Since marketing authorization, cases of neuralgic amyotrophy (NA), facial paralysis/Bell’s palsy (FP/BP), and Guillain-Barré syndrome (GBS) were reported with COVID-19 vaccines of different technologies. This study aimed to assess whether NA, FP/BP, and GBS were more frequently reported in VigiBase with COVID-19 vaccines (of any technologies) than with other viral vaccines, over the full database and across potential risk groups by sex and age. The reporting odds ratio (ROR) with 95% confidence interval (95% CI) was used as the measure of disproportionality and subgroup disproportionality analyses were performed by sex and age. Out of 808,906 safety reports with COVID-19 vaccines, 57 (0.01%) reported NA, 3320 (0.4%) FP/BP, and 632 (0.1%) GBS. There were not signals of disproportionate reporting for NA and GBS with COVID-19 vaccines against other viral vaccines. FP/BP was disproportionately more frequently reported with COVID-19 vaccines than with other viral vaccines over the full database (ROR 1.12, 95%CI 1.07–1.17), in males (ROR 1.65, 95%CI 1.54–1.78) and in age subgroups 65–74 years (ROR 1.21, 95%CI 1.05–1.39) and ≥75 years (ROR 1.84, 95%CI 1.52–2.22). Albeit not proving causation, these findings might support clinicians in decision-making for patients potentially at risk for developing an acute inflammatory neuropathy with COVID-19 vaccines.

We present here the case of a 62-year-old man, who was referred to the emergency department with fever and cough for 3 days. He underwent liver transplantation 4 years earlier due to HCV and NASH-related cirrhosis with hepatocellular carcinoma. At admission he was in reduced general conditions. Nasopharyngeal smear specimen resulted positive for SARS-CoV-2 infection. Pulmonary low-dose CT-scan revealed bilateral subpleural ground-glass infiltrates. O2 saturation was 93%. A treatment with lopinavir/ritonavir and hydroxychloroquine twice daily was started. The patient received also cefepime and remained in isolation. Seven days later imaging showed a progression of the pulmonary infiltrates. Cefepime was replaced by meropenem. During the following 3 days the fever resolved, and the general conditions of the patient significantly improved. Consequently, treatment with lopinavir/ritonavir and hydroxychloroquine was stopped. The evolution of SARS-CoV-2 interstitial pneumonia in this immunosuppressed patient was moderate to severe and liver injury was not clinically significant. Despite its limitations, this case report confirm that the liver may be only mildly affected during SARS-CoV-2 infection, also in liver transplanted patients. Further studies are needed to assess whether the outcome of SARS-CoV-2 infection is worse in immunosuppressed patients than in the general population.

Off-label prescribing occurs commonly and includes the use of a drug outside its licensed indication in special patient populations such as the elderly.1 Elderly patients are at increased risk of adverse drug events (ADEs) due to age-related pharmacodynamic and pharmacokinetic changes, underlying comorbidities, polypharmacy, and frailty.2 Quetiapine, an antipsychotic drug used for schizophrenia and bipolar disorder, is widely prescribed in elderly patients, increasingly for off-label indications such as insomnia, depression, anxiety, agitation, and dementia, in most cases with limited supporting evidence.2-5 In frail older adults, quetiapine can cause serious ADEs, even at low doses, among which hip fractures, orthostatic hypotension, and pneumonia have been reported.2, 4 Moreover, the use of atypical antipsychotics in people with Alzheimer disease and other dementia is associated with an increased risk of mortality compared with placebo (OR 1.54; 95% CI, 1.06-2.23; P=0.02).2-6 A few characteristics of prescribing physicians have been shown to influence drug prescription: Male physicians, older physicians, and physicians preferring clinical experience or opinion leaders as the best source of knowledge in clinical decision making, as compared with scientific evidence, are more prone to off-label prescribing.7 The aim of this study was to describe quetiapine use (frequency, indications, and doses) in nursing homes of Southern Switzerland and to evaluate the impact of the medical specialty of prescribing physicians on the off-label prescription of quetiapine among nursing home residents. Anonymous data were collected during September to November, 2016, in 15 nursing homes from either electronic or paper medical records, on a single day. On a total of 1173 patients, 379 (32.3%) were treated with quetiapine. Of these, 278 (73.4%) were women, and mean age was 85.8 years. Due to patients having quetiapine as both chronic treatment and PRN (pro re nata, as needed), the total number of prescriptions was 476. Quetiapine in-label indications were 23 (4.8%), whereas off-label indications were 449 (94.3%). Quetiapine was most frequently prescribed for agitation (149, 31.3%), dementia (144, 30.3%), anxiety (73, 15.3%), depression (57, 12%), insomnia (32, 6.7%), and delirium (19, 4%). In 417 (87.6%) quetiapine prescriptions, daily dose was lower than 100 mg, with the most frequently prescribed doses between 12.5 and 25 mg/day (196, 41.2%). Doses above 200 mg/day (as labelled in the summary of product characteristics for approved indications) were scheduled in 21 (4.4%) prescriptions. Out of the 379 patients who received quetiapine, it was possible to define the medical specialty of the prescribing physician in 324 (85.5%) cases. Of these, 305 (94.1%) received quetiapine off-label: In 267 (87.5%) cases, quetiapine off-label prescription originated from general practitioners (family physicians or nursing home physicians), whereas in 38 (12.5%) from specialists (geriatrists or psychiatrists). There was a significant correlation between quetiapine off-label use and prescription made by general practitioners as compared to specialist physicians (OR 3.2; 95% CI, 1.2-8.8; P=0.04). Our analysis showed that in nursing homes of Southern Switzerland, quetiapine is frequently used and often administered for off-label indications, mainly agitation and dementia. Noteworthy, previous studies found no evidence of benefit for quetiapine administered for agitation or psychosis in older adults with dementia,8-10 and its long-term use was associated with a decline in cognitive and functional abilities as compared to patients without quetiapine.8, 9 Because the study sample was selected within the area of Southern Switzerland, the results of our study cannot be generalized to a broader population of nursing home residents. Moreover, by selecting patients with quetiapine prescription at a certain time of their staying in the nursing homes, selection bias possibly affects the internal validity of our study. Indeed, we might have missed patients with an initial quetiapine prescription received in the nursing home but subsequently interrupted at the time of data retrieval. The correlation that we highlighted between quetiapine off-label use and prescription by general practitioners suggested that the medical specialty of prescribing physicians might represent a potential risk for quetiapine off-label prescribing in the elderly. Educational interventions focused on safe and aware prescribing by general practitioners, and a more frequent involvement of specialist physicians in nursing homes, might improve quetiapine prescribing in elderly nursing home residents. L.M., M.B., and A.C. contributed to the study conception and design. Material preparation, data collection, and analysis were performed by L.M., R.N., R.B., and A.C. The first draft of the manuscript was written by L.M., and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. The authors have no conflicts of interest to declare. According to the Human Research Act (810.30, of September 30th, 2011—status as of January 1st, 2014), from the Federal Assembly of the Swiss Confederation, ethical approval was not required (Art.2: "It does not apply to research which involves anonymously collected or anonymised health-related data").

