Development of eruptive pseudoangiomatosis following COVID-19 immunization - Apropos of 5 cases.

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To the editor,

In the midst of the trying times whilst the world has come to a standstill by the novel coronavirus disease 2019 (COVID‐19) or severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), there exists an urgent need for safe and effective vaccination against this deadly virus. Currently, there are 93 vaccine candidates against COVID‐19 under clinical trial, of which at least 14 vaccines have been approved or authorized. India started its national vaccination programme against COVID‐19 on 16 January 2021 by immunizing health care workers as a priority, followed by those over 60 years of age, and as of 3 May 2021, more than 28 million individuals have been fully vaccinated in India, accounting for 2% of the total population of the country. Herein, we report a series of 5 healthcare workers with negative polymerase chain reaction (PCR) testing, who developed eruptive pseudoangiomatosis following Covishield™ vaccination.

Five healthcare workers present to us between the months of January and March 2021, with complaints of multiple eruptive erythematous lesions ranging from size 2–5 mm. All the patients gave a consistent history of onset of eruptions within one week of vaccination. At least 3 patients had complaints of pruritus. The typical papular lesions were erythematous in centre with a pale perilesional halo (Fig. 1a–e). On diascopy, these lesions were completely blanchable and would fill from the centre on release of pressure.

Figure 1

(a) Discrete erythematous papules with blanching perilesional halos around some of the lesions over bilateral limbs in case 1. (b) Another patient with multiple pruritic bright red macules and surrounding pale halo over trunk, which developed 3 days after vaccination. (c) A patient with acral eruptive pseudoangioma having pruritic pinhead‐sized erythematous macules and surrounding pallor in all the lesions. (d) Multiple bright red papules with perilesional halo in a patient with generalized eruptive pseudoangioma. (e) Close‐up image of the hand in another patient with characteristics lesions. On diascopic examination, the lesions blanched completely and refilled from the centre after the release of pressure. (f) Histopathological analysis of a typical lesion revealing perivascular lymphocytic and histiocytic infiltration, plump endothelial cells, dilated vessels, and absence of RBC extravasation (H and E staining, ×400).

A detailed description of these patients has been provided in Table 1. All 5 patients had received the recombinant ChAdOx1 nCoV‐19 coronavirus vaccine (recombinant), also known as Covishield™. The mean duration between vaccination and development of eruptions was 5.2 days. The most common variant was generalized (n = 3) followed by acral (n = 2). None of the patients had any prodrome of sore throat, gastrointestinal upset or a recallable history of insect bite prior to the onset of lesions. None of the patients had any lymphadenopathy. Whilst cases 1, 2 and 5 had already undergone COVID‐19 PCR tests prior to vaccination, we subjected cases 3 and 4 to PCR testing after they presented to us. The investigation reports of all 5 patients turned out to be negative. The cases also denied development of any adverse events after the vaccination. Routine investigations revealed raised ESR in case 2 and leukocytopenia in case 4. Punch biopsy specimen revealed a distinct histology of perivascular lymphocytic and histiocytic infiltration, plump endothelial cells, dilated vessels and absence of RBC extravasation (Fig. 1f).

Table 1

Details of patients

Serial number	Age in years/sex	Duration between vaccination and eruption	Associated fever	Site of onset and sites involved	Time taken for resolution (in days)
Case 1	24 years/female	5 d	+	Onset – left hand; followed by generalized involvement	7 d
Case 2	47 years/male	3 d	+	Onset – face; followed by generalized involvement	8 d
Case 3	35 years/male	6 d	‐	Onset – forearms; confined to forearms	2 d
Case 4	27 years/male	5 d	+	Onset‐trunk; followed by generalized involvement	6 d
Case 5	25 years/male	7 d	‐	Onset – legs; confined to bilateral legs and forearms	3 d

Based on classical clinical appearance supported by histopathology and a strong temporal association with COVID‐19 vaccination, all 5 patients were diagnosed with eruptive pseudoangiomatosis secondary to COVID‐19 vaccination. Oral antihistaminics and emollients were advised to patients, followed by complete recovery within 10 days with no recurrence during the follow‐up period.

Eruptive pseudoangiomatosis (EP) is a rare, self‐resolving exanthem characterized by the sudden appearance of 2–4 mm, asymptomatic blanchable erythematous papules surrounded by a 1–2 mm pale halo resembling angiomata. The disorder results from transitory dermal blood vessel dilation and therefore blanches on pressure. It was first described in 1969 by Cherry et al. in four children with high grade fever who were infected with ECHO (enteric cytopathogenic human orphan) virus. Various other viruses including coxsackievirus, Epstein‐Barr virus, adenovirus, cytomegalovirus, insect bite, as well as vaccination, have been proposed as potential etiological agents. , The disease has an excellent prognosis and resolves spontaneously within 2‐18 days without any residual scarring.

In 2007, Chainotakis et al. had proposed a unifying hypothesis of pathogenesis of EP. According to them, EP in children and adults is caused by the same infective agent, presumably a virus that infects the pericytes of small vessels. Primary infection with the virus, after the first contact, is followed by haematogenous dissemination. Development of EP following vaccination has been reported sparsely in literature.

The development of EP has also been observed after SARS‐CoV‐2 (COVID‐19) infection. This could potentially suggest that the COVID‐19 vaccination works by stimulating host’s cellular and humoral response against the spike‐protein of virus in the same way as the SARS‐CoV‐2 infection itself. Secondly, it can be hypothesized that the development of EP occurs secondary to an immunological reaction to a viral component and not due to the direct effect of virus on blood vessels.

Our series exemplifies the importance of identifying EP as a potential mild adverse event of COVID‐19 immunization. A dermatologist must always be on the lookout for differentiating this underdiagnosed entity from similar spotters such as viral rash, papular urticaria, insect bite reaction and morbilliform rash.