key: cord-0950364-871eri3c
authors: Martinez-Lopez, Antonio; Cuenca-Barrales, Carlos; Montero-Vilchez, Trinidad; Molina-Leyva, Alejandro; Arias-Santiago, Salvador
title: Review of adverse cutaneous reactions of pharmacologic interventions for coronavirus disease 2019 (COVID-19): a guide for the dermatologist
date: 2020-08-07
journal: J Am Acad Dermatol
DOI: 10.1016/j.jaad.2020.08.006
sha: 1cb92e329386677ed0626919f0b33c5118124357
doc_id: 950364
cord_uid: 871eri3c

Abstract The new coronavirus SARS-CoV-2 is associated with a wide variety of cutaneous manifestations. While new skin manifestations caused by COVID-19 are continuously being described, other cutaneous entities should also be considered in the differential diagnosis, including adverse cutaneous reactions to drugs used in the treatment of COVID-19 infections. The aim of this review is to provide dermatologists with an overview of the cutaneous side effects associated with the most frequently prescribed drugs in patients with COVID-19. The skin reactions of antimalarials (chloroquine and hydroxychloroquine), antivirals (lopinavir/ritonavir, ribavirin +/- interferon, oseltamivir, remdesivir, favipiravir and darunavir) and treatments for complications (imatinib, tocilizumab, anakinra, immunoglobulins, corticosteroids, colchicine and low molecular weight heparins) are analyzed. Information regarding possible skin reactions, their frequency, management and key points for differential diagnosis are presented.

The new coronavirus SARS-CoV-2 is spreading rapidly worldwide. To date, there are no proven 2 effective therapies for this virus. Knowledge about SARS-CoV-2 virology is rapidly increasing 3 and a large number of potential drug targets are being investigated 1 . Currently, infection 4 management is mainly supportive and common drugs prescribed for infection control include 5 antimalarials (chloroquine and hydroxychloroquine), lopinavir/ritonavir, ribavirin, interferon, 6 oseltamivir, remdesivir, favipiravir and darunavir. Drugs prescribed for complications 7 associated with viral infections include anti-cytokines (mainly IL-6 blockers and anakinra), 8 imatinib, corticosteroids, colchicine, heparins, immunoglobulins and hyperimmune plasma 2 . 9

Cutaneous manifestations have recently been described in patients with the new coronavirus 10 infection, similar to cutaneous involvement occurring in common viral infections 3-5 . A recently-11 published nationwide consensus study in Spain has widely described these manifestations in a 12 prospective study with 375 cases. In this case collection survey, authors described five clinical 13 patterns: acral areas with erythema-edema associated with some vesicles or pustules (pseudo-14 chilblain lesions), maculopapular eruptions, urticaria, other vesicular lesions (monomorphic 15 disseminated vesicular lesions and acral vesicular-pustulous lesions) and livedo or necrosis 6 . 16

The diagnosis of cutaneous manifestations in patients with SARS-CoV-2 infection is challenging 17 for dermatologists 7, 8 . It remains unclear whether these lesions are related to the virus. Skin 18 diseases not related to coronavirus, other seasonal viral infections and drug reactions should 19 be considered in the differential diagnosis, especially in those patients suffering from 20 nonspecific manifestations such as urticaria or maculopapular eruptions. However, some 21 features may help distinguish COVID-19 cutaneous lesions from drug-related ones. Urticarial 22 lesions and maculopapular eruptions in SARS-CoV-2 infections usually appear at the same time 23

as the systemic symptoms, while drug adverse reactions are likely to arise hours to days after 24 the start of the treatment 6,9 . The aim of this review is to provide dermatologists with an 25 overview of the cutaneous side effects associated with the most frequently prescribed drugs in 26 patients with COVID-19, serving as a guide to assist dermatologists and other physicians in 27 differential diagnosis. 28

