Treatment of cutaneous lesions was done in the context of a multidisciplinary approach with other specialties, taking into account patient comorbidities and the presence of other systemic symptoms. The general treatment algorithm included a course of antihistamines and topical steroids for cases with pruritus and erythema. Macrolide-type antibiotics such as azithromycin were introduced in cases with laboratory alterations, and/or one or more clinical symptom according to the general practice recommendations for COVID-19 management.25-29 In the presence of signs vasculitis in clinical and/or dermatoscopic signs of purpura, petechia, and subsequent ulceration, laboratory tests including a partial thromboplastin time (PTT), activated partial thromboplastin time (aPTT), lactate dehydrogenase, ferritin, C-reactive protein, antiphospholipid, lupus anticoagulant, and D-dimer were conducted. In cases with elevated markers such as D-dimer, oral steroids were introduced with caution to mininmize the risk of aggravating pruritus, severe exanthematous rash/urticaria, and angioedema. Moreover, the introduction of oral steroids should be weighed against other systemic symptoms as it has been noted that steroid-dependent immunosuppression increases viral shedding.30
DISCUSSION
SARS CoV-2 mainly causes respiratory symptoms, but like any other virus can have a series of cutaneous manifestations. Since the emergence of reports regarding COVID-19-related cutaneous manifestations, dermatologists have been hypervigilant in identifying skin lesions suggestive of COVID-19 infection and prompting patients to get tested by RT-PCR and/or antibody testing. As such, in this report, we studied forty-five patients positive for COVID-19 who were referred to our clinics and followed them from COVID-19 diagnosis to treatment/disease resolution. We identified seven main types of COVID-19- associated cutaneous manifestations that appeared in different times in the course of the disease and were associated with different disease severity. Our findings corroborate with reports from other authors regarding the main types of COVID-19-related lesions.22,31-33
Exanthematous rashes, urticaria, and papular/pustular eruptions presented early in the disease or before the onset of any other clinical sign. The duration of these symptoms was relatively short-lived and managed well with a combination of topical steroids/antihistamine and azithromycin.
Livedo reticularis, petechiae, chilblains, and telogen effluvium were also observed. Most often than not, these latter symptoms appeared after the onset of fever, fatigue, and other COVID- 19-related systemic symptoms and were associated with abnormal laboratory values (lymphopenia) in mild/moderate cases. None of our cases had a severe hypercoagulable state leading to disseminated intravascular coagulation (DIC) with acral ischemia and dry gangrene.The livedoid type lesions were indicators of more severe disease whereas the chilblains were observed in mild cases. Telogen effluvium presented suddenly in patients that had other cutaneous symptoms. Four of the ten patients with telogen effluvium had pre-existing hair disorders (alopecia areata, androgenetic alopecia).
The pathophysiology of the COVID-19 cutaneous manifestations has not been elucidated. While urticaria/exanthema/papular- pustular lesions are hypothesized to have an inflammatory etiology, it is unclear where this is a secondary consequence of SARS- CoV-2 infection, a post viral immunological reaction or a primary infection of the skin due to the presence of viral nucleotides. There have been reports of COVID-2 binding ACE2 receptors in the skin vessels, as well as in the basal layer of the skin but we did not detect any viral particles during our histopathological analysis.34 Livedoid/petechiae and chilblain-type lesions are thought to have a vascular pathogenesis due to direct viral replication in the vascular endothelium or occur secondary to the induction of autoimmunity, a concomitant cytokine storm and release of C5b-9, C4d, and MASP2, leading to microvasculature thrombosis in the skin.35 Telogen effluvium is known to occur in response to viral infections,36,37 and while the exact etiology is unclear, we hypothesize that in our cases the cause was hypoxia and localized follicular vasoconstriction.
In the past few months, a remarkable amount of progress has been achieved by the dermatological community with the collective goal of identifying dermatological symptoms related to COVID-19 and their management, particularly in patients with inflammatory dermatoses or those on immunosuppressants.38,39 As of now, whether individuals of specific genetic background, are more or less at risk is not known, and only through large number of cases and retrospective epidemiological studies will we be able to disseminate the ‘’who’’ and ‘’why’’ and ‘’how’’ someone manifests cutaneous or other COVID-19 symptoms. Of note, we did not see in our cases male predominance presenting cutaneous manifestations, or any particular dermatologic comorbidity specifically correlated with a particular type of cutaneous eruption.
Exanthematous rashes, urticaria, and papular/pustular eruptions presented early in the disease or before the onset of any other clinical sign. The duration of these symptoms was relatively short-lived and managed well with a combination of topical steroids/antihistamine and azithromycin.
Livedo reticularis, petechiae, chilblains, and telogen effluvium were also observed. Most often than not, these latter symptoms appeared after the onset of fever, fatigue, and other COVID- 19-related systemic symptoms and were associated with abnormal laboratory values (lymphopenia) in mild/moderate cases. None of our cases had a severe hypercoagulable state leading to disseminated intravascular coagulation (DIC) with acral ischemia and dry gangrene.The livedoid type lesions were indicators of more severe disease whereas the chilblains were observed in mild cases. Telogen effluvium presented suddenly in patients that had other cutaneous symptoms. Four of the ten patients with telogen effluvium had pre-existing hair disorders (alopecia areata, androgenetic alopecia).
The pathophysiology of the COVID-19 cutaneous manifestations has not been elucidated. While urticaria/exanthema/papular- pustular lesions are hypothesized to have an inflammatory etiology, it is unclear where this is a secondary consequence of SARS- CoV-2 infection, a post viral immunological reaction or a primary infection of the skin due to the presence of viral nucleotides. There have been reports of COVID-2 binding ACE2 receptors in the skin vessels, as well as in the basal layer of the skin but we did not detect any viral particles during our histopathological analysis.34 Livedoid/petechiae and chilblain-type lesions are thought to have a vascular pathogenesis due to direct viral replication in the vascular endothelium or occur secondary to the induction of autoimmunity, a concomitant cytokine storm and release of C5b-9, C4d, and MASP2, leading to microvasculature thrombosis in the skin.35 Telogen effluvium is known to occur in response to viral infections,36,37 and while the exact etiology is unclear, we hypothesize that in our cases the cause was hypoxia and localized follicular vasoconstriction.
In the past few months, a remarkable amount of progress has been achieved by the dermatological community with the collective goal of identifying dermatological symptoms related to COVID-19 and their management, particularly in patients with inflammatory dermatoses or those on immunosuppressants.38,39 As of now, whether individuals of specific genetic background, are more or less at risk is not known, and only through large number of cases and retrospective epidemiological studies will we be able to disseminate the ‘’who’’ and ‘’why’’ and ‘’how’’ someone manifests cutaneous or other COVID-19 symptoms. Of note, we did not see in our cases male predominance presenting cutaneous manifestations, or any particular dermatologic comorbidity specifically correlated with a particular type of cutaneous eruption.
CONCLUSION
In conclusion, our report adds to the body of evidence that COVID-19 cutaneous presentations can be highly variable and can precede other symptoms and/or manifest in mild/asymptomatic cases. Thus, they could be the only clue to the diagnosis and thereby crucial to be recognized promptly by dermatologists to avoid community propagation of COVID-19. Rashes and lesions could be the seasonal flu, an allergic reaction, herpes-zoster or simplex, dengue, drug hypersensitivity, or COVID-19; heightened awareness of the most common forms of COVID-19 cutaneous lesions, and their prognosis/management is something that not only dermatologists, but the medical community needs in order to ensure the optimal clinical outcomes for our patients.
