Diagnosis and management of the drug hypersensitivity reactions in Coronavirus disease 19: An EAACI Position Paper

Coronavirus disease 2019 (COVID-19), a respiratory tract infection caused by a novel human coronavirus, the severe acute respiratory syndrome coronavirus 2, leads to a wide spectrum of clinical manifestations ranging from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia. Given the huge influence caused by the overwhelming COVID-19 pandemic affecting over three million people worldwide, a wide spectrum of drugs is considered for the treatment in the concept of repurposing and off-label use. There is no knowledge about the diagnosis and clinical management of the drug hypersensitivity reactions that can potentially occur during the disease. This review brings together all the published information about the diagnosis and management of drug hypersensitivity reactions due to current and candidate off-label drugs and highlights relevant recommendations. Furthermore, it gathers all the dermatologic manifestations reported during the disease for guiding the clinicians to establish a better differential diagnosis of drug hypersensitivity reactions in the course of the disease.K E Y W O R D S

## | introduc ti on
Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a novel member of human coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 1 It causes a wide spectrum of clinical manifestations ranging from asymptomatic cases to patients with mild, uncomplicated illness and severe cases, with or without pneumonia. 2 Hospitalization and oxygen support, and admission to an intensive care unit are required in 14% and 5% of the patients, respectively. 1 Gastrointestinal symptoms and positive viral nucleic acid testing on rectal swabs are considered as indicators of infection in digestive system and fecal-oral transmission of COVID-19. [bib_ref] Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral..., Xu [/bib_ref] Moreover, skin symptoms, including exanthems, may appear during the evolution of the disease leading to differential diagnosis with drug hypersensitivity reactions (DHRs). [bib_ref] Cutaneous manifestations in COVID-19: a first perspective, Recalcati [/bib_ref] In critically ill patients, COVID-19 can be complicated by acute respiratory distress syndrome (ARDS), septic shock, and multi-organ dysfunction syndrome. In such patients, in response to viral infection, the excessive activation and expansion of T lymphocytes and macrophages lead to an overproduction of cytokines, which causes a cytokine storm and a hyperinflammatory state. [bib_ref] Continuous intravenous Anakinra infusion to calm the cytokine storm in macrophage activation..., Monteagudo [/bib_ref] [bib_ref] The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R)..., Zhang [/bib_ref] Acute hyperinflammation may activate coagulation cascade and inhibit fibrinolytic reaction, thus promoting thrombosis. Coagulopathy and thrombocytopenia are serious complications which increase the risk of hemorrhage and thrombosis and progress to disseminated intravascular coagulation (DIC). [bib_ref] Coronavirus disease 2019 (COVID-19): a clinical update, Zhou [/bib_ref] The periodically updated World Health Organisation interim guidance allows reliable comparison of investigational therapeutic interventions as part of randomized controlled trials, provides recommendations for the management, and forms the basis of many institutional or national protocols. Unfortunately, none of the drugs used for COVID- [bib_ref] General considerations on rapid desensitization for drug hypersensitivity -a consensus statement, Cernadas [/bib_ref] have been proven to be truly effective yet; besides, no specific antiviral drugs have been approved for COVID-19 by health authorities. [bib_ref] Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review, Sanders [/bib_ref] [bib_ref] Favipiravir: pharmacokinetics and Concerns about clinical trials for 2019-nCoV infection, Du [/bib_ref] At the moment, there is no specific treatment for COVID-19, and standard practice of care focuses on treating the clinical symptoms with supportive care. In this review, diagnosis and management of DHRs, which are expected to be caused by current or candidate repurposed and off-label drugs used for COVID-19 treatment mostly based on prior knowledge, are discussed. [bib_ref] Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review, Sanders [/bib_ref] Drugs in this review are classified into four groups according to their potential roles in different phases of the disease as antiviral drugs, antiviral and/or immunomodulatory drugs used in viral pneumonia; anti-cytokine and anti-inflammatory drugs considered during macrophage activation syndrome (MAS) and cytokine storm; anti-inflammatory drugs in ARDS; and anti-aggregant and anti-coagulant drugs in coagulopathy . Information of DHRs due to the use of additional drugs for various purposes can be found in the relevant European Academy of Allergy and Clinical Immunology (EAACI) resources. [bib_ref] An EAACI position paper on the investigation of perioperative immediate hypersensitivity reactions, Garvey [/bib_ref] [bib_ref] Towards a more precise diagnosis of hypersensitivity to beta-lactams -an EAACI position..., Romano [/bib_ref] [bib_ref] Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations, Aberer [/bib_ref] [bib_ref] EAACI position paper on how to classify cutaneous manifestations of drug hypersensitivity, Brockow [/bib_ref] [bib_ref] Drug hypersensitivity in children: report from the pediatric task force of the..., Gomes [/bib_ref] [bib_ref] Skin test concentrations for systemically administered drugs -an ENDA/EAACI Drug Allergy Interest..., Brockow [/bib_ref] [bib_ref] In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest..., Mayorga [/bib_ref] [bib_ref] General considerations on rapid desensitization for drug hypersensitivity -a consensus statement, Cernadas [/bib_ref] [bib_ref] Desensitization in delayed drug hypersensitivity reactions -an EAACI position paper of the..., Scherer [/bib_ref] Since emerging recent findings are dynamically changing the clinical interventions, it is expected that the list of drugs determined according to current knowledge may change with upcoming recommendations in future.
F I G U R E 1 Currently investigated drugs in COVID-19 grouped according to their clinical use

## | s k in manife s tati on s induced by cov i d -19
There have been increasing reports of dermatologic manifestations associated with COVID-19 . It is knowledge, although in progress, rapidly evolving as evidenced by most publications being ahead of print and available only in an electronic version or reported in networks.
According to pathogenetic mechanisms, skin manifestations reported so far can be divided into (1) skin manifestations similar to those in other viral infections and (2) skin manifestations related to thrombovascular events and vascular pathologies.

