Urticarial vasculitis revealing immunolabelled nucleocapsid protein of SARS-CoV-2 in two Brazilian asymptomatic patients: the tip of the COVID-19 hidden iceberg?

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None of the authors have any conflicts of interest to disclose.

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Dear Editor,

Urticarial vasculitis (UV) presents with persistent urticarial lesions that resolve with residual hyperpigmentation and histopathologic features of leukocytoclastic vasculitis. Both acute urticarial lesions and exacerbation of chronic spontaneous urticaria (CSU) were described associated with COVID‐19. , , Reports of UV associated with SARS‐CoV‐2 infection/COVID‐19 are few and, to our knowledge, immunolabelled SARS‐CoV‐2 antigens in skin biopsies from UV under immunohistochemistry have never been demonstrated. ,

A 69‐year‐old Caucasian woman presented with itching and hives for 20 days. She denied any new medications or acute disease. On skin exam, >50 wheals on trunk and extremities were noted (Fig. 1a–d). Lesions often resolved in 24–36 h in the same site and no signs of UV were observed. She was started on bilastine 80 mg/day with partial control of lesions. CBC, CRP, IgE, C3, C4, CH50, ANA and rheumatoid factor (RF) were normal or negative. SARS‐CoV‐2 IgM serology was positive (immunochromatography assay; LUMIRATEK COVID‐19®, LumiraDx from Bristol, UK; positive predictive value 94% ). After 2 weeks, she was started on omalizumab 300 mg every 4 weeks, with progression of urticaria after two doses. Patient underwent two skin biopsies, from right leg and right thigh. Immunohistochemical staining was performed on Ventana Automatic Stainer – Ventana Benchmark Ultra (Ventana Medical Systems, Tucson, AZ, USA). SARSA‐CoV‐2 (2019‐nCoV) nucleocapsid antibody and rabbit MAb (Rabbit Monoclonal antibody; Cat No 40143‐ R019; Sino Biological, Beijing, China) were used at 1:1500 dilution, for 32 minutes. Skin biopsy from right leg and right thigh revealed neutrophilic urticaria (Fig. 2a) and leukocytoclastic vasculitis (Fig. 1e–f), respectively. Immunohistochemistry study in paraffinized skin sample was performed using antibodies against SARS‐CoV‐2 nucleocapsid. Immunolabelled eccrine gland cells were found in the inner portion of eccrine glands (Fig. 1g). Patient was started on colchicine 1.5 mg plus bilastine 80 mg/day with partial control. After 30 days, hydroxychloroquine was added, and patient cleared completely in one month. A 61‐year‐old Caucasian man presented with a 2‐week history of itchy lesions on trunk and limbs. He denied systemic symptoms, arthralgia or previous use of medications. Lesions were urticarial and annular on upper left abdomen (Fig. 2a,b) and wheals were noted in other areas (Fig. 2c–f). Skin biopsy from left upper abdomen demonstrated perivascular dermal inflammation (Fig. 2g,h) and oedema, as well as leukocytoclasia (Fig. 2i). Serology for SARS‐CoV‐2 demonstrated positive IgM. CBC, CRP, ANA, C3, C4, CH50, SPEP, RF, Hepatitis B, C and HIV serologies were negative or normal. Immunohistochemical staining performed under same method applied to patient 1 demonstrated immunolabelled nucleocapsid for SARS‐CoV‐2 in eccrine glands, interstitial dermal cells and small blood vessels (Fig. 2j). Patient received bilastine 80 mg/day plus hydroxychloroquine 400 mg/day with partial control of lesions.

Figure 1

(a) Patient 1 – wheals involving the bilateral thighs; (b) patient 2 – two erythematous‐oedematous lesions on the right upper abdomen; (c) patient 2 – urticated plaques on the right posterior forearm.

Figure 2

(a) Patient 1 – histopathological examination from right leg showing oedema and perivascular infiltrate around dermal blood vessels, as well as scattered neutrophils in mid‐dermis (H.E., 200×); (b) patient 1 – fibrinoid necrosis in wall of dermal blood vessel (black arrow) and leukocytoclasia in skin biopsy from right thigh (H.E., 400×); (c) patient 1 – immunohistochemical study demonstrating immunolabelled nucleocapsid (brown‐black colour) in reticular dermal eccrine glands (white arrows). (d) patient 2 – histopathological exam showing perivascular lymphocytic infiltrate around dermal blood vessels, extravasated red blood cells and nuclear dusk (leukocytoclasia; H.E., 200×) and (e) patient 2 – immunohistochemical study demonstrating immunolabelled nucleocapsid (brown‐black colour) in eccrine glands (thick line arrow) and in small dermal blood vessels (thick dotted arrow).

Urinalysis in both patients was within normal limits. Nasopharyngeal RT‐PCR testing for SARS‐CoV‐2 was not performed since it is not recommended after 7 days of symptom onset and should be limited to symptomatic patients with suspected COVID‐19. Both of our patients demonstrated uncontrolled urticaria only and did not have classical COVID‐19 general symptoms, perhaps being classified as oligosymptomatic for SARS‐CoV‐2 infection .

Our cases occurred in asymptomatic COVID‐19 patients and were refractory to conventional CSU treatment. Up until November 19, 2020, there was only one case reported of UV after symptomatic COVID‐19, but nasopharyngeal RT‐PCR was negative, and IgM/IgG serology was positive.

False‐positive immunological reactions in serum and histopathological examination were unlikely in our patients because the positive predictive value of immunochromatography assay used for SARS‐CoV‐2 IgM serology is high (94%). Furthermore, Roden et al. demonstrated 100% specificity for SARS‐CoV‐2 antigens on immunohistochemistry in human tissues.

SARS‐CoV‐2 antigens in the skin may induce leukocytoclastic vasculitis with clinical urticarial lesions, with a similar immune mechanism as in erythema nodosum leprosum.

Visconti et al. analysed data from an online survey involving 11 546 respondents to investigate skin‐specific symptoms of SARS‐CoV‐2 infection. Seventeen percentage of positive RT‐PCR for SARS‐CoV‐2 nasopharyngeal swab cases reported skin rashes as the first sign, and 21% as the only clinical sign of COVID‐19. Our two cases are examples of asymptomatic SARS‐CoV‐2 patients or with non‐classical COVID‐19 symptoms who presented associated skin eruptions.

Cutaneous disease may be potentially triggered by SARS‐CoV‐2 asymptomatic infection and antigen exposure could lead to leukocytoclastic vasculitis. In these cases, physicians should be alert and perform SARS‐CoV‐2 serology, as well as cutaneous biopsies and immunohistochemistry study for SARS‐CoV‐2 antigens in the skin, when available. A single cutaneous eruption may be the tip of the iceberg, a hidden SARS‐CoV‐2 infection.