analysis in 2017 showing proteinuria of 385 mg/day, aortic valve stenosis, and cervical radiculopathy. Home medications included olmesartan 20 mg twice daily and hydrochlorothiazide 12.5 mg daily. Notably, he had a history of non-steroidal anti-inflammatory drugs (NSAIDs) use, 400 – 800 mg of ibuprofen per day for chronic neck pain. He is a former smoker but quit in 2012 and did not have lung disease.
Initial vital signs: temperature 37.4 °C, blood pressure 166/69 mmHg, heart rate 68 beats per minute, respiratory rate 27 breaths per minute, and peripheral capillary oxygen saturation (SpO2) 95% on high-flow nasal cannula (50 L/min with FiO2 of 100%). Physical examination was notable for tachypnea with the remainder of physical examination unremarkable.
Table 1 and Table 2 show his laboratory results. Repeat SARS-CoV-2 PCR via nasopharyngeal swab was positive. He had evidence of AKI stage 3 with a serum creatinine of 7.1 mg/dL. Urinalysis demonstrated 3 – 10 red blood cells per high power field, nephrotic range proteinuria of 4.6 g per 24 hours, glycosuria, and tubular epithelial cells. He had anemia with hemoglobin of 10.3 g/dL, hypoalbuminemia of 1.7 g/dL, and multiple elevated inflammatory markers, including interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin. Kidney ultrasound revealed bilaterally increased parenchymal echogenicity consistent with CKD. Chest radiograph showed indistinct pulmonary vasculature bilaterally with bronchocentric ground glass, and bilateral patchy infiltrates, consistent with COVID-19 pneumonia. Lower extremities Doppler did not reveal deep vein thromboses, and transthoracic echocardiogram was normal.
He was enrolled in a randomized placebo-controlled clinical trial of lenzilumab (monoclonal antibody targeting GM-CSF) 600 mg for 3 doses, in addition to intravenous antibiotics for possible superimposed community-acquired pneumonia. He completed a steroid trial with 5 days of intravenous methylprednisolone. Due to increasing D-dimer to 100,000 ng/mL, low-intensity heparin infusion was initiated.
Over the first few hospitalization days, creatinine remained elevated at ~ 7 mg/dL. He did not require dialysis as he maintained excellent urine output. Serologic testing for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), tuberculosis, as well as C3, C4, anti-neutrophil cytoplasmic antibodies (ANCA), anti-glomerular basement membrane (GBM), and anti-phospholipase A2 receptors (PLA2R) were all negative. Anti-THSD7A was indeterminate due to high background. No serum monoclonal proteins were detected. Kidney biopsy was performed on hospital day 4.
On hospital day 7, the patient’s respiratory status worsened requiring intubation, mechanical ventilation, and initiation of vasopressors. Despite that, his AKI was slowly recovering and creatinine reached 3.7 mg/dL on hospital day 11. However, the shock state subsequently worsened, continuous dialysis was started but eventually the patient died on hospital day 16. Family declined an autopsy.
Kidney pathology findings
19 glomeruli were sampled for light microscopy, 8 of which were globally sclerotic and 1 was segmentally sclerotic. The glomeruli showed segmental mild mesangial hypercellularity and mesangial expansion, with thickening of their basement membranes (Figure 1A). No collapsing features, endocapillary hypercellularity, thrombi, necrosis, or crescents were seen. The tubulointerstitial compartment exhibited diffuse ATI, tubular protein reabsorption granules, mild tubular atrophy and interstitial fibrosis, and very mild mononuclear cell infiltrate without tubulitis. There was moderate arteriosclerosis and arteriolar hyalinosis.
Immunofluorescence studies were unable to be performed due to an inadequate sample. Immunohistochemistry staining for PLA2R was performed on sections prepared from the paraffin block and was negative.
In situ hybridization (ISH) staining for the presence of SARS-CoV-2 RNA was performed using RNAScope (ACD, Newark, CA, USA) and failed to show evidence of viral RNA in the kidney (methods in Supplemental Material).
Electron microscopy showed abundant small granular sub-epithelial electron-dense deposits without or associated with early basement membrane spike formation (Figure 1B). The glomerular basement membrane lamina densa was thickened. There was mild mesangial sclerosis with segmental mesangial electron-dense deposits, without sub-endothelial deposits. Abundant tubuloreticular inclusion bodies were seen in the endothelial cell cytoplasm (Figure 1C). Podocytes exhibited severe foot process effacement.
The pathological diagnosis was MN (stage 1 to early stage 2), diffuse ATI, mild mesangial sclerosing glomerulopathy (associated with hypertension, pre-diabetes, and smoking), and moderate arteriosclerosis and arteriolar hyalinosis.
Discussion
To our knowledge, MN diagnosed in a patient with COVID-19 has been reported in only 2 patients in one case series of 17 patients [16]. The finding of severe ATI in this case is not surprising as reported in recent series of COVID-19 patients [10, 15]. However, the finding of MN was unexpected.
MN, an inflammatory and autoimmune disease of the glomerulus, is one of the most common causes of nephrotic syndrome in adults. The etiology of ~ 75% of MN is unknown “primary”. Secondary MN can be secondary to infection, drugs, and malignancy [18]. Thus, the main question is whether the MN in this case is related to SARS-CoV-2 or not. This patient had a history of prostate cancer, but he was in remission for at least 6 years with normal PSA, so it is unlikely that his cancer was the underlying cause of the MN. NSAIDs can cause proteinuria and have been associated with minimal change disease as well as MN, but the patient did not have prior evidence of nephrotic syndrome despite being on NSAIDs for many years. The absence of detectable anti-PLA2R antibodies, the negative glomerular staining for PLA2R and the presence of mesangial deposits, as well as abundant tubuloreticular inclusions favor secondary MN over primary MN. The patient had mild proteinuria (385 mg/day) prior to COVID-19 which is likely due to underlying mild mesangial sclerosing glomerulopathy (associated with hypertension, prediabetes, and smoking). MN was mostly stage 1 favoring a recent development of disease temporally associated with COVID-19 over pre-existing MN.
The pathogenesis of MN involves formation and deposition of immune complexes in sub-epithelial sites [18]. The receptor for SARS-CoV-2, ACE2, is highly expressed on proximal tubular cells and glomerular podocytes [4]. In addition, TMPRSS2, an essential serine protease, is required for spike glycoprotein of SARS-CoV-2 priming after binding to ACE2, and thus activates membrane fusion facilitating to gain access to its target cells [19]. In kidneys, expression of TMPRSS2 is only detectable in the proximal tubule S3 segment [20]. An in vitro study showed that the administration of TMPRSS2 inhibitor, camostat mesylate, had a valuable treatment effect, blocking multiple SARS-CoV-2 entry routes [21]. In postmortem kidney samples, SARS-CoV-2 antigens and viral particles were detected in the tubular epithelium and podocytes [10, 17]. In the case of collapsing glomerulopathy associated with COVID-19 reported by Kissling et al. [13], the virus was seen in podocytes by electron microscopy. However, most recent biopsy series fail to show viral particles in kidney biopsies by immunohistochemistry staining or by electron microscopy arguing against a direct viral infection of the kidneys [15, 16]. Similarly, in this case we did not find evidence of viral particles in the kidneys. Rather than a direct toxic viral effect on the kidneys, the ATI is most likely cytokine mediated, although the NSAID, angiotensin receptor blocker, and diuretic exposures could also have contributed. Whether MN can be secondary to SARS-CoV-2 remains to be elucidated, but we speculate that it could result from an exaggerated immune response associated with COVID-19. In the passive Heymann nephritis model, sub-epithelial deposits with very early basement membrane reaction could be seen as early as 7 days after injection [22]. Therefore, we hypothesize that the development of MN deposits could possibly occur quickly after a viral infection, or alternatively the COVID-19-related immune response and the resulting high-grade proteinuria could unmask an underlying MN. If this is the case, the treatment of this patient’s MN is conservative and immunosuppressive therapy is not recommended.
Funding
None.
Conflict of interest
The authors declare no relevant financial interest.
Supplemental material
ISH methods
In situ hybridization was performed with RNAScope (ACD, Newark, CA) using probes directed against SARS-CoV-2 on formalin-fixed paraffin-embedded tissue sections cut at a thickness of 3 microns. 1A negative control (bacterial gene dapB) was also included to assess background signals as well as positive control probes to the housekeeping gene peptidylprolyl isomerase B (PPIB). The ISH sections were counterstained using periodic acid-Schiff. (Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012; 14: 22-29).
Table 1. Laboratory data.
Laboratory test 1 year before
admission Day 1 Day 4
(Kidney biopsy) Day 7 Reference
Arterial blood gas
pH 7.43 7.36 7.29 7.35 – 7.45
pCO2, mmHg 23 27 38 32 – 45
pO2, mmHg 137 68 72 83 – 108
HCO3
-, mmol/L 15 15 18 22 – 26
Complete blood count
WBC count, 109/L 11.2 15.0 15.1 3.4 – 9.6
Neutrophils, 109/L 10.35 1.56 – 6.45
Lymphocytes, 109/L 0.46 0.95 – 3.07
Erythrocytes, 1012/L 3.37 3.40 2.36 4.35 – 5.65
Hemoglobin, g/dL 11.3 11.4 7.9 13.2 – 16.6
Reticulocytes, % 2.12 0.6 – 2.71
Platelet count, 109/L 449 436 295 135 – 317
Serum biochemistry
Sodium, mmol/L 138 139 138 135 – 145
Potassium, mmol/L 5.4 4.5 4.1 3.6 – 5.2
Chloride, mmol/L 100 99 103 98 – 107
Bicarbonate, mmol/L 17 17 19 22 – 29
Anion gap 21 23 17 7 – 15
BUN, mg/dL 98 133 128 8 – 24
Creatinine, mg/dL 1.4 7.05 6.96 4.41 0.74 – 1.35
eGFR, mL/min/BSA 49 < 15 < 15 < 15 > 60
eGFR by cystatin C, mL/min/BSA 6 > 60
Calcium, total, mg/dL 8.9 8.3 8.1 8.8 – 10.2
Calcium, ionized, mg/dL 4.40 4.57 4.62 4.65 – 5.30
Glucose, mg/dL 127 165 145 70 – 140
Magnesium, mg/dL 3.8 2.9 1.7 – 2.3
Phosphorus, mg/dL 11.5 7.9 2.5 – 4.5
Total protein, g/dL 4.4 4.5 6.3 – 7.9
Albumin, g/dL 1.7 2.6 3.5 – 5.0
Hemoglobin A1C, % 5.9 4 – 5.6
Lactate, mmol/L 1.3 1.1 0.5 – 2.2
Liver function
ALT, U/L 45 36 11 7 – 55
AST, U/L 43 49 22 8 – 48
Bilirubin, total, mg/dL 0.6 < 0.2 0.5 < 1.2
Bilirubin, direct, mg/dL 0.3 < 0.2 0.4 0.0 – 0.3
Alkaline protease, U/L 155 70 40 – 129
Lipid/cardiac risk
Total cholesterol, mg/dL 241 226 < 200
HDL, mg/dL 38 34 ≥ 40
LDL, mg/dL 153 131 < 100
Triglycerides, mg/dL 248 304 < 150
Troponin T, ng/L 71 160 < 15
Troponin T-2h, ng/L 80 153 < 15
Troponin T-6h, ng/L 87 152 < 15
NT-pro BNP, pg/mL 220 5,030 5 – 131
Creatinine kinase, U/L 108 39 – 308
Coagulation
Antithrombin activity 91 80 – 130%
D-dimer, ng/mL 13,286 > 100,000 48,550 < 500
Fibrinogen, Clauss, mg/dL > 800 561 200 – 500
Coag factor II 101 92 75 – 145%
Coag factor V 132 110 70 – 165%
Coag factor VII 116 83 65 – 180%
Coag factor X 131 86 70 – 150%
C-reactive protein, mg/L > 400 173.3 142.1 < 8
Soluble fibrin monomer, mcg/mL > 1,100 36 ≤ 8
Plasminogen activity 98 75 – 140%
α-2 plasmin inhibitor 105 80 – 140%
Sedimentation rate, mm/h > 140 123 3 – 28
Ferritin, µg/L 1,122 1,813 911 24 – 336
Serology
HBs antigen Negative Negative
HBc total Ab Negative Negative
HCV Ab screen Negative Negative
HIV-1/-2 Ag and Ab Negative Negative
Complement C3, mg/dL 163 75 – 175
Complement C4, mg/dL 36 13 – 40
C-ANCA Negative Negative
p-ANCA Negative Negative
Anti-GBM, U < 0.2 < 1 (negative)
Anti-phospholipase A2 receptor (IF) Negative Negative
Anti-phospholipase A2 receptor (ELISA), RU/mL < 2 < 14
Interleukin 6, pg/mL 39.5 3.5 5.7 < 1.8
Monoclonal gammopathy screen
κ free light chain, mg/dL 15.5 0.33 – 1.94
λ free light chain, mg/dL 8.73 0.57 – 2.63
κ/λ ratio 1.78 0.26 – 1.65
Total protein, g/dL 5.3 6.3 – 7.9
Albumin, g/dL 1.4 3.4 – 4.7
α-1 globulin, g/dL 0.6 0.1 – 0.3
α 2-globulin, g/dL 1.5 0.6 – 1.0
β globulin, g/dL 1.0 0.7 – 1.2
γ globulin, g/dL 0.8 0.6 – 1.6
A/G ratio 0.36
M protein isotype Cannot rule out small monoclonal protein
Endocrine
TSH, mIU/L 1.1 0.2 0.3 – 4.2
T4 (thyroxine), ng/dL 1.3 0.9 – 1.7
PTH, pg/mL 231 15 – 65
Tumor/malignancy marker
Prostate specific Ag, ng/mL 0.21 0.15 ≤ 7.2
Table 2. Urinalysis data.
Laboratory test 3 years prior to admission On admission Day 2 Reference range
Source Midstream Catheter Catheter
Appearance Normal Normal Normal
Osmolality, mOsm/kg 372 339 150 – 1150
pH 5.2 5.5 4.5 – 8.0
Glucose, mg/dL 5 81 12 0 – 15
Protein, mg/dL 17 339 117 < 26
Protein/Osmolality, ratio 0.39 9.11 3.45 < 0.42
Predicted 24 h protein, mg 385 7,735 3,066
24-h urine protein, mg/24 h 4,662 < 229
Hemoglobin Negative Trace Moderate Negative
Red blood cell 3 – 10 < 3/HPF
Dysmorphic RBC (%) < 25 < 25
White blood cell 1 – 3 1 – 3 1 – 3/HPF
Casts, hyaline 1 – 3 Occasional
Casts, granular Occasional
Fat, free Occasional Occasional
Fat, in casts Occasional
Oval fat body Occasional
Renal epithelial cells 1 – 3 None seen/HPF
Ketones Negative Negative
Nitrite Negative Negative
Leukocyte Negative Negative
Figure 1. Renal pathologic findings in this COVID-19 patient. A: Glomerulus showing thickening of the glomerular basement membrane with mild mesangial sclerosis and hypercellularity (silver stain, × 400). B: Glomerular capillary loop showing abundant small sub-epithelial electron-dense deposits. The overlying podocytes show extensive foot process effacement (electron microscopy, × 11,000). C: Large glomerular endothelial tubuloreticular inclusion is shown. Tiny sub-epithelial electron-dense deposits are also evident (electron microscopy, × 30,000). | HYDROCHLOROTHIAZIDE, IBUPROFEN, OLMESARTAN | DrugsGivenReaction | CC BY | 33633925 | 19,275,153 | 2021 |
What was the administration route of drug 'HEPARIN SODIUM'? | Membranous nephropathy in a patient with coronavirus disease 2019 (COVID-19): A case report.
BACKGROUND
Though respiratory, immune, and coagulation systems are major targets of coronavirus disease 2019 (COVID-19), kidney dysfunction, presenting with acute kidney injury (AKI), is also common. Most AKI cases in COVID-19 manifest as acute tubular injury (ATI) in conjunction with multiorgan failure. While initial renal pathological findings were limited to acute tubular necrosis and collapsing glomerulopathy, a recent case series reported a larger spectrum of findings.
METHODS
Here, we report a case of membranous nephropathy (MN) in an 81-year-old Hispanic man with underlying chronic kidney disease (CKD) stage 3 who developed ATI in the setting of COVID-19. The patient was hospitalized for hypoxic respiratory failure in the setting of AKI stage 3 with serum creatinine 7.1 mg/dL 6 days after a positive-SARS-CoV-2 screening. He was found to have nephrotic range proteinuria, glycosuria (with normal serum glucose), anemia, and hypoalbuminemia. Kidney biopsy showed ATI and early MN. Workup for primary and secondary MN was unrevealing, and serum PLA2R antibody was negative. No viral particles were observed in podocytes.
CONCLUSIONS
Although the MN could be incidental, this observation raises the question of whether SARS-CoV-2 infection can trigger or worsen an underlying MN from an exaggerated immune response associated with COVID-19.
Introduction
Coronavirus disease 2019 (COVID-19), caused by a coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide since December 2019 [1].The principle feature of COVID-19 is viral pneumonia, leading to acute respiratory distress syndrome (ARDS) [2]. Similar to other coronaviruses, angiotensin-converting enzyme 2 (ACE2) may play a major role in the entry of SARS-CoV-2 to its target cells [3]. Besides the respiratory system, ACE2 is also highly expressed in the brush border of proximal tubular cells and, to a lesser extent, in glomerular podocytes [4]. Kidney involvement of COVID-19, mainly presents as acute kidney injury (AKI) [5], primarily due to acute tubular injury (ATI) in the setting of multiorgan failure. Clinically, the incidence of AKI in COVID-19 varies from 0.9 to 29% in hospitalized or critically ill patients at different centers [6, 7, 8] and is associated with worse outcomes [5, 9]. ATI and direct parenchymal infection of tubular epithelial cells and podocytes were reported in 26 postmortem examinations of patients with severe COVID-19 [10]. Proteinuria and hematuria are also common, occurring in 44 and 27%, respectively [5]. Kidney biopsy findings have been reported initially in four living COVID-19 cases, all of which showed collapsing glomerulopathy [11, 12, 13, 14]. Recently, two case series of kidney biopsy findings showed that ATI was the most common finding in COVID-19-associated kidney injury, but the series by Kudose et al. [15, 16] reported a wide spectrum of glomerular and tubular disease including minimal change disease and membranous glomerulopathy. Here, we report a case of membranous nephropathy (MN) diagnosed in the setting of AKI associated with COVID-19.
Case report
An 81-year-old Hispanic man presented to the emergency department complaining of progressive fatigue and shortness of breath 6 days after being diagnosed with COVID-19 (positive nasopharyngeal SARS-CoV-2 PCR). He reported myalgia, sore throat, intermittent dry cough, loss of smell and taste, poor appetite, and nausea without vomiting. He also had diarrhea and an episode of urinary incontinence. He denied fever or chills, chest pain, and headache. Because of hypoxemia requiring high-flow oxygen, the patient was admitted to the critical care unit.
Previous medical history includes prostate cancer treated with chemotherapy and androgen deprivation therapy in 2013, in remission with undetectable prostate-specific antigen (PSA) since 2014, prediabetes, hyperlipidemia, hypertension, chronic kidney disease (CKD) stage 3 (baseline creatinine 1.2 – 1.6 mg/dL) attributed to hypertension with prior urine analysis in 2017 showing proteinuria of 385 mg/day, aortic valve stenosis, and cervical radiculopathy. Home medications included olmesartan 20 mg twice daily and hydrochlorothiazide 12.5 mg daily. Notably, he had a history of non-steroidal anti-inflammatory drugs (NSAIDs) use, 400 – 800 mg of ibuprofen per day for chronic neck pain. He is a former smoker but quit in 2012 and did not have lung disease.
Initial vital signs: temperature 37.4 °C, blood pressure 166/69 mmHg, heart rate 68 beats per minute, respiratory rate 27 breaths per minute, and peripheral capillary oxygen saturation (SpO2) 95% on high-flow nasal cannula (50 L/min with FiO2 of 100%). Physical examination was notable for tachypnea with the remainder of physical examination unremarkable.
Table 1 and Table 2 show his laboratory results. Repeat SARS-CoV-2 PCR via nasopharyngeal swab was positive. He had evidence of AKI stage 3 with a serum creatinine of 7.1 mg/dL. Urinalysis demonstrated 3 – 10 red blood cells per high power field, nephrotic range proteinuria of 4.6 g per 24 hours, glycosuria, and tubular epithelial cells. He had anemia with hemoglobin of 10.3 g/dL, hypoalbuminemia of 1.7 g/dL, and multiple elevated inflammatory markers, including interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin. Kidney ultrasound revealed bilaterally increased parenchymal echogenicity consistent with CKD. Chest radiograph showed indistinct pulmonary vasculature bilaterally with bronchocentric ground glass, and bilateral patchy infiltrates, consistent with COVID-19 pneumonia. Lower extremities Doppler did not reveal deep vein thromboses, and transthoracic echocardiogram was normal.