## | skin manifestations similar to those in other viral infections
During the COVID-19 outbreak in China, it was not a focus to document skin manifestations. Consequently, skin rash has only been reported in 2 out of 1.099 infected patients (0.2%). [bib_ref] Clinical characteristics of coronavirus disease 2019 in China, Guan [/bib_ref] In contrast, a study by dermatologists from Italy reported skin manifestations in 18/88 patients (20.4%) with COVID-19. [bib_ref] Cutaneous manifestations in COVID-19: a first perspective, Recalcati [/bib_ref] Cutaneous manifestations seen were either erythematous rash (n = 14), widespread urticaria (n = 3), or chickenpox-like vesicular rash (n = 1). In Spain, among 375 patients with suspected or confirmed COVID-19, maculopapular eruptions (MPEs), sometimes similar to pityriasis rosea, were observed in 47% of the cases, urticarial lesions in 19%, and vesicular eruptions of the trunk in 9%. [bib_ref] Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus..., Casas [/bib_ref] Another case of urticaria was presented in France [bib_ref] Urticarial eruption in COVID-19 infection, Henry [/bib_ref] and patients with morbilliform exanthem in the USA . [bib_ref] A case of COVID-19 pneumonia in a young male with full body..., Hunt [/bib_ref] Varicella-like lesions predominantly on the trunk were described in 22 patients with proven COVID-19 infection in Italy. [bib_ref] Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of..., Marzano [/bib_ref] Predominance of vesicles was reported in 54.5% and generally mild itching in nine (40.9%) patients. The vesiculopapular exanthem appears to develop early in the course of the disease . [bib_ref] Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus..., Casas [/bib_ref] ,An outbreak of severe Kawasaki-like disease has been reported at epicenters of COVID-19 infection also associated with a polymorphic rash in 30%-50% of affected children. [bib_ref] An outbreak of severe Kawasakilike disease at the Italian epicentre of the..., Verdoni [/bib_ref] one case, picture of a urticaria-like rash in a 6-month-old child with
Kawasaki-like disease associated with COVID-19 infection is shown . [bib_ref] COVID-19 and Kawasaki disease: novel virus and novel case, Jones [/bib_ref] Two patients with bilateral flexural exanthems resembling systemic drug-related intertriginous exanthems (SDRIFE), one with axillary purpuric lesions associated with thrombocytopenia, have been published . [bib_ref] COVID-19 can present with a rash and be mistaken for Dengue": Petechial..., Jimenez-Cauhe [/bib_ref] A prospective study from

## | skin manifestations associated with thrombovascular events and vascular pathologies
COVID-19 exanthems have also been reported with petechiae and low platelet count resembling dengue. [bib_ref] COVID-19 can present with a rash and be mistaken for dengue, Joob [/bib_ref] In two patients, unilateral lesions on the thigh resembling livedo reticularis or erythema ab igne have been described with microthromboses discussed as possible etiology . [bib_ref] A dermatologic manifestation of COVID-19: transient livedo reticularis, Manalo [/bib_ref] Chilblain-like skin lesions have been frequently reported to be associated with COVID-19 22,35-37 . [bib_ref] COVID-19) infection-induced chilblains: a case report with histopathological findings, Kolivras [/bib_ref] They appear in up to 19% of patients, typically in mildly affected ones, and late in the evolution of the disease. [bib_ref] Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus..., Casas [/bib_ref] 

## | antivir al ag ents us ed for vir al pneumonia

## | clinical use in covid-19
Most antiviral agents used for COVID-19 act either by inhibiting hydroxychloroquine. [bib_ref] The epidemiology, diagnosis and treatment of COVID-19, Zhai [/bib_ref] [bib_ref] Therapeutic options for the 2019 novel coronavirus (2019-nCoV), Li [/bib_ref] [bib_ref] Treatment options for COVID-19: The reality and challenges, Jean [/bib_ref] [bib_ref] SARS-CoV-2: recent reports on antiviral therapies based on lopinavir/ritonavir, darunavir/ umifenovir, hydroxychloroquine,..., Costanzo [/bib_ref] Oseltamivir is recommended for concomitant influenza infection. [bib_ref] Oseltamivir for influenza in adults and children: systematic review of clinical study..., Jefferson [/bib_ref] Darunavir or LPV/r can be concomitantly administered with chloroquine or hydroxychloroquine. [bib_ref] SARS-CoV-2: recent reports on antiviral therapies based on lopinavir/ritonavir, darunavir/ umifenovir, hydroxychloroquine,..., Costanzo [/bib_ref] 

## | hypersensitivity reactions
Drug hypersensitivity reactions to ribavirin, darunavir, LPV/r, remdesivir, and oseltamivir are rarely reported, whereas no DHRs to favipiravir and umifenovir are known at present [bib_ref] Cochrane systematic review: pegylated interferon plus ribavirin vs. interferon plus ribavirin for..., Simin [/bib_ref] [bib_ref] A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe COVID-19, Cao [/bib_ref] [bib_ref] Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48..., Madruga [/bib_ref] [bib_ref] Oseltamivir induced Stevens-Johnson syndrome/toxic epidermal necrolysis-case report, Zuo [/bib_ref] [bib_ref] Oseltamivir-induced toxic epidermal necrolysis in a patient with Cushing's disease, Gonzalez-Ramos [/bib_ref] [bib_ref] Compassionate use of remdesivir for patients with severe COVID-19, Grein [/bib_ref].

