Stevens Johnson Syndrome in Association with Hydroxychloroquine Treatment for Covid 19 A Case Series
2 The Public Authority for Applied Education and Training, Salam, Kuwait
3 Department of Medicine, Kuwait University, Jamal Abdul Nasser St, Kuwait
Citation: Al Zuabi FH, et al. Stevens–Johnson Syndrome in Association with Hydroxychloroquine Treatment for Covid-19: A Case Series. Ann Med Health Sci Res. 2021;11:1281-1283.
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Stevens Johnson Syndrome (SJS) is a rare immune-mediated hypersensitivity disorder that present with mucocutaneous blistering reactions with epidermal detachment and extensive necrosis. Stevens-Johnson syndrome is mainly a reaction to medication, such as sulfonamide, aminopenicillin, quinolone, and cephalosporin. The aminoquinolines, chloroquine and hydroxychloroquine, are widely used in the treatment of many diseases such as malaria and rheumatoid arthritis. Recently it was suggested as a treatment for COVID-19. We report a series of 11 patients, who developed SJS after intake of hydroxychloroquine. More attention should be given for hydroxychloroquine especially with its increased use during COVID-19 pandemic.
Stevens-Johnson; Hydroxychloroquine, COVID-19
The Stevens Johnson Syndrome (SJS) as a febrile illness with SJS is a rare immune complex-mediated hypersensitivity disorder that is generally described as vesiculobullous erythema multiforme of the skin, mouth, eyes, and genitals.  Medications appear to be the most common cause of SJS and have been implicated in as many as 60% of cases studied. 
The aminoquinolines chloroquine and hydroxychloroquine are widely used in the treatment of many diseases such as malaria, rheumatic arthritis, systemic lupus erythematosus and photodermatoses. They have been suggested as effective prophylaxis and treatment for COVID-19 on the grounds of both anti-inflammatory and antiviral effects. [3,4] Hydroxychloroquine has been widely used to treat COVID-19 infection without any available data from randomized clinical trials to inform clinical guidance on the use, dosing, or duration of treatment.
There are several isolated cases reports of SJS and Toxic Epidermal Necrolysis (TEN) associated with hydroxychloroquine. [5-9] Herein, we report a series of 11 patients, who developed SJS after intake of hydroxychloroquine.
Patients and Methods
We studied a series of 11 patients who were presented to the dermatology department of farwaniya hospital, Kuwait with SJS after intake of hydroxychloroquine tablets from January 2020 to February 2021. The diagnosis of SJS was made mainly on the basis of the clinical findings, which included extensive erythema multiforme, purpuric lesions with bullae and detachment of skin involving at least two mucous membranes. Further, in each patient suspected with SJS, various laboratory tests such as complete blood count, liver function tests, metabolic panel, chest X-ray and other serological test were carried out. Skin biopsies with histopathological examination were also done. Patients were discharged when they had haemodynamically stable condition, with no lesions over oral cavity, genital, conjunctival mucosa and normal laboratory investigations.
Eleven patients of SJS were seen in a period of 13 months. They were 7 females and 4 males. Their ages ranged from 21 to 56 years with a mean of 37.54 ± 2.32 years. Clinical data of the patients were summarized in Table 1. All patients developed SJS after intake of hydroxychloroquine. Three patients out of the 11 patients administered hydroxychloroquine as a prophylaxis for infection during COVID-19 pandemic. In the other 8 patients, hydroxychloroquine was administrated as a part of treatment of COVID-19 infection after appearance of symptoms and positive PCR results.
|No.||Age||Sex||Past history of drug reactions||Family history of drug reaction||Indication for hydroxychloroquine||Dose|
|1||42||F||no||no||prophylaxis for Covid-19||400mg once then 200mg daily|
|2||48||F||no||no||prophylaxis for Covid-19||400mg once then 200mg daily|
|3||56||M||no||yes||prophylaxis for Covid-19||400mg once then 200mg daily|
|4||33||M||no||no||Treatment for Covid-19||400mg twice daily|
|5||31||F||no||no||Treatment for Covid-19||400mg twice daily|
|6||26||F||no||no||Treatment for Covid-19||400mg twice daily|
|7||43||F||no||no||Treatment for Covid-19||400mg twice daily|
|8||36||M||no||no||Treatment for Covid-19||400mg twice daily|
|9||21||F||yes||no||Treatment for Covid-19||400mg twice daily|
|10||47||M||no||no||Treatment for Covid-19||400mg twice daily|
|11||29||F||no||no||Treatment for Covid-19||400mg twice daily|
Table 1: Clinical data of 11 patients with Sevens-Johnson syndrome after hydroxychloroquine intake.