He was enrolled in a randomized placebo-controlled clinical trial of lenzilumab (monoclonal antibody targeting GM-CSF) 600 mg for 3 doses, in addition to intravenous antibiotics for possible superimposed community-acquired pneumonia. He completed a steroid trial with 5 days of intravenous methylprednisolone. Due to increasing D-dimer to 100,000 ng/mL, low-intensity heparin infusion was initiated.
Over the first few hospitalization days, creatinine remained elevated at ~ 7 mg/dL. He did not require dialysis as he maintained excellent urine output. Serologic testing for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), tuberculosis, as well as C3, C4, anti-neutrophil cytoplasmic antibodies (ANCA), anti-glomerular basement membrane (GBM), and anti-phospholipase A2 receptors (PLA2R) were all negative. Anti-THSD7A was indeterminate due to high background. No serum monoclonal proteins were detected. Kidney biopsy was performed on hospital day 4.
On hospital day 7, the patient’s respiratory status worsened requiring intubation, mechanical ventilation, and initiation of vasopressors. Despite that, his AKI was slowly recovering and creatinine reached 3.7 mg/dL on hospital day 11. However, the shock state subsequently worsened, continuous dialysis was started but eventually the patient died on hospital day 16. Family declined an autopsy.
Kidney pathology findings
19 glomeruli were sampled for light microscopy, 8 of which were globally sclerotic and 1 was segmentally sclerotic. The glomeruli showed segmental mild mesangial hypercellularity and mesangial expansion, with thickening of their basement membranes (Figure 1A). No collapsing features, endocapillary hypercellularity, thrombi, necrosis, or crescents were seen. The tubulointerstitial compartment exhibited diffuse ATI, tubular protein reabsorption granules, mild tubular atrophy and interstitial fibrosis, and very mild mononuclear cell infiltrate without tubulitis. There was moderate arteriosclerosis and arteriolar hyalinosis.
Immunofluorescence studies were unable to be performed due to an inadequate sample. Immunohistochemistry staining for PLA2R was performed on sections prepared from the paraffin block and was negative.
In situ hybridization (ISH) staining for the presence of SARS-CoV-2 RNA was performed using RNAScope (ACD, Newark, CA, USA) and failed to show evidence of viral RNA in the kidney (methods in Supplemental Material).
Electron microscopy showed abundant small granular sub-epithelial electron-dense deposits without or associated with early basement membrane spike formation (Figure 1B). The glomerular basement membrane lamina densa was thickened. There was mild mesangial sclerosis with segmental mesangial electron-dense deposits, without sub-endothelial deposits. Abundant tubuloreticular inclusion bodies were seen in the endothelial cell cytoplasm (Figure 1C). Podocytes exhibited severe foot process effacement.
The pathological diagnosis was MN (stage 1 to early stage 2), diffuse ATI, mild mesangial sclerosing glomerulopathy (associated with hypertension, pre-diabetes, and smoking), and moderate arteriosclerosis and arteriolar hyalinosis.
Discussion
To our knowledge, MN diagnosed in a patient with COVID-19 has been reported in only 2 patients in one case series of 17 patients [16]. The finding of severe ATI in this case is not surprising as reported in recent series of COVID-19 patients [10, 15]. However, the finding of MN was unexpected.
MN, an inflammatory and autoimmune disease of the glomerulus, is one of the most common causes of nephrotic syndrome in adults. The etiology of ~ 75% of MN is unknown “primary”. Secondary MN can be secondary to infection, drugs, and malignancy [18]. Thus, the main question is whether the MN in this case is related to SARS-CoV-2 or not. This patient had a history of prostate cancer, but he was in remission for at least 6 years with normal PSA, so it is unlikely that his cancer was the underlying cause of the MN. NSAIDs can cause proteinuria and have been associated with minimal change disease as well as MN, but the patient did not have prior evidence of nephrotic syndrome despite being on NSAIDs for many years. The absence of detectable anti-PLA2R antibodies, the negative glomerular staining for PLA2R and the presence of mesangial deposits, as well as abundant tubuloreticular inclusions favor secondary MN over primary MN. The patient had mild proteinuria (385 mg/day) prior to COVID-19 which is likely due to underlying mild mesangial sclerosing glomerulopathy (associated with hypertension, prediabetes, and smoking). MN was mostly stage 1 favoring a recent development of disease temporally associated with COVID-19 over pre-existing MN.
The pathogenesis of MN involves formation and deposition of immune complexes in sub-epithelial sites [18]. The receptor for SARS-CoV-2, ACE2, is highly expressed on proximal tubular cells and glomerular podocytes [4]. In addition, TMPRSS2, an essential serine protease, is required for spike glycoprotein of SARS-CoV-2 priming after binding to ACE2, and thus activates membrane fusion facilitating to gain access to its target cells [19]. In kidneys, expression of TMPRSS2 is only detectable in the proximal tubule S3 segment [20]. An in vitro study showed that the administration of TMPRSS2 inhibitor, camostat mesylate, had a valuable treatment effect, blocking multiple SARS-CoV-2 entry routes [21]. In postmortem kidney samples, SARS-CoV-2 antigens and viral particles were detected in the tubular epithelium and podocytes [10, 17]. In the case of collapsing glomerulopathy associated with COVID-19 reported by Kissling et al. [13], the virus was seen in podocytes by electron microscopy. However, most recent biopsy series fail to show viral particles in kidney biopsies by immunohistochemistry staining or by electron microscopy arguing against a direct viral infection of the kidneys [15, 16]. Similarly, in this case we did not find evidence of viral particles in the kidneys. Rather than a direct toxic viral effect on the kidneys, the ATI is most likely cytokine mediated, although the NSAID, angiotensin receptor blocker, and diuretic exposures could also have contributed. Whether MN can be secondary to SARS-CoV-2 remains to be elucidated, but we speculate that it could result from an exaggerated immune response associated with COVID-19. In the passive Heymann nephritis model, sub-epithelial deposits with very early basement membrane reaction could be seen as early as 7 days after injection [22]. Therefore, we hypothesize that the development of MN deposits could possibly occur quickly after a viral infection, or alternatively the COVID-19-related immune response and the resulting high-grade proteinuria could unmask an underlying MN. If this is the case, the treatment of this patient’s MN is conservative and immunosuppressive therapy is not recommended.
Funding
None.
Conflict of interest
The authors declare no relevant financial interest.
Supplemental material
ISH methods
In situ hybridization was performed with RNAScope (ACD, Newark, CA) using probes directed against SARS-CoV-2 on formalin-fixed paraffin-embedded tissue sections cut at a thickness of 3 microns. 1A negative control (bacterial gene dapB) was also included to assess background signals as well as positive control probes to the housekeeping gene peptidylprolyl isomerase B (PPIB). The ISH sections were counterstained using periodic acid-Schiff. (Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012; 14: 22-29).
Table 1. Laboratory data.
Laboratory test 1 year before
admission Day 1 Day 4
(Kidney biopsy) Day 7 Reference
Arterial blood gas
pH 7.43 7.36 7.29 7.35 – 7.45
pCO2, mmHg 23 27 38 32 – 45
pO2, mmHg 137 68 72 83 – 108
HCO3
-, mmol/L 15 15 18 22 – 26
Complete blood count
WBC count, 109/L 11.2 15.0 15.1 3.4 – 9.6
Neutrophils, 109/L 10.35 1.56 – 6.45
Lymphocytes, 109/L 0.46 0.95 – 3.07
Erythrocytes, 1012/L 3.37 3.40 2.36 4.35 – 5.65
Hemoglobin, g/dL 11.3 11.4 7.9 13.2 – 16.6
Reticulocytes, % 2.12 0.6 – 2.71
Platelet count, 109/L 449 436 295 135 – 317
Serum biochemistry
Sodium, mmol/L 138 139 138 135 – 145
Potassium, mmol/L 5.4 4.5 4.1 3.6 – 5.2
Chloride, mmol/L 100 99 103 98 – 107
Bicarbonate, mmol/L 17 17 19 22 – 29
Anion gap 21 23 17 7 – 15
BUN, mg/dL 98 133 128 8 – 24
Creatinine, mg/dL 1.4 7.05 6.96 4.41 0.74 – 1.35
eGFR, mL/min/BSA 49 < 15 < 15 < 15 > 60
eGFR by cystatin C, mL/min/BSA 6 > 60
Calcium, total, mg/dL 8.9 8.3 8.1 8.8 – 10.2
Calcium, ionized, mg/dL 4.40 4.57 4.62 4.65 – 5.30
Glucose, mg/dL 127 165 145 70 – 140
Magnesium, mg/dL 3.8 2.9 1.7 – 2.3
Phosphorus, mg/dL 11.5 7.9 2.5 – 4.5
Total protein, g/dL 4.4 4.5 6.3 – 7.9
Albumin, g/dL 1.7 2.6 3.5 – 5.0
Hemoglobin A1C, % 5.9 4 – 5.6
Lactate, mmol/L 1.3 1.1 0.5 – 2.2
Liver function
ALT, U/L 45 36 11 7 – 55
AST, U/L 43 49 22 8 – 48
Bilirubin, total, mg/dL 0.6 < 0.2 0.5 < 1.2
Bilirubin, direct, mg/dL 0.3 < 0.2 0.4 0.0 – 0.3
Alkaline protease, U/L 155 70 40 – 129
Lipid/cardiac risk
Total cholesterol, mg/dL 241 226 < 200
HDL, mg/dL 38 34 ≥ 40
LDL, mg/dL 153 131 < 100
Triglycerides, mg/dL 248 304 < 150
Troponin T, ng/L 71 160 < 15
Troponin T-2h, ng/L 80 153 < 15
Troponin T-6h, ng/L 87 152 < 15
NT-pro BNP, pg/mL 220 5,030 5 – 131
Creatinine kinase, U/L 108 39 – 308
Coagulation
Antithrombin activity 91 80 – 130%
D-dimer, ng/mL 13,286 > 100,000 48,550 < 500
Fibrinogen, Clauss, mg/dL > 800 561 200 – 500
Coag factor II 101 92 75 – 145%
Coag factor V 132 110 70 – 165%
Coag factor VII 116 83 65 – 180%
Coag factor X 131 86 70 – 150%
C-reactive protein, mg/L > 400 173.3 142.1 < 8
Soluble fibrin monomer, mcg/mL > 1,100 36 ≤ 8
Plasminogen activity 98 75 – 140%
α-2 plasmin inhibitor 105 80 – 140%
Sedimentation rate, mm/h > 140 123 3 – 28
Ferritin, µg/L 1,122 1,813 911 24 – 336
Serology
HBs antigen Negative Negative
HBc total Ab Negative Negative
HCV Ab screen Negative Negative
HIV-1/-2 Ag and Ab Negative Negative
Complement C3, mg/dL 163 75 – 175
Complement C4, mg/dL 36 13 – 40
C-ANCA Negative Negative
p-ANCA Negative Negative
Anti-GBM, U < 0.2 < 1 (negative)
Anti-phospholipase A2 receptor (IF) Negative Negative
Anti-phospholipase A2 receptor (ELISA), RU/mL < 2 < 14
Interleukin 6, pg/mL 39.5 3.5 5.7 < 1.8
Monoclonal gammopathy screen
κ free light chain, mg/dL 15.5 0.33 – 1.94
λ free light chain, mg/dL 8.73 0.57 – 2.63
κ/λ ratio 1.78 0.26 – 1.65
Total protein, g/dL 5.3 6.3 – 7.9
Albumin, g/dL 1.4 3.4 – 4.7
α-1 globulin, g/dL 0.6 0.1 – 0.3
α 2-globulin, g/dL 1.5 0.6 – 1.0
β globulin, g/dL 1.0 0.7 – 1.2
γ globulin, g/dL 0.8 0.6 – 1.6
A/G ratio 0.36
M protein isotype Cannot rule out small monoclonal protein
Endocrine
TSH, mIU/L 1.1 0.2 0.3 – 4.2
T4 (thyroxine), ng/dL 1.3 0.9 – 1.7
PTH, pg/mL 231 15 – 65
Tumor/malignancy marker
Prostate specific Ag, ng/mL 0.21 0.15 ≤ 7.2
Table 2. Urinalysis data.
Laboratory test 3 years prior to admission On admission Day 2 Reference range
Source Midstream Catheter Catheter
Appearance Normal Normal Normal
Osmolality, mOsm/kg 372 339 150 – 1150
pH 5.2 5.5 4.5 – 8.0
Glucose, mg/dL 5 81 12 0 – 15
Protein, mg/dL 17 339 117 < 26
Protein/Osmolality, ratio 0.39 9.11 3.45 < 0.42
Predicted 24 h protein, mg 385 7,735 3,066
24-h urine protein, mg/24 h 4,662 < 229
Hemoglobin Negative Trace Moderate Negative
Red blood cell 3 – 10 < 3/HPF
Dysmorphic RBC (%) < 25 < 25
White blood cell 1 – 3 1 – 3 1 – 3/HPF
Casts, hyaline 1 – 3 Occasional
Casts, granular Occasional
Fat, free Occasional Occasional
Fat, in casts Occasional
Oval fat body Occasional
Renal epithelial cells 1 – 3 None seen/HPF
Ketones Negative Negative
Nitrite Negative Negative
Leukocyte Negative Negative
Figure 1. Renal pathologic findings in this COVID-19 patient. A: Glomerulus showing thickening of the glomerular basement membrane with mild mesangial sclerosis and hypercellularity (silver stain, × 400). B: Glomerular capillary loop showing abundant small sub-epithelial electron-dense deposits. The overlying podocytes show extensive foot process effacement (electron microscopy, × 11,000). C: Large glomerular endothelial tubuloreticular inclusion is shown. Tiny sub-epithelial electron-dense deposits are also evident (electron microscopy, × 30,000). | Other | DrugAdministrationRoute | CC BY | 33633925 | 19,483,859 | 2021 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | Membranous nephropathy in a patient with coronavirus disease 2019 (COVID-19): A case report.
BACKGROUND
Though respiratory, immune, and coagulation systems are major targets of coronavirus disease 2019 (COVID-19), kidney dysfunction, presenting with acute kidney injury (AKI), is also common. Most AKI cases in COVID-19 manifest as acute tubular injury (ATI) in conjunction with multiorgan failure. While initial renal pathological findings were limited to acute tubular necrosis and collapsing glomerulopathy, a recent case series reported a larger spectrum of findings.
METHODS
Here, we report a case of membranous nephropathy (MN) in an 81-year-old Hispanic man with underlying chronic kidney disease (CKD) stage 3 who developed ATI in the setting of COVID-19. The patient was hospitalized for hypoxic respiratory failure in the setting of AKI stage 3 with serum creatinine 7.1 mg/dL 6 days after a positive-SARS-CoV-2 screening. He was found to have nephrotic range proteinuria, glycosuria (with normal serum glucose), anemia, and hypoalbuminemia. Kidney biopsy showed ATI and early MN. Workup for primary and secondary MN was unrevealing, and serum PLA2R antibody was negative. No viral particles were observed in podocytes.
CONCLUSIONS
Although the MN could be incidental, this observation raises the question of whether SARS-CoV-2 infection can trigger or worsen an underlying MN from an exaggerated immune response associated with COVID-19.
Introduction
Coronavirus disease 2019 (COVID-19), caused by a coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide since December 2019 [1].The principle feature of COVID-19 is viral pneumonia, leading to acute respiratory distress syndrome (ARDS) [2]. Similar to other coronaviruses, angiotensin-converting enzyme 2 (ACE2) may play a major role in the entry of SARS-CoV-2 to its target cells [3]. Besides the respiratory system, ACE2 is also highly expressed in the brush border of proximal tubular cells and, to a lesser extent, in glomerular podocytes [4]. Kidney involvement of COVID-19, mainly presents as acute kidney injury (AKI) [5], primarily due to acute tubular injury (ATI) in the setting of multiorgan failure. Clinically, the incidence of AKI in COVID-19 varies from 0.9 to 29% in hospitalized or critically ill patients at different centers [6, 7, 8] and is associated with worse outcomes [5, 9]. ATI and direct parenchymal infection of tubular epithelial cells and podocytes were reported in 26 postmortem examinations of patients with severe COVID-19 [10]. Proteinuria and hematuria are also common, occurring in 44 and 27%, respectively [5]. Kidney biopsy findings have been reported initially in four living COVID-19 cases, all of which showed collapsing glomerulopathy [11, 12, 13, 14]. Recently, two case series of kidney biopsy findings showed that ATI was the most common finding in COVID-19-associated kidney injury, but the series by Kudose et al. [15, 16] reported a wide spectrum of glomerular and tubular disease including minimal change disease and membranous glomerulopathy. Here, we report a case of membranous nephropathy (MN) diagnosed in the setting of AKI associated with COVID-19.
Case report
An 81-year-old Hispanic man presented to the emergency department complaining of progressive fatigue and shortness of breath 6 days after being diagnosed with COVID-19 (positive nasopharyngeal SARS-CoV-2 PCR). He reported myalgia, sore throat, intermittent dry cough, loss of smell and taste, poor appetite, and nausea without vomiting. He also had diarrhea and an episode of urinary incontinence. He denied fever or chills, chest pain, and headache. Because of hypoxemia requiring high-flow oxygen, the patient was admitted to the critical care unit.
Previous medical history includes prostate cancer treated with chemotherapy and androgen deprivation therapy in 2013, in remission with undetectable prostate-specific antigen (PSA) since 2014, prediabetes, hyperlipidemia, hypertension, chronic kidney disease (CKD) stage 3 (baseline creatinine 1.2 – 1.6 mg/dL) attributed to hypertension with prior urine analysis in 2017 showing proteinuria of 385 mg/day, aortic valve stenosis, and cervical radiculopathy. Home medications included olmesartan 20 mg twice daily and hydrochlorothiazide 12.5 mg daily. Notably, he had a history of non-steroidal anti-inflammatory drugs (NSAIDs) use, 400 – 800 mg of ibuprofen per day for chronic neck pain. He is a former smoker but quit in 2012 and did not have lung disease.
Initial vital signs: temperature 37.4 °C, blood pressure 166/69 mmHg, heart rate 68 beats per minute, respiratory rate 27 breaths per minute, and peripheral capillary oxygen saturation (SpO2) 95% on high-flow nasal cannula (50 L/min with FiO2 of 100%). Physical examination was notable for tachypnea with the remainder of physical examination unremarkable.
Table 1 and Table 2 show his laboratory results. Repeat SARS-CoV-2 PCR via nasopharyngeal swab was positive. He had evidence of AKI stage 3 with a serum creatinine of 7.1 mg/dL. Urinalysis demonstrated 3 – 10 red blood cells per high power field, nephrotic range proteinuria of 4.6 g per 24 hours, glycosuria, and tubular epithelial cells. He had anemia with hemoglobin of 10.3 g/dL, hypoalbuminemia of 1.7 g/dL, and multiple elevated inflammatory markers, including interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin. Kidney ultrasound revealed bilaterally increased parenchymal echogenicity consistent with CKD. Chest radiograph showed indistinct pulmonary vasculature bilaterally with bronchocentric ground glass, and bilateral patchy infiltrates, consistent with COVID-19 pneumonia. Lower extremities Doppler did not reveal deep vein thromboses, and transthoracic echocardiogram was normal.
He was enrolled in a randomized placebo-controlled clinical trial of lenzilumab (monoclonal antibody targeting GM-CSF) 600 mg for 3 doses, in addition to intravenous antibiotics for possible superimposed community-acquired pneumonia. He completed a steroid trial with 5 days of intravenous methylprednisolone. Due to increasing D-dimer to 100,000 ng/mL, low-intensity heparin infusion was initiated.
Over the first few hospitalization days, creatinine remained elevated at ~ 7 mg/dL. He did not require dialysis as he maintained excellent urine output. Serologic testing for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), tuberculosis, as well as C3, C4, anti-neutrophil cytoplasmic antibodies (ANCA), anti-glomerular basement membrane (GBM), and anti-phospholipase A2 receptors (PLA2R) were all negative. Anti-THSD7A was indeterminate due to high background. No serum monoclonal proteins were detected. Kidney biopsy was performed on hospital day 4.
