key: cord-1048680-962r2ku6 authors: Colonna, Cristiana; Restano, Lucia; Monzani, Nicola A.; Zussino, Martina; Ponziani, Alessandra; Cambiaghi, Stefano; Cavalli, Riccardo title: Rare and common manifestations of COVID‐19 in children date: 2022-02-18 journal: JEADV Clinical Practice DOI: 10.1002/jvc2.10 sha: bcf7fa8b4303f4e831099eba3287ebe3f205789d doc_id: 1048680 cord_uid: 962r2ku6 INTRODUCTION: It has been almost 2 years since the first reports on cutaneous manifestations of COVID‐19. Those reported in children are different and include macular, papular, lichenoid, vesicular, urticarial, and vascular morphologies, among others. The prognosis of isolated cutaneous involvement in COVID‐19 in children is usually self‐limiting but the extreme variety of clinical presentations complicates the clinical approach. METHODS: Numerous reviews have been systematically drafted and edited giving the clinicians a future direction for skin presentations during pandemics. RESULTS AND DISCUSSION: Hereby we report the rare and common manifestations of COVID‐19 in children and question the recurrence phenomena and age‐related distribution of the eruptions. INTRODUCTION SARS-CoV-2 infection has rapidly spread worldwide causing millions of COVID-19 cases in humans with a great variability of signs and symptoms. Children with COVID-19 are most often pauci-symptomatic with only mild respiratory symptoms. However, peculiar signs are sometimes found in this group of patients, including heterogeneous cutaneous signs. During the spring of 2020, a first perspective on the cutaneous manifestations observed was conducted in mainly adult patients with proven infection. 1, 2 By that time, a striking number of children and adolescents were seen with acral cutaneous manifestations resembling chilblains. Their clinical features ranged from erythematous to violaceous macules to dusky, purpuric plaques on their feet and/or hands, often accompanied by itch and pain. Impressed by the unexpected repetitive clinical pattern observed in a very short period, we reported such chilblain-like lesions (CLLs) in four children, to warn for a possible association with SARS-CoV-2. 3 However, so far, despite thousands of similar cases described worldwide following the spread of the pandemic, the pathogenesis of CLLs and the definite causal relation between chilblains and COVID-19 remains uncertain. Cutaneous manifestations have also been observed in children with a newly described inflammatory systemic condition leading to multiple organ failure and shock in multisystem inflammatory syndrome (MIS-C). Additionally, isolated skin phenomena have been described in children positive to SARS-CoV-2 with minimal or no systemic involvement, some of them resembling postinfective phenomena observed in other viral infections, such as erythema multiforme (EM)-like lesions, and vesicular, maculopapular, urticarial, or papulosquamous rashes. In this article, we review the frequent and the less common manifestations of COVID-19 in children reported in the medical literature. Despite the existing variability in the definition of CLLs, common features are present in most cases. The population involved consists mainly of children, adolescents and young adults, with usually mild local symptoms (pain or itch). General symptoms are absent or represented by mild fever, cough, dyspnoea and anosmia-ageusia. 4 The lesions are morphologically identical to ordinary chilblains, mostly occurring on the feet and/or hands, showing acrocyanosis or cold toes, erythema and oedema, and sometimes bullous and purpuric necrotic areas ( Figure 1 ). 5 Ordinary chilblains are usually related to cold periods, but the outbreak of CLLs was unusual for appearing during springtime and in warm climate regions. Given the concomitant pandemic, a possible association with COVID-19 was considered. Due to difficulties caused by lockdown and the lack of validated tests for SARS-CoV-2, many patients were not tested. However, in most tested cases, real-time polymerase chain reaction (RT-PCR) and serum serologic analysis did not reveal any positivity. 6 An association with lifestyle changes and cold exposure during lockdown was hypothesized as the causative agent for the CLL outbreak. 7 Furthermore, larger studies revealed very low positivity for virologic testing, thus questioning a viral aetiology. 8 On the other hand, a strong temporal association with the circulation of COVID-19 in all countries was remarkable and warranted further research. 9 Histology and immunofluorescence confirmed close similarities with pernio, sometimes associated with vasculitis and/or microthromboses. 10, 11 In detail, histopathology of chilblains and CLLs shared a superficial and deep lymphocytic inflammatory infiltrate in a lichenoid, perivascular and perieccrine distribution. 