The list of post-Covid complications seems to be only increasing with doctors now saying that there has also been an increase in skin conditions like herpes, and joint pains in patients
What is causing joint issues?
There is about four-five per cent increase in arthritis cases post Covid-19 infection, said Dr Narendra Vaidya, joint replacement surgeon and managing director, Lokmanya Hospital Pune.
“During Covid, inflammatory molecules break muscle protein and decrease its synthesis causing muscle fatigue; this also damages cartilage, causing arthritis. Arthritis can also arise as sequele of steroid and antiviral drugs used to treat Covid-19. Musculoskeletal symptoms like stiffness of joints, muscle pain are commonly seen in post-Covid patients along with decreased muscle strength. Many people complain of joint and muscle pain, and have also come with new onset of autoimmune arthritis,” he said.
According to Dr Vaidya, patients complain of joint pain or arthralgia, muscle pain or myalgia, extreme fatigue, reactive arthritis, and vasculitis (inflammation of the blood vessels). “Joint pain can be temporary or continue for months,” he said.
One more reason to develop joint pain could be the overdose of steroids or a faster. This might develop osteonecrosis of bones, leading to faster degeneration and joint pains, said Dr Richa Kulkarni, chief consulting physiotherapist, KINESIS – Sports Rehab and Physiotherapy Clinic, Pune.
How to prevent and treat the condition?
People should seek good rehabilitative care, exercise every day, maintain good posture, and follow a healthy diet to manage joint and muscle pain, said Dr Vaidya.
What are the skin conditions?
Covid has induced many autoimmune and dormant infections in people with low immunity, such as herpes and warts. “Treatment with monoclonal anti–TNF alpha antibodies can cause herpes. Since the beginning of the pandemic, many people reported herpes, joint pain, and even warts. These problems are commonly seen in females when compared to males. People come with complaints like skin rash, redness, shingles around eyes nose, lips. These infections are common among senior citizens, and pregnant women. Herpes and other skin complications are getting triggered in patients who have a previous history. Do not ignore any signs like rashes, redness of the skin, and patches, seek immediate medical attention,” said Dr Vishwajeet Chavan, orthopedic surgeon, Apollo Spectra Pune.
Dr Saurabh Shah, dermatologist at Bhatia Hospital Mumbai has been seeing about one case of herpes zoster (covid related) every week. “The reason could be low immunity since Covid attacks the immune system of the body. Herpes Zoster (also known as shingles) virus (Varicella Zoster virus) is present in the body of almost every individual. When our immunity gets compromised or jeopardised, herpes zoster, which lies dormant in the body (dorsal nerve root ganglion), becomes active and flares up. Usually this skin infection is seen in patients with poorly controlled diabetes, patients with chronic renal failure, patients on chemotherapy, post medical and surgical illness and other diseases that compromise our immunity,” he explained.
There is also an uncanny increase in the incidence of urticaria in a lot of patients, said Dr Shah. “These rashes appear as itchy, red, evanescent raised areas on most parts of the body, usually after an infection (post-Covid). These invariably disappear in a few hours,” Dr Shah told indianexpress.com.
By: Lifestyle Desk | New Delhi | Updated: February 21, 2022 4:22:15 pm
The global pandemic COVID-19 has resulted in significant global morbidity, mortality and increased healthcare demands. There is now emerging evidence of patients experiencing urticaria. We sought to systematically review current evidence, critique the literature, and present our findings. Allowing PRISMA guidelines, a comprehensive literature search was carried out with Medline, EMBASE, Scopus, Cochrane, and Google Scholar, using key MeSH words, which include “COVID-19,” “Coronavirus,” “SARS-Cov-2,” “Urticaria,” “Angioedema,” and “Skin rash” up to 01 August 2020. The key inclusion criteria were articles that reported on urticaria and/or angioedema due to COVID-19 infection and reported management and outcome. Studies were excluded if no case or cohort outcomes were observed. Our search returned 169 articles, 25 of which met inclusion criteria. All studies were case reports, reporting 26 patients with urticaria and/or angioedema, COVID-19 infection and their management and/or response. ajority of patients (n = 16, 69%) were over 50 years old. However, urticaria in the younger ages was not uncommon, with reported case of 2 months old infant. Skin lesions resolved from less than 24 hours to up to 2 weeks following treatment with antihistamines and/or steroids. There have been no cases of recurrent urticaria or cases nonresponsive to steroids. Management of urticarial in COVID-19 patients should involve antihistamines. Low dose prednisolone should be considered on an individualized basis. Further research is required in understanding urticarial pathogenesis in COVID-19. This will aid early diagnostic assessment in patients with high index of suspicion and subsequent management in the acute phase.
The global pandemic COVID-19 is caused by severe acute respiratory syndrome coronavirus-2 (SARS-COV2). It has resulted in global morbidity, mortality and significantly increased healthcare demands.1, 2 It was originally reported that the main symptoms of COVID-19 to be a cough and fever. However, as the pandemic progressed, our understanding of COVID-19 increased, leading to anosmia and/or hyposmia established as a third symptom. As our understanding of this disease increases, it is reported that SARS-COV2 can present with clinical manifestations beyond the respiratory system. We are now aware that neurological manifestation can develop which encompasses acute skeletal muscle injury as well as an impaired consciousness.3 Additionally, severe infections can have an impact on renal and cardiac function.4
More recently, there has been a growing interest regarding the dermatological manifestations in patients with COVID-19. Skin manifestations during the course of a COVID-19 infection was first reported in China, however the prevalence was low at 0.2% cases out of 1099 cases.5 There is now emerging evidence in literature making reference to some patients experiencing urticaria. Urticaria manifests itself as urticarial plaques that affect the upper dermis which can cover the skin and mucous membranes. It is described as erythematous and pruritic, and can sometimes present with angioedema, a type of swelling of the dermis subcutaneous tissue, the mucosa, and submucosal tissues.6
The objective of this systematic review is to review the current literature on urticaria in COVID-19 patients. Furthermore, we aim to provide insight into urticarial pathogenesis and management in such patients.
2.1 Literature search
This study was done according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method identifying published literature on urticaria and/or angioedema due to COVID-19 infection and its management and outcomes. The comprehensive literature search was carried out with Medline, EMBASE, Scopus, Cochrane database, and Google Scholar, using key MeSH words, which include “COVID-19,” “Coronavirus,” “SARS-Cov-2,” “Urticaria,” “Angioedema,” and “Skin rash.” Manual cross checking of reference lists of relevant articles was performed. All published articles have been reviewed, and the findings have been included in this study. The relevant articles have been cited and referenced within this study. The limits included studies in English and articles published after December 2019 until 01 August 2020. All the relevant articles identified were analyzed by two authors, and the results were appropriately summarized and reported.
2.2 Inclusion and exclusion criteria
The key inclusion criteria were articles that reported on urticaria and/or angioedema due to COVID-19 infection and reported management and outcome, and studies were excluded if no case or cohort outcomes were observed. Other exclusion criteria were consensus documents, editorials, commentaries, and narrative reviews.