On hospital day 7, the patient’s respiratory status worsened requiring intubation, mechanical ventilation, and initiation of vasopressors. Despite that, his AKI was slowly recovering and creatinine reached 3.7 mg/dL on hospital day 11. However, the shock state subsequently worsened, continuous dialysis was started but eventually the patient died on hospital day 16. Family declined an autopsy.
Kidney pathology findings
19 glomeruli were sampled for light microscopy, 8 of which were globally sclerotic and 1 was segmentally sclerotic. The glomeruli showed segmental mild mesangial hypercellularity and mesangial expansion, with thickening of their basement membranes (Figure 1A). No collapsing features, endocapillary hypercellularity, thrombi, necrosis, or crescents were seen. The tubulointerstitial compartment exhibited diffuse ATI, tubular protein reabsorption granules, mild tubular atrophy and interstitial fibrosis, and very mild mononuclear cell infiltrate without tubulitis. There was moderate arteriosclerosis and arteriolar hyalinosis.
Immunofluorescence studies were unable to be performed due to an inadequate sample. Immunohistochemistry staining for PLA2R was performed on sections prepared from the paraffin block and was negative.
In situ hybridization (ISH) staining for the presence of SARS-CoV-2 RNA was performed using RNAScope (ACD, Newark, CA, USA) and failed to show evidence of viral RNA in the kidney (methods in Supplemental Material).
Electron microscopy showed abundant small granular sub-epithelial electron-dense deposits without or associated with early basement membrane spike formation (Figure 1B). The glomerular basement membrane lamina densa was thickened. There was mild mesangial sclerosis with segmental mesangial electron-dense deposits, without sub-endothelial deposits. Abundant tubuloreticular inclusion bodies were seen in the endothelial cell cytoplasm (Figure 1C). Podocytes exhibited severe foot process effacement.
The pathological diagnosis was MN (stage 1 to early stage 2), diffuse ATI, mild mesangial sclerosing glomerulopathy (associated with hypertension, pre-diabetes, and smoking), and moderate arteriosclerosis and arteriolar hyalinosis.
Discussion
To our knowledge, MN diagnosed in a patient with COVID-19 has been reported in only 2 patients in one case series of 17 patients [16]. The finding of severe ATI in this case is not surprising as reported in recent series of COVID-19 patients [10, 15]. However, the finding of MN was unexpected.
MN, an inflammatory and autoimmune disease of the glomerulus, is one of the most common causes of nephrotic syndrome in adults. The etiology of ~ 75% of MN is unknown “primary”. Secondary MN can be secondary to infection, drugs, and malignancy [18]. Thus, the main question is whether the MN in this case is related to SARS-CoV-2 or not. This patient had a history of prostate cancer, but he was in remission for at least 6 years with normal PSA, so it is unlikely that his cancer was the underlying cause of the MN. NSAIDs can cause proteinuria and have been associated with minimal change disease as well as MN, but the patient did not have prior evidence of nephrotic syndrome despite being on NSAIDs for many years. The absence of detectable anti-PLA2R antibodies, the negative glomerular staining for PLA2R and the presence of mesangial deposits, as well as abundant tubuloreticular inclusions favor secondary MN over primary MN. The patient had mild proteinuria (385 mg/day) prior to COVID-19 which is likely due to underlying mild mesangial sclerosing glomerulopathy (associated with hypertension, prediabetes, and smoking). MN was mostly stage 1 favoring a recent development of disease temporally associated with COVID-19 over pre-existing MN.
The pathogenesis of MN involves formation and deposition of immune complexes in sub-epithelial sites [18]. The receptor for SARS-CoV-2, ACE2, is highly expressed on proximal tubular cells and glomerular podocytes [4]. In addition, TMPRSS2, an essential serine protease, is required for spike glycoprotein of SARS-CoV-2 priming after binding to ACE2, and thus activates membrane fusion facilitating to gain access to its target cells [19]. In kidneys, expression of TMPRSS2 is only detectable in the proximal tubule S3 segment [20]. An in vitro study showed that the administration of TMPRSS2 inhibitor, camostat mesylate, had a valuable treatment effect, blocking multiple SARS-CoV-2 entry routes [21]. In postmortem kidney samples, SARS-CoV-2 antigens and viral particles were detected in the tubular epithelium and podocytes [10, 17]. In the case of collapsing glomerulopathy associated with COVID-19 reported by Kissling et al. [13], the virus was seen in podocytes by electron microscopy. However, most recent biopsy series fail to show viral particles in kidney biopsies by immunohistochemistry staining or by electron microscopy arguing against a direct viral infection of the kidneys [15, 16]. Similarly, in this case we did not find evidence of viral particles in the kidneys. Rather than a direct toxic viral effect on the kidneys, the ATI is most likely cytokine mediated, although the NSAID, angiotensin receptor blocker, and diuretic exposures could also have contributed. Whether MN can be secondary to SARS-CoV-2 remains to be elucidated, but we speculate that it could result from an exaggerated immune response associated with COVID-19. In the passive Heymann nephritis model, sub-epithelial deposits with very early basement membrane reaction could be seen as early as 7 days after injection [22]. Therefore, we hypothesize that the development of MN deposits could possibly occur quickly after a viral infection, or alternatively the COVID-19-related immune response and the resulting high-grade proteinuria could unmask an underlying MN. If this is the case, the treatment of this patient’s MN is conservative and immunosuppressive therapy is not recommended.
Funding
None.
Conflict of interest
The authors declare no relevant financial interest.
Supplemental material
ISH methods
In situ hybridization was performed with RNAScope (ACD, Newark, CA) using probes directed against SARS-CoV-2 on formalin-fixed paraffin-embedded tissue sections cut at a thickness of 3 microns. 1A negative control (bacterial gene dapB) was also included to assess background signals as well as positive control probes to the housekeeping gene peptidylprolyl isomerase B (PPIB). The ISH sections were counterstained using periodic acid-Schiff. (Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012; 14: 22-29).
Table 1. Laboratory data.
Laboratory test 1 year before
admission Day 1 Day 4
(Kidney biopsy) Day 7 Reference
Arterial blood gas
pH 7.43 7.36 7.29 7.35 – 7.45
pCO2, mmHg 23 27 38 32 – 45
pO2, mmHg 137 68 72 83 – 108
HCO3
-, mmol/L 15 15 18 22 – 26
Complete blood count
WBC count, 109/L 11.2 15.0 15.1 3.4 – 9.6
Neutrophils, 109/L 10.35 1.56 – 6.45
Lymphocytes, 109/L 0.46 0.95 – 3.07
Erythrocytes, 1012/L 3.37 3.40 2.36 4.35 – 5.65
Hemoglobin, g/dL 11.3 11.4 7.9 13.2 – 16.6
Reticulocytes, % 2.12 0.6 – 2.71
Platelet count, 109/L 449 436 295 135 – 317
Serum biochemistry
Sodium, mmol/L 138 139 138 135 – 145
Potassium, mmol/L 5.4 4.5 4.1 3.6 – 5.2
Chloride, mmol/L 100 99 103 98 – 107
Bicarbonate, mmol/L 17 17 19 22 – 29
Anion gap 21 23 17 7 – 15
BUN, mg/dL 98 133 128 8 – 24
Creatinine, mg/dL 1.4 7.05 6.96 4.41 0.74 – 1.35
eGFR, mL/min/BSA 49 < 15 < 15 < 15 > 60
eGFR by cystatin C, mL/min/BSA 6 > 60
Calcium, total, mg/dL 8.9 8.3 8.1 8.8 – 10.2
Calcium, ionized, mg/dL 4.40 4.57 4.62 4.65 – 5.30
Glucose, mg/dL 127 165 145 70 – 140
Magnesium, mg/dL 3.8 2.9 1.7 – 2.3
Phosphorus, mg/dL 11.5 7.9 2.5 – 4.5
Total protein, g/dL 4.4 4.5 6.3 – 7.9
Albumin, g/dL 1.7 2.6 3.5 – 5.0
Hemoglobin A1C, % 5.9 4 – 5.6
Lactate, mmol/L 1.3 1.1 0.5 – 2.2
Liver function
ALT, U/L 45 36 11 7 – 55
AST, U/L 43 49 22 8 – 48
Bilirubin, total, mg/dL 0.6 < 0.2 0.5 < 1.2
Bilirubin, direct, mg/dL 0.3 < 0.2 0.4 0.0 – 0.3
Alkaline protease, U/L 155 70 40 – 129
Lipid/cardiac risk
Total cholesterol, mg/dL 241 226 < 200
HDL, mg/dL 38 34 ≥ 40
LDL, mg/dL 153 131 < 100
Triglycerides, mg/dL 248 304 < 150
Troponin T, ng/L 71 160 < 15
Troponin T-2h, ng/L 80 153 < 15
Troponin T-6h, ng/L 87 152 < 15
NT-pro BNP, pg/mL 220 5,030 5 – 131
Creatinine kinase, U/L 108 39 – 308
Coagulation
Antithrombin activity 91 80 – 130%
D-dimer, ng/mL 13,286 > 100,000 48,550 < 500
Fibrinogen, Clauss, mg/dL > 800 561 200 – 500
Coag factor II 101 92 75 – 145%
Coag factor V 132 110 70 – 165%
Coag factor VII 116 83 65 – 180%
Coag factor X 131 86 70 – 150%
C-reactive protein, mg/L > 400 173.3 142.1 < 8
Soluble fibrin monomer, mcg/mL > 1,100 36 ≤ 8
Plasminogen activity 98 75 – 140%
α-2 plasmin inhibitor 105 80 – 140%
Sedimentation rate, mm/h > 140 123 3 – 28
Ferritin, µg/L 1,122 1,813 911 24 – 336
Serology
HBs antigen Negative Negative
HBc total Ab Negative Negative
HCV Ab screen Negative Negative
HIV-1/-2 Ag and Ab Negative Negative
Complement C3, mg/dL 163 75 – 175
Complement C4, mg/dL 36 13 – 40
C-ANCA Negative Negative
p-ANCA Negative Negative
Anti-GBM, U < 0.2 < 1 (negative)
Anti-phospholipase A2 receptor (IF) Negative Negative
Anti-phospholipase A2 receptor (ELISA), RU/mL < 2 < 14
Interleukin 6, pg/mL 39.5 3.5 5.7 < 1.8
Monoclonal gammopathy screen
κ free light chain, mg/dL 15.5 0.33 – 1.94
λ free light chain, mg/dL 8.73 0.57 – 2.63
κ/λ ratio 1.78 0.26 – 1.65
Total protein, g/dL 5.3 6.3 – 7.9
Albumin, g/dL 1.4 3.4 – 4.7
α-1 globulin, g/dL 0.6 0.1 – 0.3
α 2-globulin, g/dL 1.5 0.6 – 1.0
β globulin, g/dL 1.0 0.7 – 1.2
γ globulin, g/dL 0.8 0.6 – 1.6
A/G ratio 0.36
M protein isotype Cannot rule out small monoclonal protein
Endocrine
TSH, mIU/L 1.1 0.2 0.3 – 4.2
T4 (thyroxine), ng/dL 1.3 0.9 – 1.7
PTH, pg/mL 231 15 – 65
Tumor/malignancy marker
Prostate specific Ag, ng/mL 0.21 0.15 ≤ 7.2
Table 2. Urinalysis data.
Laboratory test 3 years prior to admission On admission Day 2 Reference range
Source Midstream Catheter Catheter
Appearance Normal Normal Normal
Osmolality, mOsm/kg 372 339 150 – 1150
pH 5.2 5.5 4.5 – 8.0
Glucose, mg/dL 5 81 12 0 – 15
Protein, mg/dL 17 339 117 < 26
Protein/Osmolality, ratio 0.39 9.11 3.45 < 0.42
Predicted 24 h protein, mg 385 7,735 3,066
24-h urine protein, mg/24 h 4,662 < 229
Hemoglobin Negative Trace Moderate Negative
Red blood cell 3 – 10 < 3/HPF
Dysmorphic RBC (%) < 25 < 25
White blood cell 1 – 3 1 – 3 1 – 3/HPF
Casts, hyaline 1 – 3 Occasional
Casts, granular Occasional
Fat, free Occasional Occasional
Fat, in casts Occasional
Oval fat body Occasional
Renal epithelial cells 1 – 3 None seen/HPF
Ketones Negative Negative
Nitrite Negative Negative
Leukocyte Negative Negative
Figure 1. Renal pathologic findings in this COVID-19 patient. A: Glomerulus showing thickening of the glomerular basement membrane with mild mesangial sclerosis and hypercellularity (silver stain, × 400). B: Glomerular capillary loop showing abundant small sub-epithelial electron-dense deposits. The overlying podocytes show extensive foot process effacement (electron microscopy, × 11,000). C: Large glomerular endothelial tubuloreticular inclusion is shown. Tiny sub-epithelial electron-dense deposits are also evident (electron microscopy, × 30,000). | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33633925 | 19,483,859 | 2021 |
What was the outcome of reaction 'Acute kidney injury'? | Membranous nephropathy in a patient with coronavirus disease 2019 (COVID-19): A case report.
BACKGROUND
Though respiratory, immune, and coagulation systems are major targets of coronavirus disease 2019 (COVID-19), kidney dysfunction, presenting with acute kidney injury (AKI), is also common. Most AKI cases in COVID-19 manifest as acute tubular injury (ATI) in conjunction with multiorgan failure. While initial renal pathological findings were limited to acute tubular necrosis and collapsing glomerulopathy, a recent case series reported a larger spectrum of findings.
METHODS
Here, we report a case of membranous nephropathy (MN) in an 81-year-old Hispanic man with underlying chronic kidney disease (CKD) stage 3 who developed ATI in the setting of COVID-19. The patient was hospitalized for hypoxic respiratory failure in the setting of AKI stage 3 with serum creatinine 7.1 mg/dL 6 days after a positive-SARS-CoV-2 screening. He was found to have nephrotic range proteinuria, glycosuria (with normal serum glucose), anemia, and hypoalbuminemia. Kidney biopsy showed ATI and early MN. Workup for primary and secondary MN was unrevealing, and serum PLA2R antibody was negative. No viral particles were observed in podocytes.
CONCLUSIONS
Although the MN could be incidental, this observation raises the question of whether SARS-CoV-2 infection can trigger or worsen an underlying MN from an exaggerated immune response associated with COVID-19.
Introduction
Coronavirus disease 2019 (COVID-19), caused by a coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide since December 2019 [1].The principle feature of COVID-19 is viral pneumonia, leading to acute respiratory distress syndrome (ARDS) [2]. Similar to other coronaviruses, angiotensin-converting enzyme 2 (ACE2) may play a major role in the entry of SARS-CoV-2 to its target cells [3]. Besides the respiratory system, ACE2 is also highly expressed in the brush border of proximal tubular cells and, to a lesser extent, in glomerular podocytes [4]. Kidney involvement of COVID-19, mainly presents as acute kidney injury (AKI) [5], primarily due to acute tubular injury (ATI) in the setting of multiorgan failure. Clinically, the incidence of AKI in COVID-19 varies from 0.9 to 29% in hospitalized or critically ill patients at different centers [6, 7, 8] and is associated with worse outcomes [5, 9]. ATI and direct parenchymal infection of tubular epithelial cells and podocytes were reported in 26 postmortem examinations of patients with severe COVID-19 [10]. Proteinuria and hematuria are also common, occurring in 44 and 27%, respectively [5]. Kidney biopsy findings have been reported initially in four living COVID-19 cases, all of which showed collapsing glomerulopathy [11, 12, 13, 14]. Recently, two case series of kidney biopsy findings showed that ATI was the most common finding in COVID-19-associated kidney injury, but the series by Kudose et al. [15, 16] reported a wide spectrum of glomerular and tubular disease including minimal change disease and membranous glomerulopathy. Here, we report a case of membranous nephropathy (MN) diagnosed in the setting of AKI associated with COVID-19.
Case report
An 81-year-old Hispanic man presented to the emergency department complaining of progressive fatigue and shortness of breath 6 days after being diagnosed with COVID-19 (positive nasopharyngeal SARS-CoV-2 PCR). He reported myalgia, sore throat, intermittent dry cough, loss of smell and taste, poor appetite, and nausea without vomiting. He also had diarrhea and an episode of urinary incontinence. He denied fever or chills, chest pain, and headache. Because of hypoxemia requiring high-flow oxygen, the patient was admitted to the critical care unit.
Previous medical history includes prostate cancer treated with chemotherapy and androgen deprivation therapy in 2013, in remission with undetectable prostate-specific antigen (PSA) since 2014, prediabetes, hyperlipidemia, hypertension, chronic kidney disease (CKD) stage 3 (baseline creatinine 1.2 – 1.6 mg/dL) attributed to hypertension with prior urine analysis in 2017 showing proteinuria of 385 mg/day, aortic valve stenosis, and cervical radiculopathy. Home medications included olmesartan 20 mg twice daily and hydrochlorothiazide 12.5 mg daily. Notably, he had a history of non-steroidal anti-inflammatory drugs (NSAIDs) use, 400 – 800 mg of ibuprofen per day for chronic neck pain. He is a former smoker but quit in 2012 and did not have lung disease.
Initial vital signs: temperature 37.4 °C, blood pressure 166/69 mmHg, heart rate 68 beats per minute, respiratory rate 27 breaths per minute, and peripheral capillary oxygen saturation (SpO2) 95% on high-flow nasal cannula (50 L/min with FiO2 of 100%). Physical examination was notable for tachypnea with the remainder of physical examination unremarkable.
Table 1 and Table 2 show his laboratory results. Repeat SARS-CoV-2 PCR via nasopharyngeal swab was positive. He had evidence of AKI stage 3 with a serum creatinine of 7.1 mg/dL. Urinalysis demonstrated 3 – 10 red blood cells per high power field, nephrotic range proteinuria of 4.6 g per 24 hours, glycosuria, and tubular epithelial cells. He had anemia with hemoglobin of 10.3 g/dL, hypoalbuminemia of 1.7 g/dL, and multiple elevated inflammatory markers, including interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin. Kidney ultrasound revealed bilaterally increased parenchymal echogenicity consistent with CKD. Chest radiograph showed indistinct pulmonary vasculature bilaterally with bronchocentric ground glass, and bilateral patchy infiltrates, consistent with COVID-19 pneumonia. Lower extremities Doppler did not reveal deep vein thromboses, and transthoracic echocardiogram was normal.
He was enrolled in a randomized placebo-controlled clinical trial of lenzilumab (monoclonal antibody targeting GM-CSF) 600 mg for 3 doses, in addition to intravenous antibiotics for possible superimposed community-acquired pneumonia. He completed a steroid trial with 5 days of intravenous methylprednisolone. Due to increasing D-dimer to 100,000 ng/mL, low-intensity heparin infusion was initiated.
Over the first few hospitalization days, creatinine remained elevated at ~ 7 mg/dL. He did not require dialysis as he maintained excellent urine output. Serologic testing for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), tuberculosis, as well as C3, C4, anti-neutrophil cytoplasmic antibodies (ANCA), anti-glomerular basement membrane (GBM), and anti-phospholipase A2 receptors (PLA2R) were all negative. Anti-THSD7A was indeterminate due to high background. No serum monoclonal proteins were detected. Kidney biopsy was performed on hospital day 4.
On hospital day 7, the patient’s respiratory status worsened requiring intubation, mechanical ventilation, and initiation of vasopressors. Despite that, his AKI was slowly recovering and creatinine reached 3.7 mg/dL on hospital day 11. However, the shock state subsequently worsened, continuous dialysis was started but eventually the patient died on hospital day 16. Family declined an autopsy.
Kidney pathology findings
19 glomeruli were sampled for light microscopy, 8 of which were globally sclerotic and 1 was segmentally sclerotic. The glomeruli showed segmental mild mesangial hypercellularity and mesangial expansion, with thickening of their basement membranes (Figure 1A). No collapsing features, endocapillary hypercellularity, thrombi, necrosis, or crescents were seen. The tubulointerstitial compartment exhibited diffuse ATI, tubular protein reabsorption granules, mild tubular atrophy and interstitial fibrosis, and very mild mononuclear cell infiltrate without tubulitis. There was moderate arteriosclerosis and arteriolar hyalinosis.
Immunofluorescence studies were unable to be performed due to an inadequate sample. Immunohistochemistry staining for PLA2R was performed on sections prepared from the paraffin block and was negative.
In situ hybridization (ISH) staining for the presence of SARS-CoV-2 RNA was performed using RNAScope (ACD, Newark, CA, USA) and failed to show evidence of viral RNA in the kidney (methods in Supplemental Material).
Electron microscopy showed abundant small granular sub-epithelial electron-dense deposits without or associated with early basement membrane spike formation (Figure 1B). The glomerular basement membrane lamina densa was thickened. There was mild mesangial sclerosis with segmental mesangial electron-dense deposits, without sub-endothelial deposits. Abundant tubuloreticular inclusion bodies were seen in the endothelial cell cytoplasm (Figure 1C). Podocytes exhibited severe foot process effacement.