BackgroundImmune checkpoint inhibitor (ICI) use in clinical practice has unravelled a spectrum of immune-related adverse events (irAEs) due to immune system hyper-activation. ICI-related haemophagocytic lymphohistiocytosis (HLH) has been recently outlined in single case reports, raising a concern about the need of increasing our knowledge on this rare yet life threatening ICI haematological toxicity.MethodsTo determine ICI-related HLH clinical, haematological, and coagulation features, its timing and outcome, concurrent irAEs and concomitant infections, we performed a retrospective observational cross-sectional study and queried VigiBase, the WHO global database of suspected adverse drug reactions (ADRs), on September 30th, 2018. We retrieved the individual case safety reports reporting HLH in association with ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab or durvalumab, gathered in the database starting from the ICIs’ approval dates by the US Food and Drug Administration. The main outcome measures were co-suspected drugs, concurrent irAEs, HLH clinical, haematological and coagulation features, concomitant infections, HLH median time to onset and outcome.ResultsAmong 49′883 ICI-related ADRs collated in VigiBase as of September 30th, 2018, HLH was reported in 38 cases of which 34 (90%) mentioned ICIs as the solely suspected drugs. ICI-related HLH showed clinical, haematological and coagulation features similar to those of HLH with different etiology. Concurrent irAEs occurred in 5 (13%) patients and 6 (16%) reported concomitant viral infections. 31 (82%) cases defined ICI-related HLH outcome, which resolved in 19 (61%) cases. HLH developed a median of 6.7 weeks after initiation of ICI treatment (IQR 2.9–15.4, n = 18, 47%).ConclusionsBy evaluating the largest cohort of ICI-related HLH cases, we observed that ICI-related HLH arises with a delayed timing with respect to initiation of ICI treatment, and usually presents without other irAEs and concomitant infections. Keeping in mind these findings, clinicians should consider ICIs’ involvement in the onset of HLH whenever they diagnose a disease of this group of syndromes in cancer patients treated with ICIs.