## | ribavirin
Ribavirin is used in combination with pegylated-interferon 2a
(peg-IFN-2a) for treating chronic hepatitis C, and both have been associated with several cutaneous DHRs. [bib_ref] Ribavirin for chronic hepatitis C: and the mystery goes on, Brillanti [/bib_ref].
The etiological diagnosis is difficult in case of combination therapy. A drug provocation test (DPT) confirmed the diagnosis of ribavirin hypersensitivity in a patient having MPE due to combined use of peg-IFN-2a and ribavirin. [bib_ref] Delayed hypersensitivity to ribavirin confirmed by provocation test, Barreira [/bib_ref] In another case, an erythema multiforme-type drug eruption occurred with peg-IFN-2a, ribavirin, and/or fluvastatin sodium therapy and a positive lymphocyte transformation test (LTT) confirmed the diagnosis of ribavirin hypersensitivity. [bib_ref] Adverse skin reactions due to ribavirin in hepatitis C combination therapy with..., Shindo [/bib_ref] Successful desensitization protocols were reported [bib_ref] Successful desensitization to ribavirin in a patient with chronic hepatitis C, Ladd [/bib_ref] [bib_ref] Ribavirin desensitization in chronic hepatitis C, Toker [/bib_ref].

## | lopinavir/ritonavir (lpv/r)
Lopinavir/ritonavir, either alone or in combination, has been rarely reported to be associated with DHRs. In human immunodeficiency virus (HIV)-infected patients who received LPV/r combination, MPE rate was reported as 2%-4%.Acute generalized exanthematous pustulosis (AGEP) was described in two cases receiving LPV/r 61.
In a multicentre randomized study that evaluated the long-term efficacy and safety of the combination of efavirenz or LPV/r plus abacavir/lamivudine, 2/63 patients in the LPV/r group discontinued the study because of a DHR.In a recent cohort of 199 severe COVID-19-infected patients who received LPV/r combination, only two (1%) experienced self-limited skin eruptions. [bib_ref] A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe COVID-19, Cao [/bib_ref] A recent study evaluating 217 patients from China revealed that most of the adverse drug reactions (ADRs)
were associated with LPV/r and umifenovir with 63.8% and 18.1%, respectively, and history of a drug allergy was higher in these patients (8.5%) comparing with the ones without ADRs (2.2% vs, P < .044). 63

## | darunavir
Darunavir can induce a variety of delayed skin eruptions from mild MPE in most cases, to severe bullous cutaneous reactions in HIVinfected patients. [bib_ref] Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48..., Madruga [/bib_ref] [bib_ref] Safety and efficacy of darunavir (TMC114) with low-dose ritonavir in treatment-experienced patients:..., Molina [/bib_ref] A phase III randomized clinical trial performed in 604 patients treated with darunavir/r or LPV/r showed that the percentage of patients experiencing rash was higher in those receiving darunavir/r compared with others (16% vs 7%). Two patients receiving darunavir/r required treatment cessation due to a severe rash. [bib_ref] Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48..., Madruga [/bib_ref] Darunavir contains a sulfonamide moiety and should be used with caution in patients with a known sulfonamide allergy. [bib_ref] Cross-reactivity between darunavir and trimethoprim-sulfamethoxazole in HIV-infected patients, Buijs [/bib_ref] Desensitization was reported to be successful in patients with nonimmediate hypersensitivity reactions (NIHRs) to darunavir [bib_ref] Hypersensitivity reaction to darunavir and desensitization protocol, Bravo [/bib_ref] [bib_ref] Hypersensitivity and desensitization to darunavir in a case of HIV infection with..., Lorber [/bib_ref].

## | oseltamivir
Oseltamivir, used in influenza, causes rare hypersensitivity reactions although close monitoring of patients is important as two cases with Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) have been reported, [bib_ref] Oseltamivir induced Stevens-Johnson syndrome/toxic epidermal necrolysis-case report, Zuo [/bib_ref] [bib_ref] Oseltamivir-induced toxic epidermal necrolysis in a patient with Cushing's disease, Gonzalez-Ramos [/bib_ref] with only one being confirmed by LTT. [bib_ref] Oseltamivir-induced toxic epidermal necrolysis in a patient with Cushing's disease, Gonzalez-Ramos [/bib_ref] Another case report revealed anaphylaxis due to oseltamivir confirmed by a skin prick test (SPT) [bib_ref] Anaphylaxis after Oseltamivir (Tamiflu) therapy in a patient with sensitization to star..., Hirschfeld [/bib_ref].

## | remdesivir
A recent multicentre study showed that only one (1.6%) out of 61 patients with COVID-19, experienced MPE during remdesivir treatment and therefore discontinued it prematurely 51.

## | antivir al and/or immunomodul atory drug s us ed for vir al pneumonia

## | azithromycin

## | clinical use in covid-19
Azithromycin interferes with virus internalization process in influenza infection [bib_ref] Azithromycin, a 15-membered macrolide antibiotic, inhibits influenza A(H1N1)pdm09 virus infection by interfering..., Tran [/bib_ref] and has shown clinical effects in COVID-19infected patients, although its mechanism against SARS-CoV-2 remains unclear. 70

## | hypersensitivity reactions
Regarding immediate hypersensitivity reactions (IHRs), urticaria is the most frequent manifestation [bib_ref] Macrolides allergy, Araujo [/bib_ref] ; furthermore, anaphylaxis can occur. [bib_ref] Azithromycin anaphylaxis in children, Mori [/bib_ref] Concerning NIHRs, MPE is described to occur independently 73 or only in the presence of a concurrent infection. [bib_ref] Azithromycin eruption in infectious mononucleosis: a proposed mechanism of interaction, Schissel [/bib_ref] Azithromycin has been implicated in contact dermatitis in occupational 75 and nonoccupational settings. [bib_ref] Non-occupational allergic contact dermatitis caused by azithromycin in an eye solution, Mendes-Bastos [/bib_ref].
Diagnosis is complex as skin testing is not validated, presenting discrepancies in nonirritating dilutions for SPT and intradermal test (IDT). [bib_ref] Nonirritating intradermal skin test concentrations for commonly prescribed antibiotics, Empedrad [/bib_ref] [bib_ref] Determination of nonirritating concentrations of antibiotics for intradermal skin tests in Korean..., Won [/bib_ref] For NIHRs, positive responses to patch tests (PTs)were described. [bib_ref] Occupational allergic contact dermatitis from azithromycin in pharmaceutical workers: a case series, Milkovic-Kraus [/bib_ref] In addition, no validated in vitro tests are available. [bib_ref] Suspicion of macrolide allergy after treatment of infectious diseases including Helicobacter pylori:..., Seitz [/bib_ref] Oral DPT remains as the gold standard for diagnosis. [bib_ref] Diagnostic value of oral challenge testing in the diagnosis of macrolide hypersensitivity, Unal [/bib_ref] A successful desensitization protocol was reported in a case of mast cell activation syndrome 88.