The pathological diagnosis was MN (stage 1 to early stage 2), diffuse ATI, mild mesangial sclerosing glomerulopathy (associated with hypertension, pre-diabetes, and smoking), and moderate arteriosclerosis and arteriolar hyalinosis.
Discussion
To our knowledge, MN diagnosed in a patient with COVID-19 has been reported in only 2 patients in one case series of 17 patients [16]. The finding of severe ATI in this case is not surprising as reported in recent series of COVID-19 patients [10, 15]. However, the finding of MN was unexpected.
MN, an inflammatory and autoimmune disease of the glomerulus, is one of the most common causes of nephrotic syndrome in adults. The etiology of ~ 75% of MN is unknown “primary”. Secondary MN can be secondary to infection, drugs, and malignancy [18]. Thus, the main question is whether the MN in this case is related to SARS-CoV-2 or not. This patient had a history of prostate cancer, but he was in remission for at least 6 years with normal PSA, so it is unlikely that his cancer was the underlying cause of the MN. NSAIDs can cause proteinuria and have been associated with minimal change disease as well as MN, but the patient did not have prior evidence of nephrotic syndrome despite being on NSAIDs for many years. The absence of detectable anti-PLA2R antibodies, the negative glomerular staining for PLA2R and the presence of mesangial deposits, as well as abundant tubuloreticular inclusions favor secondary MN over primary MN. The patient had mild proteinuria (385 mg/day) prior to COVID-19 which is likely due to underlying mild mesangial sclerosing glomerulopathy (associated with hypertension, prediabetes, and smoking). MN was mostly stage 1 favoring a recent development of disease temporally associated with COVID-19 over pre-existing MN.
The pathogenesis of MN involves formation and deposition of immune complexes in sub-epithelial sites [18]. The receptor for SARS-CoV-2, ACE2, is highly expressed on proximal tubular cells and glomerular podocytes [4]. In addition, TMPRSS2, an essential serine protease, is required for spike glycoprotein of SARS-CoV-2 priming after binding to ACE2, and thus activates membrane fusion facilitating to gain access to its target cells [19]. In kidneys, expression of TMPRSS2 is only detectable in the proximal tubule S3 segment [20]. An in vitro study showed that the administration of TMPRSS2 inhibitor, camostat mesylate, had a valuable treatment effect, blocking multiple SARS-CoV-2 entry routes [21]. In postmortem kidney samples, SARS-CoV-2 antigens and viral particles were detected in the tubular epithelium and podocytes [10, 17]. In the case of collapsing glomerulopathy associated with COVID-19 reported by Kissling et al. [13], the virus was seen in podocytes by electron microscopy. However, most recent biopsy series fail to show viral particles in kidney biopsies by immunohistochemistry staining or by electron microscopy arguing against a direct viral infection of the kidneys [15, 16]. Similarly, in this case we did not find evidence of viral particles in the kidneys. Rather than a direct toxic viral effect on the kidneys, the ATI is most likely cytokine mediated, although the NSAID, angiotensin receptor blocker, and diuretic exposures could also have contributed. Whether MN can be secondary to SARS-CoV-2 remains to be elucidated, but we speculate that it could result from an exaggerated immune response associated with COVID-19. In the passive Heymann nephritis model, sub-epithelial deposits with very early basement membrane reaction could be seen as early as 7 days after injection [22]. Therefore, we hypothesize that the development of MN deposits could possibly occur quickly after a viral infection, or alternatively the COVID-19-related immune response and the resulting high-grade proteinuria could unmask an underlying MN. If this is the case, the treatment of this patient’s MN is conservative and immunosuppressive therapy is not recommended.
Funding
None.
Conflict of interest
The authors declare no relevant financial interest.
Supplemental material
ISH methods
In situ hybridization was performed with RNAScope (ACD, Newark, CA) using probes directed against SARS-CoV-2 on formalin-fixed paraffin-embedded tissue sections cut at a thickness of 3 microns. 1A negative control (bacterial gene dapB) was also included to assess background signals as well as positive control probes to the housekeeping gene peptidylprolyl isomerase B (PPIB). The ISH sections were counterstained using periodic acid-Schiff. (Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012; 14: 22-29).
Table 1. Laboratory data.
Laboratory test 1 year before
admission Day 1 Day 4
(Kidney biopsy) Day 7 Reference
Arterial blood gas
pH 7.43 7.36 7.29 7.35 – 7.45
pCO2, mmHg 23 27 38 32 – 45
pO2, mmHg 137 68 72 83 – 108
HCO3
-, mmol/L 15 15 18 22 – 26
Complete blood count
WBC count, 109/L 11.2 15.0 15.1 3.4 – 9.6
Neutrophils, 109/L 10.35 1.56 – 6.45
Lymphocytes, 109/L 0.46 0.95 – 3.07
Erythrocytes, 1012/L 3.37 3.40 2.36 4.35 – 5.65
Hemoglobin, g/dL 11.3 11.4 7.9 13.2 – 16.6
Reticulocytes, % 2.12 0.6 – 2.71
Platelet count, 109/L 449 436 295 135 – 317
Serum biochemistry
Sodium, mmol/L 138 139 138 135 – 145
Potassium, mmol/L 5.4 4.5 4.1 3.6 – 5.2
Chloride, mmol/L 100 99 103 98 – 107
Bicarbonate, mmol/L 17 17 19 22 – 29
Anion gap 21 23 17 7 – 15
BUN, mg/dL 98 133 128 8 – 24
Creatinine, mg/dL 1.4 7.05 6.96 4.41 0.74 – 1.35
eGFR, mL/min/BSA 49 < 15 < 15 < 15 > 60
eGFR by cystatin C, mL/min/BSA 6 > 60
Calcium, total, mg/dL 8.9 8.3 8.1 8.8 – 10.2
Calcium, ionized, mg/dL 4.40 4.57 4.62 4.65 – 5.30
Glucose, mg/dL 127 165 145 70 – 140
Magnesium, mg/dL 3.8 2.9 1.7 – 2.3
Phosphorus, mg/dL 11.5 7.9 2.5 – 4.5
Total protein, g/dL 4.4 4.5 6.3 – 7.9
Albumin, g/dL 1.7 2.6 3.5 – 5.0
Hemoglobin A1C, % 5.9 4 – 5.6
Lactate, mmol/L 1.3 1.1 0.5 – 2.2
Liver function
ALT, U/L 45 36 11 7 – 55
AST, U/L 43 49 22 8 – 48
Bilirubin, total, mg/dL 0.6 < 0.2 0.5 < 1.2
Bilirubin, direct, mg/dL 0.3 < 0.2 0.4 0.0 – 0.3
Alkaline protease, U/L 155 70 40 – 129
Lipid/cardiac risk
Total cholesterol, mg/dL 241 226 < 200
HDL, mg/dL 38 34 ≥ 40
LDL, mg/dL 153 131 < 100
Triglycerides, mg/dL 248 304 < 150
Troponin T, ng/L 71 160 < 15
Troponin T-2h, ng/L 80 153 < 15
Troponin T-6h, ng/L 87 152 < 15
NT-pro BNP, pg/mL 220 5,030 5 – 131
Creatinine kinase, U/L 108 39 – 308
Coagulation
Antithrombin activity 91 80 – 130%
D-dimer, ng/mL 13,286 > 100,000 48,550 < 500
Fibrinogen, Clauss, mg/dL > 800 561 200 – 500
Coag factor II 101 92 75 – 145%
Coag factor V 132 110 70 – 165%
Coag factor VII 116 83 65 – 180%
Coag factor X 131 86 70 – 150%
C-reactive protein, mg/L > 400 173.3 142.1 < 8
Soluble fibrin monomer, mcg/mL > 1,100 36 ≤ 8
Plasminogen activity 98 75 – 140%
α-2 plasmin inhibitor 105 80 – 140%
Sedimentation rate, mm/h > 140 123 3 – 28
Ferritin, µg/L 1,122 1,813 911 24 – 336
Serology
HBs antigen Negative Negative
HBc total Ab Negative Negative
HCV Ab screen Negative Negative
HIV-1/-2 Ag and Ab Negative Negative
Complement C3, mg/dL 163 75 – 175
Complement C4, mg/dL 36 13 – 40
C-ANCA Negative Negative
p-ANCA Negative Negative
Anti-GBM, U < 0.2 < 1 (negative)
Anti-phospholipase A2 receptor (IF) Negative Negative
Anti-phospholipase A2 receptor (ELISA), RU/mL < 2 < 14
Interleukin 6, pg/mL 39.5 3.5 5.7 < 1.8
Monoclonal gammopathy screen
κ free light chain, mg/dL 15.5 0.33 – 1.94
λ free light chain, mg/dL 8.73 0.57 – 2.63
κ/λ ratio 1.78 0.26 – 1.65
Total protein, g/dL 5.3 6.3 – 7.9
Albumin, g/dL 1.4 3.4 – 4.7
α-1 globulin, g/dL 0.6 0.1 – 0.3
α 2-globulin, g/dL 1.5 0.6 – 1.0
β globulin, g/dL 1.0 0.7 – 1.2
γ globulin, g/dL 0.8 0.6 – 1.6
A/G ratio 0.36
M protein isotype Cannot rule out small monoclonal protein
Endocrine
TSH, mIU/L 1.1 0.2 0.3 – 4.2
T4 (thyroxine), ng/dL 1.3 0.9 – 1.7
PTH, pg/mL 231 15 – 65
Tumor/malignancy marker
Prostate specific Ag, ng/mL 0.21 0.15 ≤ 7.2
Table 2. Urinalysis data.
Laboratory test 3 years prior to admission On admission Day 2 Reference range
Source Midstream Catheter Catheter
Appearance Normal Normal Normal
Osmolality, mOsm/kg 372 339 150 – 1150
pH 5.2 5.5 4.5 – 8.0
Glucose, mg/dL 5 81 12 0 – 15
Protein, mg/dL 17 339 117 < 26
Protein/Osmolality, ratio 0.39 9.11 3.45 < 0.42
Predicted 24 h protein, mg 385 7,735 3,066
24-h urine protein, mg/24 h 4,662 < 229
Hemoglobin Negative Trace Moderate Negative
Red blood cell 3 – 10 < 3/HPF
Dysmorphic RBC (%) < 25 < 25
White blood cell 1 – 3 1 – 3 1 – 3/HPF
Casts, hyaline 1 – 3 Occasional
Casts, granular Occasional
Fat, free Occasional Occasional
Fat, in casts Occasional
Oval fat body Occasional
Renal epithelial cells 1 – 3 None seen/HPF
Ketones Negative Negative
Nitrite Negative Negative
Leukocyte Negative Negative
Figure 1. Renal pathologic findings in this COVID-19 patient. A: Glomerulus showing thickening of the glomerular basement membrane with mild mesangial sclerosis and hypercellularity (silver stain, × 400). B: Glomerular capillary loop showing abundant small sub-epithelial electron-dense deposits. The overlying podocytes show extensive foot process effacement (electron microscopy, × 11,000). C: Large glomerular endothelial tubuloreticular inclusion is shown. Tiny sub-epithelial electron-dense deposits are also evident (electron microscopy, × 30,000). | Recovering | ReactionOutcome | CC BY | 33633925 | 19,275,153 | 2021 |
What was the outcome of reaction 'Proteinuria'? | Membranous nephropathy in a patient with coronavirus disease 2019 (COVID-19): A case report.
BACKGROUND
Though respiratory, immune, and coagulation systems are major targets of coronavirus disease 2019 (COVID-19), kidney dysfunction, presenting with acute kidney injury (AKI), is also common. Most AKI cases in COVID-19 manifest as acute tubular injury (ATI) in conjunction with multiorgan failure. While initial renal pathological findings were limited to acute tubular necrosis and collapsing glomerulopathy, a recent case series reported a larger spectrum of findings.
METHODS
Here, we report a case of membranous nephropathy (MN) in an 81-year-old Hispanic man with underlying chronic kidney disease (CKD) stage 3 who developed ATI in the setting of COVID-19. The patient was hospitalized for hypoxic respiratory failure in the setting of AKI stage 3 with serum creatinine 7.1 mg/dL 6 days after a positive-SARS-CoV-2 screening. He was found to have nephrotic range proteinuria, glycosuria (with normal serum glucose), anemia, and hypoalbuminemia. Kidney biopsy showed ATI and early MN. Workup for primary and secondary MN was unrevealing, and serum PLA2R antibody was negative. No viral particles were observed in podocytes.
CONCLUSIONS
Although the MN could be incidental, this observation raises the question of whether SARS-CoV-2 infection can trigger or worsen an underlying MN from an exaggerated immune response associated with COVID-19.
Introduction
Coronavirus disease 2019 (COVID-19), caused by a coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide since December 2019 [1].The principle feature of COVID-19 is viral pneumonia, leading to acute respiratory distress syndrome (ARDS) [2]. Similar to other coronaviruses, angiotensin-converting enzyme 2 (ACE2) may play a major role in the entry of SARS-CoV-2 to its target cells [3]. Besides the respiratory system, ACE2 is also highly expressed in the brush border of proximal tubular cells and, to a lesser extent, in glomerular podocytes [4]. Kidney involvement of COVID-19, mainly presents as acute kidney injury (AKI) [5], primarily due to acute tubular injury (ATI) in the setting of multiorgan failure. Clinically, the incidence of AKI in COVID-19 varies from 0.9 to 29% in hospitalized or critically ill patients at different centers [6, 7, 8] and is associated with worse outcomes [5, 9]. ATI and direct parenchymal infection of tubular epithelial cells and podocytes were reported in 26 postmortem examinations of patients with severe COVID-19 [10]. Proteinuria and hematuria are also common, occurring in 44 and 27%, respectively [5]. Kidney biopsy findings have been reported initially in four living COVID-19 cases, all of which showed collapsing glomerulopathy [11, 12, 13, 14]. Recently, two case series of kidney biopsy findings showed that ATI was the most common finding in COVID-19-associated kidney injury, but the series by Kudose et al. [15, 16] reported a wide spectrum of glomerular and tubular disease including minimal change disease and membranous glomerulopathy. Here, we report a case of membranous nephropathy (MN) diagnosed in the setting of AKI associated with COVID-19.
Case report
An 81-year-old Hispanic man presented to the emergency department complaining of progressive fatigue and shortness of breath 6 days after being diagnosed with COVID-19 (positive nasopharyngeal SARS-CoV-2 PCR). He reported myalgia, sore throat, intermittent dry cough, loss of smell and taste, poor appetite, and nausea without vomiting. He also had diarrhea and an episode of urinary incontinence. He denied fever or chills, chest pain, and headache. Because of hypoxemia requiring high-flow oxygen, the patient was admitted to the critical care unit.
Previous medical history includes prostate cancer treated with chemotherapy and androgen deprivation therapy in 2013, in remission with undetectable prostate-specific antigen (PSA) since 2014, prediabetes, hyperlipidemia, hypertension, chronic kidney disease (CKD) stage 3 (baseline creatinine 1.2 – 1.6 mg/dL) attributed to hypertension with prior urine analysis in 2017 showing proteinuria of 385 mg/day, aortic valve stenosis, and cervical radiculopathy. Home medications included olmesartan 20 mg twice daily and hydrochlorothiazide 12.5 mg daily. Notably, he had a history of non-steroidal anti-inflammatory drugs (NSAIDs) use, 400 – 800 mg of ibuprofen per day for chronic neck pain. He is a former smoker but quit in 2012 and did not have lung disease.
Initial vital signs: temperature 37.4 °C, blood pressure 166/69 mmHg, heart rate 68 beats per minute, respiratory rate 27 breaths per minute, and peripheral capillary oxygen saturation (SpO2) 95% on high-flow nasal cannula (50 L/min with FiO2 of 100%). Physical examination was notable for tachypnea with the remainder of physical examination unremarkable.
Table 1 and Table 2 show his laboratory results. Repeat SARS-CoV-2 PCR via nasopharyngeal swab was positive. He had evidence of AKI stage 3 with a serum creatinine of 7.1 mg/dL. Urinalysis demonstrated 3 – 10 red blood cells per high power field, nephrotic range proteinuria of 4.6 g per 24 hours, glycosuria, and tubular epithelial cells. He had anemia with hemoglobin of 10.3 g/dL, hypoalbuminemia of 1.7 g/dL, and multiple elevated inflammatory markers, including interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin. Kidney ultrasound revealed bilaterally increased parenchymal echogenicity consistent with CKD. Chest radiograph showed indistinct pulmonary vasculature bilaterally with bronchocentric ground glass, and bilateral patchy infiltrates, consistent with COVID-19 pneumonia. Lower extremities Doppler did not reveal deep vein thromboses, and transthoracic echocardiogram was normal.
He was enrolled in a randomized placebo-controlled clinical trial of lenzilumab (monoclonal antibody targeting GM-CSF) 600 mg for 3 doses, in addition to intravenous antibiotics for possible superimposed community-acquired pneumonia. He completed a steroid trial with 5 days of intravenous methylprednisolone. Due to increasing D-dimer to 100,000 ng/mL, low-intensity heparin infusion was initiated.
Over the first few hospitalization days, creatinine remained elevated at ~ 7 mg/dL. He did not require dialysis as he maintained excellent urine output. Serologic testing for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), tuberculosis, as well as C3, C4, anti-neutrophil cytoplasmic antibodies (ANCA), anti-glomerular basement membrane (GBM), and anti-phospholipase A2 receptors (PLA2R) were all negative. Anti-THSD7A was indeterminate due to high background. No serum monoclonal proteins were detected. Kidney biopsy was performed on hospital day 4.
On hospital day 7, the patient’s respiratory status worsened requiring intubation, mechanical ventilation, and initiation of vasopressors. Despite that, his AKI was slowly recovering and creatinine reached 3.7 mg/dL on hospital day 11. However, the shock state subsequently worsened, continuous dialysis was started but eventually the patient died on hospital day 16. Family declined an autopsy.
Kidney pathology findings
19 glomeruli were sampled for light microscopy, 8 of which were globally sclerotic and 1 was segmentally sclerotic. The glomeruli showed segmental mild mesangial hypercellularity and mesangial expansion, with thickening of their basement membranes (Figure 1A). No collapsing features, endocapillary hypercellularity, thrombi, necrosis, or crescents were seen. The tubulointerstitial compartment exhibited diffuse ATI, tubular protein reabsorption granules, mild tubular atrophy and interstitial fibrosis, and very mild mononuclear cell infiltrate without tubulitis. There was moderate arteriosclerosis and arteriolar hyalinosis.
Immunofluorescence studies were unable to be performed due to an inadequate sample. Immunohistochemistry staining for PLA2R was performed on sections prepared from the paraffin block and was negative.
In situ hybridization (ISH) staining for the presence of SARS-CoV-2 RNA was performed using RNAScope (ACD, Newark, CA, USA) and failed to show evidence of viral RNA in the kidney (methods in Supplemental Material).
Electron microscopy showed abundant small granular sub-epithelial electron-dense deposits without or associated with early basement membrane spike formation (Figure 1B). The glomerular basement membrane lamina densa was thickened. There was mild mesangial sclerosis with segmental mesangial electron-dense deposits, without sub-endothelial deposits. Abundant tubuloreticular inclusion bodies were seen in the endothelial cell cytoplasm (Figure 1C). Podocytes exhibited severe foot process effacement.
The pathological diagnosis was MN (stage 1 to early stage 2), diffuse ATI, mild mesangial sclerosing glomerulopathy (associated with hypertension, pre-diabetes, and smoking), and moderate arteriosclerosis and arteriolar hyalinosis.
Discussion
To our knowledge, MN diagnosed in a patient with COVID-19 has been reported in only 2 patients in one case series of 17 patients [16]. The finding of severe ATI in this case is not surprising as reported in recent series of COVID-19 patients [10, 15]. However, the finding of MN was unexpected.
MN, an inflammatory and autoimmune disease of the glomerulus, is one of the most common causes of nephrotic syndrome in adults. The etiology of ~ 75% of MN is unknown “primary”. Secondary MN can be secondary to infection, drugs, and malignancy [18]. Thus, the main question is whether the MN in this case is related to SARS-CoV-2 or not. This patient had a history of prostate cancer, but he was in remission for at least 6 years with normal PSA, so it is unlikely that his cancer was the underlying cause of the MN. NSAIDs can cause proteinuria and have been associated with minimal change disease as well as MN, but the patient did not have prior evidence of nephrotic syndrome despite being on NSAIDs for many years. The absence of detectable anti-PLA2R antibodies, the negative glomerular staining for PLA2R and the presence of mesangial deposits, as well as abundant tubuloreticular inclusions favor secondary MN over primary MN. The patient had mild proteinuria (385 mg/day) prior to COVID-19 which is likely due to underlying mild mesangial sclerosing glomerulopathy (associated with hypertension, prediabetes, and smoking). MN was mostly stage 1 favoring a recent development of disease temporally associated with COVID-19 over pre-existing MN.