Background: The spectrum of inflammatory marker response in DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome has not been systematically characterized. Methods: An epidemiological biomarker study of C-reactive protein (CRP) and procalcitonin (PCT) values in patients with DRESS syndrome reported at 2 regional pharmacovigilance centers in Switzerland or published in the medical literature 2008–2016 was performed. Results: Ninety-four DRESS cases were studied. All cases showed a CRP value > 10 mg/L (the upper limit of normal). The mean CRP value was 109.2 ± 79.4 mg/L. CRP values were significantly higher in 22 cases where a cause of inflammation besides DRESS could not be excluded (mean 162.1 vs. 92.9 mg/L; p = 0.003). Receiver operator characteristics curve analysis showed a moderate performance with a CRP cut-off value of 99.4 mg/L (AUC 0.717) to distinguish between patients with and without a possible additional cause of inflammation. The mean and median PCT values were 2.44 ± 5.94 and 0.69 ng/mL, respectively (n = 25 patients). Patients in whom an additional cause of inflammation besides DRESS could not be excluded showed a median PCT of 1.37 ng/mL (n = 9) versus 0.67 ng/mL (n = 16) in patients with DRESS only. PCT values were above the normal cut-off of 0.1 ng/mL, suggestive of bacterial infection in all but 1 case. Furthermore, there was a correlation between PCT values and hepatic enzyme measurements. Conclusions: Evaluating CRP and PCT values might be of use in helping physicians to distinguish between cases of DRESS syndrome with and without concurrent infection or other causes of inflammation. Further prospective investigation is required to define the use of these inflammatory markers in the management of DRESS.

We report a novel association between the commonly used antimalarial medication atovaquone/proguanil and drug‐induced autoimmune‐like hepatitis. The patient developed severe liver disease fulfilling biochemical, immunologic, and histologic criteria for the diagnosis of autoimmune hepatitis after the inadvertent rechallenge with the offending drug, which had caused self‐limited hepatitic symptoms a year previously. Over a period of 18 months, the patient underwent two follow‐up liver biopsies showing progressive resolution of the liver inflammation and achieved complete biochemical and immunologic remission on steroids. This remission persisted for 20 months following treatment withdrawal. Conclusion: This well documented case raises awareness of the potential hepatotoxicity of atovaquone/proguanil. (Hepatology Communications 2017;1:293–298)

A 45-year-old previously healthy caucasian man was admitted for pruritus, scleral icterus and dark urine. The patient was reported to have taken a spoon of a preparation containing camu-camu (myrciaria dubia) a day. He took no other drugs and did not drink alcohol or use illicit substance. Laboratory studies reveiled an elevated aspartate transaminase of 403 U/L, and alanine transaminase of 1185 U/L, alkalinephosphatase of 335 U/L, gamma glutamyl transpeptidase of 300 U/L, and elevated total bilirubin of 142 μmol/L. His complete blood count was normal. Tests for viral, metabolic or autoimmune causes of liver injury were negative. Liver biopsy demonstrated centrilobular hepatocellular damage was compatible with drug toxicity which was not of very recent origin. Clinical and laboratory signs of liver injury gradually improved and the patient was discharged. Myrciaria dubia is used as a dietary supplement with antioxidant properties. To our knowledge, this is the first report of liver injury probably related to use of camu-camu. Exclusion of other causes and the histological diagnosis were compatible with drug toxicity render camu-camu which was most likely as the cause of acute heaptitis most likely. It is important to increase the awareness of both clinicians and patients about the potential dangers of herbal remedies in absence of reliable studies of clinical efficacy and benefit-risk assessment.

Es wird der Fall einer ansonsten gesunden 59-jährigen Patientin beschrieben, die unter der gleichzeitigen Einnahme von Tizanidin (Sirdalud®), Diclofenac (Voltaren®) und Rofecoxib (Vioxx®) eine extreme Sinusbradykardie (30/min) mit retrosternalen Schmerzen und akuter Rechtsherzbelastung sowie gastrointestinale Symptome mit Erhöhung der Leberenzyme entwickelte. Nach Absetzen der Medikation besserte sich die Symptomatik rasch.

@ Case Record: The case of a 59-year-old healthy woman is described, who developed an extreme sinus bradycardia (30/min) with chest pain and acute right heart failure associated with gastrointestinal symptoms and elevation of the liver enzymes while simultaneously taking tizanidine (Sirdalud®), diclofenac (Voltaren®), and rofecoxib (Vioxx®). The symptomatology resolved promptly after stopping the medication. □ Discussion: The usual causes ofsinusbradycardia like hypothyroidism, hypothermia, intracranial pressure elevation, typhoid fever, sick sinus syndrome, hyperreactive carotid sinus reflex, organic heart disease, electrolyte disorders, and pharmacotherapy with β-blockers, digitalis, and antiarrhythmics have been excluded in this case. Bradycardia can occur as a side effect of tizanidine. As this substance is metabolized by cytochrome P450 1A2 and rofecoxib inhibits this enzyme, an interaction between these drugs is probable. Liver function disorders and gastrointestinal symptoms, in the present case mainly due to the acute right heart failure, have also been described as side effects under tizanidine, diclofenac as well as rofecoxib. Supposedly, the combination of tizanidine/rofecoxib used to be prescribed frequently for lumbar pain as selective cyclooxygenase-(COX-)2 inhibitors are visibly replacing the nonsteroidal antirheumatics due to their better side effect profile. An augmented risk of cardiovascular events under rofecoxib led to its withdrawal from the market at the end of September 2004. □ Conclusion: When prescribing Sirdalud®, the possible pharmacological side effects and interactions should be taken into careful account.