Cutaneous manifestations and SARS-CoV-2 infection

Viruses are non-living microorganisms replicating only by the metabolic machinery of living organisms which become their host cells. They differ from bacteria, which are free-living cells that can live in or outside another organism, by being incapable of independent reproduction. Viruses contain genetic material, RNA or DNA, encased inside a protein coat/shell containing antigens specific for a given species [1].

Coronaviruses in humans are known to cause illness ranging from mild to severe respiratory infections, such as severe pneumonia leading to respiratory distress and potentially death. While they are recognized as the second most common group of causative agents of the common cold after rhinoviruses, within their family there have also emerged some highly infective and potentially lethal pathogens. The name of the coronavirus family was prompted by the characteristic appearance of their virion under the electron microscope, with spikes projecting from the surface, resembling a solar crown (corona) [1, 2, 3].

Coronavirus virions have a diameter of 8 to 160 nm and vary in shape. They contain a protein-binding RNA genome of approximately 27,000 to 30,000 bases. Glycoproteins located on the surface of the envelope resemble club-shaped projections. The glycoproteins enable survival in the gastrointestinal tract and transmission via the fecal-oral route. The virions contain glycoproteins E1(20,000 to 30,000 Da) and E2 (160,000 to 200,000 Da) and a core nucleoprotein (N[47,000 to 55,000 Da]) [2, 4].

The genome is shielded with a helical ribonucleoprotein (RNP) complex called nucleocapsid, facilitated by the function of highly phosphorylated nucleoprotein (N protein). Both in coronaviruses and togaviruses, proteins are synthesised in two phases [2, 4].

Emergence of new coronaviruses in humans has been periodically documented. Since 2002 waves of infections with novel pathogens such as SARS, MERS, and COVID-19 have occurred. In November 2002 there was a breakout of infections with a novel, highly contagious SARS-CoV virus, which began in China's Guangdong province. A total of 8,273 cases and 775 deaths were documented in the subsequent months. In 2003, the WHO declared the breakout contained due to the implementation of effective counteractive measures. Yet, it was followed by emergence of another zoonotic disease caused by a virus crossing the species barrier a mere 10 years later. This was MERS-CoV, originally diagnosed in a Saudi Arabian patient. Krzysztof Pyrć of the Microbiology Unit of the Biochemistry, Biophysics, and Biotechnology Department of the Jagiellonian University in Kraków reports the MERS mortality rate to have been 35%. By November 2014, the WHO had reported 897 cases, 325 of which were fatal [5].

Reviewing a currently much-discussed topic has required analysis of reliable sources complying with the guidelines and policies of evidence-based medicine (EBM). For this purpose, original papers and case reports available via PubMed as well as key relevant reports and guidelines by the World Health Organization have been accessed and analyzed. A total of 29 academic publications have been cited or referenced in our review, 21 of which directly report and/or discuss cutaneous manifestations associated with COVID-19. A brief outline of the characteristics of the coronavirus group has been provided, followed by an account of COVID-19 outbreak, pathogenesis and symptoms, description of reported cutaneous manifestations, and relevant discussion.

According to the WHO, the first official records of an infection breakout date back to December 2019, when the Wuhan Municipal Health Commission, China, confirmed a cluster of 27 cases of pneumonia of unknown etiology in the Chinese province of Hubei (Wuhan city). Since all the reported cases were linked to the local seafood market, suggesting a zoonotic origin, on January 1, 2020 the local authorities closed down Huanan Seafood Wholesale Market in Wuhan for disinfection. The first epidemiological report of January 20 documented the total number of cases to have been 44, between December 31, 2019, and January 3, 2020, and the virus was already spreading rapidly. By January 10, the Chinese authorities were able to identify the genome of a novel coronavirus, which had been isolated on January 7. By January 20, 2020, a total of 282 cases had been confirmed, over the following locations: China (278 cases), Thailand (2 cases), Japan (1 case), and South Korea (1 case). Also, the report of January 20 mentioned first cases of infection in medical staff [6].