The pathogenesis of MN involves formation and deposition of immune complexes in sub-epithelial sites [18]. The receptor for SARS-CoV-2, ACE2, is highly expressed on proximal tubular cells and glomerular podocytes [4]. In addition, TMPRSS2, an essential serine protease, is required for spike glycoprotein of SARS-CoV-2 priming after binding to ACE2, and thus activates membrane fusion facilitating to gain access to its target cells [19]. In kidneys, expression of TMPRSS2 is only detectable in the proximal tubule S3 segment [20]. An in vitro study showed that the administration of TMPRSS2 inhibitor, camostat mesylate, had a valuable treatment effect, blocking multiple SARS-CoV-2 entry routes [21]. In postmortem kidney samples, SARS-CoV-2 antigens and viral particles were detected in the tubular epithelium and podocytes [10, 17]. In the case of collapsing glomerulopathy associated with COVID-19 reported by Kissling et al. [13], the virus was seen in podocytes by electron microscopy. However, most recent biopsy series fail to show viral particles in kidney biopsies by immunohistochemistry staining or by electron microscopy arguing against a direct viral infection of the kidneys [15, 16]. Similarly, in this case we did not find evidence of viral particles in the kidneys. Rather than a direct toxic viral effect on the kidneys, the ATI is most likely cytokine mediated, although the NSAID, angiotensin receptor blocker, and diuretic exposures could also have contributed. Whether MN can be secondary to SARS-CoV-2 remains to be elucidated, but we speculate that it could result from an exaggerated immune response associated with COVID-19. In the passive Heymann nephritis model, sub-epithelial deposits with very early basement membrane reaction could be seen as early as 7 days after injection [22]. Therefore, we hypothesize that the development of MN deposits could possibly occur quickly after a viral infection, or alternatively the COVID-19-related immune response and the resulting high-grade proteinuria could unmask an underlying MN. If this is the case, the treatment of this patient’s MN is conservative and immunosuppressive therapy is not recommended.
Funding
None.
Conflict of interest
The authors declare no relevant financial interest.
Supplemental material
ISH methods
In situ hybridization was performed with RNAScope (ACD, Newark, CA) using probes directed against SARS-CoV-2 on formalin-fixed paraffin-embedded tissue sections cut at a thickness of 3 microns. 1A negative control (bacterial gene dapB) was also included to assess background signals as well as positive control probes to the housekeeping gene peptidylprolyl isomerase B (PPIB). The ISH sections were counterstained using periodic acid-Schiff. (Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012; 14: 22-29).
Table 1. Laboratory data.
Laboratory test 1 year before
admission Day 1 Day 4
(Kidney biopsy) Day 7 Reference
Arterial blood gas
pH 7.43 7.36 7.29 7.35 – 7.45
pCO2, mmHg 23 27 38 32 – 45
pO2, mmHg 137 68 72 83 – 108
HCO3
-, mmol/L 15 15 18 22 – 26
Complete blood count
WBC count, 109/L 11.2 15.0 15.1 3.4 – 9.6
Neutrophils, 109/L 10.35 1.56 – 6.45
Lymphocytes, 109/L 0.46 0.95 – 3.07
Erythrocytes, 1012/L 3.37 3.40 2.36 4.35 – 5.65
Hemoglobin, g/dL 11.3 11.4 7.9 13.2 – 16.6
Reticulocytes, % 2.12 0.6 – 2.71
Platelet count, 109/L 449 436 295 135 – 317
Serum biochemistry
Sodium, mmol/L 138 139 138 135 – 145
Potassium, mmol/L 5.4 4.5 4.1 3.6 – 5.2
Chloride, mmol/L 100 99 103 98 – 107
Bicarbonate, mmol/L 17 17 19 22 – 29
Anion gap 21 23 17 7 – 15
BUN, mg/dL 98 133 128 8 – 24
Creatinine, mg/dL 1.4 7.05 6.96 4.41 0.74 – 1.35
eGFR, mL/min/BSA 49 < 15 < 15 < 15 > 60
eGFR by cystatin C, mL/min/BSA 6 > 60
Calcium, total, mg/dL 8.9 8.3 8.1 8.8 – 10.2
Calcium, ionized, mg/dL 4.40 4.57 4.62 4.65 – 5.30
Glucose, mg/dL 127 165 145 70 – 140
Magnesium, mg/dL 3.8 2.9 1.7 – 2.3
Phosphorus, mg/dL 11.5 7.9 2.5 – 4.5
Total protein, g/dL 4.4 4.5 6.3 – 7.9
Albumin, g/dL 1.7 2.6 3.5 – 5.0
Hemoglobin A1C, % 5.9 4 – 5.6
Lactate, mmol/L 1.3 1.1 0.5 – 2.2
Liver function
ALT, U/L 45 36 11 7 – 55
AST, U/L 43 49 22 8 – 48
Bilirubin, total, mg/dL 0.6 < 0.2 0.5 < 1.2
Bilirubin, direct, mg/dL 0.3 < 0.2 0.4 0.0 – 0.3
Alkaline protease, U/L 155 70 40 – 129
Lipid/cardiac risk
Total cholesterol, mg/dL 241 226 < 200
HDL, mg/dL 38 34 ≥ 40
LDL, mg/dL 153 131 < 100
Triglycerides, mg/dL 248 304 < 150
Troponin T, ng/L 71 160 < 15
Troponin T-2h, ng/L 80 153 < 15
Troponin T-6h, ng/L 87 152 < 15
NT-pro BNP, pg/mL 220 5,030 5 – 131
Creatinine kinase, U/L 108 39 – 308
Coagulation
Antithrombin activity 91 80 – 130%
D-dimer, ng/mL 13,286 > 100,000 48,550 < 500
Fibrinogen, Clauss, mg/dL > 800 561 200 – 500
Coag factor II 101 92 75 – 145%
Coag factor V 132 110 70 – 165%
Coag factor VII 116 83 65 – 180%
Coag factor X 131 86 70 – 150%
C-reactive protein, mg/L > 400 173.3 142.1 < 8
Soluble fibrin monomer, mcg/mL > 1,100 36 ≤ 8
Plasminogen activity 98 75 – 140%
α-2 plasmin inhibitor 105 80 – 140%
Sedimentation rate, mm/h > 140 123 3 – 28
Ferritin, µg/L 1,122 1,813 911 24 – 336
Serology
HBs antigen Negative Negative
HBc total Ab Negative Negative
HCV Ab screen Negative Negative
HIV-1/-2 Ag and Ab Negative Negative
Complement C3, mg/dL 163 75 – 175
Complement C4, mg/dL 36 13 – 40
C-ANCA Negative Negative
p-ANCA Negative Negative
Anti-GBM, U < 0.2 < 1 (negative)
Anti-phospholipase A2 receptor (IF) Negative Negative
Anti-phospholipase A2 receptor (ELISA), RU/mL < 2 < 14
Interleukin 6, pg/mL 39.5 3.5 5.7 < 1.8
Monoclonal gammopathy screen
κ free light chain, mg/dL 15.5 0.33 – 1.94
λ free light chain, mg/dL 8.73 0.57 – 2.63
κ/λ ratio 1.78 0.26 – 1.65
Total protein, g/dL 5.3 6.3 – 7.9
Albumin, g/dL 1.4 3.4 – 4.7
α-1 globulin, g/dL 0.6 0.1 – 0.3
α 2-globulin, g/dL 1.5 0.6 – 1.0
β globulin, g/dL 1.0 0.7 – 1.2
γ globulin, g/dL 0.8 0.6 – 1.6
A/G ratio 0.36
M protein isotype Cannot rule out small monoclonal protein
Endocrine
TSH, mIU/L 1.1 0.2 0.3 – 4.2
T4 (thyroxine), ng/dL 1.3 0.9 – 1.7
PTH, pg/mL 231 15 – 65
Tumor/malignancy marker
Prostate specific Ag, ng/mL 0.21 0.15 ≤ 7.2
Table 2. Urinalysis data.
Laboratory test 3 years prior to admission On admission Day 2 Reference range
Source Midstream Catheter Catheter
Appearance Normal Normal Normal
Osmolality, mOsm/kg 372 339 150 – 1150
pH 5.2 5.5 4.5 – 8.0
Glucose, mg/dL 5 81 12 0 – 15
Protein, mg/dL 17 339 117 < 26
Protein/Osmolality, ratio 0.39 9.11 3.45 < 0.42
Predicted 24 h protein, mg 385 7,735 3,066
24-h urine protein, mg/24 h 4,662 < 229
Hemoglobin Negative Trace Moderate Negative
Red blood cell 3 – 10 < 3/HPF
Dysmorphic RBC (%) < 25 < 25
White blood cell 1 – 3 1 – 3 1 – 3/HPF
Casts, hyaline 1 – 3 Occasional
Casts, granular Occasional
Fat, free Occasional Occasional
Fat, in casts Occasional
Oval fat body Occasional
Renal epithelial cells 1 – 3 None seen/HPF
Ketones Negative Negative
Nitrite Negative Negative
Leukocyte Negative Negative
Figure 1. Renal pathologic findings in this COVID-19 patient. A: Glomerulus showing thickening of the glomerular basement membrane with mild mesangial sclerosis and hypercellularity (silver stain, × 400). B: Glomerular capillary loop showing abundant small sub-epithelial electron-dense deposits. The overlying podocytes show extensive foot process effacement (electron microscopy, × 11,000). C: Large glomerular endothelial tubuloreticular inclusion is shown. Tiny sub-epithelial electron-dense deposits are also evident (electron microscopy, × 30,000). | Recovering | ReactionOutcome | CC BY | 33633925 | 19,275,153 | 2021 |
What was the outcome of reaction 'Renal tubular injury'? | Membranous nephropathy in a patient with coronavirus disease 2019 (COVID-19): A case report.
BACKGROUND
Though respiratory, immune, and coagulation systems are major targets of coronavirus disease 2019 (COVID-19), kidney dysfunction, presenting with acute kidney injury (AKI), is also common. Most AKI cases in COVID-19 manifest as acute tubular injury (ATI) in conjunction with multiorgan failure. While initial renal pathological findings were limited to acute tubular necrosis and collapsing glomerulopathy, a recent case series reported a larger spectrum of findings.
METHODS
Here, we report a case of membranous nephropathy (MN) in an 81-year-old Hispanic man with underlying chronic kidney disease (CKD) stage 3 who developed ATI in the setting of COVID-19. The patient was hospitalized for hypoxic respiratory failure in the setting of AKI stage 3 with serum creatinine 7.1 mg/dL 6 days after a positive-SARS-CoV-2 screening. He was found to have nephrotic range proteinuria, glycosuria (with normal serum glucose), anemia, and hypoalbuminemia. Kidney biopsy showed ATI and early MN. Workup for primary and secondary MN was unrevealing, and serum PLA2R antibody was negative. No viral particles were observed in podocytes.
CONCLUSIONS
Although the MN could be incidental, this observation raises the question of whether SARS-CoV-2 infection can trigger or worsen an underlying MN from an exaggerated immune response associated with COVID-19.
Introduction
Coronavirus disease 2019 (COVID-19), caused by a coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide since December 2019 [1].The principle feature of COVID-19 is viral pneumonia, leading to acute respiratory distress syndrome (ARDS) [2]. Similar to other coronaviruses, angiotensin-converting enzyme 2 (ACE2) may play a major role in the entry of SARS-CoV-2 to its target cells [3]. Besides the respiratory system, ACE2 is also highly expressed in the brush border of proximal tubular cells and, to a lesser extent, in glomerular podocytes [4]. Kidney involvement of COVID-19, mainly presents as acute kidney injury (AKI) [5], primarily due to acute tubular injury (ATI) in the setting of multiorgan failure. Clinically, the incidence of AKI in COVID-19 varies from 0.9 to 29% in hospitalized or critically ill patients at different centers [6, 7, 8] and is associated with worse outcomes [5, 9]. ATI and direct parenchymal infection of tubular epithelial cells and podocytes were reported in 26 postmortem examinations of patients with severe COVID-19 [10]. Proteinuria and hematuria are also common, occurring in 44 and 27%, respectively [5]. Kidney biopsy findings have been reported initially in four living COVID-19 cases, all of which showed collapsing glomerulopathy [11, 12, 13, 14]. Recently, two case series of kidney biopsy findings showed that ATI was the most common finding in COVID-19-associated kidney injury, but the series by Kudose et al. [15, 16] reported a wide spectrum of glomerular and tubular disease including minimal change disease and membranous glomerulopathy. Here, we report a case of membranous nephropathy (MN) diagnosed in the setting of AKI associated with COVID-19.
Case report
An 81-year-old Hispanic man presented to the emergency department complaining of progressive fatigue and shortness of breath 6 days after being diagnosed with COVID-19 (positive nasopharyngeal SARS-CoV-2 PCR). He reported myalgia, sore throat, intermittent dry cough, loss of smell and taste, poor appetite, and nausea without vomiting. He also had diarrhea and an episode of urinary incontinence. He denied fever or chills, chest pain, and headache. Because of hypoxemia requiring high-flow oxygen, the patient was admitted to the critical care unit.
Previous medical history includes prostate cancer treated with chemotherapy and androgen deprivation therapy in 2013, in remission with undetectable prostate-specific antigen (PSA) since 2014, prediabetes, hyperlipidemia, hypertension, chronic kidney disease (CKD) stage 3 (baseline creatinine 1.2 – 1.6 mg/dL) attributed to hypertension with prior urine analysis in 2017 showing proteinuria of 385 mg/day, aortic valve stenosis, and cervical radiculopathy. Home medications included olmesartan 20 mg twice daily and hydrochlorothiazide 12.5 mg daily. Notably, he had a history of non-steroidal anti-inflammatory drugs (NSAIDs) use, 400 – 800 mg of ibuprofen per day for chronic neck pain. He is a former smoker but quit in 2012 and did not have lung disease.
Initial vital signs: temperature 37.4 °C, blood pressure 166/69 mmHg, heart rate 68 beats per minute, respiratory rate 27 breaths per minute, and peripheral capillary oxygen saturation (SpO2) 95% on high-flow nasal cannula (50 L/min with FiO2 of 100%). Physical examination was notable for tachypnea with the remainder of physical examination unremarkable.
Table 1 and Table 2 show his laboratory results. Repeat SARS-CoV-2 PCR via nasopharyngeal swab was positive. He had evidence of AKI stage 3 with a serum creatinine of 7.1 mg/dL. Urinalysis demonstrated 3 – 10 red blood cells per high power field, nephrotic range proteinuria of 4.6 g per 24 hours, glycosuria, and tubular epithelial cells. He had anemia with hemoglobin of 10.3 g/dL, hypoalbuminemia of 1.7 g/dL, and multiple elevated inflammatory markers, including interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin. Kidney ultrasound revealed bilaterally increased parenchymal echogenicity consistent with CKD. Chest radiograph showed indistinct pulmonary vasculature bilaterally with bronchocentric ground glass, and bilateral patchy infiltrates, consistent with COVID-19 pneumonia. Lower extremities Doppler did not reveal deep vein thromboses, and transthoracic echocardiogram was normal.
He was enrolled in a randomized placebo-controlled clinical trial of lenzilumab (monoclonal antibody targeting GM-CSF) 600 mg for 3 doses, in addition to intravenous antibiotics for possible superimposed community-acquired pneumonia. He completed a steroid trial with 5 days of intravenous methylprednisolone. Due to increasing D-dimer to 100,000 ng/mL, low-intensity heparin infusion was initiated.
Over the first few hospitalization days, creatinine remained elevated at ~ 7 mg/dL. He did not require dialysis as he maintained excellent urine output. Serologic testing for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), tuberculosis, as well as C3, C4, anti-neutrophil cytoplasmic antibodies (ANCA), anti-glomerular basement membrane (GBM), and anti-phospholipase A2 receptors (PLA2R) were all negative. Anti-THSD7A was indeterminate due to high background. No serum monoclonal proteins were detected. Kidney biopsy was performed on hospital day 4.
On hospital day 7, the patient’s respiratory status worsened requiring intubation, mechanical ventilation, and initiation of vasopressors. Despite that, his AKI was slowly recovering and creatinine reached 3.7 mg/dL on hospital day 11. However, the shock state subsequently worsened, continuous dialysis was started but eventually the patient died on hospital day 16. Family declined an autopsy.
Kidney pathology findings
19 glomeruli were sampled for light microscopy, 8 of which were globally sclerotic and 1 was segmentally sclerotic. The glomeruli showed segmental mild mesangial hypercellularity and mesangial expansion, with thickening of their basement membranes (Figure 1A). No collapsing features, endocapillary hypercellularity, thrombi, necrosis, or crescents were seen. The tubulointerstitial compartment exhibited diffuse ATI, tubular protein reabsorption granules, mild tubular atrophy and interstitial fibrosis, and very mild mononuclear cell infiltrate without tubulitis. There was moderate arteriosclerosis and arteriolar hyalinosis.
Immunofluorescence studies were unable to be performed due to an inadequate sample. Immunohistochemistry staining for PLA2R was performed on sections prepared from the paraffin block and was negative.
In situ hybridization (ISH) staining for the presence of SARS-CoV-2 RNA was performed using RNAScope (ACD, Newark, CA, USA) and failed to show evidence of viral RNA in the kidney (methods in Supplemental Material).
Electron microscopy showed abundant small granular sub-epithelial electron-dense deposits without or associated with early basement membrane spike formation (Figure 1B). The glomerular basement membrane lamina densa was thickened. There was mild mesangial sclerosis with segmental mesangial electron-dense deposits, without sub-endothelial deposits. Abundant tubuloreticular inclusion bodies were seen in the endothelial cell cytoplasm (Figure 1C). Podocytes exhibited severe foot process effacement.
The pathological diagnosis was MN (stage 1 to early stage 2), diffuse ATI, mild mesangial sclerosing glomerulopathy (associated with hypertension, pre-diabetes, and smoking), and moderate arteriosclerosis and arteriolar hyalinosis.
Discussion
To our knowledge, MN diagnosed in a patient with COVID-19 has been reported in only 2 patients in one case series of 17 patients [16]. The finding of severe ATI in this case is not surprising as reported in recent series of COVID-19 patients [10, 15]. However, the finding of MN was unexpected.
MN, an inflammatory and autoimmune disease of the glomerulus, is one of the most common causes of nephrotic syndrome in adults. The etiology of ~ 75% of MN is unknown “primary”. Secondary MN can be secondary to infection, drugs, and malignancy [18]. Thus, the main question is whether the MN in this case is related to SARS-CoV-2 or not. This patient had a history of prostate cancer, but he was in remission for at least 6 years with normal PSA, so it is unlikely that his cancer was the underlying cause of the MN. NSAIDs can cause proteinuria and have been associated with minimal change disease as well as MN, but the patient did not have prior evidence of nephrotic syndrome despite being on NSAIDs for many years. The absence of detectable anti-PLA2R antibodies, the negative glomerular staining for PLA2R and the presence of mesangial deposits, as well as abundant tubuloreticular inclusions favor secondary MN over primary MN. The patient had mild proteinuria (385 mg/day) prior to COVID-19 which is likely due to underlying mild mesangial sclerosing glomerulopathy (associated with hypertension, prediabetes, and smoking). MN was mostly stage 1 favoring a recent development of disease temporally associated with COVID-19 over pre-existing MN.