12 Immunohistochemical staining of lesional skin biopsies revealed positive marking of the vascular endothelium and eccrine epithelium with SARS-CoV/SARS-CoV-2 spike protein antibody. 13 However, these findings were not replicated in a case series of CLLs. 14 COVID-19-associated CLLs may be due to a direct effect of SARS-Cov-2 on endothelial cells leading to thrombosis or be the result of an enhanced type I interferon (IFN-I) response in the pathogenesis of CLLs; however, these potential mechanisms are not necessarily mutually exclusive and may be interdependent. 15, 16 An association of CLLs with the cutaneous expression of IFN-I 10 was supported by activation of the IFN-I immune response in histopathological specimens of CLLs, with endothelial cells expressing the type I IFN-induced proteins MxA and pJAK1. In addition, lesional vessels showed complement and Ig deposition. 17 The authors' proposed pathogenesis was a local response to endothelial infection by SARS-CoV-2, driven by type I IFN immunity. 17 Furthermore, CLLs are mostly observed in F I G U R E 1 (a−f) Moderately painful chilblain-like lesions localized on the toes and fingers in male and female adolescents aged 12−17 years old patients without severe COVID-19 organ manifestations, who express low rate of specific antibody positivity against SARS-CoV-2. The high levels of IFN-I could be associated with a precocious effective response against the virus leading to a milder course of the disease with suppressed antibody production. 18 The role of IFN-I pathway in the induction of CLLs is further supported by the observation that patients with chronic type I IFN activation in the setting of rare type I interferonopathies frequently develop chilblain-like lesions too. 17 Further studies are still required to definitely confirm the link between CLLs and COVID-19. CLLs have been mainly seen in children above 10 years of age and adolescents in good health with involvement of feet (75%−100% of the cases) and less frequently of the hands. The erythematous, violaceous or purpuric patches are usually multiple, round and vary from a few millimetres to centimetres in size. The periungual skin could be affected as well. There is a rare tendency to vesiculation and presentation with dark-purple or black crusts. The plantar region and the lateral margin of the feet and the heels may also be involved, with coarse, ecchymotic and infiltrated lesions. 19 Unlike adults, children and adolescents are usually asymptomatic or present local pain and itch. Round or targeted lesions resembling erythema multiforme are seen in some cases of CLLs, involving mainly upper limbs and hands. Dermoscopy features of CLLs include a background area, described as varying from redpurple to grey-brown, globules and reticular network. Globules have been observed in most cases and range from red to purple. The grey-brown reticular network is usually located peripherally within the background area. 19 On capillaroscopy, anomalies in fingers and toes are reported, also in those cases in which skin lesions are mostly located on the feet only. These include slow capillary flow, enlarged loops, and major and minor tortuosity. A personal or familiar history of low-grade fever and systemic symptoms (cough, diffuse asthenia, gastrointestinal disorders) has been frequently reported before the appearance of CLLs, but even in these cases molecular or serologic SARS-CoV-2 tests are usually negative. 19, 20 Despite an auto-resolving progression and a mean duration time of 40−60 days, some recent reports indicate the possibility of a prolonged course with reactivation phenomena before complete disappearance. Recurrence has been also reported in the same patient in consecutive disease waves suggesting a viral correlation. All children and adolescents published so far have had a favourable outcome with spontaneous regression of the lesions and no relevant complications. Reported resolution time ranged from 12 days to 12 weeks. 20 Oral analgesics, antihistamines and local pentoxifylline were administered in isolated cases, with poor results. The increased number of patients and the lack of therapeutical guidelines encouraged the use of heterogeneous therapies including nifedipine, pentoxifylline, tadalafil, topical glyceryl trinitrate, topical minoxidil, diltiazem, corticosteroids and vitamin D. A systematic review 21 showed moderate evidence to support the use of nifedipine and pentoxifylline in the treatment of severe or refractory cases of idiopathic chilblains, while other therapies had inadequate evidence or nonsignificant results compared with placebo. When preventive measures alone are inadequate, oral nifedipine is generally recommended as first-line pharmacologic therapy. One of the most severe consequences of COVID-19 infection in children is MIS-C. It is defined as a hyperinflammatory response to SARS-CoV-2 infection that leads to multiorgan dysfunction. The Centers for Disease Control and Prevention (CDC) define an MIS-C case as an individual under 21 years old with current or recent SARS-CoV-2 infection (or exposure), a fever lasting greater than 24 h, laboratory inflammatory marker evidence and the presence of severe illness involving more than two organs (cardiac, respiratory, gastrointestinal, dermatologic, renal, haematologic or neurologic), requiring hospital admission that cannot be explained by other illness. 