## | hydroxychloroquine/chloroquine

## | clinical use in covid-19
Hydroxychloroquine/chloroquine have in vitro antiviral effects against SARS-Cov-2 by preventing virus/cell fusion, and immunomodulatory effects by inhibiting production of inflammatory cytokines. 89

## | hypersensitivity reactions
Dermatologic ADRs are difficult to be distinguished as a side effect of or an allergic reaction to these drugs or a flare of the underlying dermatological disease. [bib_ref] Cutaneous adverse drug reactions with antimalarials and allergological skin tests, Soria [/bib_ref] [bib_ref] Early cutaneous eruptions after oral hydroxychloroquine in a lupus erythematosus patient: A..., Matsuda [/bib_ref] The most common manifestation is mild pruritic MPEs within initial 4 weeks of treatment. [bib_ref] Cutaneous adverse drug reactions with antimalarials and allergological skin tests, Soria [/bib_ref] Recently, a 5-hour desensitization protocol for nonimmediate urticaria was successfully administered 108.
Two cases of IHR were reported [bib_ref] Successful desensitization for hydroxychloroquine anaphylaxis, Donado [/bib_ref] [bib_ref] Short desensitization in an adolescent with hydroxychloroquine anaphylaxis, Perez-Sanchez [/bib_ref] and one was confirmed by SPTs 109 ; however, there are no available data for in vitro diagnosis.
A hydroxychloroquine desensitization procedure that enables the turning of positive SPTs into negative was published. [bib_ref] Successful desensitization for hydroxychloroquine anaphylaxis, Donado [/bib_ref] In a case of anaphylaxis, a 7 day-desensitization procedure was successfully performed with premedication 110.

## | auranofin

## | clinical use in covid-19
Auranofin is an anti-inflammatory compound that can possibly inhibit the replication of SARS-CoV-2 in cell culture and reduce the expression of cytokines caused by SARS-CoV-2 and the associated lung damage. 111

## | hypersensitivity reactions
There are no reported hypersensitivity reactions due to auranofin.

## | interferons

## | clinical use in covid-19
Type

## | hypersensitivity reactions
Cutaneous eruptions induced by IFNs are common, with an incidence of 13%-23%. [bib_ref] Eczema-like lesions and disruption of therapy in patients treated with interferon-alfa and..., Vazquez-Lopez [/bib_ref] 

## | ivermectin

## | clinical use in covid-19
Ivermectin is an antiparasitic drug also shown to have an in vitro activity against SARS-CoV-2 by inhibition of viral replication. 128

## | hypersensitivity reactions
Rare case reports of multiple FDEs, [bib_ref] Ivermectin-induced fixed drug eruption in an elderly Cameroonian: a case report, Ngwasiri [/bib_ref] confirmed DRESS by skin biopsy and blood eosinophilia, [bib_ref] Ivermectininduced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Kerneuzet [/bib_ref] confirmed SJS 131 and TEN 132 by skin biopsy were published (

## | nitazoxanide

## | clinical use in covid-19
Nitazoxanide is an antiparasitic agent which also has antiviral activities. Combined with hydroxychloroquine or azithromycin, a synergistic effect has been suggested as hydroxychloroquine and azithromycin inhibit viral entry and fusion, while nitazoxanide upregulates innate immune response to prevent ongoing viral replication in COVID-19. 133

## | hypersensitivity reactions
No DHRs to nitazoxanide are reported.

## | anti -c y tok ine/anti -infl ammatory drug s us ed for ma s/ c y tokine s torm/ards

## | tocilizumab

## | clinical use in covid-19
Tocilizumab, an anti-IL-6 receptor humanized monoclonal antibody, is under investigation for treatment of COVID-19 and has shown promising results in cytokine storm. 6

## | hypersensitivity reactions
The rate of all ADRs to tocilizumab is reported to be around 8%, among them 0.1%-0.7% are DHRs. [bib_ref] Hypersensitivity to biological agents-Updated diagnosis, management and treatment, Regnier Galvao [/bib_ref] revealed that STs have a low negative predictive value in NIHR. [bib_ref] Management of hypersensitivity reactions to Tocilizumab, Tetu [/bib_ref] Desensitization to tocilizumab in NIHRs was effectively applied in a weekly scheme with premedication in one case. [bib_ref] Effective desensitization to tocilizumab in delayed hypersensitivity reaction, Cortellini [/bib_ref] Rapid drug desensitization is successfully and routinely used for IHRs [bib_ref] General considerations on rapid desensitization for drug hypersensitivity -a consensus statement, Cernadas [/bib_ref] [bib_ref] Hypersensitivity to biological agents-Updated diagnosis, management and treatment, Regnier Galvao [/bib_ref].