2.3 Data extraction
All studies were screened by two authors independently (E.A. and A.D); disagreement was resolved by consensus or involvement of other authors (R.S. and A.H.). The extracted data then were crosschecked by a third author to validate their accuracy (A.H.).
Following an extensive database search, 169 articles were identified. Of these, 34 were selected for full text review based on their title and abstract. Full text screening resulted in the final selection of 25 articles (Figure 1),7–26 reporting 26 patients with urticaria and/or angioedema and COVID-19 infection and their management plan and/or response to management. Table 1 includes the summarized key findings of the studies included in this review. All included articles were case reports.
TABLE 1. Management and response of patients with urticaria and/or angioedema during COVID-19 infection
Asymptomatic. 2 weeks after COVID-19 confirmed by RT-PCR
Not correlated with drugs (topical or systemic), bacterial or parasitic infections, inhalant exposure, or insect bites.Allergies such as allergic rhinitis, atopic dermatitis, and food allergy were not reported.
Laboratory findings were within the normal ranges.Betamethasone (soluble tablets, 0.5 mg/day for 7 days)
62-year-old current smoker man with diagnosed T4N2M1b G3 stage IV squamous cell lung carcinoma with pleuro-pulmonary involvement
Urticarial papular lesions, with marked itching and minimal erythema
Lower dorsal, lumbar and gluteal region
2 days after first reportingCOVID-19 symptoms. Two days before COVID-19 confirmed by RT-PCR
Vasculitis involving the superficial and deep dermis, with signs of microangiothrombosis, showing fibrinoid changes of vessel wall with some granulomas, neutrophilic infiltrate, and nuclear debris.
2 days after the last immunotherapy dose—ipilimumab (1 mg/kg every 6 weeks) plus nivolumab (3 mg/kg every 2 weeks)
Serial ferritin, D-Dimer (DD), and IL6 in addition to ANAS and C4, to discard differential diagnoses, were evaluated.Elevation of ferritin (940 ng/mL) and DD (2.600 ng/dL) was documented.Hydroxychloroquine (400 mg BID on day 1200 mg BID for 14 days).Azithromycin (500 mg day 1250 mg days 2–5)Methylprednisolone 1 mg/.kgEnoxaparin 40 mg SC/day
Within 14 days, dominant skin lesions disappeared, cough and chest CT-scan normalized.ANAS and complement C4 normalized, as were clotting times and fibrinogen. Serial evaluation of IL6 levels by ELISA only had a slightly elevated value of 246 pg/mL (range 6.25-200 pg/mL,) and throughout the 18-day follow-up period there was lymphopenia that became less evident
46-year-old female nurse with history of hay fever and mild asthma
Widespread urticarial eruption; red-raised blanching and itchy rash with angioedema of lips and hands
Face, arms, torso, legs, and loins
48 hours before developing COVID-19 symptoms.2 days before COVID-19 confirmed by RT-PCR
Not carried out
No prescribed regular medications no over-the-counter medications
Started fexofenadine hydrochloride 180 mg, two to four times per day.Rash worsened following day and was associated with angioedema.Advised to continue taking fexofenadine hydrochloride 180 mg four times per day and she was commenced on prednisolone 40 mg once daily for 3 days.Prednisolone helped lip and hand swelling, but rash remained itchy.Chlorphenamine maleate 4 mg four times/day was subsequently added.
The rash resolved completely over next few days. The patient made a full clinical recovery
Generalized urticaria with angioedema of face and neck
At same time as COVID-19 symptoms
Initial biochemical tests showed low numbers of white blood cells (WBC) (WBC = 2.75 × 103). Lymphopenia was detected (lymphocytes = 852).RT-PCR for COVID-19 was not performed. CT chest was carried out, which showed pneumonia with bilateral and subpleural areas of ground-glass opacification, consolidation affecting the lower lobes and confirming the diagnosis of COVID-19.
Elderly woman admitted to the hospital with bilateral pneumonia testing positive for COVID-19
Painful erythematous patches which left residual purpura when fading
Trunk, buttocks, and hips
> 5 days after first reporting COVID-19 symptoms
Histologic changes characteristic of small-vessel urticarial.Vasculitis: blood extravasation and neutrophilic perivascular inflammation with prominent karyorrhexis. There are some macrophages with a cytoplasm full of nuclear debris
Treatment with hydroxychloroquine, lopinavir/ritonavir, and azithromycin for 5 days
A sudden worsening of respiratory condition led to the patient’s death, and therefore, no treatment could be prescribed.
Middle-aged man with a 14-day history of fever, cough and anosmia
Erythematous and edematous plaques with active border and purpuric center
14 days after first reporting COVID-19 symptoms
Evidence of small-vessel damage: preserved epidermis with moderate perivascular neutrophilic inflammation and blood extravasation in the dermis. Endothelial swelling, necrosis and fibrin deposition
Therapy with hydroxychloroquine and azithromycin was started as treatment for COVID-19.Prednisone and antihistamines were administered for his skin condition.
51-year-old otherwise healthy woman with a 3-day history of dry cough and arthralgias
Widespread pruritic evanescent skin lesions (lasting <24 hours).Multiple well-demarcated erythematous edematous papules and plaques with diffuse underlying erythema
Trunk, thighs, upper limbs, and predominantly on the facial area and dorsal aspects of bilateral hands
3 days after first reported COVID-19 symptoms and confirmation of COVID-19 by RT-PCR
The patient had not taken any medication before the onset of the symptoms.No recent contact with plants, chemicals, or topical products. No urticarial lesions before, and no precipitating factors were found.Review of systems was negative for diarrhea, dysphagia, or other suggestive symptoms of anaphylaxis.
Blood test showed lymphopenia and elevated C-reactive protein (5.4 mg/L) and LDH (388 U/L). Chest radiography revealed bilateral pulmonary infiltrates.Treatment with loratadine 10 mg every 12 hours
Early improvement of pruritus and resolution of skin lesions within 2 days.The patient did not experience recurrent episodes of urticaria after 7 days of antihistaminic treatment.
12 days after admission, first reported COVID-19 symptoms and confirmation of COVID-19 by RT-PCR
Not carried out
Treatment included hydroxychloroquine, lopinavir/ritonavir, thymosin, and methylprednisolone.
A CT scan of the lung showed ground-glass changes.Treatment included hydroxychloroquine, lopinavir/ritonavir, thymosin, and methylprednisolone. (unclear which medications were started before/after development of urticaria—possible reaction to medication?)
65-year-old subfebrile (98.6 F) Wuhan woman had dry cough, fatigue and diarrhea (four times a day)
Disseminated, variable size, erythematous patches, which fade on pressure. Few patches were confluent.
1 day after admission
Not carried out
CT scan showed bilateral ground-glass changes.RT-PCR swabs did not detect SAR-Cov-2.Symptoms considered as unspecific viral rash due to COVID-19 and included as differential diagnosis a drug eruption due to the antineoplastic drug ruxolitinib.
Metformin and a combination of irbesartan and hydrochlorothiazide treatment for years due to diabetes mellitus and hypertension.No atopy in dermatological examination. Similar reaction occurred 9 years ago lasting a few weeks.