The pathogenesis of MN involves formation and deposition of immune complexes in sub-epithelial sites [18]. The receptor for SARS-CoV-2, ACE2, is highly expressed on proximal tubular cells and glomerular podocytes [4]. In addition, TMPRSS2, an essential serine protease, is required for spike glycoprotein of SARS-CoV-2 priming after binding to ACE2, and thus activates membrane fusion facilitating to gain access to its target cells [19]. In kidneys, expression of TMPRSS2 is only detectable in the proximal tubule S3 segment [20]. An in vitro study showed that the administration of TMPRSS2 inhibitor, camostat mesylate, had a valuable treatment effect, blocking multiple SARS-CoV-2 entry routes [21]. In postmortem kidney samples, SARS-CoV-2 antigens and viral particles were detected in the tubular epithelium and podocytes [10, 17]. In the case of collapsing glomerulopathy associated with COVID-19 reported by Kissling et al. [13], the virus was seen in podocytes by electron microscopy. However, most recent biopsy series fail to show viral particles in kidney biopsies by immunohistochemistry staining or by electron microscopy arguing against a direct viral infection of the kidneys [15, 16]. Similarly, in this case we did not find evidence of viral particles in the kidneys. Rather than a direct toxic viral effect on the kidneys, the ATI is most likely cytokine mediated, although the NSAID, angiotensin receptor blocker, and diuretic exposures could also have contributed. Whether MN can be secondary to SARS-CoV-2 remains to be elucidated, but we speculate that it could result from an exaggerated immune response associated with COVID-19. In the passive Heymann nephritis model, sub-epithelial deposits with very early basement membrane reaction could be seen as early as 7 days after injection [22]. Therefore, we hypothesize that the development of MN deposits could possibly occur quickly after a viral infection, or alternatively the COVID-19-related immune response and the resulting high-grade proteinuria could unmask an underlying MN. If this is the case, the treatment of this patient’s MN is conservative and immunosuppressive therapy is not recommended.
Funding
None.
Conflict of interest
The authors declare no relevant financial interest.
Supplemental material
ISH methods
In situ hybridization was performed with RNAScope (ACD, Newark, CA) using probes directed against SARS-CoV-2 on formalin-fixed paraffin-embedded tissue sections cut at a thickness of 3 microns. 1A negative control (bacterial gene dapB) was also included to assess background signals as well as positive control probes to the housekeeping gene peptidylprolyl isomerase B (PPIB). The ISH sections were counterstained using periodic acid-Schiff. (Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012; 14: 22-29).
Table 1. Laboratory data.
Laboratory test 1 year before
admission Day 1 Day 4
(Kidney biopsy) Day 7 Reference
Arterial blood gas
pH 7.43 7.36 7.29 7.35 – 7.45
pCO2, mmHg 23 27 38 32 – 45
pO2, mmHg 137 68 72 83 – 108
HCO3
-, mmol/L 15 15 18 22 – 26
Complete blood count
WBC count, 109/L 11.2 15.0 15.1 3.4 – 9.6
Neutrophils, 109/L 10.35 1.56 – 6.45
Lymphocytes, 109/L 0.46 0.95 – 3.07
Erythrocytes, 1012/L 3.37 3.40 2.36 4.35 – 5.65
Hemoglobin, g/dL 11.3 11.4 7.9 13.2 – 16.6
Reticulocytes, % 2.12 0.6 – 2.71
Platelet count, 109/L 449 436 295 135 – 317
Serum biochemistry
Sodium, mmol/L 138 139 138 135 – 145
Potassium, mmol/L 5.4 4.5 4.1 3.6 – 5.2
Chloride, mmol/L 100 99 103 98 – 107
Bicarbonate, mmol/L 17 17 19 22 – 29
Anion gap 21 23 17 7 – 15
BUN, mg/dL 98 133 128 8 – 24
Creatinine, mg/dL 1.4 7.05 6.96 4.41 0.74 – 1.35
eGFR, mL/min/BSA 49 < 15 < 15 < 15 > 60
eGFR by cystatin C, mL/min/BSA 6 > 60
Calcium, total, mg/dL 8.9 8.3 8.1 8.8 – 10.2
Calcium, ionized, mg/dL 4.40 4.57 4.62 4.65 – 5.30
Glucose, mg/dL 127 165 145 70 – 140
Magnesium, mg/dL 3.8 2.9 1.7 – 2.3
Phosphorus, mg/dL 11.5 7.9 2.5 – 4.5
Total protein, g/dL 4.4 4.5 6.3 – 7.9
Albumin, g/dL 1.7 2.6 3.5 – 5.0
Hemoglobin A1C, % 5.9 4 – 5.6
Lactate, mmol/L 1.3 1.1 0.5 – 2.2
Liver function
ALT, U/L 45 36 11 7 – 55
AST, U/L 43 49 22 8 – 48
Bilirubin, total, mg/dL 0.6 < 0.2 0.5 < 1.2
Bilirubin, direct, mg/dL 0.3 < 0.2 0.4 0.0 – 0.3
Alkaline protease, U/L 155 70 40 – 129
Lipid/cardiac risk
Total cholesterol, mg/dL 241 226 < 200
HDL, mg/dL 38 34 ≥ 40
LDL, mg/dL 153 131 < 100
Triglycerides, mg/dL 248 304 < 150
Troponin T, ng/L 71 160 < 15
Troponin T-2h, ng/L 80 153 < 15
Troponin T-6h, ng/L 87 152 < 15
NT-pro BNP, pg/mL 220 5,030 5 – 131
Creatinine kinase, U/L 108 39 – 308
Coagulation
Antithrombin activity 91 80 – 130%
D-dimer, ng/mL 13,286 > 100,000 48,550 < 500
Fibrinogen, Clauss, mg/dL > 800 561 200 – 500
Coag factor II 101 92 75 – 145%
Coag factor V 132 110 70 – 165%
Coag factor VII 116 83 65 – 180%
Coag factor X 131 86 70 – 150%
C-reactive protein, mg/L > 400 173.3 142.1 < 8
Soluble fibrin monomer, mcg/mL > 1,100 36 ≤ 8
Plasminogen activity 98 75 – 140%
α-2 plasmin inhibitor 105 80 – 140%
Sedimentation rate, mm/h > 140 123 3 – 28
Ferritin, µg/L 1,122 1,813 911 24 – 336
Serology
HBs antigen Negative Negative
HBc total Ab Negative Negative
HCV Ab screen Negative Negative
HIV-1/-2 Ag and Ab Negative Negative
Complement C3, mg/dL 163 75 – 175
Complement C4, mg/dL 36 13 – 40
C-ANCA Negative Negative
p-ANCA Negative Negative
Anti-GBM, U < 0.2 < 1 (negative)
Anti-phospholipase A2 receptor (IF) Negative Negative
Anti-phospholipase A2 receptor (ELISA), RU/mL < 2 < 14
Interleukin 6, pg/mL 39.5 3.5 5.7 < 1.8
Monoclonal gammopathy screen
κ free light chain, mg/dL 15.5 0.33 – 1.94
λ free light chain, mg/dL 8.73 0.57 – 2.63
κ/λ ratio 1.78 0.26 – 1.65
Total protein, g/dL 5.3 6.3 – 7.9
Albumin, g/dL 1.4 3.4 – 4.7
α-1 globulin, g/dL 0.6 0.1 – 0.3
α 2-globulin, g/dL 1.5 0.6 – 1.0
β globulin, g/dL 1.0 0.7 – 1.2
γ globulin, g/dL 0.8 0.6 – 1.6
A/G ratio 0.36
M protein isotype Cannot rule out small monoclonal protein
Endocrine
TSH, mIU/L 1.1 0.2 0.3 – 4.2
T4 (thyroxine), ng/dL 1.3 0.9 – 1.7
PTH, pg/mL 231 15 – 65
Tumor/malignancy marker
Prostate specific Ag, ng/mL 0.21 0.15 ≤ 7.2
Table 2. Urinalysis data.
Laboratory test 3 years prior to admission On admission Day 2 Reference range
Source Midstream Catheter Catheter
Appearance Normal Normal Normal
Osmolality, mOsm/kg 372 339 150 – 1150
pH 5.2 5.5 4.5 – 8.0
Glucose, mg/dL 5 81 12 0 – 15
Protein, mg/dL 17 339 117 < 26
Protein/Osmolality, ratio 0.39 9.11 3.45 < 0.42
Predicted 24 h protein, mg 385 7,735 3,066
24-h urine protein, mg/24 h 4,662 < 229
Hemoglobin Negative Trace Moderate Negative
Red blood cell 3 – 10 < 3/HPF
Dysmorphic RBC (%) < 25 < 25
White blood cell 1 – 3 1 – 3 1 – 3/HPF
Casts, hyaline 1 – 3 Occasional
Casts, granular Occasional
Fat, free Occasional Occasional
Fat, in casts Occasional
Oval fat body Occasional
Renal epithelial cells 1 – 3 None seen/HPF
Ketones Negative Negative
Nitrite Negative Negative
Leukocyte Negative Negative
Figure 1. Renal pathologic findings in this COVID-19 patient. A: Glomerulus showing thickening of the glomerular basement membrane with mild mesangial sclerosis and hypercellularity (silver stain, × 400). B: Glomerular capillary loop showing abundant small sub-epithelial electron-dense deposits. The overlying podocytes show extensive foot process effacement (electron microscopy, × 11,000). C: Large glomerular endothelial tubuloreticular inclusion is shown. Tiny sub-epithelial electron-dense deposits are also evident (electron microscopy, × 30,000). | Recovering | ReactionOutcome | CC BY | 33633925 | 19,275,153 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypersensitivity'. | Concomitant Treatment of Chronic Hepatitis C With Direct-Acting Antivirals and Multidrug-Resistant Tuberculosis Is Effective and Safe.
We assessed effectiveness and safety of concomitant chronic hepatitis C virus (HCV) treatment with direct-acting antivirals (DAAs) and multidrug-resistant tuberculosis (MDR-TB). Of 322 MDR-TB patients (19.4% HCV), 30 were treated concomitantly (23.3% human immunodeficiency virus-positive). Overall, 76.7% achieved HCV treatment success (95.8% among tested). One patient (3.3%) experienced a serious adverse event.
Multidrug-resistant tuberculosis (MDR-TB) and hepatitis C virus (HCV) infection are 2 alarming public health threats [1, 2]. Multidrug-resistant tuberculosis patients coinfected with HCV are more likely to develop drug-induced liver injury [3], one of the most common adverse events (AEs) during MDR-TB treatment with reported rates at 9.7%–22.3% [3–5]. Hence, the treatment of HCV coinfection patients with MDR-TB might be beneficial. The safety and effectiveness of direct-acting antivirals (DAAs) for the treatment of HCV infection have been evaluated in clinical trials and real-life settings [6–11]. However, to our knowledge, there are no studies assessing the safety and effectiveness of providing DAA treatment to patients also being treated for MDR-TB. The only evidence available is 2 case reports from Italy [12].
In Armenia, the seroprevalence of HCV is estimated at 4% in the general population [13]. In 2016, Médecins Sans Frontières (MSF) facilitated the use of DAAs to treat MDR-TB patients with chronic HCV infection in the country. The objective of this study was to assess the prevalence of chronic HCV infection among MDR-TB patients in Armenia and the safety and effectiveness of the concomitant treatment of chronic HCV infection with DAAs and MDR-TB disease.
MATERIALS AND METHODS
Study Design and Population
This observational study included consecutive MDR-TB patients over 18 years diagnosed with chronic HCV infection from January 2016 until December 2018 in Armenia. Patients were observed until June 2019. Data on effectiveness and safety are reported from patients who received concomitant DAAs and MDR-TB treatment only.
Study Procedures
From January 2016, HCV diagnosis with HCV antibody test (enzyme-linked immunosorbent assay or rapid test) followed by HCV polymerase chain reaction (PCR) test was offered to all patients on or starting MDR-TB treatment in Armenia. From December 2016, treatment with DAAs including 12 weeks of daclatasvir 60 mg/sofosbuvir 400 mg (DCV/SOF) or ledipasvir 90 mg/sofosbuvir 400 mg (LDV/SOF) was offered to patients with chronic HCV infection. The dose of DCV was increased to 90 mg when coadministered with efavirenz or nevirapine. The duration of treatment was extended to 24 weeks, and ribavirin (RBV) was added to the regimen in patients with genotype 3a and advanced fibrosis on FibroScan (>14.5 kPa). Exclusion criteria to start DAA included the following: end stage liver disease, evidence of hepatocellular carcinoma, presence of terminal disease, human immunodeficiency virus (HIV) viral load above 1000 copies/mL, severe, uncontrolled psychiatric disease and baseline hemoglobin below 9 g/dL for regimens containing RBV.
Before DAA start, all patients underwent initial assessment including the following: medical history, clinical evaluation, grading of fibrosis, testing for HCV genotype, HBsAg and anti-HBc antibodies, HIV, CD4 count, HIV viral load, pregnancy, complete blood count, liver enzymes, bilirubin, creatinine, glucose, and ultrasound. Endoscopy was indicated if FibroScan >20 kPa and platelets <150 000 cells/µL (none of the patients met these criteria). Monthly follow-up was performed throughout the HCV treatment and at 12 weeks after treatment completion and included clinical evaluation, complete blood count, liver enzymes, bilirubin, and creatinine. Hepatitis C virus PCR was performed at the end of DAA treatment and 12 weeks posttreatment. Adverse events deemed to be of clinical significance were identified and reported by treating doctors based on clinical assessment and laboratory results. Patients who started DAA treatment after May 2018 were followed prospectively, and patient files of those who started DAAs before this date were reviewed retrospectively.
Definitions
Chronic HCV infection is defined as positive HCV antibody and positive HCV PCR. Sustained virological response 12 weeks after treatment completion (SVR12) is defined as follows: at least 1 HCV ribonucleic acid result undetectable or viral load concentration below 12I U/mL 12 weeks after the end of treatment. This was the measure of HCV treatment success. Treatment failure was defined as detectable viral load at 12 weeks posttreatment.
Adverse events deemed to be of clinical significance were as follows: creatinine clearance <50 mL/mm, alanine aminotransferase and/or aspartate aminotransferase levels >5 times of upper limit of normal, any AE that resulted in a temporary interruption, permanent discontinuation, or change in the dose of 1 or more DAA or MDR-TB drug as decided by the doctor. Serious AEs (SAEs) were defined as events that resulted in death or significant disability, were life-threatening, or required hospitalization.
Data Analysis
We perform descriptive analyses to characterize the population and determine proportions of patients that achieved SVR12 or had an AE. The effectiveness endpoint was the proportion of participants with SVR12 among patients who started DAAs and among those tested with HCV PCR. The safety endpoint was the frequency of AEs of clinical significance and SAEs that occurred during DAA treatment and 12 weeks posttreatment. Analyses were done using Stata 13 (StataCorp College Station, TX).
Ethics
The study protocol was approved by the MSF Ethics Review Board (ERB) and the Yerevan State Medical University Ethics Committee in Armenia. Written informed consent was obtained from patients enrolled prospectively and from patients under care enrolled retrospectively. The ERBs waived consent provision from patients enrolled retrospectively who were no longer under follow-up for MDR-TB.
RESULTS
Patients’ Flow and prevalence of HCV infection
From January 2016 to December 2018, 322 adult patients started MDR-TB treatment in Armenia. Hepatitis C virus antibody test was positive in 29.3% (78 of 266) and HCV PCR was positive in 71.4% (50 of 70) of them. Overall, among the MDR-TB patients tested, 19.4% (50 of 258; 95% confidence interval, 14.7–24.7) had chronic HCV infection. An additional 20 patients were diagnosed with chronic HCV infection during the study period among patients who had started MDR-TB treatment before 2016 (Figure 1). In total, 40 of 70 (60.6%) started DAA treatment during the study period (Figure 1). Of the 40 patients treated, 30 received concomitant DAA and MDR-TB treatment, whereas 10 had already completed MDR-TB treatment when DAA treatment was initiated.
Figure 1. Study patient flow.
Patient Characteristics
Table 1 shows the characteristics of the 30 patients who received concomitant DAAs and MDR-TB drugs. Median age was 51.5 years, 96.7% were men, and 23.3% HIV positive. All patients were DAA treatment naive. The median time from MDR-TB treatment initiation to the start of DAAs was 5.4 (interquartile range, 2.1–12.1) months. At DAA treatment start, all HIV-positive patients were receiving antiretroviral therapy and were virally suppressed. The majority of the patients (26 of 30, 86.7%) were treated with 12 weeks of DCV/SOF irrespective of the genotype. Two (6.7%) patients with genotype 3a and advanced fibrosis received 24 weeks of DCV/SOF/RBV. Two patients (6.7%) with genotype 1b received 12 weeks of LDV/SOF. No patients had liver lesions attributable to TB.
Table 1. Sociodemographic and Clinical Characteristics and Adverse Events in Patients With Chronic Hepatitis C Who Received DAAs With MDR-TB Drugs Concomitantly (N = 30)
Characteristics Patients Started DAAa, n (%)
Age (median in years, IQR) 52 (41–56)
Body mass index <18.5 kg/m2 6 (20.0)
Men 29 (96.7)
Incarceration (former or current) 16 (53.3)
Alcohol consumption (current) 15 (50.0)
Intravenous drug user (former or current) 11 (36.7)
Comorbidities
- HIV positive 7 (23.3)
- Anti-HBc-total positive (N = 28) 9 (32.1)
HCV Genotype
- 1b 9 (30.0)
- 2 4 (13.3)
- 3a 15 (50.0)
- 4 1 (3.3)
- Indeterminate 1 (3.3)
FibroScan
- F0-F1 (2.5–7.0 kPa) 22 (73.3)
- F2 (7.1–9.4 kPa) 3 (10.0)
- F3 (9.514.5 kPa) 2 (6.7)
- F4 (>14.5 kPa) 3 (10.0)
Antiretroviral Therapy
Tenofovir 5 (16.7)
- Efavirenz, nevirapine 6 (20.0)
- Emtricitabine, abacavir, lamivudine 9 (30%)
- Lopinavir/ritonavir 2 (6.7)
MDR-TB Drugs
Group A
- Levofloxacin 18 (60.0)
- Linezolid 16 (53.3)
- Bedaquiline 6 (20.0)
- Moxifloxacin 5 (16.7)
Group B
- Cycloserine 26 (86.7)
- Clofazimine 19 (63.3)
Group C
- Delamanid 13 (43.4)
- p-aminosalicylic acid 13 (43.3)
- Prothionamide 12 (40.0)
- Pyrazinamide 8 (26.7)
- Imipenem/cilastatin 6 (20.0)
- Kanamycin 4 (13.3)
- Capreomycin 4 (13.3)
Adverse Eventa
Serious adverse events (SAE) 1 (3.3)
Adverse events of clinical significance (not SAE) 4 (13.3)
Adverse events possibly related to DAA 1 (3.3)
Adverse events leading to temporary DAA discontinuation 1 (3.3)
Abbreviations: DAAs, direct-acting antivirals; HB, hepatitis B; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IQR, interquartile range; MDR-TB, multidrug-resistant tuberculosis.
aAdverse events: 1 allergic reaction (severity grade 3, SAE), 1 anemia (severity grade 2), 1 dizziness (severity grade 1), 1 peripheral neuropathy (severity grade 1), 1 platelet decrease (severity grade 1).
Effectiveness
SVR12 was achieved in 76.7% (23 of 30) of the patients who initiated DAAs. Among patients who were tested at 12 weeks posttreatment, 95.8% (23 of 24) achieved SVR12. One (4.2%) patient experienced DAA treatment failure. This patient was HIV positive, had genotype 3a HCV infection, stage F0-F1 hepatic fibrosis, and was prescribed 12 weeks of DCV/SOF. Hepatitis C virus PCR was not done at 12 weeks for 6 patients, 4 of whom had a HCV PCR test done at the end of treatment, all with negative results.
Safety
During concomitant treatment with DAA and MDR-TB drugs, 1 patient (3.3%) experienced a SAE and 4 (13.3%) experienced AEs of clinical significance. The SAE was reported by the treating doctor as possibly related to DAAs. This patient experienced a severe allergic reaction 16 days after initiation of DAA treatment with DCV/SOF, which led to temporary interruption of the DAAs and MDR-TB drugs and resolved after treatment with antihistamine drugs. Both HCV infection and MDR-TB treatments were completed successfully. The 4 AEs of clinical significance were reported as related to the TB drugs. From DAA treatment completion until 12 weeks posttreatment, no AEs related to the DAA treatment were reported.
DISCUSSION
In a context of high prevalence of chronic HCV infection among MDR-TB patients, HCV treatment success was achieved in a high proportion of patients treated concomitantly with DAAs and MDR-TB drugs with no major safety problems. To our knowledge this is the first study reporting concomitant use of DAAs and MDR-TB drugs. The effectiveness results found are consistent with treatment success rates reported in clinical and observational studies of LDV/SOF and DCV/SOF±RBV use among non-TB patients [6–11, 14].
In our study, the patient who experienced DAA treatment failure was HIV positive, had HCV genotype 3a infection, without advanced liver damage (stage F0-F1), and was prescribed 12 weeks of DCV/SOF. A possible contributing factor to DAA treatment failure could be poor adherence because the patient interrupted MDR-TB treatment for 3 weeks while on DAAs and possibly could have also interrupted DAAs. The genotype 3a is a subtype of HCV infection with lower response rates [10] when accompanied with cirrhosis [11], although this was not the case for this patient.
