key: cord-0897411-dfxp0ed7
authors: Atzori, Laura; Perla, Stefania; Atzori, Maria Giovanna; Ferreli, Caterina; Rongioletti, Franco
title: CUTANEOUS DRUG ERUPTIONS ASSOCIATED WITH COVID-19 THERAPY
date: 2020-06-05
journal: JAAD international
DOI: 10.1016/j.jdin.2020.05.004
sha: 1656e8e95711763ddbb9e62318355f7e779cd541
doc_id: 897411
cord_uid: dfxp0ed7

nan

To the Editor:

The emergency conditions imposed by the coronavirus disease (COVID-19) 1 pandemic have forced drug regulatory agencies, from the Food and Drug Administration to the European Medicines Agency, to allow the use of drugs that are not tested and approved for this precise condition. Severe cutaneous adverse drug reactions (cADRs), 2 are rare, ranging from 5 cases in a million of acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia systemic symptoms (DRESS), to 1 case in a million of toxic epidermal necrolysis (TEN). However, hundreds of lives could be affected if millions of patients are exposed. The cADRs rate may increase as a consequence of the virus and drug interactions, as already occurs with Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, and human immunodeficiency virus. Thus, reporting cases is of paramount importance to allow pharmacovigilance agencies to estimate the effective incidence. Table 1 shows drugs empirically used to treat COVID-19 and several possible skin reaction patterns for rapid consultation by clinicians.

A typical example of a wide spectrum of cADRs associated to a drug used to treat COVID-19 is hydroxychloroquine (HCLQ), which is associated with AGEP, DRESS, and lethal TEN. 3 Antibiotics, as well as antiretrovirals, are associated with a high risk of drug eruptions, 2 while other experimental drugs, such as remdesivir, are poorly characterized in the literature, with unknown frequencies and risk factors for cADRs. Tocilizumab is a potential inhibitor of multiple cytochrome enzymes, including CYp450, and increased levels of concomitant drugs or unstable metabolites may lead to skin toxicity, as well as delayed hypersensitivity reactions. Intravenous immunoglobulins are associated with cutaneous adverse events in up to 6% of patients. A recent Italian study on skin manifestations associated with COVID-19 revealed that approximately 40% of eruptions are potentially drug-related. 4

Another challenge is cADR management in the COVID-19 course, owing to the risk of additional side effects, mainly due to drug interactions. Symptomatic treatment with antihistamines, such as mizolastine and ebastine, can prolong the QT interval and worsen the potential effects of HCLQ or azithromycin, triggering severe cardiac arrhythmia. 1 Cetirizine might be a safer drug in cases of itching maculopapular and urticaria angioedema reactions. Systemic corticosteroids are controversial for severe cADRs, with case-control analysis 5 suggesting prolonged disease duration or progression, which are the same concerns that are currently emerging with The effects of the COVID-19 pandemic are without precedents, and the exponential rate of lethal disease has entailed the use of empirical drug protocols, often borrowed from other diseases, in the wait for a vaccine. Occurrence of severe cADRs is predictable, and dire consequences can be avoided if the medical community is aware of the problem. Dermatologists' expertise might be an added value, to promptly recognize different cutaneous reaction patterns, support patient assessment and provide adequate management. 

Urticarial eruption • Skin infections • Ulcer • Psoriasiform dermatitis • Anaphylaxis • Koryürek ÖM

Interferons (Alpha; Beta) • Hair loss • Induce, reveal, or worsen some dermatoses

Polymorphic erythema • Vasculitis • Lichenoid drug eruption • Descamps V

Abbreviations: AGEP = acute generalized exanthematous pustulosis

DRESS = drug reaction with eosinophilia and systemic symptoms syndrome

GPEF = generalized pustular figurate erythema

s Johnson syndrome; TEN = toxic epidermal necrolysis

Expected incidence of the events might range from common (1/100 and<1/10 exposed persons) for pruritus, urticaria, maculo-papular exanthem to rare 1/10000 and < 1/1000 for the majority of other reactions, and very rare for severe drug reactions: 5/1 million for AGEP, SJS, DRESS and 1/1 million for TEN