Detailed investigation including thorax computed tomography and testing coronavirus.Treated with hydroxychloroquine, azithromycin, and oseltamivir in intensive care unit for 7 days.As etiology of her diffuse urticaria, viral infection itself, drugs she received, and psychological stress of the clinical condition were considered.Cetirizine 10 mg twice a day.
Urticarial reaction was partially controlled on Cetirizine 10 mg twice a day
55-year-old woman admitted for pyrexia, dry cough, and dyspnea
Urticarial skin rash characterized by erythematous, smooth, slightly elevated papules and wheals, associated to severe pruritus.
3 days before admission and confirmation of COVID-19 by RT-PCR
No new medication before the rash appeared.The patient did not report neither similar episodes in the past, nor allergies to drugs or foods.
High-resolution computed tomography scan of the chest revealed a diffuse bilateral ground-glass opacity.Blood test revealed normal blood count (no lymphopenia or lymphocytosis or eosinophilia), slight increase of procalcitonin serum level (0.14 ng/mL), C-reactive protein (CRP, 12.1 mg/dL), and liver enzymes (GOT, GPT, LDH, GGT fourfold levels).A systemic treatment with intravenous daily administration of betamethasone sodium phosphate 4 mg and chlorphenamine maleate 10 mg, in addition to antiviral therapy with lopinavir/ritonavir for pneumonia
In the following days urticaria improved gradually.Twenty-five days after admission, patient was discharged.
64-year-old patient with acute respiratory distress syndrome (PaO2/FiO2 ≤ 100 mm Hg) caused by COVID-19
Skin rash was already present at the time of hospital admission
Treatment with lopinavir/ritonavir and hydroxychloroquine from 1 week, and no new drug introduction had been made in the last 3 weeks before skin rash development.No history of allergy to drugs or foods, nor recent intake of new drugs
Blood test revealed abnormal blood count with neutrophil leukocytosis (neutrophil granulocytes 8.600/mm3), and mild lymphopenia (lymphocytes 700/mm3), moderate increase of pro-calcitonin serum levels (0.87 ng/mL), marked increase of CRP (10.2 mg/dL), and liver enzymes (GOT, GPT, LDH, GGT fourfold levels) serum levels.Mechanical ventilation for respiratory failure.Intravenous administration of methylprednisolone 40 mg/die and bilastine 20 mg/die.
Skin rash is slightly improved after 48 hours from the beginning of the treatment.Patient in stable condition.
First episode: Painful erythematous-edematous plaques.Some lesions evolved into bruises.Second episode: Exuberant urticarial lesions. Light erythema and edema with intense itching
First episode: Flexor face of forearms and leg extensors|.Second episode: Exuberant urticarial lesions on shoulders. and inguinal region. Light erythema and edema on palms
First episode: 5 days after contact with COVID-19 ICU patient.Second episode: 2 days after second exposure with COVID-19 ICU patient. At same time as COVID-19 symptoms
First episode: Betamethasone cream 0.1% once a day.Second episode: Bilastine 20 mg one tablet a day for 15 days.Betamethasone ointment 0.1% cream once a day for 2 daysConfirmation of COVID-19 by RT-PCR.
First episode: lesion resolution in 3 days.Second episode: Within 48 hours, there were no more wheals and erythematous-edematous plaques appeared without itching in the antecubital and popliteal fossae.Lesions regressed after the use of betamethasone
On day 3 of hospitalization, after presenting with COVID-19 symptoms
History of hypertension, diabetes, dyslipidemia and hyperuricemia on therapy.No urticaria triggers other than viral infection were found, as there was no history of food allergy, drug allergy, chronic urticaria, or other allergies. There was no history of consuming new medicine in 15 days prior besides COVID-19 treatment in hospital.
Patient was treated with azithromycin, hydroxychloroquine, cefoperazone-sulbactam, omeprazole, and medicines for his comorbidities.Oral antihistamine loratadine was added to his treatment with improvement of symptom on the next day. The suspicion of urticaria caused by the medicines given in hospital could be eliminated by the fact his urticaria improved even the medicines continued to be given.
Rapidly spreading wheals.In a few hours, face wheals promptly converted to facial angioedema, with preferential involvement of periocular region and mild edema of the lips, without compromise of the tongue, uvula, vocal cords, or the airway.
Face, trunk, abdomen, and limbs
On day +11 of disease evolution, after resolution of previous COVID-19 symptoms
No relevant past medical history except for pine seeds allergy, following a strict nut-free diet since she was diagnosed.Family history of hereditary angioedema.Not on any medication.She had not taken nonsteroidal inflammatory drugs or angiotensin-converting enzyme inhibitors the previous 15 days.She had not exercised, had not drunk alcohol, nor was on menstrual period.
Oral antihistamine (ebastine 10 mg ter in die)
24 hours after the onset of the cutaneous symptoms, both the wheals and angioedema started to fade off, turning into erythematous macules until complete resolution.
37-year-old Caucasian woman, in her 10th postpartum day
Craniocaudal cutaneous manifestation characterized by erythematous maculopapular lesions
Trunk, neck, and face
3 days after first reporting COVID-19 symptoms
No signs of dyspnea, and the vital signs (including saturation) were all in normal range.A symptomatic treatment with only acetaminophen was prescribed seventh postpartum day prior development of rash.Breastfeeding has not been suspended.
After 8 days, the cutaneous lesions clearly improved along with improvement of the general symptoms and absence of fever and dry cough.The newborn did not show any symptom of the disease and did not develop any cutaneous lesion.
Erythematous, rash, edematous nonpruritic annular fixed plaques of various diameters
Upper limbs, chest, neck, abdomen and palms, sparing the face, and mucous membranes
At same time as COVID-19 symptoms
Histological findings were unspecific, consistent with viral exanthemata: superficial perivascular lymphocytic infiltrate, papillary dermal edema, mild spongiosis, lichenoid and vacuolar interface dermatitis, dyskeratotic basilar eratinocytes, occasional neutrophils but no eosinophils within the dermal infiltrate.
No relevant medical history.Taken no medications in the days and weeks prior to onset of symptoms
Oral hydroxychloroquine sulfate 200 mg three times per day for 10 days
No pulmonary symptoms developed.Rash fully recovered on day 6 of treatment
12 hours of slightly asymmetric, and nonpitting edema of cheeks and lips
Lip and facial swelling.He had no other sites of swelling and had no rash.
12 days before COVID-19 symptoms
Leukocytosis with relative lymphopenia and elevated high-sensitivity C-reactive protein and D-dimer. Functional C1 inhibitor levels (59.7 mg/dL), C3 levels (206 mg/dL), and C4 levels (46 mg/dL) were all elevated.Intravenous methylprednisolone, famotidine, and diphenhydramine. His lisinopril was held.
By hospital day 2, swelling markedly improved.Discharged home in stable condition.
The majority of patients (n = 16, 69%) were over 50 years old. However, urticaria in the younger ages was not uncommon, with reported case of 2 months old girl. Skin lesions were reported resolve from less than 24 hours to up to 2 weeks following treatment with antihistamines and/or steroids. There have been no cases of recurrent urticaria or cases nonresponsive to steroids.