To date, 433,139,235 confirmed cases have been noted globally, according to the WHO report of March 1, 2022, including 5,939,137 deaths. In Europe 177,622,681 confirmed cases and 1,867,028 deaths have been reported. In the Americas 146,848,490 cases and 2,626,396 deaths were confirmed by March 1. In the Eastern Mediterranean Region 21,124,902 cases, with 333,190 deaths were confirmed. In the Western Pacific Region there have been 23,542,040 cases and 181,193 deaths by March 1. In South-East Asia, 55,680,401cases and 761,642 deaths have been noted by the same date. In Africa there have been 8,319,957 cases and 169,702 deaths. The highest incidence in Europe has been reported in Germany (1,119,632 new cases; 1346,3 new cases per 100,000), the Russian Federation (920,697 new cases; 630,9 new cases per 100,000), and Turkey (541,259 new cases; 641,8 new cases per 100,000). European countries with high mortality rates have included Russian Federation (5427 new deaths; 3,7 new deaths per 100,000), Turkey (1838 new deaths; 2,2 new deaths per 100,000), and Italy (1568 new deaths; 2,6 new deaths per 100, 000) [7].

SARS-CoV-2 infection is primarily transmitted by respiratory droplets (aerosols) disseminated by coughing, sneezing, and talking [2]. Many cases are asymptomatic yet infectious, and thus pose a threat for elderly and chronically ill people they come in contact with. The systemic manifestations in COVID-19 patients include, primarily, fever (87.9%), unproductive cough (60.7%), malaise/fatigue (38.1%), shallow breathing (18.6%), myalgia and arthralgia (14.8%), sore throat (13.9%), headache (13.6%), and chills (11.4%). Some patients also present with conjunctivitis and diarrhea [3, 8].

In the incubation period, which lasts on average 4 to 7 days, the symptoms tend to be mild, exacerbating after 5 to 19 days, as the infection sets in. In 80% of cases, the symptoms subside with no hospitalization required. Approximately 1 in 5 patients with a confirmed case of SARS-CoV-2 infection has concomitant diseases, especially geriatric patients with hypertension, diabetes, and cardiovascular diseases. They are considered to be at a higher risk of complications. The most common complications of SARS-CoV-2 include acute respiratory distress syndrome (ARDS) (29%), developed on day 2 to 3, viremia (15%), acute myocardial injury (12%), as well as secondary bacterial infections [3].

Controlling the spread of a pathogen transmitted by respiratory droplets poses many challenges, especially considering the asymptomatic course of the disease in many patients. Strict 2-week isolation (quarantine) of travellers returning from areas with high incidence helps reduce the risk of transmission in a given population. Recommended safety measures include avoiding crowded places; physical distancing (keeping a 1-meter distance from others); practicing hand hygiene entailing frequent use of disinfectants or thorough hand washing with soap; avoiding touching one's eyes, mouth and nose; as well as use of face masks or shields in public settings [9].

SARS-CoV-2, a still novel and understudied virus, may cause numerous systemic but also dermatological manifestations, previously not classified. Skin findings in some patients may also represent cutaneous reactions to medication or may represent a post-viral process. Close surveillance of patients is becoming increasingly helpful in timely diagnosis. Case series from different countries have so far reported a range of potential cutaneous manifestations of SARS-CoV-2, including rashes; erythematous, urticarial, vesicular and vascular skin lesions; dyshidrotic eczema; petechiae; lesions resembling allergic eczema; urticaria; generalized papulopustular erythema; purpura, Steven-Johnson syndrome, as well as exacerbation of chronic skin conditions. According to a report by Krajewski et al., SARS-CoV-2 infection may also be associated with tactile hyperaesthesia [10].

Rodriguez-Cerdeira et al. documented 31 cases of COVID-19 with cutaneous manifestations from 5 countries, including Argentina, Dominican Republic, India, Mexico, and Spain. Based on the International Dermatological Registry, a case series was conducted in those countries for their study, documenting 29 patients with confirmed COVID-19 and 2 patients with previous contact with COVID-19-positive patients who showed a variety of cutaneous manifestations located predominantly on the trunk. The most common dermatological manifestations were maculopapular rashes (16.10%), urticarial lesions (26.80%), pseudochilblains (22.60%), petechiae/purpura (6.50%), and distal ischemia and necrosis (6.50%) [11].

Dermatological manifestations were identified in 20% of all Italian patients who had tested positive for COVID-19 studied to date. Their characteristics seemed to vary depending on the age group. Pediatric patients have predominantly been reported to present with chilblain-like lesions, livedoid eruptions, maculopapular rashes, and petechial lesions. In a cohort study by Rodriguez-Cerdeira et al., which also included also pediatric patients, a 1-year-old boy with COVID-19 presented with urticarial lesions with mucosal involvement, initially affecting the face and upper extremities but later spreading to the trunk and lower extremities. A 3-month-old girl, in turn, presented with generalized morbilliform rash (resembling measles) at birth, affecting the palms and soles. Following relevant blood tests, the patient was diagnosed with multisystem inflammatory syndrome in children (MIS-C). No mucosal involvement in the oral or nasal cavities was seen, however, as opposed to the 1-year-old boy with COVID-19 [11, 12, 13].

