Dermatological manifestations of the Coronavirus disease 2019 in children: a systemic review

Chilblain-like lesions

Vascular dermatoses in the form of acute ischaemic lesions were initially described in adult patients with severe SARS-CoV-2 infection [11]. The above changes are likely to result from clotting disorders and are associated with microthrombi formation, leading to pulmonary embolism, strokes, and disseminated intravascular coagulation [12, 13].

However, recently, an increasing number of paediatricians, particularly those from regions most affected by COVID-19, have reported the occurrence of chilblain-like dermatoses among patients who have never previously experienced perniosis or Raynaud symptoms [14–16].

These changes initially manifest as erythematous-bluish spots usually limited to the distal parts of the limbs, often with blisters, erosions and dry scab-covered ulcers. Upon healing, these lesions become spotted lesions [14, 17, 18].

Pseudo-chilblain skin lesions occurred in 173 patients. The average age in this group of patients was 13.2 years and most of them were female. Dermatoses were most often located only on feet (143 patients). In 13 patients, lesions concerned only hands, in 13 cases both hands and feet. The average duration of skin lesions was 18.5 days; in 54.9% they were accompanied by the following symptoms: pruritus, pain, burning and coldness (Table 2).

Authors of many publications show that patients with pseudo-chilblain-like lesions present mild or no symptoms of viral disease, and RT-PCR tests from the nasopharyngeal swabs are often negative. This is probably due to the delayed occurrence of skin lesions in the course of COVID-19 in children and young adults [15, 19–21].

In our analysis, extradermal symptoms appeared only in 44 out of 173 described patients and were preceded by chilblain-like lesions by 10.4 days on average. The most common symptoms were cough, gastrointestinal symptoms and fever.

Of the 49 RT-PCR tests performed from nasopharyngeal swabs, only 10 were positive for SARS-CoV-2 (Table 2). Kolivras et al. [22] presented a histopathological picture of chilblain skin lesions, in which they described the papillary oedema of the skin with perivascular lymphocytic infiltration together with diffuse necrotic keratinocytes in superficial layers of the epidermis. Microangiopathic changes may be caused by an increased reaction associated with increased type 1 interferon production, which occurs during SARS-COV-2 infection, especially in children and young adults. However, it may be a protective factor against the occurrence of a ‘cytokine storm’ and full COVID-19 [19, 22, 23].

Erythema multiforme-like lesions

Erythema multiforme-like dermatosis (n = 12/196) is another type of a skin lesion described in the publications we analysed. The mean age was 12.1 years, the lesions were more common in boys.

Erythema multiforme-like dermatoses were most often located on feet. Less commonly, they were found on hands face, conjunctiva, lips, and in the oral cavity. The average duration of skin lesions was 16.7 days; 58.3% of them were accompanied by pruritus and pain. General symptoms associated with COVID-19 appeared in 5 out of 12 described patients and were preceded by erythema multiforme-like lesions by 21 days on average. The most common symptoms were fever and gastrointestinal symptoms. RT-PCR tests from nasopharyngeal swabs were performed in majority of the patients from this group (n = 8), positive results for SARS-CoV-2 were found only in two children (Table 2).

Torrelo et al. and Andina et al. [19, 24] presented an interesting description of 4 children aged 11–17 years who had erythema multiforme-like lesions in addition to chilblain-like lesions on the feet (in 4 patients) and hands (in 2 patients). The subjects had never before experienced such symptoms, had not taken new medications, and had not received vaccinations during the previous 30 days, and did not have any symptoms of or exposure to herpes virus, Epstein-Barr virus, varicella, adenovirus, cytomegalovirus, or orf. RT-PCR testing for SARS-CoV-2 was positive in only 1 of the patients; another had contact with a family member with suspected infection; 3 had mild symptoms of COVID-19 a few days before the appearance of skin lesions. Histopathological examination performed in 2 patients did not show an erythema multiforme characteristic picture, but immunohistochemistry was positive for SARS-CoV/SARS-CoV-2 spike protein. Oral corticosteroids have been administered in 1 patient and topical corticosteroids were used in another. Skin lesions disappeared without complications in all patients within one to 3 weeks [19, 24].