22 Cases have been reported from 1 month to 20 years old 23 with median age estimated between 5 and 11.5 years. 22 Although the exact mechanisms are not yet understood, MIS-C is described as the result of a cytokine storm in response to COVID-19 infection. 24 A great variety of cutaneous signs are associated with MIS-C. In 50%−83% of children with MIS-C, purpuric, erythematous, retiform, reticular, scarlatiniform, livedoid, urticarial, papular, macular, targetoid, maculopapular, desquamative, EM-like and morbilliform exanthems have been described. [25] [26] [27] [28] The presence of CLLs in an MIS-C patient with severe cardiac involvement has also been noted (personal observation, Figure 2) . MIS-C with multiorgan failure requires supportive or invasive care. 23, 29 Mortality is estimated at 2% while the posthospitalization sequelae of MIS-C are just beginning to RARE be appreciated. Reports of alopecia areata and telogen effluvium have been published which could be related directly to the infection, as well as postinfectious sequelae or associated stress. 30 Nonspecific and nondiagnostic skin findings may represent potential sequelae, and follow-up examination is necessary in children with past MIS-C who present new skin eruptions. Macules and papules are a manifestation of many different reaction patterns in the skin. In the setting of COVID-19, children with this type of rash are mainly pre-school and school age, but cases may also occur in adolescents and adults. 31 Prevalence of these lesions has varied among studies including a small number of cases. The anatomic distribution favours the trunk and diaper area, with a centrifugal pattern. The limbs are also frequently involved. We observed clinically acrosyringial involvement with a major distribution in perspiration areas ( Figure 3 ). Urticaria is a common cutaneous manifestation described in association with SARS-CoV-2 infection in all ages, accounting for 10%−20% of all COVID-19-related rashes. 32 COVID-19 urticaria shares the characteristics of other urticarial reactions with transient duration (1−5 days) and association with itch. In consideration of the great variability of common causes of urticaria in children, including viruses, bacterial infection and parasites, the diagnosis of SARS-CoV-2 infection is challenging in a child with urticaria. 33, 34 Children with urticaria and COVID-19 usually present mild general symptoms, especially below the age of 2 ( Figure 4 ). EM is an acute, self-limiting hypersensitivity condition with a distinctive skin eruption with pink to red macules, papules, and plaques with a peculiar target arrangement. 35 Common locations include the forearms, thighs, knees, arms, especially around the elbows, and the dorsal aspect of the hands and feet. In children, the two pathogens most frequently involved in EM are herpes simplex virus (HSV) and Mycoplasma pneumoniae 36 but an association with SARS-CoV-2 infection has been observed, with typical EM lesions and EM-like atypical targets. 37 In COVID-19associated EM, CLLs may coexist ( Figure 5 ). EM in COVID-19 is reported to resolve after several days, even without any treatment. Adolescents and young adults seem to be the most frequently affected subgroup, as is the case in HSV and Mycoplasma pneumoniae infections. No or mild respiratory or gastrointestinal symptoms have been observed in COVID-19 EM. 38 SARS-CoV-2 causes a varicella-like papulovesicular rash, most frequently in adults, in particular middle-aged woman, but also in children. 39, 40 Mildly pruritic vesicles with haemorrhagic crusts occur mainly on the trunk. These lesions appear in the earlier stages of COVID-19 Papulosquamous rashes in COVID-19 consist of scaly macules and papules that may be localized or confluent. Characteristic papules are perifollicular and itchy. Some patients develop purpura and pseudo-vesicles. A frequent presentation in this group mimics pityriasis rosea. 44 In other patients, the rash features punctate purpura or pseudo-vesicular papules on the extremities. Mean duration of papulosquamous eruptions is around 20 days, but they may last up to 70 days in some patients. 