Casas et al., in turn, in their study found the following morphological patterns in COVID-19 patients: maculopapular eruptions (47%), pseudochilblains (19%), urticarial lesions (19%), vesicular eruptions (9%), and livedo or necrosis (6%) [14].

It should be duly noted that some of the skin abnormalities seen in COVID-19 patients may have only an indirect relationship to the viral agent. The actual classification of skin lesions in COVID-19 patients relies on histological findings, allowing differentiation of viral urticaria (hives) and similar lesions in dermoscopy, from a rash caused by SARS-CoV-2 [15, 16, 17, 18]. Histological analysis along with imaging and molecular tests enable a more tailored approach to and management of individual COVID-19 cases. Italian authors based in Lombardy have reported cutaneous involvement in the form of erythematous rash noted in 15.9% of the cases they studied, generalized urticaria in 3.4%, and chickenpox-like lesions in 1.4%. Furthermore, some patients presented with lesions visually suggestive of infections caused by the members of the Herpesviridae family [15, 17, 18].

When discussing cutaneous manifestations associated with COVID-19 it is only justified to also mention those experienced as a result of using protective measures against the infection. The group of patients most at risk of developing dermatological symptoms include medical staff, as well as those with concomitant cutaneous conditions and autoimmune diseases. According to Stefaniak et al., health care workers tend to be at risk of epidermal barrier dysfunction due to enhanced hand hygiene (use of disinfectants) and wearing protective gloves for a long time. One of the studies they cite is by Lan et al., who conducted a survey covering 52 health care professionals (physicians and nurses) working in isolation hospitals and fever clinics in Hubei province in China. The participants reported hand skin damage (74%) and itching (52%). Another study cited by Stefaniak et al. showed that 74.5% of studied health care workers reported cutaneous symptoms experienced due to hand washing and disinfecting. Even though in that study itch as a symptom was not accounted for, excessive skin dryness was reported (commonly associated with itch) by 68.6% of the respondents. Also, enhanced individual protection measures, including wearing scrubs, hazmat suits, face shields, goggles, and gloves led to overheating and sweating in the medical staff covered by the study, causing itch in 52.5% of the respondents. Individual protection measures used not only by health care workers but also patients with pre-existing cutaneous disorders may additionally lead to aggravation of conditions such as acne vulgaris, rosacea, seborrhoea, seborrhoeic dermatitis, atopic dermatitis, and psoriasis [19].

A study conducted by Krajewski et al. showed that wearing face masks may also cause itch. While the authors of that study admitted that itch may also accompany such cutaneous manifestations in COVID-19 as urticaria and erythematous rash, they concluded there was at the time a lack of sufficient data available to confirm this fully. Among their respondents, subjects with tendency for atopic skin, rosacea, and seborrhoeic dermatitis were more prone to itch associated with wearing face masks [20].

Szepietowski et al., conducting a study of 2315 respondents wearing medical and cloth face masks, showed that itch was more intense in participants using cloth masks. A majority of the respondents reported moderate itch (64.5%), and 30% reported itchiness of the face both while wearing the mask and after taking it off. Itch was described as tingling (37.4%), burning (26.3%), pinching (18.3%), and stinging (9.1%). In some cases, the respondents reported using topical emollients (53.2%), antihistamines (15.9%), and mild steroids to manage their symptoms [21].

Apart from flare-up of underlying dermatological conditions, COVID-19 patients are prone to developing cutaneous hypersensitivity and allergic response, potentially leading even to anaphylactic shock. It is currently difficult to ascertain the likelihood of such complications of SARS-CoV-2 infection, yet they must not be ruled out. Also, the infection may trigger a dermatologic condition affecting the function of the immune system. Concomitant autoimmune conditions, in turn, also tend to exacerbate the course of SARSCoV-2 infection, as they compromise the immune system. In such cases, the prevalence and severity of cutaneous manifestations tend to be greater, with the majority of them presenting as vesicular, urticarial, and petechial lesions [22, 23, 24, 25].

An important factor in the occurrence of skin manifestations is underlying chronic skin conditions such as psoriasis, compromising the patient's dermal and epidermal immunity and requiring continuous medication. According to Brownstone et al., psoriasis patients testing positive for COVID-19 should be advised to hold their biologic therapy until their infection clears. Treatment of psoriasis may be cautiously restarted approximately 30 days after resolution of respiratory symptoms and fever [16, 22].