The concomitant use of DAA with second-line antituberculosis drugs was well tolerated. Data on interactions between DCV, LDV, and SOF and second-line antituberculosis drugs are very limited. Theoretically, ethionamide/prothionamide and clofazimine can interact with DCV because both are CYP3A4 inhibitors in vitro. However, the clinical relevance is unknown. Concomitant use of the first-line antituberculosis drug rifampicin and DAAs is not recommended [15]. Overall, the rate of untoward medical occurrences in this cohort of patients (2.6%) was not higher than described in experimental and nonexperimental settings [6, 9–11].
The study has some limitations. It was not possible to evaluate whether HCV treatment could reduce hepatotoxicity during MDR-TB treatment in coinfected patients due to the limited number of participants. In addition, some patients did not have a viral load measurement 12 weeks posttreatment. However, almost all of them had a measurement at the end of the DAA treatment.
CONCLUSIONS
This novel study shows that DAAs can be successfully used to treat chronic HCV infection in MDR-TB patients without major safety concerns. Further research with more participants is needed to generate additional evidence on the safety and effectiveness of the concomitant use of DAAs with second-line antituberculosis drugs. The colocation of the HCV/MDR-TB care is an important step towards patient-centered care and the achievement of the HCV elimination goal.
Acknowledgments
We acknowledge the continuous support from the National Tuberculosis Program in Armenia to the study. We also thank to the Médecins Sans Frontières staff in Armenia and elsewhere who has participated in the project.
Financial support. This work was funded by Médecins Sans Frontières.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
Presented in part: 7th Regional TB Symposium Eastern Europe and Central Aisa, Ministry of Health of the Kyrgyz Republic and Médecins Sans Frontières, March 1–2, 2018, Bishkek, Kyrgyzstan; Scientific Day Médecins Sans Frontières, May 24–25, 2018, London, UK; 49th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease (The Union), October 24–27, 2018, The Hague, The Netherlands; 9th Regional TB Symposium Eastern Europe and Central Aisa, Ministry of Health of Ukraine and Médecins Sans Frontières, March 5–6, 2020, Kyiv, Ukraine. | DACLATASVIR DIHYDROCHLORIDE, SOFOSBUVIR | DrugsGivenReaction | CC BY-NC-ND | 33634203 | 19,405,338 | 2021-02 |
What was the outcome of reaction 'Hypersensitivity'? | Concomitant Treatment of Chronic Hepatitis C With Direct-Acting Antivirals and Multidrug-Resistant Tuberculosis Is Effective and Safe.
We assessed effectiveness and safety of concomitant chronic hepatitis C virus (HCV) treatment with direct-acting antivirals (DAAs) and multidrug-resistant tuberculosis (MDR-TB). Of 322 MDR-TB patients (19.4% HCV), 30 were treated concomitantly (23.3% human immunodeficiency virus-positive). Overall, 76.7% achieved HCV treatment success (95.8% among tested). One patient (3.3%) experienced a serious adverse event.
Multidrug-resistant tuberculosis (MDR-TB) and hepatitis C virus (HCV) infection are 2 alarming public health threats [1, 2]. Multidrug-resistant tuberculosis patients coinfected with HCV are more likely to develop drug-induced liver injury [3], one of the most common adverse events (AEs) during MDR-TB treatment with reported rates at 9.7%–22.3% [3–5]. Hence, the treatment of HCV coinfection patients with MDR-TB might be beneficial. The safety and effectiveness of direct-acting antivirals (DAAs) for the treatment of HCV infection have been evaluated in clinical trials and real-life settings [6–11]. However, to our knowledge, there are no studies assessing the safety and effectiveness of providing DAA treatment to patients also being treated for MDR-TB. The only evidence available is 2 case reports from Italy [12].
In Armenia, the seroprevalence of HCV is estimated at 4% in the general population [13]. In 2016, Médecins Sans Frontières (MSF) facilitated the use of DAAs to treat MDR-TB patients with chronic HCV infection in the country. The objective of this study was to assess the prevalence of chronic HCV infection among MDR-TB patients in Armenia and the safety and effectiveness of the concomitant treatment of chronic HCV infection with DAAs and MDR-TB disease.
MATERIALS AND METHODS
Study Design and Population
This observational study included consecutive MDR-TB patients over 18 years diagnosed with chronic HCV infection from January 2016 until December 2018 in Armenia. Patients were observed until June 2019. Data on effectiveness and safety are reported from patients who received concomitant DAAs and MDR-TB treatment only.
Study Procedures
From January 2016, HCV diagnosis with HCV antibody test (enzyme-linked immunosorbent assay or rapid test) followed by HCV polymerase chain reaction (PCR) test was offered to all patients on or starting MDR-TB treatment in Armenia. From December 2016, treatment with DAAs including 12 weeks of daclatasvir 60 mg/sofosbuvir 400 mg (DCV/SOF) or ledipasvir 90 mg/sofosbuvir 400 mg (LDV/SOF) was offered to patients with chronic HCV infection. The dose of DCV was increased to 90 mg when coadministered with efavirenz or nevirapine. The duration of treatment was extended to 24 weeks, and ribavirin (RBV) was added to the regimen in patients with genotype 3a and advanced fibrosis on FibroScan (>14.5 kPa). Exclusion criteria to start DAA included the following: end stage liver disease, evidence of hepatocellular carcinoma, presence of terminal disease, human immunodeficiency virus (HIV) viral load above 1000 copies/mL, severe, uncontrolled psychiatric disease and baseline hemoglobin below 9 g/dL for regimens containing RBV.
Before DAA start, all patients underwent initial assessment including the following: medical history, clinical evaluation, grading of fibrosis, testing for HCV genotype, HBsAg and anti-HBc antibodies, HIV, CD4 count, HIV viral load, pregnancy, complete blood count, liver enzymes, bilirubin, creatinine, glucose, and ultrasound. Endoscopy was indicated if FibroScan >20 kPa and platelets <150 000 cells/µL (none of the patients met these criteria). Monthly follow-up was performed throughout the HCV treatment and at 12 weeks after treatment completion and included clinical evaluation, complete blood count, liver enzymes, bilirubin, and creatinine. Hepatitis C virus PCR was performed at the end of DAA treatment and 12 weeks posttreatment. Adverse events deemed to be of clinical significance were identified and reported by treating doctors based on clinical assessment and laboratory results. Patients who started DAA treatment after May 2018 were followed prospectively, and patient files of those who started DAAs before this date were reviewed retrospectively.
Definitions
Chronic HCV infection is defined as positive HCV antibody and positive HCV PCR. Sustained virological response 12 weeks after treatment completion (SVR12) is defined as follows: at least 1 HCV ribonucleic acid result undetectable or viral load concentration below 12I U/mL 12 weeks after the end of treatment. This was the measure of HCV treatment success. Treatment failure was defined as detectable viral load at 12 weeks posttreatment.
Adverse events deemed to be of clinical significance were as follows: creatinine clearance <50 mL/mm, alanine aminotransferase and/or aspartate aminotransferase levels >5 times of upper limit of normal, any AE that resulted in a temporary interruption, permanent discontinuation, or change in the dose of 1 or more DAA or MDR-TB drug as decided by the doctor. Serious AEs (SAEs) were defined as events that resulted in death or significant disability, were life-threatening, or required hospitalization.
Data Analysis
We perform descriptive analyses to characterize the population and determine proportions of patients that achieved SVR12 or had an AE. The effectiveness endpoint was the proportion of participants with SVR12 among patients who started DAAs and among those tested with HCV PCR. The safety endpoint was the frequency of AEs of clinical significance and SAEs that occurred during DAA treatment and 12 weeks posttreatment. Analyses were done using Stata 13 (StataCorp College Station, TX).
Ethics
The study protocol was approved by the MSF Ethics Review Board (ERB) and the Yerevan State Medical University Ethics Committee in Armenia. Written informed consent was obtained from patients enrolled prospectively and from patients under care enrolled retrospectively. The ERBs waived consent provision from patients enrolled retrospectively who were no longer under follow-up for MDR-TB.
RESULTS
Patients’ Flow and prevalence of HCV infection
From January 2016 to December 2018, 322 adult patients started MDR-TB treatment in Armenia. Hepatitis C virus antibody test was positive in 29.3% (78 of 266) and HCV PCR was positive in 71.4% (50 of 70) of them. Overall, among the MDR-TB patients tested, 19.4% (50 of 258; 95% confidence interval, 14.7–24.7) had chronic HCV infection. An additional 20 patients were diagnosed with chronic HCV infection during the study period among patients who had started MDR-TB treatment before 2016 (Figure 1). In total, 40 of 70 (60.6%) started DAA treatment during the study period (Figure 1). Of the 40 patients treated, 30 received concomitant DAA and MDR-TB treatment, whereas 10 had already completed MDR-TB treatment when DAA treatment was initiated.
Figure 1. Study patient flow.
Patient Characteristics
Table 1 shows the characteristics of the 30 patients who received concomitant DAAs and MDR-TB drugs. Median age was 51.5 years, 96.7% were men, and 23.3% HIV positive. All patients were DAA treatment naive. The median time from MDR-TB treatment initiation to the start of DAAs was 5.4 (interquartile range, 2.1–12.1) months. At DAA treatment start, all HIV-positive patients were receiving antiretroviral therapy and were virally suppressed. The majority of the patients (26 of 30, 86.7%) were treated with 12 weeks of DCV/SOF irrespective of the genotype. Two (6.7%) patients with genotype 3a and advanced fibrosis received 24 weeks of DCV/SOF/RBV. Two patients (6.7%) with genotype 1b received 12 weeks of LDV/SOF. No patients had liver lesions attributable to TB.
Table 1. Sociodemographic and Clinical Characteristics and Adverse Events in Patients With Chronic Hepatitis C Who Received DAAs With MDR-TB Drugs Concomitantly (N = 30)
Characteristics Patients Started DAAa, n (%)
Age (median in years, IQR) 52 (41–56)
Body mass index <18.5 kg/m2 6 (20.0)
Men 29 (96.7)
Incarceration (former or current) 16 (53.3)
Alcohol consumption (current) 15 (50.0)
Intravenous drug user (former or current) 11 (36.7)
Comorbidities
- HIV positive 7 (23.3)
- Anti-HBc-total positive (N = 28) 9 (32.1)
HCV Genotype
- 1b 9 (30.0)
- 2 4 (13.3)
- 3a 15 (50.0)
- 4 1 (3.3)
- Indeterminate 1 (3.3)
FibroScan
- F0-F1 (2.5–7.0 kPa) 22 (73.3)
- F2 (7.1–9.4 kPa) 3 (10.0)
- F3 (9.514.5 kPa) 2 (6.7)
- F4 (>14.5 kPa) 3 (10.0)
Antiretroviral Therapy
Tenofovir 5 (16.7)
- Efavirenz, nevirapine 6 (20.0)
- Emtricitabine, abacavir, lamivudine 9 (30%)
- Lopinavir/ritonavir 2 (6.7)
MDR-TB Drugs
Group A
- Levofloxacin 18 (60.0)
- Linezolid 16 (53.3)
- Bedaquiline 6 (20.0)
- Moxifloxacin 5 (16.7)
Group B
- Cycloserine 26 (86.7)
- Clofazimine 19 (63.3)
Group C
- Delamanid 13 (43.4)
- p-aminosalicylic acid 13 (43.3)
- Prothionamide 12 (40.0)
- Pyrazinamide 8 (26.7)
- Imipenem/cilastatin 6 (20.0)
- Kanamycin 4 (13.3)
- Capreomycin 4 (13.3)
Adverse Eventa
Serious adverse events (SAE) 1 (3.3)
Adverse events of clinical significance (not SAE) 4 (13.3)
Adverse events possibly related to DAA 1 (3.3)
Adverse events leading to temporary DAA discontinuation 1 (3.3)
Abbreviations: DAAs, direct-acting antivirals; HB, hepatitis B; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IQR, interquartile range; MDR-TB, multidrug-resistant tuberculosis.
aAdverse events: 1 allergic reaction (severity grade 3, SAE), 1 anemia (severity grade 2), 1 dizziness (severity grade 1), 1 peripheral neuropathy (severity grade 1), 1 platelet decrease (severity grade 1).
Effectiveness
SVR12 was achieved in 76.7% (23 of 30) of the patients who initiated DAAs. Among patients who were tested at 12 weeks posttreatment, 95.8% (23 of 24) achieved SVR12. One (4.2%) patient experienced DAA treatment failure. This patient was HIV positive, had genotype 3a HCV infection, stage F0-F1 hepatic fibrosis, and was prescribed 12 weeks of DCV/SOF. Hepatitis C virus PCR was not done at 12 weeks for 6 patients, 4 of whom had a HCV PCR test done at the end of treatment, all with negative results.
Safety
During concomitant treatment with DAA and MDR-TB drugs, 1 patient (3.3%) experienced a SAE and 4 (13.3%) experienced AEs of clinical significance. The SAE was reported by the treating doctor as possibly related to DAAs. This patient experienced a severe allergic reaction 16 days after initiation of DAA treatment with DCV/SOF, which led to temporary interruption of the DAAs and MDR-TB drugs and resolved after treatment with antihistamine drugs. Both HCV infection and MDR-TB treatments were completed successfully. The 4 AEs of clinical significance were reported as related to the TB drugs. From DAA treatment completion until 12 weeks posttreatment, no AEs related to the DAA treatment were reported.
DISCUSSION
In a context of high prevalence of chronic HCV infection among MDR-TB patients, HCV treatment success was achieved in a high proportion of patients treated concomitantly with DAAs and MDR-TB drugs with no major safety problems. To our knowledge this is the first study reporting concomitant use of DAAs and MDR-TB drugs. The effectiveness results found are consistent with treatment success rates reported in clinical and observational studies of LDV/SOF and DCV/SOF±RBV use among non-TB patients [6–11, 14].
In our study, the patient who experienced DAA treatment failure was HIV positive, had HCV genotype 3a infection, without advanced liver damage (stage F0-F1), and was prescribed 12 weeks of DCV/SOF. A possible contributing factor to DAA treatment failure could be poor adherence because the patient interrupted MDR-TB treatment for 3 weeks while on DAAs and possibly could have also interrupted DAAs. The genotype 3a is a subtype of HCV infection with lower response rates [10] when accompanied with cirrhosis [11], although this was not the case for this patient.
The concomitant use of DAA with second-line antituberculosis drugs was well tolerated. Data on interactions between DCV, LDV, and SOF and second-line antituberculosis drugs are very limited. Theoretically, ethionamide/prothionamide and clofazimine can interact with DCV because both are CYP3A4 inhibitors in vitro. However, the clinical relevance is unknown. Concomitant use of the first-line antituberculosis drug rifampicin and DAAs is not recommended [15]. Overall, the rate of untoward medical occurrences in this cohort of patients (2.6%) was not higher than described in experimental and nonexperimental settings [6, 9–11].
The study has some limitations. It was not possible to evaluate whether HCV treatment could reduce hepatotoxicity during MDR-TB treatment in coinfected patients due to the limited number of participants. In addition, some patients did not have a viral load measurement 12 weeks posttreatment. However, almost all of them had a measurement at the end of the DAA treatment.
CONCLUSIONS
This novel study shows that DAAs can be successfully used to treat chronic HCV infection in MDR-TB patients without major safety concerns. Further research with more participants is needed to generate additional evidence on the safety and effectiveness of the concomitant use of DAAs with second-line antituberculosis drugs. The colocation of the HCV/MDR-TB care is an important step towards patient-centered care and the achievement of the HCV elimination goal.
Acknowledgments
We acknowledge the continuous support from the National Tuberculosis Program in Armenia to the study. We also thank to the Médecins Sans Frontières staff in Armenia and elsewhere who has participated in the project.
Financial support. This work was funded by Médecins Sans Frontières.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
Presented in part: 7th Regional TB Symposium Eastern Europe and Central Aisa, Ministry of Health of the Kyrgyz Republic and Médecins Sans Frontières, March 1–2, 2018, Bishkek, Kyrgyzstan; Scientific Day Médecins Sans Frontières, May 24–25, 2018, London, UK; 49th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease (The Union), October 24–27, 2018, The Hague, The Netherlands; 9th Regional TB Symposium Eastern Europe and Central Aisa, Ministry of Health of Ukraine and Médecins Sans Frontières, March 5–6, 2020, Kyiv, Ukraine. | Recovered | ReactionOutcome | CC BY-NC-ND | 33634203 | 19,405,338 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug interaction'. | Acute heart transplantation from mechanical circulatory support in a human immunodeficiency virus-positive patient with fulminant myocarditis.
Since the establishment of highly active antiretroviral therapy, survival rates have improved among patients with human immunodeficiency virus infection giving them the possibility to become transplant candidates. Recent publications revealed that human immunodeficiency virus-positive heart transplant recipients' survival is similar to non-infected patients. We present the case of a 40-year-old human immunodeficiency virus infected patient, who was hospitalized due to severely decreased left ventricular function with a possible aetiology of acute myocarditis, that has later been confirmed by histological investigation of myocardial biopsy. Due to rapid progression to refractory cardiogenic shock, extracorporeal membrane oxygenation implantation had been initiated, which was upgraded to biventricular assist device later. On the 35th day of upgraded support, the patient underwent heart transplantation uneventfully. Our clinical experience confirms that implementation of temporary mechanical circulatory support and subsequent cardiac transplantation might be successful in human immunodeficiency virus-positive patients even in case of new onset, irreversible acute heart failure.
Introduction
Since the establishment of highly active antiretroviral therapy (HAART), survival rates have improved among patients with human immunodeficiency virus (HIV) infection with a parallel decrease in the incidence of acquired immunodeficiency syndrome, turning HIV infection into a chronic disease. 1 , 2 Nowadays, HIV‐positive patients' life expectancy mostly depends on chronic organ dysfunctions, including chronic hepatic, renal and pulmonary disorders, or cardiomyopathy. 3 The risk of cardiovascular disease and the prevalence of chronic heart failure are significantly higher in HIV‐positive patients as compared with non‐HIV‐infected patients. 3 , 4 , 5 HIV infection had been a contraindication for solid organ transplantation until recently, due to concern about the interference of the immunosuppression therapy, viral load, and immune status. 4 , 6 , 7 The findings of three recent publications confirmed that HIV‐positive heart transplant recipients' survival is comparable with non‐HIV‐infected patients. 8 , 9 , 10 Furthermore, the occurrences of acute rejection, chronic allograft vasculopathy, infection, and malignancy after heart transplantation (HTx) in HIV‐positive patients are also similar to general patient population. 10 Correspondingly, based on the listing criteria of the updated consensus guidelines generated by the International Society of Heart and Lung Transplantation (ISHLT), HIV infection is not considered an absolute contraindication for HTx anymore. 11 Even though, there are only a few transplant centres performing HTx in HIV‐positive patients. 6
Case report
We present a case report of a 40‐year‐old male patient with well‐controlled HIV infection in previous medical history. He was diagnosed with HIV infection in 2012, when he had cytomegalovirus infection. In the same year, he underwent opportunistic infections including perianal fistula and pneumonia leading to septic shock. Since then, HAART had been started including darunavir/cobicistat and INN‐etravirine. HIV viral load was undetectable, and CD4+ count was greater than 200 cells per microlitre for several years.
At present, the patient was first hospitalized by a district hospital due to new onset, worsening dyspnoea. The clinical examinations confirmed severely decreased left ventricular function [ejection fraction (EF): 20%, cardiac index: 1.37 L/min/m2] and a negative coronary angiography with a possible aetiology of acute viral myocarditis. Despite of 5 days of combined inotropic support, patient developed refractory cardiogenic shock; therefore, he was referred for mechanical circulatory support (MCS) implantation and transferred to our tertiary centre. On admission to the intensive care unit, the patient's clinical parameters were as follows: left ventricular EF: 14%, APACHE II score: 9 points, SOFA score: 8 points. The patient went for urgent central venoarterial extracorporeal membrane oxygenation (VA‐ECMO) implantation. Intraoperative myocardial biopsy confirmed the diagnosis of subacute active lymphocytic myocarditis, which was considered to be independent of HIV infection, according to the undetectable viral load for many years. Eosinophil granulocytes, giant cells or granulomatous inflammation were excluded. Over the first four postoperative days, the patient stabilized on VA‐ECMO support of median of 3.5 (3.4, 3.9) L/min, his vasopressor requirement decreased. On the 2nd postoperative day, the patient has been extubated uneventfully; however, 2 days later, he required an urgent reintubation due to bleeding from the respiratory tract. Laboratory tests showed thrombocytopenia (lowest platelet count: 64 g/L), and the rotational thromboelastometry (ROTEM) revealed pronounced substrate deficiency and prolonged clotting time (Figure 1 ).