4.1 Demographic of COVID-19 patients with urticaria development
The review population revealed that the majority of patients (18 patients) affected by urticaria were over 50 years old. However, urticaria in the younger ages was not uncommon. Typically, urticaria has a peak onset of 20-40 years and affects females more than males, which was found to be the case in this review. Lifetime incidence of urticaria is reported to be 15%.32 It has been reported that urticaria may be a rare manifestation of COVID-19, which has been observed in just under 4% of COVID-19 patients.33
Of note, most case reports have found skin manifestations to not be associated with disease severity33, 29 Conversely, a prospective Spanish cohort study reported that the presentation of urticaria and maculopapular skin lesions were associated with higher morbidity (severe COVID-19 illness) and higher mortality rate (2%).34 Further observational studies will aid further understanding of the association of COVID-19 disease progression and dermatological manifestations.
4.2 Pathophysiology of urticaria in COVID-19
The pathophysiology was previously hypothesized to be attributed to drug-induced urticaria. Urticaria is a well-known cutaneous manifestation of a drug eruption,35 however, urticaria has been debated in COVID-19 patients as to whether the virus directly results in urticaria, or if urticaria is caused by a drug eruption. There have been reports of COVID-19 positive cases with urticaria, where there had been no changes in their medication regime.26, 33 This may suggest that urticaria could be directly related to the pathogenesis of the SARS-CoV2. However, individual case reports have reported urticaria manifestation prior to commencement of therapy for COVID-19 as well as reports of remission from urticaria despite continuation of drug therapy.29 This suggests that urticaria in COVID-19 is likely multifactorial and drug-associated skin manifestations to not account for all cases.
SARS-CoV-2 entry into a cell is mediated through binding to angiotensin-converting enzyme-2 (ACE2) protein and subsequent endocytosis in epithelial targets in the lung.36 Of note, systemic response may be owed to the presentation of ACE2 on other tissues, including kidney, brain and importantly, the vasculature. Angiotensin (Ang) I and Ang II are deactivated by ACE2 Ang I and Ang II are associated with inflammation, oxidative stress and fibrotic scarring.37 In the instance of coronavirus infection, the binding of SARS-CoV-2 with ACE2 disrupts normal ACE2 activity. This may result in increased activity of Ang II, leading to formation of reactive oxygen species, disrupt antioxidant and vasodilatory molecules, and result in complement activation.38 Such disrupted physiological processes were observed in a rat model with aberrant expression of Ang II.39
COVID-19 associated skin manifestations may be mediated by the systemic inflammatory response that follows the human body’s response to an acute infection.40 This includes activation of the complement system and adjustment of the cytokine-chemokine milieu.10 Consequently, this progresses to aberrant activation and sequential degranulation of mast cells. It is hypothesized that mast cell degranulation is the principal pathophysiology associated with subsequent systemic organ damage in COVID-19.41 Of note, most patients with COVID-19 were reported to have elevated levels of circulating interleukin-6 (IL-6).42 Furthermore, colocalization of SARS-CoV-2 glycoproteins and respective complement mediators have been reported in peripheral cutaneous blood vessels.43 Therefore, it is possible that these mediators may be attributed to urticarial pathogenesis.
Urticaria has sometimes been associated with eosinophilia (>500 eosinophils/mm3), which has been observed in a number of COVID-19 cases.44 Moreover, eosinophilia seems to have a protective mechanism and has been associated with a better prognosis.45 There have also been some cases where patients initially presented with urticaria only before experiencing the typical COVID-19 symptoms and testing positive. What was evident in these cases was that they had been taking some form of prescribed medication prior to testing positive to COVID-19.46, 47 Despite some patients having no medication changes, they still were taking medication at the time of onset of urticaria, suggesting that COVID-19 may cause eosinophilia, resulting in drug hypersensitivity and thus urticaria. However, more research is needed to formally establish this relation.
4.3 Diagnosis assessment
It is important to ensure that urticaria is correctly diagnosed so that appropriate treatment can be administered. A diagnostic characteristic of urticaria is that the cutaneous lesions must be evanescent. Multiple case reports have not detailed this characteristic in their studies, so it is important this is taken into consideration. Furthermore, some case reports have mentioned how a skin biopsy for histopathological studies may aid in a diagnosis of urticaria.48 One case report has discussed that a skin biopsy of a COVID-19 patient with urticaria revealed perivascular infiltrate of lymphocytes, some eosinophils and upper dermal oedema.49 A skin biopsy and awareness of evanescent lesions may allow for the differentiation to be made between urticaria and other cutaneous manifestations, limiting the chance of a misdiagnosis.
On clinical assessment clinicians should consider the possibility of glucose-6-pyruvate dehydrogenase (G6PD) deficiency in COVID-19 patients as this group of patients may have a dominance of high-producing IL-6 allele. In one study group, this correlation has been reported in 71% of patients.50
4.4 Patient management
Classically, the recommended algorithm for treating urticaria includes the use of second-generation antihistamines, and if inadequate control within 2-4 weeks, the dose can be increased up to four times the original dose. If this is still inadequate control after a further 2-4 weeks, specialist referral should be considered, where specialists can consider prescribing omalizumab and ciclosporin to help alleviate symptoms.51 However, in most patients, second generation oral antihistamines provide adequate control of urticaria.52 The pathophysiology of COVID-19 related urticaria demonstrates that antihistamines alone will not stop mast cell histamine degranulation but will only act to reduce the severity of urticaria.
Low systemic steroids, on the other hand, target the COVID-19 inflammatory storm, which prevents mast cell activation, and thus histamine release. Therefore, low dose systemic steroids may be able to effectively manage urticaria in COVID-19 through their proposed mechanism of action. Combining this with antihistamines can improve patients’ clinical response to urticaria10. A further benefit of low dose steroids, shown through a randomized control trial, has demonstrated an increase in survival rate in COVID-19 patients (Randomized Evaluation of COVID-19 Therapy [RECOVERY], ClinicalTrials.gov Identifier: NCT04381936). Although corticosteroids are promising, it may increase the risk of prolonged viral replication, so it may be best to use them for the shortest duration possible until symptoms are controlled. After this, consideration should be made to promptly switch to omalizumab. Ciclosporin is currently not recommended in COVID-19 patients.52
All included articles were case. Only three case reports detailed pathological study results.9, 13, 28 A diagnostic characteristic of urticaria is that the cutaneous lesions must be evanescent (no one lesion should last more than 24 hours), however this was only noted by Falkenhain-López et al.14
Urticaria is a significant manifestation of COVID-19, notably affecting patient morbidity. As such the clinical presentation of urticaria can aid diagnostic assessment, while considering risk factors, such as G6PD deficiency and aberrant IL-6 expression. Management of COVID-19 patients should involve antihistamines. Low dose prednisolone should be considered on an individualized basis. Further research is required in understanding urticarial pathogenesis in COVID-19. This will aid early diagnostic assessment in patients with high index of suspicion and subsequent management in the acute phase.