After 8-10 days of hydroxychloroquine consumption, patients developed pruritic skin rash extending from the trunk towards the extremities, associated with progressive dysphagia, dysuria, and photophobia. Bullous skin lesions, with erosions and crusting, started forming over the face, scalp, and neck then progressed to involve the trunk and upper and lower limbs. Erythema multiforme-like lesions were mainly over the trunk and upper limbs. In addition, the erythematous rash coalesced with many small vesicles, some forming bullae with positive Nikolsky’s sign. Oral affection in the form of erosions and crusting of both lips and vesicles were present in all patients. The groin, mainly the genital area, was severely affected in 9 patients [Figures 1 and 2].
At the time of admission, the patients had shown abnormal vital parameters including tachycardia (2 patients) and raised blood pressure (2 patients). Some patients showed abnormal laboratory tests like raised serum creatinine level (one patients), leukocytosis (2 patients) and leukocytopenia (one patients).Oropharyngeal swab tested positive for SARS-CoV-2 by PCR assay in 8 patients.
Skin biopsies of the lesions were performed for the patients and histopathologic examination showed basket weave hyperkeratosis, acanthosis, intraepidermal vesicle formation, necrotic keratinocytes in epidermis, basal vacuolar degeneration of basal layer, and dense superficial perivascular lymphohistiocytic in the superficial dermis, a picture consistent with SJS.
As the presumptive cause was hydroxychloroquine intake, so it was stopped and a regimen of methylprednisolone 1 mg/kg-2 mg/kg IV daily was started. The skin lesions were treated twice daily with a mixture of urea and triamcinolone in a lotion base. Clinical improvement occurred after a mean of 14.8 ± 1.32 days and the dose of methylprednisolone was tapered. However, in two patients, SJS progressed to toxic epidermal necrolysis and of which one led to death.
Stevens Johnson Syndrome (SJS) is an immunologic reaction to several stimuli, mostly medications, which presents as a spectrum of primarily widespread mucocutaneous lesions, but also with other organ involvement . SJS can be preceded by a prodrome including fever, malaise, sore throat, nausea, vomiting, arthralgias, and myalgias. This prodrome is followed by conjunctivitis, in addition to bullae on the skin and mucosal membranes of the mouth, nares, pharynx, esophagus, urethra, genital and anal regions.  Many medications have been blamed of causing SJS such as sulfonamide, aminopenicillin, quinolone, and cephalosporin.  SJS also has been linked to herpes simplex virus, mycoplasma bacterial species, and measles vaccine. 
Hydroxychloroquine is a well-known treatment for certain inflammatory autoimmune diseases such as rheumatoid arthritis and lupus erythematosus, and has a noteworthy influence on Toll-Like Receptor 9 (TLR-9) activity. 
Chloroquine analogs have been shown to inhibit the acidification of endosomes and to exhibit in vitro a non-specific antiviral activity at high micromolar concentration against a broad range of emerging viruses (HIV, dengue, hepatitis C, chikungunya, influenza, Ebola, SARS and MERS viruses).  Hydroxychloroquine has been shown to have in vitro activity against SARS-CoV and SARS-CoV-2 (COVID-19). [12,13]
Hydroxychloroquine treatment for COVID-19 has been described as it lowers coronavirus levels in the blood and shortens recovery time.  In their study, Gautret et al. reported a 100% viral clearance in nasopharyngeal swabs in 6 patients after 5 and 6 days of the combination of hydroxychloroquine and azithromycin. In the United States, the Food and Drug Administration issued an Emergency Use Authorization on March 30, 2020, that allowed the use of these drugs in patients with COVID-19 who were not enrolled in clinical trials. Hydroxychloroquine was suggested as treatment for hospitalized patients with COVID-19 and respiratory difficulty, as indicated by low resting oxygen saturation, during the period in which patients in this report were admitted. 
Sharma et al.  revised the adverse dermatologic effects of hydroxychloroquine. The review involved 94 articles encompassing 689 dermatologic adverse effects. A total of 21 unique dermatologic reactions were described, most commonly drug eruption or rash (358 cases), cutaneous hyperpigmentation (116), pruritus (62), acute generalized exanthematous pustulosis (27), Stevens Johnson Syndrome (SJS) or toxic epidermal necrolysis (26), hair loss (12), and stomatitis (11). The range of reported mean cumulative dosages was wide, with some adverse reactions found after as little as 3 g or as much as 2500 g.
SJS is a potentially fatal multiorgan disease with a strong etiologic link to some medications. Severe skin eruptions to hydroxychloroquine were uncommon; however, we reported a case series of 11 patients with SJS due to hydroxychloroquine drug hypersensitivity reactions. The probable dermatologic adverse effects of hydroxychloroquine should be highlighted specially with its increased use during COVID-19 epidemic.
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