Skin Diseases Associated With COVID-19: A Narrative Review

Telogen effluvium (excessive and temporary shedding of normal telogen club hairs of the entire scalp due to the disturbance of the hair cycle) is reportedly frequent in patients (48%) 1 month after COVID-19 infection, but it may appear later (after 12 weeks).³⁵ Alopecia also is frequently reported during long (or postacute) COVID-19 (ie, the symptomatic disease phase past the acute 4 weeks’ stage of the infection) and shows a female predominance³⁶; it likely represents the telogen effluvium seen 90 days after a severe illness. Trichodynia (pruritus, burning, pain, or paresthesia of the scalp) also is reportedly common (developing in more than 58% of patients) and is associated with telogen effluvium in 44% of cases. Several cases of alopecia areata (AA) triggered or aggravated by COVID-19 also have been reported^37,38; they could be explained by the “cytokine storm” triggered by the infection, involving T and B lymphocytes; plasmacytoid dendritic cells; natural killer cells with oversecretion of IL-6, IL-4, tumor necrosis factor α, and IFN type I; and a cytotoxic reaction associated with loss of the immune privilege of hair follicles.

Nail Manifestations

The red half-moon nail sign is an asymptomatic purplish-red band around the distal margin of the lunula that affects some adult patients with COVID-19.³⁹ It appears shortly after onset of symptoms, likely the manifestation of vascular inflammation in the nail bed, and regresses slowly after approximately 1 week.⁴⁰ Beau lines are transverse grooves in the nail plate due to the temporary arrest of the proximal nail matrix growth accompanying systemic illnesses; they appear approximately 2 to 3 weeks after the onset of COVID-19.⁴¹ Furthermore, nail alterations can be caused by drugs used to treat COVID-19, such as longitudinal melanonychia due to treatment with hydroxychloroquine or fluorescence of the lunula or nail plate due to treatment with favipiravir.⁴²

Multisystem Inflammatory Syndrome

Multisystem inflammatory syndrome (MIS) is clinically similar to Kawasaki disease; it typically affects children⁴³ and more rarely adults with COVID-19. It manifests with fever, weakness, and biological inflammation and also frequently with skin lesions (72%), which are polymorphous and include morbilliform rash (27%); urticaria (24%); periorbital edema (24%); nonspecific erythema (21.2%); retiform purpura (18%); targetoid lesions (15%); malar rash (15.2%); and periareolar erythema (6%).⁴⁴ Compared to Kawasaki disease, MIS affects slightly older children (mean age, 8.5 vs 3 years) and more frequently includes cardiac and gastrointestinal manifestations; the mortality rate also is slightly higher (2% vs 0.17%).⁴⁵

Confirmed COVID-19 Infection

At the beginning of the pandemic, skin manifestations were reported in patients who were suspected of having COVID-19 but did not always have biological confirmation of SARS-CoV-2 infection due to the unavailability of diagnostic tests or the physical impossibility of testing. However, subsequent studies have confirmed that most of these dermatoses were indeed associated with COVID-19 infection.^9,46 For example, a study of 655 patients with confirmed COVID-19 infection reported maculopapular (38%), vascular (22%), urticarial (15%), and vesicular (15%) rashes; erythema multiforme or Stevens-Johnson–like syndrome (3%, often related to the use of hydroxychloroquine); generalized pruritus (1%); and MIS (0.5%). The study confirmed that CBLLs were mostly seen in young patients with mild disease, whereas livedo (fixed rash) and retiform purpura occurred in older patients with a guarded prognosis.⁴⁶

Remarkably, most dermatoses associated with SARS-CoV-2 infection were reported during the initial waves of the pandemic, which were due to the α and δ viral variants. These manifestations were reported more rarely when the ο variant was predominant, even though most patients (63%) who developed CBLLs in the first wave also developed them during the second pandemic wave.⁴⁷ This decrease in the incidence of COVID-19–associated dermatoses could be because of the lower pathogenicity of the o variant,³ a lower tropism for the skin, and variations in SARS-CoV-2 antigenicity that would induce a different immunologic response, combined with an increasingly stronger herd immunity compared to the first pandemic waves achieved through vaccination and spontaneous infections in the population. Additional reasons may include different baseline characteristics in patients hospitalized with COVID-19 (regarding comorbidities, disease severity, and received treatments), and the possibility that some of the initially reported COVID-19–associated skin manifestations could have been produced by different etiologic agents.⁴⁸ In the last 2 years, COVID-19–related skin manifestations have been reported mainly as adverse events to COVID-19 vaccination.

CUTANEOUS ADVERSE EFFECTS OF DRUGS USED TO TREAT COVID-19

Prior to the advent of vaccines and specific treatments for SARS-CoV-2, various drugs were used—namely hydroxychloroquine, ivermectin, and tocilizumab—that did not prove efficacious and caused diverse adverse effects, including cutaneous eruptions such as urticaria, maculopapular eruptions, erythema multiforme or Stevens-Johnson syndrome, vasculitis, longitudinal melanonychia, and acute generalized exanthematous pustulosis.^49,50 Nirmatrelvir 150 mg–ritonavir 100 mg, which was authorized for emergency use by the US Food and Drug Administration for the treatment of COVID-19, is a viral protease inhibitor blocking the replication of the virus. Ritonavir can induce pruritus, maculopapular rash, acne, Stevens-Johnson syndrome, and toxic epidermal necrolysis; of note, these effects have been observed following administration of ritonavir for treatment of HIV at higher daily doses and for much longer periods of time compared with treatment of COVID-19 (600–1200 mg vs 200 mg/d, respectively). These cutaneous drug side effects are clinically similar to the manifestations caused either directly or indirectly by SARS-CoV-2 infection; therefore, it may be difficult to differentiate them.

DERMATOSES DUE TO PROTECTIVE DEVICES

Dermatoses due to personal protective equipment such as masks or face shields affected the general population and mostly health care professionals⁵¹; 54.4% of 879 health care professionals in one study reported such events.⁵² These dermatoses mainly include contact dermatitis of the face (nose, forehead, and cheeks) of irritant or allergic nature (eg, from preservatives releasing formaldehyde contained in masks and protective goggles). They manifest with skin dryness; desquamation; maceration; fissures; or erosions or ulcerations of the cheeks, forehead, and nose. Cases of pressure urticaria also have been reported. Irritant dermatitis induced by the frequent use of disinfectants (eg, soaps, hydroalcoholic sanitizing gels) also can affect the hands. Allergic hand dermatitis can be caused by medical gloves.