Coronavirus disease-19 (COVID-19) is an ongoing global pandemic caused by the “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), which was isolated for the first time in Wuhan (China) in December 2019. Common symptoms include fever, cough, fatigue, dyspnea and hypogeusia/hyposmia. Among extrapulmonary signs associated with COVID-19, dermatological manifestations have been increasingly reported in the last few months.
The polymorphic nature of COVID-19-associated cutaneous manifestations led our group to propose a classification, which distinguishes the following six main clinical patterns: (i) urticarial rash, (ii) confluent erythematous/maculopapular/morbilliform rash, (iii) papulovesicular exanthem, (iv) chilblain-like acral pattern, (v) livedo reticularis/racemosa-like pattern, (vi) purpuric “vasculitic” pattern. This review summarizes the current knowledge on COVID-19-associated cutaneous manifestations, focusing on clinical features and therapeutic management of each category and attempting to give an overview of the hypothesized pathophysiological mechanisms of these conditions.Keywords: COVID-19, Cutaneous manifestations, SARS-CoV-2Go to:
In December 2019, a novel zoonotic RNA virus named “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2) was isolated in patients with pneumonia in Wuhan, China. Since then, the disease caused by this virus, called “coronavirus disease-19” (COVID-19), has spread throughout the world at a staggering speed becoming a pandemic emergency . Although COVID-19 is best known for causing fever and respiratory symptoms, it has been reported to be associated also with different extrapulmonary manifestations, including dermatological signs . Whilst the COVID-19-associated cutaneous manifestations have been increasingly reported, their exact incidence has yet to be estimated, their pathophysiological mechanisms are largely unknown, and the role, direct or indirect, of SARS-CoV-2 in their pathogenesis is still debated. Furthermore, evidence is accumulating that skin manifestations associated with COVID-19 are extremely polymorphic . In this regard, our group proposed the following six main clinical patterns of COVID-19-associated cutaneous manifestations in a recently published review article: (i) urticarial rash, (ii) confluent erythematous/maculopapular/morbilliform rash, (iii) papulovesicular exanthem, (iv) chilblain-like acral pattern, (v) livedo reticularis/racemosa-like pattern, (vi) purpuric “vasculitic” pattern (shown in Fig. Fig.1)1) . Other authors have attempted to bring clarity in this field, suggesting possible classifications of COVID-19-associated cutaneous manifestations [4, 5, 6]. Finally, distinguishing nosological entities “truly” associated with COVID-19 from cutaneous drug reactions or exanthems due to viruses other than SARS-CoV-2 remains a frequent open problem.
Clinical features of COVID-19-associated cutaneous manifestations.
Herein, we have striven to provide a comprehensive overview of the cutaneous manifestations associated with COVID-19 subdivided according to the classification by Marzano et al. , focusing on clinical features, histopathological features, hypothesized pathophysiological mechanisms and therapeutic management.Go to:
Clinical Features and Association with COVID-19 Severity
It is well known that urticaria and angioedema can be triggered by viral and bacterial agents, such as cytomegalovirus, herpesvirus, and Epstein-Barr virus and mycoplasma. However, establishing a cause-effect relationship may be difficult in single cases [7, 8]. Urticarial eruptions associated with COVID-19 have been first reported by Recalcati  in his cohort of hospitalized patients, accounting for 16.7% of total skin manifestations. Urticaria-like eruptions have been subsequently described in other cohort studies. Galván Casas et al.  stated that urticarial rash occurred in 19% of their cohort, tended to appear simultaneously with systemic symptoms, lasted approximately 1 week and was associated with medium-high severity of COVID-19. Moreover, itch was almost always present . Freeman et al.  found a similar prevalence of urticaria (16%) in their series of 716 cases, in which urticarial lesions predominantly involved the trunk and limbs, relatively sparing the acral sites. As shown in Table Table1,1, urticaria-like signs accounted for 11.9% of cutaneous manifestations seen in an Italian multicentric cohort study on 159 patients [unpubl. data]. Urticarial lesions associated with fever were reported to be early or even prodromal signs of COVID-19, in the absence of respiratory symptoms, in 3 patients [11, 12, 13]. Therefore, the authors of the reports suggested that isolation is needed for patients developing such skin symptoms if COVID-19 infection is suspected in order to prevent possible SARS-CoV-2 transmission [11, 12, 13]. COVID-19-related urticaria occurred also in a familial cluster, involving 2 patients belonging to a Mexican family of 5 people, all infected by SARS-CoV-2 and suffering also from anosmia, ageusia, chills and dizziness . Angioedema may accompany COVID-19-related urticaria, as evidenced by the case published in June 2020 of an elderly man presenting with urticaria, angioedema, general malaise, fatigue, fever and pharyngodynia . Urticarial vasculitis has also been described in association with COVID-19 in 2 patients .
Prevalence of different clinical patterns in the main studies on COVID-19-associated cutaneous manifestations
First author (total size of study population)
Number of patients with urticarial rash (%)
Number of patients with confluent erythematous/maculopapular/morbilliform rash (%)
Number of patients with papulo-vesicular exanthem (%)
Number of patients with chilblain-like acral pattern (%)
Number of patients with livedo reticularis/racemosa-like pattern (%)
Number of patients with purpuric “vasculitic” pattern (%)
Histopathological studies of urticarial rashes are scant. In a 60-year-old woman with persistent urticarial eruption and interstitial pneumonia who was not under any medication, Rodriguez-Jiménez et al.  found on histopathology slight vacuolar interface dermatitis with occasional necrotic keratinocytes curiously compatible with an erythema multiforme-like pattern. Amatore et al.  documented also the presence of lichenoid and vacuolar interface dermatitis, associated with mild spongiosis, dyskeratotic basal keratinocytes and superficial perivascular lymphocytic infiltrate, in a biopsy of urticarial eruption associated with COVID-19 (Fig. (Fig.22).
Histopathological features of the main cutaneous patterns associated with COVID-19. a Urticarial rash. b Confluent erythematous maculopapular/morbilliform rash. c Chilblain-like acral lesions. d Purpuric “vasculitic” pattern.
Shanshal  suggested low-dose systemic corticosteroids as a therapeutic option for COVID-19-associated urticarial rash. Indeed, the author hypothesized that low-dose systemic corticosteroids, combined with nonsedating antihistamines, can help in managing the hyperactivity of the immune system in COVID-19, not only to control urticaria, but also to improve possibly the survival rate in COVID-19.Go to:
Clinical Features and Association with COVID-19 Severity
Maculopapular eruptions accounted for 47% of all cutaneous manifestations in the cohort of Galván Casas et al. , for 44% of the skin manifestations included in the study by Freeman et al. , who further subdivided this group of cutaneous lesions into macular erythema (13%), morbilliform exanthems (22%) and papulosquamous lesions (9%), and for 30.2% of the cutaneous manifestations included in the unpublished Italian multicentric study shown in Table Table1.1. The prevalence of erythematous rash was higher in other studies, like that published by De Giorgi et al.  in May 2020, in which erythematous rashes accounted for 70% of total skin manifestations. In the series by Freeman et al. , macular erythema, morbilliform exanthems and papulosquamous lesions were predominantly localized on the trunk and limbs, being associated with pruritus in most cases. In the same series, these lesions occurred more frequently after COVID-19 systemic symptoms’ onset . The clinical picture of the eruptions belonging to this group may range from erythematous confluent rashes to maculopapular eruptions and morbilliform exanthems. Erythematous lesions may show a purpuric evolution  or coexist from the beginning with purpuric lesions . Erythematous papules may also be arranged in a morbilliform pattern . In a subanalysis of the COVID-Piel Study  on maculopapular eruptions including also purpuric, erythema multiforme-like, pityriasis rosea-like, erythema elevatum diutinum-like and perifollicular eruptions, morbilliform exanthems were the most frequent maculopapular pattern (n = 80/176, 45.5%) . This study showed that in most cases lesions were generalized, symmetrical and started on the trunk with centrifugal progression. In the same subanalysis, hospital admission due to pneumonia was very frequent (80%) in patients with a morbilliform pattern . In this group, the main differential diagnoses are represented by exanthems due to viruses other than SARS-CoV-2 and drug-induced cutaneous reactions.
