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Abstract
Background: Cutaneous manifestations of coronavirus disease 2019 (COVID-19) range from mild skin rashes to severe vasculitis. In the current study, we evaluated the demographic characteristics of the patients with cutaneous vasculitis following COVID-19 infection. Materials and Methods: In the current study, we evaluated 799 hospitalised patients with COVID-19 infection for development of cutaneous vasculitis. Demographic and clinical characteristics of the patients were obtained using questionnaires and patients' records. Cutaneous vasculitis of the suspected patients were confirmed using skin biopsy and direct immunofluorescence. Results: We detected 24 hospitalised cases with cutaneous vasculitis presenting with petechia, purpura, livedoretcularis and acrocyanosis. Our data showed a significant relationship between male sex, advanced age, C-reactive protein (CRP) level and presence of comorbidities with development of cutaneous vasculitis. In addition, we found a positive association between the severity of COVID-19 infection and occurrence of cutaneous vasculitis. Conclusion: Our findings are suggestive that clinicians must be aware of cutaneous vasculitis risk as prognostic value in the patients with severe COVID-19 infection.
Keywords: C-reactive protein (CRP), COVID-19, cutaneous vasculitis
Introduction 
Coronavirus disease 2019 (COVID-19) is a pandemic respiratory and vascular infection caused by the RNA virus of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[1] The prevalence of COVID-19 from the start of the pandemic until the end of April 2020 was estimated as 17.1% in Iran.[2] Although the disease is more common in women, the disease severity and mortality are higher in men. The severity of disease is very variable, especially among patients with high risk factors (such as old age, male gender, diabetes, chronic hypertension and other cardiovascular comorbidities).[3] The angiotensin-converting enzyme 2 (ACE2) receptor combined with the transmembrane protease serine 2 (TMPRSS2) is entry way of virus to the host cells that is found in organs such as lungs, heart, intestines, liver etc.[4] Skin is one of target tissues for COVID-19 that can cause cutaneous lesions in these patients.[5]
The cutaneous lesions have been classified in inflammatory or exanthematous eruptions that manifest from mild to severe forms (between 1.8% and 20.4%) in confirmed or suspected COVID-19 cases before, during and after disease.[6] These inflammatory lesions include urticaria, erythematous/maculopapular/morbilliform rash, papulovesicular exanthem and vasculopathic/vasculitis.[6],[7]
The cutaneous vasculitis involves superficial and mid-dermal small to medium-sized blood vessels and it's manifests include urticaria, purpura, hemorrhagic vesicles, ulcers, nodules, livedo, infarcts and/or digital gangrene on the lower and upper limbs.[8] Probably, the pathophysiology behind these occurrences is the major systemic occlusive vascular disease in these patients. SARS-CoV-2 triggers a cytokine storm such as IL-6 that could activate dermal dendritic cells, lymphocytes and neutrophils, inducing the vasculitic process. Furthermore, the high level of inflammation markers like CRP and ferritin supports the skin inflammatory process and the viral load leads to coagulation system activation and present skin lesions in COVID-19 patients.[9]
To date, several case reports have explained COVID-19-associated cutaneous vasculitis that appeared with mild to severe manifestations in different phases of the disease.[10],[11],[12],[13],[14],[15]
Given the possible role of COVID-19 in pathogenicity of cutaneous vasculitis, we performed the present study to better evaluate the relationship between cutaneous vasculitis in COVID-19 infection and demographic and clinical factors of the patients.
Materials and Methods Study area
The present study was conducted in 2020–2021 in Isfahan, Iran. The prevalence of COVID-19 in this city was 41,498 patients up to 13 June, 2020.[16]
Study design
This was a descriptive study in which 799 hospitalised patients with confirmed COVID-19 were selected. Our target hospital for this research was Khorsid hospital, Isfahan, Iran which was a referral centre for patients with COVID-19 infection.
This study was approved by the Ethical Committee of Isfahan University of Medical Sciences (IR.MUI.MED.REC.1399.598). Our inclusion criteria for this study was confirmed COVID-19 infection that caused patient hospitalisation. Previous history of vasculitis or any vascular collagen disease were considered as exclusion criteria. After giving relevant information, informed consent was obtained from all of the participants.
