These authors contributed equally to the work.

Since the 1960s, several drugs have been linked to the onset or aggravation of pulmonary arterial hypertension (PAH): dasatinib, some amphetamine‐like appetite suppressants (aminorex, fenfluramine, dexfenfluramine, benfluorex) and recreational drugs (methamphetamine). Moreover, in numerous cases, the implication of other drugs with PAH have been suggested, but the precise identification of iatrogenic aetiologies of PAH is challenging given the scarcity of this disease and the potential long latency period between drug intake and PAH onset. In this context, we used the World Health Organization's pharmacovigilance database, VigiBase, to generate new hypotheses about drug associated PAH. Methods We used VigiBase, the largest pharmacovigilance database worldwide to generate disproportionality signals through the Bayesian neural network method. All disproportionality signals were further independently reviewed by experts in pulmonary arterial hypertension, pharmacovigilance and vascular pharmacology and their plausibility ranked according to World Health Organization causality categories. Results We included 2184 idiopathic PAH cases, yielding a total of 93 disproportionality signals. Among them, 25 signals were considered very likely, 15 probable, 28 possible and 25 unlikely. Notably, we identified 4 new protein kinases inhibitors (lapatinib, lorlatinib, ponatinib and ruxolitinib), 1 angiogenesis inhibitor (bevacizumab), and several chemotherapeutics (etoposide, trastuzumab), antimetabolites (cytarabine, fludarabine, fluorouracil, gemcitabine) and immunosuppressants (leflunomide, thalidomide, ciclosporin). Conclusion Such signals represent plausible adverse drug reactions considering the knowledge of iatrogenic PAH, the drugs' biological and pharmacological activity and the characteristics of the reported case. Although confirmatory studies need to be performed, the signals identified may help clinicians envisage an iatrogenic aetiology when faced with a patient who develops PAH.

AWADA et al. [1] recently published in the European Respiratory Journal an interesting pre-clinical study suggesting that crizotinib may exacerbate and predispose to pulmonary arterial hypertension (PAH). Crizotinib is a first-in-class anaplastic lymphocyte kinase (ALK) inhibitor and is now a standard first-line therapy for advanced ALK-positive non-small cell lung cancer (NSCLC) [2]. Its inconsistent efficacy and its limited ability to control brain metastases pushed the development of second-generation ALK tyrosine kinase inhibitors (TKIs) (ceritinib, alectinib and brigatinib), which are characterised by higher selectivity and distribution to the central nervous system. Furthermore, third-generation ALK-TKIs, such as lorlatinib and entrectinib, have been recently developed to overcome acquired resistance due to secondary ALK mutations, which concern more than half of patients treated by second-generation ALK-TKIs [3]. Cases of PAH onset have also been reported in patients with metastatic NSCLC who received other ALK-TKIs, such as brigatinib and lorlatinib [4,5]. Subsequently, one can ask if this adverse event is specific to crizotinib or a class effect of ALK-TKIs, and whether on-target or off-target tyrosine kinases are implicated in its pathophysiology. To further add knowledge on this potential adverse drug reaction, we aimed to comprehensively characterise PAH reported with ALK-TKI use, using the World Health Organization (WHO) pharmacovigilance database to describe cases' clinical features and to assess its causality.We first extracted all cases of PAH reported with commercialised ALK-TKIs (crizotinib, ceritinib, brigatinib, lorlatinib, alectinib and entrectinib) from the WHO pharmacovigilance database, VigiBase. VigiBase is the world's largest pharmacovigilance database, collecting reports from among the 150 countries participating in the WHO Programme for International Drug Monitoring since 1968. At the date of extraction (May 2021) more than 25 million cases were reported in this database. We identified cases of PAH using the following search terms of the MedDRA dictionary: "pulmonary arterial hypertension" ( preferred term). We also broadened our searches using the high-level term "pulmonary hypertension" and the standardised medical query "pulmonary hypertension". Standardised medical queries are internationally validated, pre-determined collections of MedDRA terms associated with a common disease, allowing for high-sensitivity searches (e.g. PAH, right ventricular failure, acute cor pulmonale, tricuspid valve incompetence). Secondly, we performed a disproportionality analysis to compare the proportion of PAH cases reported with ALK-TKIs against other antineoplastic drugs used in NSCLC [6]. Disproportionality analyses are statistical methods that quantify the extent to which an adverse event occurs more than expected with a drug. Such methods are widely used by national drug agencies, industries and researchers for safety signal detection in pharmacovigilance spontaneous reporting systems databases. T...

Background The SARS-CoV-2 pandemic has caused over 400,000 deaths worldwide thus far, and poses therapeutic challenges for millions of patients. There is currently no treatment for SARS-CoV-2 infection approved by the United States Food and Drug Administration. Multiple agents have been used off-label to treat SARS-CoV-2 infection based on small observational cohorts and in vitro data. Here we present the experience of a large academic medical center in treating SARS-CoV-2 infection. Methods We performed a retrospective cohort study of patients admitted for greater than 24 hours with a nasopharyngeal, oropharyngeal, and/or bronchoalveolar lavage sample positive for SARS-CoV-2 by polymerase chain reaction (PCR). Demographic data, comorbidities, clinical data, and treatment data were collected from the electronic medical record. Off-label therapies were used at the discretion of the treating providers guided by regularly updated treatment guidelines assembled by infectious diseases physicians and antimicrobial stewardship pharmacists. The primary outcome assessed was in-hospital mortality. Secondary outcomes included admission to the intensive care unit (ICU), endotracheal intubation, initiation of vasopressors, and drug-related adverse events. Results Data collection was completed for 448 patients admitted between March 18, 2020 and May 8, 2020. All-cause in-hospital mortality was 13.4% (60/448) during this time. Mortality rates increased with age, up to 45% for patients over 80 years old. Male sex, hypertension, chronic pulmonary disease, end-stage renal disease, chronic liver disease were also risk factors for increased mortality. QTc interval prolongation occurred significantly more frequently in patients who received hydroxychloroquine (HCQ) with or without azithromycin(AZM) than those who did not (HCQ 6%, HCQ+AZM 7.8% vs all other patients, 0%, p< .0001). Review of treatment trends showed close adherence to the treatment recommendations at that time (Figure 1). Patient Characteristics Admission Laboratory Data by Disease Severity QTc Prolongation Conclusion SARS-CoV-2 infection is associated with significant inpatient mortality, and use of off-label treatments was associated with significant drug-related adverse events. Treatment regimens changed rapidly, and providers adhered closely to institutional guidelines as they evolved. Treatment Trends by Week QTC pre/post Treatment by Hydroxychloroquine Use vs. No Hydroxychloroquine Use Disclosures Samir Gupta, MD, Gilead Sciences (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member)ViiV (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support)