Histopathology of erythematous eruptions was described by Gianotti et al. , who found vascular damage in all the 3 cases examined. A clinicopathological characterization of late-onset maculopapular eruptions related to COVID-19 was provided also by Reymundo et al. , who observed a mild superficial perivascular lymphocytic infiltrate on the histology of 4 patients. In contrast, Herrero-Moyano et al.  observed dense neutrophilic infiltrates in 8 patients with late maculopapular eruptions. The authors of the former study postulated that this discrepancy could be attributable to the history of new drug assumptions in the series of Herrero-Moyano et al.  (Fig. (Fig.22).
The management of confluent erythematous/maculopapular/morbilliform rash varies according to the severity of the clinical picture. Topical corticosteroids can be sufficient in most cases , systemic corticosteroids deserving to be administered just in more severe and widespread presentations.Go to:
Clinical Features and Association with COVID-19 Severity
COVID-19-associated papulovesicular exanthem was first extensively reported in a multicenter Italian case series of 22 patients published in April 2020 . In this article, it was originally described as “varicella-like” due to resemblance of its elementary lesions to those of varicella. However, the authors themselves underlined that the main clinical features of COVID-19-associated papulovesicular exanthem, namely trunk involvement, scattered distribution and mild/absent pruritus, differentiated it from “true” varicella. In this study, skin lesions appeared on average 3 days after systemic symptoms’ onset and healed after 8 days, without scarring sequelae . The exact prevalence of papulovesicular exanthems is variable. Indeed, in a cohort of 375 patients with COVID-19-associated cutaneous manifestations , patients with papulovesicular exanthem were 34 (9%), while they were 3 out of 52 (5.8%), 1 out of 18 (5.5%) and 2 out of 53 (4%) in the cohorts published by Askin et al. , Recalcati  and De Giorgi et al. , respectively. In the Italian multicentric study shown in Table Table1,1, papulovesicular rash accounted for 18.2% of skin manifestations. Furthermore, even if papulovesicular exanthem tends to involve more frequently the adult population, with a median age of 60 years in the study by Marzano et al. , also children may be affected . Galván Casas et al.  reported that vesicular lesions generally involved middle-aged patients, before systemic symptoms’ onset in 15% of cases, and were associated with intermediate COVID-19 severity. Fernandez-Nieto et al.  conducted a prospective study on 24 patients diagnosed with COVID-19-associated vesicular rash. In this cohort, the median age (40.5 years) was lower than that reported by Marzano et al. , and COVID-19 severity was mostly mild or intermediate, with only 1 patient requiring intensive unit care support. In our cohort of 22 patients, a patient was hospitalized in the intensive care unit and 3 patients died . Vesicular rash, which was generally pruritic, appeared after COVID-19 diagnosis in most patients (n = 19; 79.2%), with a median latency time of 14 days . Two different morphological patterns were found: a widespread polymorphic pattern, more common and consisting of small papules, vesicles and pustules of different sizes, and a localized pattern, less frequent and consisting of monomorphic lesions, usually involving the mid chest/upper abdominal region or the back .
Mahé et al.  reported on 3 patients with typical COVID-19-associated papulovesicular rash, in which the histological pattern of skin lesions showed prominent acantholysis and dyskeratosis associated with the presence of an unilocular intraepidermal vesicle in a suprabasal location. Based on these histopathological findings, the authors refused the term “varicella-like rash” and proposed a term which was more suitable in their view: “COVID-19-associated acantholytic rash.” Histopathological findings of another case of papulovesicular eruption revealed extensive epidermal necrosis with acantholysis and swelling of keratinocytes, ballooning degeneration of keratinocytes and signs of endotheliitis in the dermal vessels . Acantholysis and ballooned keratinocytes were found also by Fernandez-Nieto et al.  in 2 patients.
The differential diagnosis with infections caused by members of the Herpesviridae family has been much debated. Tammaro et al.  described the onset of numerous, isolated vesicles on the back 8 days after COVID-19 diagnosis in a Barcelonan woman and reported on 2 patients from Rome presenting with isolated, mildly pruritic erythematous-vesicular lesions on their trunk, speculating that these manifestations might be due to viruses belonging to the Herpesviridae family. On the other hand, classic herpes zoster has been reported to complicate the course of COVID-19 .
The controversy regarding the role of herpesvirus in the etiology of papulovesicular exanthems fuelled an intense scientific debate. Indeed, some authors raised the question whether papulovesicular exanthem associated with COVID-19 could be diagnosed without ruling out varicella zoster virus and herpes simplex virus with Tzanck smear or polymerase chain reaction (PCR) for the Herpesviridae family in the vesicle fluid or on the skin [36, 37]. In our opinion, even if seeking DNA of Herpesviridae family members is ideally advisable, clinical diagnosis may be reliable in most cases, and the role of herpes viruses as mere superinfection in patients with dysfunctional immune response associated with COVID-19 needs to be considered . To our knowledge, SARS-CoV-2 has not been hitherto isolated by means of reverse transcriptase PCR in the vesicle fluid of papulovesicular rash [33, 31].
No standardized treatments for COVID-19-related papulovesicular exanthem are available, also given that it is self-healing within a short time frame. Thus, a “wait-and-see” strategy may be recommended.Go to:
Chilblain-Like Acral Pattern
Clinical Features and Association with COVID-19 Severity
COVID-19-related chilblain-like acral lesions have been first described in a 13-year-old boy by Italian authors in early March . Since then, several “outbreaks” of chilblain-like acral lesions chiefly involving young adults and children from different countries worldwide have been posted on social media and published in the scientific literature [40, 41, 42, 43, 44, 45, 46]. Caucasians seem to be significantly more affected than other ethnic groups [47, 48]. Chilblain-like acral lesions were the second most frequent cutaneous manifestation (n = 46/159; 28.9%) in the multicenter Italian study shown in Table Table1.1. Different pathogenetic hypotheses, including increased interferon release induced by COVID-19 and consequent cytokine-mediated inflammatory response, have been suggested . Furthermore, virus-induced endothelial damage as well as an obliterative microangiopathy and coagulation abnormalities could be mechanisms involved in the pathogenesis of these lesions . Chilblain-like acral lesions associated with COVID-19 were depicted as erythematous-violaceous patches or plaques predominantly involving the feet and, to a lesser extent, hands [40, 51]. Rare cases of chilblain-like lesions involving other acral sites, such as the auricular region, were also reported . The occurrence of blistering lesions varied according to the case series analyzed; Piccolo et al. , indeed, reported the presence of blistering lesions in 23 out of 54 patients, while other authors did not describe bullous lesions in their series [40, 47]. Dermoscopy of these lesions revealed the presence of an indicative pattern represented by a red background area with purpuric globules . Pain/burning sensation as well as pruritus were commonly reported symptoms, even if a small proportion of patients presented with asymptomatic lesions [40, 44, 47]. Unlike other COVID-19-related cutaneous findings, chilblain-like acral lesions tended to mostly involve patients without systemic symptoms.