Hydroxychloroquine and chloroquine are antimalarial agents that have been widely used in the 30 treatment of some chronic inflammatory diseases. They are currently being investigated in 31 over 160 clinical trials 10 , and have been approved for the treatment of COVID-19 by the Food 32 and Drug Administration (FDA) as an Emergency Use Authorization (EUA), and by the European 33 J o u r n a l P r e -p r o o f Medicines Agency for hospitalized patients, in the context of clinical trials or as part of national 1 emergency programs 11, 12 . Although their mechanism of action against SARS-CoV-2 is not fully 2 understood, both drugs may change the pH at the cell membrane surface and inhibit viral 3 fusion and glycosylation of viral proteins. Moreover, hydroxychloroquine can also inhibit 4 nucleic acid replication as well as viral assembly 13, 14 . Despite the lack of high-quality scientific 5 articles, several studies have shown improved survival of patients with COVID-19 who were 6 treated with antimalarials. Although two studies have shown an increased mortality in patients 7 treated with antimalarials, these papers have been retracted as the authors cannot vouch for 8 the veracity of the data 15,16 . Both treatments are generally well tolerated, with retinopathy 9 being the best-known side effect. However, cutaneous adverse events might appear in up to 10 11.5% of patients 17 and some of them can be mistaken for skin manifestations of SARS-CoV-2, 11 especially those with maculopapular rash or exanthematous reactions. This itchy 12 maculopapular eruption tends to appear two weeks after the start of the treatment, mainly on 13 the trunk and limbs and may mean treatment has to be stopped in some patients [18] [19] [20] . 14 Exacerbation of psoriasis is probably the most common cutaneous side effect that appears 15 during treatment with antimalarials, with some cases described in patients with autoimmune 16 diseases and also with COVID-19. Lesions of plaque psoriasis, pustular psoriasis, inverse 17 psoriasis and even erythroderma have been described in patients undergoing treatment with 18 chloroquine and hydroxychloroquine 21-24 . It is important to screen for a personal history of 19 psoriasis in patients with COVID-19 who are candidates for antimalarials in order to prevent 20 severe flares 25 . Cutaneous hyperpigmentation is another well-known skin adverse effect of 21 antimalarial agents that usually appears after long-term treatment, especially under 22 chloroquine treatment. Melanonychia and mucosal pigmentation can also appear due to the 23 high drug binding of both chloroquine and hydroxychloroquine and frequently arise months or 24 years after the beginning of treatment [26] [27] [28] to HIV studies, skin rashes may appear in 5% of adult patients and up to 12% of children. This 3 maculopapular pruritic rash often starts shortly after the start of treatment and is usually well 4 tolerated, although Steven-Johnson syndrome (SJS) associated with serious multi-organ 5 toxicity has been described 37-39 . In HIV patients treated with this combination, inflammatory, 6 painful leg edema appearing three or four weeks after starting the treatment has been 7 described, which might be associated with skin rash 40, 41 . Alopecia areata has also been 8 reported as an infrequent and delayed adverse reaction, and treatment needs to be 9 discontinued for improvement to occur 42, 43 (table 1) . 20

Oseltamivir is a neuraminidase inhibitor that was successfully used during the 2010 influenza 22 H1N1 outbreak. At the beginning of the SARS-CoV-2 pandemic, oseltamivir was used in many 23 patients, but recent clinical trials did not show significant effectiveness. It is currently being 24 investigated in 6 clinical trials 10 . Cutaneous side effects are unusual, but the appearance of SJS 25 and toxic epidermal necrolysis (TEN) should be monitored, especially in children 58,59 . 26

Remdesivir (GS-5734) is a nucleotide analogue prodrug that inhibits viral RNA polymerases 60 . It 28 was developed to treat Ebola disease and other RNA viruses 61 and it has been shown to have 29 potent in vitro activity against SARS-CoV-2 by interfering with NSP12 62 . Its effectiveness in the 30 treatment of COVID-19 is currently being tested in 11 ongoing randomized trials 10 , it has been 31 approved by the FDA as an EUA 11 and as of 3 July 2020, the European Commission granted its 32 conditional marketing authorization for the treatment of COVID-19 in adults and adolescents 33 J o u r n a l P r e -p r o o f (from 12 years of age and weighing at least 40 kilograms) with pneumonia requiring 1 supplemental oxygen 12 . Although there is little information on remdesivir adverse events, 2 cutaneous manifestations may not be very frequent. A randomized controlled trial assessing 3 investigational therapies for Ebola disease showed cutaneous adverse events in 1.7% (3/175) 4 of patients treated with remdesivir 63 . More recently, a cohort of 53 patients receiving a 10-day 5 course of remdesivir were followed up, and 7.55% (4/53) had developed a cutaneous rash 64 . 6

Nevertheless, no information is provided about rash morphology, distribution or timeline in 7 relation to remdesivir that may help clinicians differentiate from cutaneous manifestations of 8 COVID-19 65 . A combination of oral antihistamines and topical corticosteroids could be an 9 effective treatment for this adverse event. rash is a common adverse event associated with darunavir 71-73 and should be differentiated 20 from rashes related to COVID-19 65 . The median interval between darunavir initiation and rash 21 development is 14 days (range, 1-150 days) and a previous history of rashes linked to non-22 nucleoside reverse-transcriptase inhibitors is a risk factor for darunavir-related rashes 71 . 23

Although darunavir-related rashes are often self-limiting and usually mild to moderate in 24 severity 73,74 , they can occasionally be severe, without improvement following treatment with 25 oral antihistamines or steroids, in which case it is necessary to discontinue darunavir 26 treatment 71 . Other cutaneous manifestations are detailed in table 1 73-75 . 27