## | anakinra

## | clinical use in covid-19
Anakinra, a recombinant IL-1 receptor antagonist, is under investigation for the treatment of cytokine storm seen during COVID-19. 5

## | hypersensitivity reactions
Anakinra causes ADRs in 75% of patients. Many of them are related to injection site reactions within the first weeks of application and can present either as an IHR or NIHR. [bib_ref] Observational study on efficacy, safety, and drug survival of anakinra in rheumatoid..., Den Broeder [/bib_ref] [bib_ref] Injection-site reactions upon Kineret (anakinra) administration: experiences and explanations, Kaiser [/bib_ref] Systemic IHRs such as urticaria, angioedema, anaphylaxis, [bib_ref] Successful desensitization with anakinra in a case with immediate hypersensitivity reaction, Soyyigit [/bib_ref] [bib_ref] Anaphylactic reaction to anakinra in a rheumatoid arthritis patient intolerant to multiple..., Desai [/bib_ref] [bib_ref] Successful rapid subcutaneous desensitization to anakinra in a case with a severe..., Ylmaz [/bib_ref] and NIHRs 152 as infiltrating erythematous skin plaques were rarely reported as single cases. IHR after a first dose of anakinra was reported in a case possibly due to components that are able to induce a direct mast cell degranulation [bib_ref] Successful rapid subcutaneous desensitization to anakinra in a case with a severe..., Ylmaz [/bib_ref] [bib_ref] Cutaneous mast cell degranulation in rats receiving injections of recombinant human interleukin-1..., Bendele [/bib_ref].
For evaluating IHRs to anakinra, SPTs and IDTs were performed with the undiluted drug. [bib_ref] Anaphylactic reaction to anakinra in a rheumatoid arthritis patient intolerant to multiple..., Desai [/bib_ref] [bib_ref] Successful rapid subcutaneous desensitization to anakinra in a case with a severe..., Ylmaz [/bib_ref] For both IHRs [bib_ref] Successful desensitization with anakinra in a case with immediate hypersensitivity reaction, Soyyigit [/bib_ref] [bib_ref] Successful rapid subcutaneous desensitization to anakinra in a case with a severe..., Ylmaz [/bib_ref] and NIHRs, [bib_ref] Rapid desensitization to anakinra-related delayed reaction: Need for a standardized protocol, Emmi [/bib_ref] successful desensitization protocols were reported .

## | sarilumab

## | clinical use in covid-19
Sarilumab, another IL-6 receptor antagonist, is under investigation in a phase II/III clinical trial in patients with severe COVID-19
infection. 154

## | hypersensitivity reactions
It is generally a well-tolerated drug; however, it can cause local reactions on injection site. In an open-label study, in 3% of the patients it caused a pruritic generalized rash which did not affect the treatment [bib_ref] Immunogenicity of sarilumab monotherapy in patients with rheumatoid arthritis who were inadequate..., Wells [/bib_ref].

## | canakinumab

## | clinical use in covid-19
Canakinumab, a high-affinity human anti-IL-1 monoclonal antibody, is considered as a candidate in treatment of severe COVID-19. 156

## | hypersensitivity reactions
This anti-IL-1 agent is normally well tolerated and indicated as an alternative in cases with an anaphylactic reaction to anakinra. [bib_ref] Drug reactions in children with rheumatic diseases receiving parenteral therapies: 9 years'..., Koc [/bib_ref] However, there is a recently reported case who developed immediate diffuse urticaria after the tenth canakinumab administration and was prevented from further reactions with cetirizine premedication 137 .

## | janus kinase (jak) inhibitors (baricitinib, ruxolitinib, tofacitinib)

## | clinical use in covid-19
Janus kinase inhibitors are under investigation for their potential role in regulating the overactive signaling in the JAK-STAT pathway seen during cytokine storm in critically ill COVID-19-infected patients.
Baricitinib with its potential to inhibit clathrin-mediated endocytosis, and its ability to ameliorate associated chronic inflammation in interferonopathies is expected to show promising results in ongoing clinical trials of COVID-19. 157,158

## | hypersensitivity reactions
Few cases were reported: one with a morbiliform eruption and exfoliative dermatitis due to ruxolitinib, [bib_ref] Drug-associated skin lesions in a patient with myelofibrosis receiving ruxolitinib, Fournier [/bib_ref] another one with palmoplantar pustulosis due to baricitinib, [bib_ref] Palmoplantar pustulosis-like eruption induced by baricitinib for treatment of rheumatoid athritis, Koumaki [/bib_ref] and cases of acute urticaria [bib_ref] An urticarial drug eruption caused by tofacitinib for alopecia universalis, Doohan [/bib_ref] and palmoplantar pustulosis 162 due to tofacitinib .

## | cyclosporine

## | clinical use in covid-19
Cyclosporine A prevents the transcription of genes encoding cytokines like IL-2 and inhibits the replication of diverse coronaviruses at noncytotoxic, low-micromolar concentrations in vitro. [bib_ref] Cyclosporin A inhibits the replication of diverse coronaviruses, De Wilde [/bib_ref] 

## | hypersensitivity reactions
Rare cases of pruritus, urticaria, angioedema, and anaphylaxis were reported. [bib_ref] Anaphylaxis to intravenous cyclosporine and tolerance to oral cyclosporine: case report and..., Volcheck [/bib_ref] [bib_ref] Intravenous tacrolimus and cyclosporine induced anaphylaxis: what is next?, Kang [/bib_ref] [bib_ref] IgE-mediated anaphylaxis after first intravenous infusion of cyclosporine, Ebo [/bib_ref] The possible mechanisms can be both immunologic and nonimmunologic, which seems to depend on the administration route and formulation. [bib_ref] Anaphylaxis to intravenous cyclosporine and tolerance to oral cyclosporine: case report and..., Volcheck [/bib_ref] In some cases, DHRs have been attributed to the additives such as castor oil [bib_ref] Intravenous tacrolimus and cyclosporine induced anaphylaxis: what is next?, Kang [/bib_ref] or Cremophor EL. [bib_ref] IgE-mediated anaphylaxis after first intravenous infusion of cyclosporine, Ebo [/bib_ref] SPTs and
IDTs or basophil activation test (BAT) can be used for the diagnosis of cyclosporine-and additive-induced IgE-mediated IHRs [bib_ref] In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest..., Mayorga [/bib_ref] [bib_ref] Anaphylaxis to intravenous cyclosporine and tolerance to oral cyclosporine: case report and..., Volcheck [/bib_ref] [bib_ref] IgE-mediated anaphylaxis after first intravenous infusion of cyclosporine, Ebo [/bib_ref].