The frequent occurrence of chilblain-like lesions in the absence of cold exposure and the involvement of patients without evident COVID-19-related symptoms raised the question whether these manifestations were actually associated with SARS-CoV-2 infection.
Histopathological and Pathophysiological Findings
Chilblain-like lesions share many histopathological features with idiopathic and autoimmunity-related chilblains, including epidermal necrotic keratinocytes, dermal edema, perivascular and perieccrine sweat gland lymphocytic inflammation. Vascular changes such as endotheliitis and microthrombi may be found [40, 45, 54, 55] (Fig. (Fig.22).
Data on the real association between chilblain-like acral lesions and COVID-19 are controversial.
The first case series failed to perform SARS-CoV-2 testing in all patients, also due to logistic problems and economic restrictions, and diagnosed COVID-19 only in a minority of patients with chilblain-like acral lesions [40, 44, 47]. Subsequently, some authors systematically sought SARS-CoV-2 with serology and/or nasopharyngeal swab in patients with chilblain-like acral lesions. In their cohort of 38 children with pseudo-chilblain, Caselli et al.  showed no evidence of SARS-CoV-2 infection by PCR or serology. Chilblain-like acral lesions appeared not to be directly associated with COVID-19 also in the case series by Herman et al. . These authors failed to detect SARS-CoV-2 in nasopharyngeal swabs and skin biopsies and demonstrated no specific anti-SARS-CoV-2 immunoglobulin IgM or IgG antibodies in blood samples. Therefore, they concluded that lifestyle changes associated with lockdown measures might be a possible explanation for these lesions . Similar results were obtained also by other authors [58, 59, 60, 61, 62, 63] weakening the hypothesis of a direct etiological link between SARS-CoV-2 and chilblain-like acral lesions.
Opposite conclusions have been drawn by Colmenero et al. , who demonstrated by immunohistochemistry and electron microscopy the presence of SARS-CoV-2 in endothelial cells of skin biopsies of 7 children with chilblain-like acral lesions, suggesting that virus-induced vascular damage and secondary ischemia could explain the pathophysiology of these lesions.
In the absence of definitive data on chilblain-like acral lesions’ pathogenesis, the occurrence of such lesions should prompt self-isolation and confirmatory testing for SARS-CoV-2 infection .
In the absence of significant therapeutic options for chilblain-like acral lesions associated with COVID-19 and given their tendency to spontaneously heal, a “wait-and-see” strategy may be suggested.Go to:
Livedo Reticularis/Racemosa-Like Pattern
Clinical Features and Association with COVID-19 Severity
Livedo describes a reticulate pattern of slow blood flow, with consequent desaturation of blood and bluish cutaneous discoloration. It has been divided into: (i) livedo reticularis, which develops as tight, symmetrical, lace-like, dusky patches forming complete rings surrounding a pale center, generally associated with cold-induced cutaneous vasoconstriction or vascular flow disturbances such as seen in polycythemia and (ii) livedo racemosa, characterized by larger, irregular and asymmetrical rings than seen in livedo reticularis, more frequently associated with focal impairment of blood flow, as it can be seen in Sneddon’s syndrome .
In our classification, the livedo reticularis/racemosa-like pattern has been distinguished by the purpuric “vasculitic” pattern because the former likely recognizes a occlusive/microthrombotic vasculopathic etiology, while the latter can be more likely considered the expression of a “true” vasculitic process . Instead, the classification by Galván Casas et al.  merged these two patterns into the category “livedo/necrosis”.
In a French study on vascular lesions associated with COVID-19, livedo was observed in 1 out of 7 patients . In the large cases series of 716 patients by Freeman et al. , livedo reticularis-like lesions, retiform purpura and livedo racemosa-like lesions accounted for 3.5, 2.6 and 0.6% of all cutaneous manifestations, respectively. In the multicentric Italian study, livedo reticularis/racemosa-like lesions accounted for 2.5% of cutaneous manifestations (Table (Table11).
The pathogenic mechanisms at the basis of small blood vessel occlusion are yet unknown, even if neurogenic, microthrombotic or immune complex-mediated etiologies have been postulated .
Livedo reticularis-like lesions are frequently mild, transient and not associated with thromboembolic complications [68, 69]. On the contrary, livedo racemosa-like lesions and retiform purpura have often been described in patients with severe coagulopathy [60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72].
Histopathological and Pathophysiological Findings
The histopathology of livedoid lesions associated with COVID-19 has been described by Magro et al. , who observed in 3 patients pauci-inflammatory microthrombotic vasculopathy. The same group demonstrated that in the thrombotic retiform purpura of patients with severe COVID-19, the vascular thrombosis in the skin and internal organs is associated with a minimal interferon response permitting increased viral replication with release of viral proteins that localize to the endothelium inducing widespread complement activation , which is frequent in COVID-19 patients and probably involved in the pathophysiology of its clinical complications .
In view of the absence of significant therapeutic options for livedo reticularis/racemosa-like lesions associated with COVID-19, a “wait-and-see” strategy may be suggested.Go to:
Purpuric “Vasculitic” Pattern
Clinical Features and Association with COVID-19 Severity
The first COVID-19-associated cutaneous manifestation with purpuric features was reported by Joob et al. , who described a petechial rash misdiagnosed as dengue in a COVID-19 patient. Purpuric lesions have been suggested to occur more frequently in elderly patients with severe COVID-19, likely representing the cutaneous manifestations associated with the highest rate of COVID-19-related mortality . This hypothesis is corroborated by the unfavorable prognosis observed in several cases reported in the literature [77, 78].
The purpuric pattern reflects the presence of vasculitic changes probably due to the direct damage of endothelial cells by the virus or dysregulated host inflammatory responses induced by COVID-19.
These lesions are likely to be very rare, representing 8.2% of skin manifestations included in the Italian multicentric study shown in Table Table1.1. In their case series of 7 patients with vascular skin lesions related to COVID-19, Bouaziz et al.  reported 2 patients with purpuric lesions with (n = 1) and without (n = 1) necrosis. In the series by Freeman et al. , 12/716 (1.8%) and 11/716 (1.6%) cases of patients with palpable purpura and dengue-like eruption, respectively, have been reported. Galván Casas et al.  reported 21 patients with “livedo/necrosis,” most of whom presenting cutaneous signs in concomitance with systemic symptoms’ onset.