There is also an increased risk for an allergic response to COVID-19 pharmacotherapy in psoriasis patients, as well as for an altered response to psoriasis medication previously used as a result of the viral infection. Thus, chronic conditions such as psoriasis must be managed with great caution. It should also be kept in mind that epidermal lesions may flare up due to SARS-CoV-2 infection; these, however, should not be considered direct cutaneous manifestations of the viral infection itself [16, 22, 24].

On the other hand, for patients with autoimmune diseases the discontinuance of immunosuppressive therapy may lead both to a flare-up of their underlying condition and a more severe course of the viral infection, resulting in exacerbated skin symptoms, especially vesicular lesions. Hence, special care must be taken in regard to prevention and management of COVID-19 infection in this group of patients. Recommendations regarding the medication of patients receiving immunomodulators involve temporarily discontinuing the use of azathioprine, mycophenolate mofetil/sodium, cyclophosphamide, methotrexate and cyclosporine for the duration of COVID-19 infection, while maintaining therapy with topical corticosteroids, sulphapyridine, doxycycline/tetracycline, colchicine, and IVIG.

No clinical studies–supported data are available to date regarding the impact of biologics in patients treated for COVID-19. The existing reports and case studies seem to indicate a possibility of complications due to an ongoing biologic therapy, postulating the prudence of discontinuing this type of treatment in patients infected with SARS-CoV-2 [16, 22, 23, 24, 26].

Di Altobrando et al. have suggested a possible molecular mimicry existing between viral and epidermal proteins, and over-activation of the immune system as a consequence of the viral attack, as the most probable and significant hypothesis in the case of autoimmune conditions. Thus, the formation of blisters in the dermal and epidermal layer could be considered an early symptom of SARS-CoV-2 infection, facilitating a prompt response to the presence of skin lesions as part of COVID-19 diagnosis in this group of patients [24].

According to Türsen et al., skin manifestations such as SARS-CoV-2-induced rash may be relied on as one of the criteria for differential diagnosis. For instance, the presence of an erythematous rash associated with cough, fever, and shortness of breath is sufficiently suggestive of COVID-19 in their opinion. Hence, identification of a full spectrum of dermatological manifestations may aid COVID-19 diagnosis. In their paper, they also speculate on emergence of COVID-19 vaccine-related skin eruptions in future years. The cutaneous symptoms they list include erythema nodosum, erythema multiforme, maculopapular rashes, localized scleroderma, and urticaria. Thus, they stress the importance of providing adequate dermatological care to COVID-19 patients to facilitate a better knowledge and understanding of the course and extent of complications related to the infection and potential vaccine-related skin responses [25].

There have been reports of isolated cases of SARSCoV-2 infection with a febrile non-pruritic erythematous and edematous rash involving the upper and lower limbs, chest, and stomach, without mucosal involvement, as the sole clinical manifestation of COVID-19. In a case study by Tammaro et al., after a histological examination of the lesions was performed, the patient was medicated with hydroxychloroquine sulfate for 10 days, resulting in recovery and a negative test for the presence of SARS-CoV-2 RNA upon completion of treatment. Such cases demonstrate the importance of dermatological diagnosis and the potential efficacy of well-established medications for management of COVID-19 symptoms [15, 17]. Van Damme et al., in turn, have reported urticaria lasting a few days as the first manifestation of COVID-19 infection. According to their report, the skin lesions are characteristic for an otherwise asymptomatic course of the infection, thus their presence should be taken into consideration when diagnosing for SARS-CoV-2 infection. Therefore, there is need for thorough dermatological examination of hospitalized patients. Identifying the prevalence of skin manifestations of COVID-19 could potentially lead to improved diagnosis of COVID-19 infections in the future [17, 18].

An article by Boscia, in turn, raises the crucial subject of preventing COVID-19 infections in neonates and infants and discusses the challenges associated with the varying guidelines regarding safety procedures during labor and in the postpartum period. Screening for cutaneous manifestations of COVID-19 improves the likelihood of timely diagnosis and implementation of relevant procedures to safeguard the mother and the infant against possible complications [27].

In their Letter to the Editor, Joob and Wiwanitkit have stressed the importance of educating the medical community about the fact that some otherwise asymptomatic patients may present with a skin rash as an early sign of SARSCoV-2 infection. Citing their own misdiagnosis in Thailand, they report a case of febrile rash misattributed to another condition common in that region (dengue fever). Hence, they have called for adopting a uniform approach, warranting consistent testing for SARS-CoV-2 whenever suspicious cutaneous symptoms occur [12, 28].