## | colchicine

## | clinical use in covid-19
It is a nonselective inhibitor of NLRP3 inflammasome which is thought to be a major pathophysiologic component of ARDS and/or acute lung injury seen in COVID-19. 167

## | hypersensitivity reactions
Rare cases of anaphylaxis, [bib_ref] Successful rapid subcutaneous desensitization to anakinra in a case with a severe..., Ylmaz [/bib_ref] confirmed FDE with DPT 168 and successfully desensitized MPE [bib_ref] Reporting a desensitization protocol for colchicine treatment, Levinger [/bib_ref] were reported. For PTs, it is recommended to dilute colchicine to 1% in petrolatum [bib_ref] Relevance of skin tests with drugs in investigating cutaneous adverse drug reactions, Barbaud [/bib_ref].

## | eculizumab

## | clinical use in covid-19
Eculizumab, a humanized anti-C5 monoclonal antibody, is under investigation as a candidate drug to play a role in the thrombotic microvascular injury mediated by complement activation causing lung injury either due to severe pneumonia or ARDS in severe COVID-19. 21,36,171

## | hypersensitivity reactions
Immediate hypersensitivity reactions or infusion reactions due to eculizumab are very rare. [bib_ref] Safety and efficacy of eculizumab in Guillain-Barre syndrome: a multicentre, double-blind, randomised..., Misawa [/bib_ref] [bib_ref] Eculizumab safety: five-year experience from the global atypical hemolytic uremic syndrome registry, Rondeau [/bib_ref] A case of anaphylaxis diagnosed with STs was successfully desensitized with a rapid protocol 174 .

## | glucocorticoids

## | clinical use in covid-19
In COVID-19-infected patients, the use of glucocorticoids (GCs) is rather controversial. [bib_ref] Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury, Russell [/bib_ref] [bib_ref] Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia, Zhou [/bib_ref] Early start of GCs could be helpful for patients who have an overly exuberant inflammatory response or are at high risk of developing ARDS, whereas the benefit of GCs as rescue treatment remains doubtful. 177