45 Acute PLEVA-like dermatitis was observed in scholar children and adolescents with symmetrical round purplish papules that occurred in successive crops and evolved into crusted and necrotic lesions, sometimes coalescing into larger plaques ( Figure 6 ). The purpuric characteristic of the lesions is notorious on dermoscopy (Figure 7 ). There is a predominant trunk involvement with facial sparing and extension to the upper and lower limbs. Histologically, this eruption is characterized by a massive lymphocytic infiltration of the acrosyringia and eccrine glands. 46 A number of cutaneous nonspecific exanthems have been attributed to SARS-CoV-2. These include purpuric thrombocytopenic purpura, dengue-like exanthem, 47 F I G U R E 5 CLLs (a) and EM-like lesions (b,c) appearing in a 14-year-old, SARS-Cov-2-positive boy. CLL, chilblain-like lesion; EM, erythema multiforme F I G U R E 6 Diffuse, slightly elevated, purpuric papules on the trunk in an adolescent with PLEVA-like exanthem (a). Widespread, red-purple papules on the limbs in the same patient (b). PLEVA-like, papular-purpuric dermatitis of childhood livedoid eruptions, vasculopathic rashes, and have been reported in adults and occasionally in children as well. 48 Finally, various dermatological lesions are being reported possibly associated with SARS-CoV-2 vaccination. To date, the difficulties in identifying a clear correlation between cutaneous symptoms, especially CLLs, and SARS-CoV-2 represent an unsolved challenge. For more than 1 year, the main limitation was the lack of positive testing. As previously highlighted, a temporal correlation with the spread of the pandemic seems to support a causal link. Reappearance of skin phenomena during subsequent pandemic waves could strengthen a causative association. During the second SARS-CoV-2 spread, we observed a new call for dermatological evaluation. As previously detected, CLLs played the main role in the same asymptomatic or pauci-symptomatic cohort of children and adolescents. Clinical features and time to resolution were consistent with the data collected during the first COVID-19 wave (unpublished data). Again, a very low percentage of positive viral tests has been detected again. Isolated cases 3 and case series have reported recurrence of CLLs. A small number of children admitted for chilblains during the first pandemic wave and dismissed to follow-up because of a complete resolution without complications, presented again with CLLs in the same locations, months apart. Lack of positive testing was also constant. 4 We investigated retrospectively the possible relation of the multiple varieties of cutaneous manifestations observed with age. One hundred and ninetyeight patients presenting all the clinical presentations discussed in this paper followed a particular age distribution ( Figure 8 ). Seventy percent of all the lesions reported were CLLs, mainly present in adolescents. EMlike lesions showed a similar age correlated distribution. PLEVA-like lesions mainly involved 8-to 13-year-old children, while vesicular and papular-purpuric eruptions affected pre-school and school children (2−8 years old), with a relevant variability range. Interestingly, we observed in our patients relevant urticarial manifestations, specifically in infants and toddlers, with no cases observed beyond the age of 2. MIS-C involves patients between 5 and 11 years of age. Further studies are F I G U R E 7 Non-confluent, erythematous papules on the trunk and limbs on the 10th of a PLEVA-like eruption (a). Purpuric and haemorrhagic aspect on dermoscopy (b). Histopathology in this patient shows superficial and deep perivascular dermatitis, extravasated red blood cells in the papillary dermis (red arrow) and dermal eccrine ducts surrounded by heavy lymphocytic infiltration (black arrow), Hematoxylin and eosin stain, original magnification ×40 (c). PLEVA-like, papular-purpuric dermatitis of childhood warranted to identify a definitive correlation between age and infection or reinfection with SARS-CoV-2. Almost 2 years passed since the first clinical reports on chilblain-like lesions during COVID-19 pandemic. A lot has been found out, clinical features and new pathogenetic mechanisms have been detailed, and more sensitive tests have been developed and widely applied. A more comprehensive general view of COVID-19 cutaneous manifestations has been obtained. Larger studies will lead to a greater understanding of these worldwide diffuse clinical aspects, including recurrence phenomena and age-related distribution. Cambiaghi, Christiana Colonna and Riccardo Cavalli. All authors discussed the results and contributed to the final manuscript. The data that support the findings of this study are available from the corresponding author, N. A. M., upon reasonable request. 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