All of the demographic characteristics of the patients and some relevant clinical factors including sex, age, occupation, positivity of PCR test, percentage of lung involvement (low [10%–15%], moderate [15%–30%], severe [30%<]),[17] presence or absence of associated skin lesions (petechiae, purpura, acrocyanosis, maculopapular, erythema multiforme like lesions and vasculitis), the onset time of vasculitis, the type of medications prescribed (antivirals, antibiotics and steroid drugs), history of other illnesses such as nervous diseases (Dementia, Guillain–Barré Syndrome), heart diseases (ischemic heart disease [IHD]), hematocrit level, hypertension (HTN or HT), hyperlipidemia (HLP), hypothyroidism and diabetes mellitus (DM) were obtained and recorded.
Statistical analysis
Statistical tests including Chi-squared and cross-tab tests were used to analyse the collected data using Statistical Package for Social Sciences (SPSS) 22 software. P value < 0.05 was considered significant.
Results Subjects
A total of 799 patients (362 females and 437 males F:M =1/1.2), with positive polymerase chain reaction (PCR) test for COVID-19 were included in the study. The mean age of patients was 55.6 ± 15.8 years. The clinical factors of the patients are shown in [Table 1].
The most common skin manifestations of patients with moderate and severe COVID-19 infection were maculopapular rash, erythema-multiforme, Steven–Johonson and vasculitis that occurred following COVID-19. Out of 799 patients with COVID-19 infection, three patients (0.37%) had erythma_multiforme. Also, 24 patients (%3.08) (8 females and 16 males F:M = 1/2 with the mean age of 70.25 ± 12.49 years) had cutaneous vasculitis presenting with petechiae (20.8%), purpura (4.2%), livedoretcularis (4.2%) and acrocyanosis (20.8%) predominantly in the lower and upper trunk and lower limb.
Out of 24 patients with cutaneous vasculitis, 17 patients (70.83%) had severe pulmonary involvement, six patients (25%) had moderate pulmonary involvement and one patient (4.16%) had mild pulmonary involvement [Figure 1].
Figure 1: Various manifestations of the cutaneous vasculitis in COVID-19 evaluated patientsFurthermore, among vasculitis patients, five patients (20.8%) had maculopapular rash, one patient (4.2%) had Steven–Johonson and one patient (4.2%) had erythema-multiforme-like lesions.
All of the patients developed skin rash during hospitalisation and the mean duration between the onset of COVID-19 symptoms and development of cutaneous lesion manifestations was (14.2 ± 7.7) days. Also, mean duration of disease and hospitalisation of these patients was (20.7 ± 11.28) and (13.4 ± 8.8) days, respectively.
During hospitalisation, cutaneous vasculitis lesions markedly involved the sacral area of the patients and 18 patients showed sparing of the palms and soles. Oral cavity involvement was found in two patients.
Our results showed a significantly higher incidence of cutaneous vasculitis in men than in women (P < 0.04).
Out of 24 patients with cutaneous vasculitis, 13 patients were admitted to the ICU (54.2%) because of severe pulmonary symptoms and were treated with ACTEMRA® (tocilizumab).[9] out of these patients (40.9%) (3 females and 6 males) died due to infection severity. Other 11 patients received Remdesivir. In the meantime, 11 vasculitis patients (45.8%) with comorbidities were also treated with anti-diabetic, anti-hyperlipidemic and anti-hypertensive drugs or antibiotics.
Most of the patients with cutaneous vasculitis were also treated with systemic corticosteroids with resolution of skin lesions within 2–3 weeks.
Laboratory tests at the onset of skin lesions showed increased level of CRP, there was correlation between the mean of CRP and age, gender, duration of the disease, severity of lung involvement and mortality Also, there was correlation between age and duration of the disease, rate of lung involvement and mortality.
Discussion The possible effects of SARS-CoV-2 infection on the human physiology still is a lot unknown.[18] From the beginning of the COVID-19 so far, the report of cutaneous manifestations in patients with COVID-19 are increasing, as SARS-CoV-2 triggers an immunological process that leads to cutaneous vasculitis with various signs during different phases of disease.[19]
According to several case reports that previously identified a possible pathogenic role of COVID-19 in cutaneous vasculitis (Iraji,[11] Oghowan Abdelrahman,[10] Maria Camprodon Gómez,[12] Katrin Kösters,[13] S. Negrini[20] and Farhat Fatima,[14]) the results of our study also showed the significant relation between COVID-19 and cutaneous vasculitis in 24 COVID-19 patients.