García-Gil et al. [25] in their publication presented a clinical case of a 12-year-old boy with erythema multiforme-like skin changes which presented as purple erythematous lesions and vesicular blisters.

Histopathological examination of skin lesions revealed partial epidermal necrosis and perivascular lymphoid infiltrate in superficial and deep dermis, microthrombi of the papillary dermis accompanied by extravasation of red blood cells, thickening of the vessel wall, and activation of the endothelium with nuclear enlargement. The authors of the publication emphasized the similarity of the histopathological image of erythema multiforme-like lesions (pauci-inflammatory thrombogenic vasculopathy) to vascular lesions occurring in adult patients with severe COVID-19. This suggests that SARS-CoV-2 may be an etiological factor in the development of acute vascular lesions in children despite often negative test results confirming the infection.

Maculopapular changes

The clinical picture of patients with maculopapular lesions was quite diverse. In the analysed articles, 16 cases of children with maculopapular exanthema (8.2%) were described. The average age of patients in the analysed articles was 7.22 years, the changes were more frequent in boys. In all described clinical cases, the changes concerned hands and feet. Moreover, in 14 patients a generalized rash on whole upper and lower extremities and trunk was found.

The average duration of the exanthema was 9.3 days. Only itching was described among the accompanying symptoms. The most frequently described general symptoms of COVID-19 were: fever, conjunctivitis and gastrointestinal symptoms. Extracutaneous symptoms in this group of patients appeared on average 3.5 days before the occurrence of maculopapular rash. RT-PCR tests of nasopharyngeal swabs were performed in all children in analysed clinical cases, most of the results were negative (Table 2).

Bursal Duramaz et al. [26] described two clinical cases of patients with confirmed SARS-CoV-2 infection who did not require systemic treatment. In an 8-month-old infant, an erythematous rash of the face and trunk resembling roseola was found. These skin changes and a fever appeared and subsided simultaneously. An 11-year-old girl presented with a pruritic, morbiliform rash on the face and back. The changes disappeared spontaneously after 5 days.

The course of COVID-19 among paediatric patients is often asymptomatic or has few symptoms [27, 28]; thus, systemic treatment is less frequently used compared to in the adult population.

However, Bursal Duramaz et al. [26] described a case report of a 17-year-old female patient experiencing a drug eruption on day 3 of hydroxychloroquine use. Erythematous and maculopapular changes occurred on the face and limbs with slight itching. Symptoms disappeared upon termination of hydroxychloroquine treatment.

Morey-Olivé et al. [29] described an interesting clinical case of a 6-year-old boy with cholestatic liver disease of unknown aetiology. Two weeks after a slight fever, elevated bilirubin and hepatic transaminases in blood, the patient had a positive result of RT-PCR smear test for the presence of SARS-CoV-2. After the next 48 h an itchy, non-smelling, generalised, dewy sediment appeared. Skin lesions persisted in the boy for a total of 5 days, were not accompanied by any symptoms associated with COVID-19 and upon their subsidence, liver parameters normalised. Interestingly, no SARS-CoV-2 was detected in the liver extract.

However, in 3 of the publications we analysed [30–32], the erythematous and papular lesions occurred in the form of a generalised rash with subsequent epidermal exfoliation with often accompanying erythema or firm induration of hands and feet, erythema of the lips or oral cavity, and cracking of the lips.

In addition, the patients were found to have additional symptoms characteristic of Kawasaki’s disease, namely fever, coronary artery abnormalities, hypotension and/or elevated inflammatory markers.

Labé et al. [31] presented a clinical case of a 3-year-old patient hospitalized for 8 days of high fever, whose mother was diagnosed with SARS-COV-2 infection 3 weeks earlier. The patient was described as generalized exanthema with desquamation of the extremities, bilateral palmar oedema, glossitis, and cervical lymphadenopathy. Laboratory tests showed an increase in inflammation parameters.