## | hypersensitivity reactions
IHRs to GCs are overall rare and mostly IgE-mediated. [bib_ref] Cross-reactivity in cell-mediated and IgE-mediated hypersensitivity to glucocorticoids, Ventura [/bib_ref] [bib_ref] Allergic hypersensitivity to topical and systemic corticosteroids: a review, Baeck [/bib_ref] [bib_ref] Skin testing for immediate hypersensitivity to corticosteroids: a case series and literature..., Baker [/bib_ref] [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] [bib_ref] IgE-mediated hypersensitivity reactions to methylprednisolone, Aranda [/bib_ref] [bib_ref] Immediate hypersensitivity to corticosteroids, Venturini [/bib_ref] In a review of the literature from 2004 to 2014, anaphylaxis was the most common manifestation reported (60.8%, 73/120 reactions) followed by urticaria and/or angioedema (26.7%). Methylprednisolone was implicated in 41% of reactions, followed by prednisolone (20%), triamcinolone (14%), and hydrocortisone (10%). [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] In most subjects with IHRs, it is possible to identify the culprit and safe alternative GCs by performing immediate-reading STs. [bib_ref] Cross-reactivity in cell-mediated and IgE-mediated hypersensitivity to glucocorticoids, Ventura [/bib_ref] [bib_ref] Allergic hypersensitivity to topical and systemic corticosteroids: a review, Baeck [/bib_ref] [bib_ref] Skin testing for immediate hypersensitivity to corticosteroids: a case series and literature..., Baker [/bib_ref] [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] [bib_ref] IgE-mediated hypersensitivity reactions to methylprednisolone, Aranda [/bib_ref] [bib_ref] Immediate hypersensitivity to corticosteroids, Venturini [/bib_ref] [bib_ref] Hypersensitivity to systemic corticosteroids: an infrequent but potentially life-threatening condition, Rachid [/bib_ref] [bib_ref] Steroid allergy: clinical features and the importance of excipient testing in a..., Li [/bib_ref] In the aforementioned review, 74.1% of 112 STs carried out with GCs suspected of being responsible for reactions were positive. [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] In some subjects, positive STs were associated with positive serum-specific IgE assays and BATs [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] [bib_ref] IgE-mediated hypersensitivity reactions to methylprednisolone, Aranda [/bib_ref].
Immediate hypersensitivity reactions to medication components other than the GC itself, such as succinate ester used to enhance the solubility in parenteral preparations, have been described. [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] [bib_ref] Steroid allergy: clinical features and the importance of excipient testing in a..., Li [/bib_ref] Hence, when evaluating a reaction to an esterified GC, it is advisable to include in STs the suspected GC and the same GC without the ester component, or with a different ester.
Immediate hypersensitivity reactions to excipients or preservatives in GC preparations, such as lactose, carboxymethylcellulose, polyethylene glycol, and hexylene glycol, have also been reported. [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] [bib_ref] Steroid allergy: clinical features and the importance of excipient testing in a..., Li [/bib_ref] Therefore, testing should be performed with a preservative free GC, in addition to preservative testing per se if needed 185 . A study proposed a comprehensive diagnostic algorithm to evaluate hypersensitivity reactions to GCs, as well as to their components and preservatives. [bib_ref] Steroid allergy: clinical features and the importance of excipient testing in a..., Li [/bib_ref] This algorithm included STs with Carmellose  eye drops in subjects who had reacted to carboxymethylcellulose-containing GCs and with cow's milk proteins in those who had reacted to lactose-containing GCs.
In the allergy workup, negative results in STs should be confirmed with DPTs. [bib_ref] Skin testing for immediate hypersensitivity to corticosteroids: a case series and literature..., Baker [/bib_ref] [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] [bib_ref] IgE-mediated hypersensitivity reactions to methylprednisolone, Aranda [/bib_ref] [bib_ref] Immediate hypersensitivity to corticosteroids, Venturini [/bib_ref] [bib_ref] Hypersensitivity to systemic corticosteroids: an infrequent but potentially life-threatening condition, Rachid [/bib_ref] [bib_ref] Steroid allergy: clinical features and the importance of excipient testing in a..., Li [/bib_ref] DPTs are also recommended to ensure tolerance of alternative preparations. [bib_ref] Hypersensitivity to systemic corticosteroids: an infrequent but potentially life-threatening condition, Rachid [/bib_ref] Cross-reactivity patterns based on structural characteristics have not been clearly established for IHRs as they have been for allergic contact dermatitis. [bib_ref] Allergic hypersensitivity to topical and systemic corticosteroids: a review, Baeck [/bib_ref] DPTs have shown that patients often tolerate alternative GCs belonging to the same chemical group as the responsible GC. [bib_ref] IgE-mediated hypersensitivity reactions to methylprednisolone, Aranda [/bib_ref] [bib_ref] Immediate hypersensitivity to corticosteroids, Venturini [/bib_ref] Desensitization to methylprednisolone has been successfully performed [bib_ref] Successful rapid desensitization to methylprednisolone sodium hemisuccinate: a case report, Angel-Pereira [/bib_ref] [bib_ref] Successful methylprednisolone desensitization in a pediatric patient, Guvenir [/bib_ref].
Nonimmediate hypersensitivity reactions following systemic administration of GCs have been more rarely reported than IHRs; most reports concerned isolated cases of eczematous or exanthematous skin eruptions [bib_ref] Cross-reactivity in cell-mediated and IgE-mediated hypersensitivity to glucocorticoids, Ventura [/bib_ref] [bib_ref] Allergic hypersensitivity to topical and systemic corticosteroids: a review, Baeck [/bib_ref] [bib_ref] High rate of skin complications due to low-molecular-weight heparins in pregnant women, Bank [/bib_ref] [bib_ref] Non-immediate heparin and heparinoid cutaneous allergic reactions: a role for fondaparinux, Tan [/bib_ref] If the treatment is continued regardless of a local reaction, the patient may develop generalized eczema or exanthem. [bib_ref] Enoxaparin-induced generalized exanthem, Kim [/bib_ref] [bib_ref] Management of allergy to heparins in postoperative care: subcutaneous allergy and intravenous..., Seitz [/bib_ref] Patients with a NIHR to UFH or LMWH at injection site usually tolerate intravenous administration of UFH. [bib_ref] Heparin allergy: delayed-type non-IgE-mediated allergic hypersensitivity to subcutaneous heparin injection, Trautmann [/bib_ref] Cross-reactivity among LMWHs has been reported in NIHRs. [bib_ref] Clinical patterns of heparin allergy: cross-reactivity between low-molecular-weight heparins and unfractionated heparins, Rodriguez-Fernandez [/bib_ref] However, fondaparinux is generally well tolerated in patients who react to LMWHs. [bib_ref] Non-immediate heparin and heparinoid cutaneous allergic reactions: a role for fondaparinux, Tan [/bib_ref] Heparin may induce DRESS Immune-mediated heparin-induced thrombocytopenia (HIT) is induced by IgG antibodies against complex of heparin and platelet-factor 4 tetramers. [bib_ref] Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin..., Greinacher [/bib_ref] HIT manifests as a more than 50% decrease in the platelet count in 5-10 days after the onset of treatment. [bib_ref] Heparin-Induced Thrombocytopenia, Greinacher [/bib_ref] The risk of HIT is increased exclusively with UFH. [bib_ref] Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis, Martel [/bib_ref] Treatment includes the discontinuation of heparin and the introduction of an alternative anti-coagulant such as argatroban, fondaparinux, danaparoid, or bivalirudin. [bib_ref] Heparin-induced recurrent anaphylaxis, Berkun [/bib_ref] The IgE-mediated reactions to heparin manifesting as urticaria, angioedema, and anaphylaxis are rare. [bib_ref] Clinical patterns of heparin allergy: cross-reactivity between low-molecular-weight heparins and unfractionated heparins, Rodriguez-Fernandez [/bib_ref] [bib_ref] Heparin-induced recurrent anaphylaxis, Berkun [/bib_ref] [bib_ref] Allergic anaphylaxis due to subcutaneously injected heparin, Anders [/bib_ref] Positive STs with UFH and LMWHs have been reported [bib_ref] Clinical patterns of heparin allergy: cross-reactivity between low-molecular-weight heparins and unfractionated heparins, Rodriguez-Fernandez [/bib_ref] [bib_ref] Heparin-induced recurrent anaphylaxis, Berkun [/bib_ref] [bib_ref] Allergic anaphylaxis due to subcutaneously injected heparin, Anders [/bib_ref] [bib_ref] Immediate type hypersensitivity to Heparins: two case reports and a review of..., Cesana [/bib_ref]. Crossreactivity in IHRs has been reported between UFH and LMWH and among LMWHs. [bib_ref] Immediate type hypersensitivity to Heparins: two case reports and a review of..., Cesana [/bib_ref] For IHRs with heparins, diagnostic approach primarily consists of SPTs and IDTs. [bib_ref] Skin test concentrations for systemically administered drugs -an ENDA/EAACI Drug Allergy Interest..., Brockow [/bib_ref] The results of BAT with UFH and LMWH are controversial. [bib_ref] Allergic anaphylaxis due to subcutaneously injected heparin, Anders [/bib_ref] [bib_ref] Recurrent anaphylaxis due to enoxaparin, Leguisamo [/bib_ref] [bib_ref] Allergy to heparin: a new in vitro diagnostic technique, Caballero [/bib_ref] Heparin itself may cause a release of histamine, leading to a false-positive ST. Further serial dilutions of heparin
(1:100, 1:1000, 1:10 000) might be needed. [bib_ref] Allergic anaphylaxis due to subcutaneously injected heparin, Anders [/bib_ref] IDTs and PTs with the culprit and alternative heparin are performed in NIHRs. [bib_ref] Skin test concentrations for systemically administered drugs -an ENDA/EAACI Drug Allergy Interest..., Brockow [/bib_ref] PTs, with tape stripping, are less sensitive but may be positive [bib_ref] Hypersensitivity reactions to anticoagulant drugs: diagnosis and management options, Bircher [/bib_ref].
Drug provocation test is considered when the diagnosis is obscure, tissue pathology is unavailable, or an alternative anti-coagulant needs to be determined. [bib_ref] Heparin-induced skin lesions, Schindewolf [/bib_ref] been established yet and published as case reports [bib_ref] Heparin allergy: successful desensitization for cardiopulmonary bypass, Parekh [/bib_ref] [bib_ref] Rush desensitization in heparin hypersensitivity: a case report, Patriarca [/bib_ref].