In the current study, as we had already excluded patients with the previous history of vasculitis and collagen vascular diseases, we assumed that all of the vasculitis cases were induced by the COVID-19 virus.
Older people and those with comorbidity diseases are especially vulnerable, as numerous researchers reported that adult patients exhibiting COVID-19 cutaneous manifestations.[21] In the present study, there was an age-related increased frequency of vasculitis that possibly could be explained by the poly-pharmacy and higher prevalence of comorbidities such as diabetes, hypertension and cardiovascular diseases in the elderly population.
Furthermore, the impact of the COVID-19 pandemic will be amplified according to gender differences.[22] As in agreement to Channappanavar study,[23] in our study men were more frequently affected than females. Moreover, researches showed the relation between the incidence of COVID-19 and occupational exposure,[24],[25] but considerable percent of our cases were housewives or retired individuals.
Also, one of the heterogeneous factors in COVID-19 mortality is gender, as men are at higher risk than women, probably due to sex hormones like testosterone that are important in adapting the body's immune response and the presence of other risk factors, like diabetes, hypertension and cardiovascular diseases, that are affecting more men than women.[26] In consistent with our study, the rate of male sex mortality was more than female sex.
Some previous studies have proposed that COVID-19 infection are mainly asymptomatic before the onset of skin lesions[27] and that skin manifestations could present late in the COVID-19 course[27] or after its recovery[14]; however, the results of our study showed that patients may have a severe COVID-19 infection before the onset of skin lesions. In addition, our results revealed that skin manifestations could outbreak during of COVID-19. In addition, the mean interval between the onset of COVID infection and onset of cutaneous manifestation was less than Català et al.[28] study and all of our patients developed the skin rash during hospitalisation. Moreover, Iraji[11] and Manzo[29] also detected cutaneous vasculitis manifested in COVID-19 patients in the late phase of disease.
Furthermore, previous studies has suggested palpable purpura and erythematous papules as the main presentation[30]; however, we also found that many cases of vasculitis in the COVID.
Patients may present with erythema multiforme-like lesions, livedo reticularis and acrocyanosis. These erythema-multiforme lesions and Stevens–Johnson-like lesions could be due to the medications that have been used for treatment of the COVID-19 infection or the COVID-19 virus, itself.
Also, patients before COVID-19 had no clear systemic disease that causes cutaneous manifestations of vasculitis, and these cutaneous manifestations occurred following COVID-19. Therefore, the possibility of systemic disease that causes skin manifestations of vasculitis is eliminated; however, we did not find any case of systemic vasculitis in our patients.
Furthermore, the involvement of the nervous system by the SARS-CoV-2 was reported,[31] but none of our patients showed neurological symptoms or dementia secondary to cutaneous vasculitis. One of our COVID-19 patients with cutaneous vasculitis also developed Guillain–Barre' syndrome.
Conclusion Our study confirmed the development of the cutaneous vasculitis following COVID-19 infection, especially in male patients older than 70 years with severe involvement of the lung. Therefore, cutaneous vasculitis could be regarded as a prognostic factor in the patients with severe COVID-19 infection.
Ethical approval
Experimental protocols of this study were approved by the Institutional Research and Ethics Committee of Medical Sciences from the Isfahan University of Medical Science with the code number of (IR.MUI.MED.REC.1399.598).
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Author contribution
F.I contributed to the conception of the work, conducting the study, drafting and revising the draft and approval of the final version of the manuscript. F.M approved the final version of the manuscript. A.Z contributed to drafting and revising the draft, and approval of the final version of the manuscript. M.A contributed to writing and approval of the final version of the manuscript. SM.H analysed the data. N.O contributed to collecting data. N.S contributed to collecting data. F.S contributed to drafting and revising the draft. M.Gh contributed to drafting and revising the draft. A.S contributed to revising and approval of the final version of the manuscript. Sh.Sh contributed to revising and approval of the final version of the manuscript.
Financial support and sponsorship
This research was funded by the Research Vice-Presidency from Isfahan University of Medical Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflicts of interest
There are no conflicts of interest.
References 
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