Purpuric lesions may be generalized , localized in the intertriginous regions  or arranged in an acral distribution . Vasculitic lesions may evolve into hemorrhagic blisters . In most severe cases, extensive acute necrosis and association with severe coagulopathy may be seen . Dermoscopy of purpuric lesions revealed the presence of papules with incomplete violaceous rim and a central yellow globule .
When performed, histopathology of skin lesions showed leukocytoclastic vasculitis [77, 79], severe neutrophilic infiltrate within the small vessel walls and in their proximity , intense lymphocytic perivascular infiltrates , presence of fibrin [79, 81] and endothelial swelling  (Fig. (Fig.22).
Topical corticosteroids have been successfully used for treating mild cases of purpuric lesions . Cases with necrotic-ulcerative lesions and widespread presentation may be treated with systemic corticosteroids.Go to:
Other COVID-19-Associated Cutaneous Manifestations
Other peculiar rare COVID-19-related cutaneous manifestations that cannot be pigeonholed in the classification proposed by our group  include, among others, the erythema multiforme-like eruption , pityriasis rosea-like rash , multi-system inflammatory syndrome in children , anagen effluvium  and a pseudoherpetic variant of Grover disease . However, the spectrum of possible COVID-19-associated skin manifestations is likely to be still incomplete, and it is expected that new entities associated with this infection will be described.Go to:
COVID-19-associated cutaneous manifestations have been increasingly reported in the last few months, garnering attention both from the international scientific community and from the media. A few months after the outbreak of the pandemic, many narrative and systematic reviews concerning the dermatological manifestations of COVID-19 have been published [2, 3, 6, 88, 89, 90, 91]. A summary of clinical features, histopathological findings, severity of COVID-19 systemic symptoms and therapeutic options of COVID-19-related skin manifestations has been provided in Table Table22.
Summary of clinical features, histopathological findings, severity of COVID-19 systemic symptoms and therapeutic options of COVID-19-related skin manifestations
Itching urticarial rash predominantly involving the trunk and limbs; angioedema may also rarely occur
Vacuolar interface dermatitis associated with superficial perivascular lymphocytic infiltrate
Low-dose systemic corticosteroids combined with nonsedating antihistamines
Topical corticosteroids for mild cases; systemic corticosteroids for severe cases
(i) Widespread polymorphic pattern consisting of small papules, vesicles and pustules of different sizes; (ii) localized pattern consisting of papulovesicular lesions, usually involving the mid chest/upper abdominal region or the back
Prominent acantholysis and dyskeratosis associated with unilocular intraepidermal vesicles in a suprabasal location
Wait and see
Chilblain-like acral pattern
Erythematous-violaceous patches or plaques predominantly involving the feet or, to a lesser extent, hands. Pain/burning sensation as well as pruritus were commonly reported symptoms
Perivascular and periadnexal dermal lymphocytic infiltrates
Wait and see
Livedo reticularis/racemosa-like pattern
Livedo reticularis-like lesions: mild, transient, symmetrical, lace-like, dusky patches forming complete rings surrounding a pale center. Livedo racemosa-like lesions: large, irregular and asymmetrical violaceous annular lesions frequently described in patients with severe coagulopathy
Livedo reticularis-like lesions: intermediate severity; livedo racemosa-like lesions: high severity
Pauci-inflammatory microthrombotic vasculopathy
Wait and see
Purpuric “vasculitic” pattern
Purpuric lesions may be generalized, arranged in an acral distribution or localized in the intertriginous regions. Purpuric elements may evolve into hemorrhagic blisters, possibly leading to necrotic-ulcerative lesions
Leukocytoclastic vasculitis, severe perivascular neutrophilic and lymphocytic infiltrate, presence of fibrin and endothelial swelling
Topical corticosteroids for mild cases; systemic corticosteroids for severe cases
The correlation between severity of COVID-19 systemic symptoms and skin manifestations has been inferred mainly from the study by Freeman et al. .
Albeit several hypotheses on pathophysiological mechanisms at the basis of these skin findings are present in the literature [50, 92, 93], none of them is substantiated by strong evidence, and this field needs to be largely elucidated. Moreover, cutaneous eruptions due to viruses other than SARS-CoV-2 [35, 37] or drugs prescribed for the management of this infection [94, 95] always need to be ruled out.
Experimental pathophysiological studies and clinical data derived from large case series are still needed for shedding light onto this novel, underexplored and fascinating topic.
Although COVID-19-associated cutaneous manifestations have been increasingly reported, their pathophysiological mechanisms need to be extensively explored. The conditions may be distinguished in six clinical phenotypes, each showing different histopathological patterns.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.:
This paper did not receive any funding.
Giovanni Genovese wrote the paper with the contribution of Chiara Moltrasio. Angelo Valerio Marzano and Emilio Berti supervised the work and revised the paper for critical revision of important intellectual content.Go to:
We would like to thank Dr. Cosimo Misciali, Dr. Paolo Sena and Prof. Pietro Quaglino for kindly providing us with histopathological pictures.Go to:
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Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a spectrum of acute, delayed-type hypersensitivity reactions that affect the skin and the mucous membranes. Medications are the culprit cause of these disorders in addition to infections and in very rare instances vaccinations. We report a case of TEN in a 49-year-old woman with no previous medical history. The disorder developed one week after receiving the first dose of COVID-19 vaccine with no other identifiable causes. The patient received two doses of tumor necrosis factor-alpha inhibitor (etanercept) and she stopped developing new lesions after two days of the initial dose; complete healing was observed after 22 days and no side effects were observed in our patient. This case demonstrates an extremely rare complication to the COVID-19 vaccine. The benefits of receiving the COVID-19 outweigh the potential risk.
Toxic epidermal necrolysis (TEN) is a rare immune-mediated, life-threatening skin reaction characterized by blistering and extensive epidermal detachment of more than 30% of body surface area. The incidence is estimated to be 0.4 to 1.9 cases per million population per year worldwide and an estimated mortality rate of 25% to 35% [1, 2]. Medication is usually the cause of TEN (e.g., certain antibiotics and antiepileptics) . Vaccination-induced Stevens-Johnson syndrome (SJS)/TEN is rare, with less than twenty reported cases in the published literature, with the measles vaccine being reported to cause both SJS and TEN, varicella, smallpox, anthrax, tetanus, and influenza vaccines were reported to cause SJS alone, and MMR (measles, mumps, rubella), hantavirus and meningococcal B vaccines were reported to cause TEN [4, 5, 6]. The patient usually develops a fever and other flu-like symptoms one to three weeks after being exposed to medication followed by painful erythematous to purpuric skin lesions that tend to coalescence. Next erosions and vesiculobullous lesions and epidermal detachment over wide body surface area develop. Mucous membranes are also involved, and the patient develops oral ulcers, vaginal ulcers, and possible acute conjunctivitis . In this paper, we report a case of TEN following the administration of the Pfizer COVID-19 vaccine (Pfizer, Inc., New York, USA).