Figure 1 Rotational thromboelastometry test performed at the time of the first respiratory tract bleeding on venoarterial extracorporeal membrane oxygenation support. A5, amplitude 5 min after CT; A10, amplitude 10 min after CT; A20, amplitude 20 min after CT; A30, amplitude 30 min after CT; CFT, clot formation time; CT, clotting time.
Excluding any improvement or recovery in patient's cardiac function, the multidisciplinary team decided to upgrade VA‐ECMO system to paracorporeal biventricular assist device (BiVAD), which was performed 7 days after the VA‐ECMO implantation. The patient's general condition showed slow stabilization while being on BiVAD support. Based on echocardiography results, both the left and right ventricular functions remained severely deteriorated. Over the first 2 weeks after BiVAD implantation, several bleeding episodes occurred from the respiratory tract and from the exit points of the BiVAD cannulas, which were first considered the consequence of the persistent thrombocytopenia. Interestingly, ROTEM follow‐up tests showed hypercoagulable state (Figure 2 ).
Figure 2 Rotational thromboelastometry test during bleeding from the respiratory tract and from the exit points of the biventricular assist device cannulas. A5, amplitude 5 min after CT; A10, amplitude 10 min after CT; A20, amplitude 20 min after CT; A30, amplitude 30 min after CT; CFT, clot formation time; CT, clotting time.
To clarify the developed complex coagulopathy, additional haematological examinations have been performed, which confirmed secondary thrombotic microangiopathy (TMA). The ADAMTS13 activity had been severely decreased; the activity of both classical and alternative complement pathways had been markedly reduced (Table 1 ). According to these results, we supposed that the cause of TMA was an MCS‐associated immune modulation combined with a consumptive coagulopathy leading to global over‐activation of the complement system. With the aim to control severe TMA, patient received regular fresh frozen plasma transfusions, which resulted in recovery of the TMA after 1 week (Table 1 ).
Table 1 Follow‐up parameters of secondary thrombotic microangiopathy
Parameter (reference range) Postoperative day
5 11 19 32
ADAMTS13 activity (67–137%) 30 29 61 31
Total complement activity (48–103 CH50/mL) 93 26 103 129
Alternative pathway activity (70–130%) 64 52 89 107
Complement 3 (0.9–1.8 g/L) 1.29 1.22 1.66 1.78
Complement 4 (0.15–0.55 g/L) 0.20 0.19 0.26 0.36
Terminal pathway activation marker SC5b‐9 (110–252 ng/mL) 335 473 261 225
Haptoglobin (0.3–2.0 g/L) 0.04 2.56 N/A N/A
Platelet (150–400 G/L) 85 147 196 139
On the 21st day of BiVAD support, the patient developed a spontaneous progressive right side haemothorax, which compromised his haemodynamics and led to transient haematological disturbance. Patient was referred for urgent cardiothoracic discussion and went for emergency right‐side thoracotomy. The operation revealed an unspecific bleeding source from the pericardial region of the visceral pleura, which was presumed to be associated to BiVAD support. Taking into account the patient's stable general condition (including intact cognitive status, minimal invasive mechanical ventilation support, well‐preserved extracardiac organ functions, undetectable HIV viral load with an absolute CD4+ of 244 cells per microlitre), the absence of recovery in cardiac function and the high risk for the recurrence of life‐threatening bleeding and/or thromboembolic complications, the multidisciplinary team decided to refer the patient for Eurotransplant high urgent status. On the 33rd day of BiVAD support, the patient was accepted to Eurotransplant high urgent waiting list. Two days later, he underwent heart transplantation (HTx) uneventfully. The histological investigation of the explanted heart also confirmed the diagnosis of active lymphocytic myocarditis. In places, granulation tissue and replacement fibrosis were identifiable as chronic signs. After the HTx, he tolerated an extended mobilization and a weaning programme on mechanical ventilation, which was completed on the 9th post‐transplant day. Two days later, the patient was emitted to the transplant cardiology ward. The maintenance immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil, and methylprednisolone. Despite applying very low doses of tacrolimus, the trough drug levels were over the therapeutic range in the subsequent series (Figure 3 ). As tacrolimus is metabolized by the CYP3A enzymes, the patient's CYP3A status was determined, that resulted in intermediate CYP3A4 expression (1.48 × 10−6), which did not explain the extremely high tacrolimus blood concentrations. As cobicistat is a CYP3A enzyme inhibitor, we decided to switch darunavir/cobicistat to emtricitabine/tenofovir alafenamide/bictegravir. This change resulted in significant response in drug metabolism leading to subtherapeutic trough tacrolimus levels within few days (Figure 3 ). Withdrawal of darunavir/cobicistat induced an approximately seven‐fold increase in CYP3A4 expression (9.87 × 10−6), according to the follow‐up CYP3A4 expression measurement.
Figure 3 Tacrolimus trough drug levels and its applied doses during the post‐transplant period. The blue spotted line represents the daily applied tacrolimus dose (mg); the green bars represent tacrolimus trough levels (ng/mL). The red arrows display highly active antiretroviral therapy applied in the perioperative period. HAART, highly active antiretroviral therapy; TAC, tacrolimus.
The third routine endomyocardial biopsy on post‐transplant Day 26 revealed moderate acute cellular rejection (ISHLT Grade 2R) that recovered with steroid shot therapy. Echocardiography proved excellent graft function during the follow‐up period. The patient was discharged home in medically well condition 6 weeks after HTx. At that time, the patient's HIV infection was well controlled with undetectable viral load and absolute CD4+ of 270 cells per cubic millimetre. Four months after HTx, the patient is stable with outstanding general condition, excellent graft function, and without developing any post‐transplant opportunistic infections.
Discussion
Mechanical circulatory support implantation and performing HTx in HIV‐infected patients is exceptionally rare, despite the fact that prevalence of chronic heart failure is significantly higher in this patient group than in non‐HIV‐infected subjects. 3 , 4 , 5 The main challenges of the post‐transplant care are to prevent drug–drug interactions and HIV reactivation by immunosuppressants. 6 Bontempo et al. reported the first case of HTx in a HIV‐positive patient performed in the USA in 1988. 12 The first European report was published in 2011. 13 Several subsequent studies have highlighted that post‐transplant survival rates among patients with well‐controlled HIV infection and stable chronic heart failure are the same as compared with general patient population. 8 , 9 , 10 Despite these encouraging data, less than 80 HIV‐infected patients went through cardiac transplantation until the end of the year 2019. 14 To the best of our knowledge, there have been only a few case reports regarding VA‐ECMO implantation in HIV‐infected patients. In one of these cases, ECMO was upgraded to long‐term LVAD, and the patient underwent successful HTx later. 15 Another recent publication described heart‐lung transplantation bridged by VA‐ECMO in an HIV‐positive patient. 16 In comparison, experiences of VV‐ECMO implementation among HIV‐infected patients with respiratory failure are already more relevant. Favourable outcomes on the widespread use of VV‐ECMO were published by Brogan et al. and Capatos et al. according to the results of their multicentre‐based analysis and an observational study, respectively. 17 , 18 Moreover, the first case of HTx bridged by BiVAD support in an HIV‐positive patient suffering from acute heart failure was reported by Peters et al. most recently. 19 Our clinical experience demonstrates that bridge‐to‐transplant implementation of temporary MCS and performing acute HTx could be feasible and successful in HIV‐infected patients with convincing outcome, without any major complications even in case of new onset, irreversible acute heart failure.
Conflict of interest
Zsofia Szakál‐Tóth, Janos Szlavik, Adam Soltesz, Viktor Berzsenyi, Gergely Csikos, Tamas Varga, Kristof Racz, Akos Kiraly, Balazs Sax, Istvan Hartyanszky, Attila Fintha, Zoltan Prohaszka, Katalin Monostory, Bela Merkely, and Endre Nemeth declare that they have no conflicts of interest to disclose.
Consent for publication
Written informed consent was obtained from the patient for publication.
Acknowledgements
The authors would like to acknowledge Beata Nagy, MD, for participating in the histopathological investigations and Gyorgy Sinkovits, MD, for assisting in the haematological investigations. | COBICISTAT\DARUNAVIR ETHANOLATE, ETRAVIRINE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, TACROLIMUS | DrugsGivenReaction | CC BY-NC-ND | 33634606 | 19,973,241 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Immunosuppressant drug level increased'. | Acute heart transplantation from mechanical circulatory support in a human immunodeficiency virus-positive patient with fulminant myocarditis.
Since the establishment of highly active antiretroviral therapy, survival rates have improved among patients with human immunodeficiency virus infection giving them the possibility to become transplant candidates. Recent publications revealed that human immunodeficiency virus-positive heart transplant recipients' survival is similar to non-infected patients. We present the case of a 40-year-old human immunodeficiency virus infected patient, who was hospitalized due to severely decreased left ventricular function with a possible aetiology of acute myocarditis, that has later been confirmed by histological investigation of myocardial biopsy. Due to rapid progression to refractory cardiogenic shock, extracorporeal membrane oxygenation implantation had been initiated, which was upgraded to biventricular assist device later. On the 35th day of upgraded support, the patient underwent heart transplantation uneventfully. Our clinical experience confirms that implementation of temporary mechanical circulatory support and subsequent cardiac transplantation might be successful in human immunodeficiency virus-positive patients even in case of new onset, irreversible acute heart failure.
Introduction
Since the establishment of highly active antiretroviral therapy (HAART), survival rates have improved among patients with human immunodeficiency virus (HIV) infection with a parallel decrease in the incidence of acquired immunodeficiency syndrome, turning HIV infection into a chronic disease. 1 , 2 Nowadays, HIV‐positive patients' life expectancy mostly depends on chronic organ dysfunctions, including chronic hepatic, renal and pulmonary disorders, or cardiomyopathy. 3 The risk of cardiovascular disease and the prevalence of chronic heart failure are significantly higher in HIV‐positive patients as compared with non‐HIV‐infected patients. 3 , 4 , 5 HIV infection had been a contraindication for solid organ transplantation until recently, due to concern about the interference of the immunosuppression therapy, viral load, and immune status. 4 , 6 , 7 The findings of three recent publications confirmed that HIV‐positive heart transplant recipients' survival is comparable with non‐HIV‐infected patients. 8 , 9 , 10 Furthermore, the occurrences of acute rejection, chronic allograft vasculopathy, infection, and malignancy after heart transplantation (HTx) in HIV‐positive patients are also similar to general patient population. 10 Correspondingly, based on the listing criteria of the updated consensus guidelines generated by the International Society of Heart and Lung Transplantation (ISHLT), HIV infection is not considered an absolute contraindication for HTx anymore. 11 Even though, there are only a few transplant centres performing HTx in HIV‐positive patients. 6
Case report
We present a case report of a 40‐year‐old male patient with well‐controlled HIV infection in previous medical history. He was diagnosed with HIV infection in 2012, when he had cytomegalovirus infection. In the same year, he underwent opportunistic infections including perianal fistula and pneumonia leading to septic shock. Since then, HAART had been started including darunavir/cobicistat and INN‐etravirine. HIV viral load was undetectable, and CD4+ count was greater than 200 cells per microlitre for several years.
At present, the patient was first hospitalized by a district hospital due to new onset, worsening dyspnoea. The clinical examinations confirmed severely decreased left ventricular function [ejection fraction (EF): 20%, cardiac index: 1.37 L/min/m2] and a negative coronary angiography with a possible aetiology of acute viral myocarditis. Despite of 5 days of combined inotropic support, patient developed refractory cardiogenic shock; therefore, he was referred for mechanical circulatory support (MCS) implantation and transferred to our tertiary centre. On admission to the intensive care unit, the patient's clinical parameters were as follows: left ventricular EF: 14%, APACHE II score: 9 points, SOFA score: 8 points. The patient went for urgent central venoarterial extracorporeal membrane oxygenation (VA‐ECMO) implantation. Intraoperative myocardial biopsy confirmed the diagnosis of subacute active lymphocytic myocarditis, which was considered to be independent of HIV infection, according to the undetectable viral load for many years. Eosinophil granulocytes, giant cells or granulomatous inflammation were excluded. Over the first four postoperative days, the patient stabilized on VA‐ECMO support of median of 3.5 (3.4, 3.9) L/min, his vasopressor requirement decreased. On the 2nd postoperative day, the patient has been extubated uneventfully; however, 2 days later, he required an urgent reintubation due to bleeding from the respiratory tract. Laboratory tests showed thrombocytopenia (lowest platelet count: 64 g/L), and the rotational thromboelastometry (ROTEM) revealed pronounced substrate deficiency and prolonged clotting time (Figure 1 ).
Figure 1 Rotational thromboelastometry test performed at the time of the first respiratory tract bleeding on venoarterial extracorporeal membrane oxygenation support. A5, amplitude 5 min after CT; A10, amplitude 10 min after CT; A20, amplitude 20 min after CT; A30, amplitude 30 min after CT; CFT, clot formation time; CT, clotting time.
Excluding any improvement or recovery in patient's cardiac function, the multidisciplinary team decided to upgrade VA‐ECMO system to paracorporeal biventricular assist device (BiVAD), which was performed 7 days after the VA‐ECMO implantation. The patient's general condition showed slow stabilization while being on BiVAD support. Based on echocardiography results, both the left and right ventricular functions remained severely deteriorated. Over the first 2 weeks after BiVAD implantation, several bleeding episodes occurred from the respiratory tract and from the exit points of the BiVAD cannulas, which were first considered the consequence of the persistent thrombocytopenia. Interestingly, ROTEM follow‐up tests showed hypercoagulable state (Figure 2 ).
Figure 2 Rotational thromboelastometry test during bleeding from the respiratory tract and from the exit points of the biventricular assist device cannulas. A5, amplitude 5 min after CT; A10, amplitude 10 min after CT; A20, amplitude 20 min after CT; A30, amplitude 30 min after CT; CFT, clot formation time; CT, clotting time.
To clarify the developed complex coagulopathy, additional haematological examinations have been performed, which confirmed secondary thrombotic microangiopathy (TMA). The ADAMTS13 activity had been severely decreased; the activity of both classical and alternative complement pathways had been markedly reduced (Table 1 ). According to these results, we supposed that the cause of TMA was an MCS‐associated immune modulation combined with a consumptive coagulopathy leading to global over‐activation of the complement system. With the aim to control severe TMA, patient received regular fresh frozen plasma transfusions, which resulted in recovery of the TMA after 1 week (Table 1 ).
Table 1 Follow‐up parameters of secondary thrombotic microangiopathy
Parameter (reference range) Postoperative day
5 11 19 32
ADAMTS13 activity (67–137%) 30 29 61 31
Total complement activity (48–103 CH50/mL) 93 26 103 129
Alternative pathway activity (70–130%) 64 52 89 107
Complement 3 (0.9–1.8 g/L) 1.29 1.22 1.66 1.78
Complement 4 (0.15–0.55 g/L) 0.20 0.19 0.26 0.36
Terminal pathway activation marker SC5b‐9 (110–252 ng/mL) 335 473 261 225
Haptoglobin (0.3–2.0 g/L) 0.04 2.56 N/A N/A
Platelet (150–400 G/L) 85 147 196 139
On the 21st day of BiVAD support, the patient developed a spontaneous progressive right side haemothorax, which compromised his haemodynamics and led to transient haematological disturbance. Patient was referred for urgent cardiothoracic discussion and went for emergency right‐side thoracotomy. The operation revealed an unspecific bleeding source from the pericardial region of the visceral pleura, which was presumed to be associated to BiVAD support. Taking into account the patient's stable general condition (including intact cognitive status, minimal invasive mechanical ventilation support, well‐preserved extracardiac organ functions, undetectable HIV viral load with an absolute CD4+ of 244 cells per microlitre), the absence of recovery in cardiac function and the high risk for the recurrence of life‐threatening bleeding and/or thromboembolic complications, the multidisciplinary team decided to refer the patient for Eurotransplant high urgent status. On the 33rd day of BiVAD support, the patient was accepted to Eurotransplant high urgent waiting list. Two days later, he underwent heart transplantation (HTx) uneventfully. The histological investigation of the explanted heart also confirmed the diagnosis of active lymphocytic myocarditis. In places, granulation tissue and replacement fibrosis were identifiable as chronic signs. After the HTx, he tolerated an extended mobilization and a weaning programme on mechanical ventilation, which was completed on the 9th post‐transplant day. Two days later, the patient was emitted to the transplant cardiology ward. The maintenance immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil, and methylprednisolone. Despite applying very low doses of tacrolimus, the trough drug levels were over the therapeutic range in the subsequent series (Figure 3 ). As tacrolimus is metabolized by the CYP3A enzymes, the patient's CYP3A status was determined, that resulted in intermediate CYP3A4 expression (1.48 × 10−6), which did not explain the extremely high tacrolimus blood concentrations. As cobicistat is a CYP3A enzyme inhibitor, we decided to switch darunavir/cobicistat to emtricitabine/tenofovir alafenamide/bictegravir. This change resulted in significant response in drug metabolism leading to subtherapeutic trough tacrolimus levels within few days (Figure 3 ). Withdrawal of darunavir/cobicistat induced an approximately seven‐fold increase in CYP3A4 expression (9.87 × 10−6), according to the follow‐up CYP3A4 expression measurement.
Figure 3 Tacrolimus trough drug levels and its applied doses during the post‐transplant period. The blue spotted line represents the daily applied tacrolimus dose (mg); the green bars represent tacrolimus trough levels (ng/mL). The red arrows display highly active antiretroviral therapy applied in the perioperative period. HAART, highly active antiretroviral therapy; TAC, tacrolimus.
The third routine endomyocardial biopsy on post‐transplant Day 26 revealed moderate acute cellular rejection (ISHLT Grade 2R) that recovered with steroid shot therapy. Echocardiography proved excellent graft function during the follow‐up period. The patient was discharged home in medically well condition 6 weeks after HTx. At that time, the patient's HIV infection was well controlled with undetectable viral load and absolute CD4+ of 270 cells per cubic millimetre. Four months after HTx, the patient is stable with outstanding general condition, excellent graft function, and without developing any post‐transplant opportunistic infections.
Discussion
Mechanical circulatory support implantation and performing HTx in HIV‐infected patients is exceptionally rare, despite the fact that prevalence of chronic heart failure is significantly higher in this patient group than in non‐HIV‐infected subjects. 3 , 4 , 5 The main challenges of the post‐transplant care are to prevent drug–drug interactions and HIV reactivation by immunosuppressants. 6 Bontempo et al. reported the first case of HTx in a HIV‐positive patient performed in the USA in 1988. 12 The first European report was published in 2011. 13 Several subsequent studies have highlighted that post‐transplant survival rates among patients with well‐controlled HIV infection and stable chronic heart failure are the same as compared with general patient population. 8 , 9 , 10 Despite these encouraging data, less than 80 HIV‐infected patients went through cardiac transplantation until the end of the year 2019. 14 To the best of our knowledge, there have been only a few case reports regarding VA‐ECMO implantation in HIV‐infected patients. In one of these cases, ECMO was upgraded to long‐term LVAD, and the patient underwent successful HTx later. 15 Another recent publication described heart‐lung transplantation bridged by VA‐ECMO in an HIV‐positive patient. 16 In comparison, experiences of VV‐ECMO implementation among HIV‐infected patients with respiratory failure are already more relevant. Favourable outcomes on the widespread use of VV‐ECMO were published by Brogan et al. and Capatos et al. according to the results of their multicentre‐based analysis and an observational study, respectively. 17 , 18 Moreover, the first case of HTx bridged by BiVAD support in an HIV‐positive patient suffering from acute heart failure was reported by Peters et al. most recently. 19 Our clinical experience demonstrates that bridge‐to‐transplant implementation of temporary MCS and performing acute HTx could be feasible and successful in HIV‐infected patients with convincing outcome, without any major complications even in case of new onset, irreversible acute heart failure.
Conflict of interest
Zsofia Szakál‐Tóth, Janos Szlavik, Adam Soltesz, Viktor Berzsenyi, Gergely Csikos, Tamas Varga, Kristof Racz, Akos Kiraly, Balazs Sax, Istvan Hartyanszky, Attila Fintha, Zoltan Prohaszka, Katalin Monostory, Bela Merkely, and Endre Nemeth declare that they have no conflicts of interest to disclose.
Consent for publication
Written informed consent was obtained from the patient for publication.
Acknowledgements
The authors would like to acknowledge Beata Nagy, MD, for participating in the histopathological investigations and Gyorgy Sinkovits, MD, for assisting in the haematological investigations. | COBICISTAT\DARUNAVIR ETHANOLATE, ETRAVIRINE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, TACROLIMUS | DrugsGivenReaction | CC BY-NC-ND | 33634606 | 19,973,241 | 2021-04 |
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