Imatinib, a tyrosine kinase inhibitor, is another drug that may be effective in treating COVID-19 29 and which is currently being investigated in 4 clinical trials 10 . Its activity occurs in the early 30 stages of infection, after internalization and endosomal trafficking, by inhibiting the fusion of 31 the virions at the endosomal membrane 76 . More than 20% of patients treated with imatinib 32 may develop a rash, presenting as erythematous and maculopapular lesions 77 . The median 1 time to develop a severe rash requiring major interventions was 2.8 months (range, 0.2 to 8.4 2 months). Serial eosinophil blood levels during imatinib treatment showed direct correlation 3 with the development of erythematous and maculopapular skin rash and its severity. Major 4 interventions, including systemic steroids and imatinib dose modification/reduction, are rarely 5 needed (5%) and discontinuation is extremely rare 77 . Other cutaneous manifestations are 6 detailed in table 1 78-82 . 7

Anti-cytokine or immunomodulatory agents 8 Different monoclonal antibodies against cytokines potentially involved in the so-called 9 "cytokine storm", a dysfunctional stimulation of the immune system leading to organ damage, 10 have been proposed for the management of COVID-19 83 . Tocilizumab, an IL-6 blocker, is the 11 most investigated drug in this field 2 , and it is being used at this time in over 30 clinical trials 10 . 12

Its cutaneous manifestations may be divided into true cutaneous adverse effects (urticarial, 13 purpuric and ulcerating lesions) and those secondary to infection 84 . The most common adverse 14 cutaneous reactions to tocilizumab are maculopapular rash, urticaria and cellulitis 85,86 . 15

Necrotizing fasciitis, cutaneous sarcoidosis and pustular eruptions have also been reported 87-89 . 16

Maculopapular rash and urticarial lesions will be the main differential diagnosis for skin 17 manifestations of COVID-19 65 . Treatment will require the use of antihistamines and 18 corticosteroids. Although less frequent, the increased risk of skin infections associated with IL-19 6 blockers should always be considered, as cellulitis and necrotizing fasciitis can be life-20 threatening conditions which must be adequately and promptly treated. Colchicine has been proposed for the treatment of COVID-19 106 . It is currently being 31 investigated for the treatment of COVID-19 in over 10 clinical trials 10 . Cutaneous adverse 32 events with colchicine are very infrequent, mainly occurring due to intoxication (table 1) 

a retrospective cohort study

The right place of interleukin-1 inhibitors in the 3 treatment of Behçet's syndrome: a systematic review

Refractory Adult-Onset Still's Disease: Multicenter Study of 41 Patients and Literature 7 Review

Long-term efficacy and 9 safety of the interleukin-1 inhibitors anakinra and canakinumab in refractory Behçet 10 disease uveitis and concomitant bladder papillary carcinoma. Internal medicine 11 journal

US Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Coordinates 15 National Effort to Develop Blood-Related Therapies for COVID-19

Convalescent Plasma

Eczematous Reaction to 25 Intravenous Immunoglobulin: An Alternative Cause of Eczema

Adverse Reactions of 28

Prophylactic Intravenous Immunoglobulin; A 13-Year Experience With 3004 Infusions 29 in Iranian Patients With Primary Immunodeficiency Diseases

Prospective audit of adverse 32 reactions occurring in 459 primary antibody-deficient patients receiving intravenous 33 immunoglobulin

Management of adverse events in the treatment 35 of patients with immunoglobulin therapy: A review of evidence

Morbilliform Exanthem Associated with COVID-19. JAAD case reports

A distinctive skin rash 40 associated with Coronavirus Disease 2019 ? J Eur Acad Dermatol Venereol. 2020. 41 103. Effect of dexamethasone in hospitalized patients with COVID-19-preliminary report

COVID-19 can present with a rash and be mistaken for 46

Petechial rash in a patient with COVID-19 infection

A Dermatologic Manifestation of COVID-19: 49 Transient Livedo Reticularis

Treatments for COVID-19: emerging drugs 51 against the coronavirus

Late diagnosis of severe colchicine 5 intoxication

Colchicine intoxication diagnosed in a skin 7 biopsy: a case report

Toxic epidermal 9 necrolysis-like reaction secondary to colchicine overdose. The British journal of 10 dermatology

ISTH interim guidance on recognition and 12 management of coagulopathy in COVID-19

Anticoagulants in dermatology. Indian journal of 15 dermatology, venereology and leprology

Adverse Drug Reactions and Cutaneous Manifestations 17 Associated With Anticoagulation

Colchicine: old and new. The 22 American journal of medicine

Adverse events during oral 24 colchicine use: a systematic review and meta-analysis of randomised controlled trials. 25 Arthritis research & therapy

Heparin-induced skin necrosis

Management of heparin-induced thrombocytopenia. 29 Current opinion in hematology