Although the result of the RT-PCR swab test for SARS-CoV-2 was negative, the ground-glass opacities and consolidation in the right posterobasal area clearly supported the diagnosis of COVID-19. According to the authors, the clinical case presented in the publication suggests that SARS-CoV-2 infection may be the trigger for Kawasaki-like disease [31].

In April 2020, there were reports from Europe and North America about a severe form of Paediatric Inflammatory Multisystem Syndrome (PIMS) sharing common features with other paediatric inflammatory conditions including: Kawasaki disease (KD), staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis and macrophage activation syndromes. A possible temporal association of PIMS with SARS-COV-2 infection has been proposed as some paediatric patients have tested positively for SARS-CoV-2 infection using either polymerase chain reaction (PCR) or serological testing [30–34].

The initial definition of the Paediatric Inflammatory Multisystem Syndrome temporally associated with SARS-CoV-2 infection [35, 36] based on a document published by the WHO on 15 May 2020 [37] covers children and adolescents under 19 years of age with a fever lasting 3 days or more, presenting at least two of the following symptoms:

Additionally, diagnosis requires elevated inflammatory markers, exclusion of other infectious causes of presented symptoms, and either confirmation of COVID-19 or probable contact with an infected individual [37].

PIMS-TS symptoms are similar to those of KD, including persistent fever and coronary artery damage; however, relatively older children are typically affected [38, 39].

Verdoni et al. pointed out a significant increase in the incidence of KD symptoms in the Italian Bergamo area since the beginning of the SARS-COV-2-related pandemic, particularly a 30-fold increase in the incidence of Kawasaki-like disease between 18.02.2020 and 20.04.2020. Compared to patients admitted before February 2020, only in the group of children hospitalized after the beginning of coronavirus epidemic, KD shock syndrome and features of macrophage activation syndrome were reported [30].

While the aetiology of KD is still not fully understood, available studies suggest that the disease may be due to abnormal regulation of the immune system in response to the infectious agent. This inappropriate immune response is most probably genetic as indicated by the limited number of cases of children with KD in the course of infectious diseases. A hypothesis to explain the aetiology of PIMS-TS has yet been put forward [40, 41].

Patients with PIMS-TS symptoms require immediate hospitalization. Treatment of this disease is similar to that of KD. First-line treatment is high-dose intravenous immunoglobulin (IVIG) (2g/kg) to reduce the risk of coronary artery damage. Additionally, acetylsalicylic acid, corticosteroids, and anti-TNF monoclonal antibodies may be used to reduce inflammation [42].

Varicella-like exanthema

Genovese et al. [43] presented a description of an 8-year-old girl, hospitalized due to varicella-like exanthema lasting for 3 days and a positive RT-PCR result from nasopharyngeal swabs for SARS-CoV-2 (in the patient and her closest family). In the history, the patient had smallpox a year earlier.

On admission, disseminated papular, papular-bladder lesions with a tendency to crack and scab formation in the area of the torso skin were found. The skin lesions were accompanied by only a slight cough, which occurred 3 days before the onset of the skin lesions, and a fever, which occurred on the 2^nd day of dermatosis. Laboratory tests were all within normal range except for slight thrombocytopenia. Skin lesions and general ailments disappeared without any treatment within 7 days.

Urticaria

Urticaria is a rare disease in childhood (3.4% UK, 4.4% Germany, 5.4% Denmark) and the risk of transformation into a chronic form is negligible (0.1–0.3%) [44–46]. Scientific studies show that viral infections can also be an etiological factor in urticaria [47, 48].

Morey-Olivé et al. [29] described a clinical case of a 2-month-old girl with itchy acute urticaria skin lesions lasting 4 days and accompanied by a slight fever. The girl had contact with two people with confirmed SARS-CoV-2 infection. The urticaria initially occurred on the face and upper limbs and subsequently spread to the trunk and lower limbs. The palms and soles remained free of lesions and no angioedema was found. After oral symptomatic treatment, all symptoms disappeared within 5 days.