Young and Fernandez have pointed out that various skin abnormalities present in 19 out of 88 studied patients from Italy and in 2 out of 1099 patients from China may have been induced by numerous medications the patients received in the course of their treatment. While citing (among other things) the case of a 64-year-old female patient in France with COVID-19, who developed a rash consistent with symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) 4 days after becoming febrile, they admit having been unable to attribute it conclusively to any culprit factor. Another cited case in their study is a 68-year-old male COVID-19 patient who presented with a morbilliform rash on his trunk. Both cases seem to confirm the need to extend the diagnostics in COVID-19 patients to study closely and document the effect of various medications on the course of the infection to better determine the potential for and actual prevalence of medication-induced complications as opposed to actual COVID-19 manifestations [29].

In a study from Kuwait, 2 otherwise asymptomatic patients diagnosed with COVID-19 are reported as having perniosis-like acral lesions, while in the case of a 28-year-old woman described in a report from Spain, the patient developed pruritic erythematous papules specifically on her heels. It has been speculated that similar cutaneous eruptions may arise due to the presence of other disorders and may be mistakenly attributed to the novel coronavirus, or, alternatively, be the sole existing COVID-19 manifestation in young patients. Both hypotheses point to the need for thorough dermatologic and systemic differential diagnosis among COVID-19 patients [29].

In 9 studied patients who presented with classical COVID-19 symptoms such as high fever, malaise, and dry cough, 2 also had cutaneous manifestations, such as itchy eruptions, while in one of them an allergic reaction to acetominophen was considered possible [10].

To exclude or confirm the hypotheses put forward to date and discussed above, further studies in a larger group of patients are required to establish a comprehensive picture of possible cutaneous manifestations of SARS-CoV-2 infection, its possible cutaneous sequelae, as well as medication-induced cutaneous abnormalities related to its treatment [12, 15, 17, 18, 24, 25, 27, 28, 29].

COVID-19 disease causes a variety of systemic manifestations and is a potentially life-threatening condition. The data currently being collected will help better estimate survival and mortality rates for the disease. Due to its high infectivity, the spread of the novel coronavirus has now turned into a global pandemic. Certain similarities (the common presence of respiratory complications) and differences (SARS and MERS are far less infectious than SARS-CoV-2) have been established to exist between given pathogens from the coronavirus group. One of the clear differences between COVID-19 and infections with previous dangerous coronaviruses has been a lack of skin manifestations in the course of the latter (SARS/MERS). Considering the dynamics of COVID-19 transmission and its severity in some patients, it seems vital that any possible measures limiting its further spread be pursued. Also, timely diagnosis is of essence, as effective methods of COVID-19 management are still being investigated and searched for.

Multiple studies documenting the course of COVID-19 cases have reported the presence of cutaneous manifestations. The documented skin lesions include rashes, erythema, dyshidrotic eczema, petechiae, lesions resembling allergic eczema, urticaria, blistering, vascular lesions, as well as flare-ups of underlying skin conditions. Cutaneous eruptions seen in COVID-19 patients may be either directly associated with the viral agent, or have a completely distinct etiology. In light of the above discussion and the existing guidelines on prevention of infection and recommendations for treatment of skin manifestations in the course of COVID-19, histological analysis seems essential, allowing for differential diagnosis of the manifesting skin lesions. Management of autoimmune and chronic skin conditions in COVID-19 patients and in the setting of the COVID-19 epidemic comes with its own distinctive set of guidelines, as according to most researchers this group of patients may be particularly prone to the occurrence of skin abnormalities in the course of COVID-19, as well as being at risk of developing COVID-19 complications.

Direct conclusions arising from the above discussion comprise the importance of dermatological care in diagnosis and management of COVID-19 patients, the need for frequent and well-timed dermatological consultations for patients with chronic skin conditions and autoimmune diseases in the setting of the current COVID-19 pandemic, consistent inclusion of dermatological examination whenever COVID-19 is suspected, increased dermatological surveillance of patients medicated for COVID-19 and future vaccinations, as well as dermatological follow-up of recovered SARSCoV-2 cases. Doing so could eventually help guide diagnosis and facilitate a fuller understanding of COVID-19, proving potentially crucial for the diagnosis of otherwise asymptomatic cases and translating into increased survival rates. Ultimately, it could also lead to acquiring insight valuable for the development of a potential COVID-19 cure.