## | dipyridamole

## | clinical use in covid-19
Dipyridamole is an inhibitor of phosphodiesterase 3 and 5; thereby, it increases intracellular cAMP and/or cGMP in platelets and inhibits platelet aggregation. [bib_ref] Anti-platelet therapy: phosphodiesterase inhibitors, Gresele [/bib_ref] 

## | hypersensitivity reactions
Drug hypersensitivity reactions related to dipyridamole are extremely rare. An adult patient with delayed eczematous lesions revealed positive PT results. [bib_ref] Dipyridamole-induced eczematous drug eruption with positive patch test reaction, Salava [/bib_ref] Anaphylaxis or anaphylaxis like reactions were described in two cases; however, they lack diagnostic tests [bib_ref] Acute reaction to dipyridamole during myocardial scintigraphy, Angelides [/bib_ref] [bib_ref] Anaphylaxis-like reaction induced by dipyridamole during myocardial scintigraphy, Weinmann [/bib_ref].

## | d iag nos is , d ifferential d iag nos is , and manag ement of dhr s due to drug s inve s ti g ated for the tre atment of covid -19
Considering the severity of the disease and the emergent need for Our recommendations for the diagnosis and management of DHRs due to drugs administered during COVID-19 are listed in Box 1. This review also highlights the presence of two different groups of disease-related exanthems as an important cause of differential diagnosis of DHRs expected during the treatment of the disease. We think that it is extremely important to distinguish these disease-related eruptions from true DHR-related skin manifestations considering that the majority of the drugs used are more associated with drug-related nonimmediate skin reactions.

## | con clus ion
In near future, further data from ongoing clinical studies and registries established in different countries will enlighten the obscure parts of our understanding on DHRs due to the drugs used in the treatment of COVID-19 and will possibly enable us to establish accurate diagnostic and treatment approaches for these reactions.

## Co n fli c t o f i nte r e s t
None of the authors declare conflict of interest.

## O rci d

## Box 1 recommendations for diagnosis and management of dhrs in covid-19
- No equivalent alternatives for the currently off-label repurposed drugs or novel drugs used in COVID-19 do exist.
- We should extrapolate our knowledge on DHRs from other clinical situations to COVID-19 considering the scarce experience for the DHRs during the disease.
- Various drugs being used in different phases of the disease seem to cause rare but potentially severe DHRs, mostly nonimmediate cutaneous hypersensitivity reactions based on data from limited number of case reports.
- The most important differential diagnosis of these DHRs is disease-related exanthems, which can further be classified into the ones similar to those in other viral infections and the others related to thrombovascular events and vascular pathologies seen during COVID-19.
- Experience of diagnostic and management methods for DHRs due to the drugs used in COVID-19 depend mostly on few case reports or series.
- Knowledge of DHRs is urgently needed from pharmacovigilance registries and data from ongoing clinical trials ofCOVID-19.
- Quick diagnostic and therapeutic decisions in case of DHRs during COVID-19 are mandatory.
- Clinical diagnosis of DHRs during COVID-19 might mostly rely on clinical observations and basic laboratory findings regarding the need of urgent treatment of COVID-19.
- If the risks of a DHR outweigh the benefits obtained from the drug administration, the offending drug should be discontinued.
- When introducing an alternative drug, a DPT may be preferred in order to reduce the risk of a possible DHR.
- If an alternative drug cannot be replaced, the offending drug can be administered via desensitization with published or tailored protocols when there are no contraindications.
- "Treating through" concept, the continued administration of a drug despite a suspected allergic hypersensitivity reaction, can also be considered under strict surveillance measures if the underlying DHR is mild and self-limiting, and an alternative drug does not exist.
[fig] France: reported a prevalence of 5/103 (4.9%) and confirmed association of pruritic erythematous rash (n = 2) and urticaria (n = 2) with COVID-19 infections 31 ; they additionally observed one oral herpes simplex virus type 1 reactivation. The histopathological picture of exanthematic skin lesions generally resembles that of viral exanthems. However, in individual patients, early microthrombi and an interface dermatitis with necrotic keratinocytes surrounded by lymphocytes have been reported.32 [/fig]
[fig] F I G U R E 3 E 2: Skin manifestations associated with thrombovascular events and vascular pathologies. A, Transient unilateral livedo reticularis (erythema ab igne), 34 B, COVID-19-induced chilblains, 35 C, Acro-ischemia with cyanosis, skin bulla, and dry gangrene in critically ill patient 38 Hypersensitivity reactions due to drugs with antiviral properties investigated for the treatment of COVID-19 in clinical trials or in vitro studies Drug groups Drugs Purpose of use in COVID-19 [/fig]
[table] Table 2: No data about STs, in vitro tests, or DPT are available. In addition, no cases of desensitization were reported. [/table]