key: cord-0700735-z2hmida2 authors: Rocha, Kelvin Oliveira; Zanuncio, Virgínia Vinha; de Freitas, Brunnella Alcântara Chagas; Lima, Luciana Moreira title: “COVID toes”: A meta‐analysis of case and observational studies on clinical, histopathological, and laboratory findings date: 2021-09-13 journal: Pediatr Dermatol DOI: 10.1111/pde.14805 sha: 022bc15c32d635c0954ee9bc321c39e677dfef6f doc_id: 700735 cord_uid: z2hmida2 BACKGROUND: Coronavirus disease (COVID‐19) is related to several extrapulmonary disorders; however, little is known about the clinical, laboratory, and histopathological characteristics of pernio‐like skin lesions associated with COVID‐19 infection. OBJECTIVE: To evaluate and summarize the clinical, laboratory, and histopathological characteristics of pernio‐like lesions reported in the literature. METHODS: We conducted a search of the PubMed, SciELO, and ScienceDirect databases for articles published between January 1, 2020 and November 30, 2020, following the PRISMA recommendations (PROSPERO registration ID: CRD42020225055). The target population was individuals with suspected or laboratory‐confirmed COVID‐19 with pernio‐like lesions. Observational studies, research letters, and case/series reports were all eligible for inclusion. Observational studies were evaluated using a random‐effects model to calculate the weighted mean prevalence, overall mean, and 95% confidence interval. We evaluated case studies using the chi‐square test for dichotomous variables and the Mann‐Whitney test for continuous variables. RESULTS: A total of 187 patients from case reports and 715 patients from 18 observational studies were included. The mean age of patients was 16.6 years (range 14.5‐18.8). Feet were affected in 91.4% (87.0‐94.4%) of patients in observational studies. The proportion of patients with a positive RT‐PCR test was less than 15%. Lesion topography and morphology were associated with age. CONCLUSION: Lesions mostly occurred in pediatric patients, and the morphological characteristics tended to differ between pediatric and non‐pediatric populations. There is a possible multifactorial component in lesion pathophysiology. The non‐positivity of laboratory tests does not exclude an association with COVID‐19. Pernio‐like lesions may be a late manifestation of COVID‐19. Pediatric Dermatology ROCHA et Al. The observational studies included patients from four countries: Spain (68.8%), France (15.9%), Italy (10.9%), and Belgium (4.3%). Overall, the mean age of patients was 16.6 years (95% CI [14.5, 18.8] ). Regarding the location of lesions, the feet and hands had an estimated prevalence of 91.4% and 17.9%, respectively. These studies showed significant heterogeneity and publication bias (P < .001) in the feet and hand proportions. The statistical results from observational studies are presented in Table 1 . The morphology, color, secondary characteristics, and treatments were not included in the observational studies. The case reports included patients from nine countries: Italy (47.6%), Spain (15.5%), United Kingdom (13.9%), USA (10.7%), France (5.9%), Austria (3.7%), Canada (1.1%), Kuwait (1.1%), and Germany (0.5%). Overall, the median age of patients was 15 years (range 12-28): 15 years (range 12.5-25) for males and 15 years (range [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] for females. The age data did not show a symmetrical distribution (P < .001; Figure 2 ), with 125 (66.8%) cases younger than 20 years and 62 (33.2%) cases 20 years or older. There was no significant age difference between the sexes (P = .838). Hand and foot involvement was evaluated in 187 cases. The frequency of foot involvement was significantly associated with male sex (P = .037), with 90.7% of males and 80.0% of females presenting with foot involvement. Hand involvement was significantly associated with females (30.0%) compared with males (17.5%) (P = .045). Foot involvement was significantly associated with patients under 20 years of age (P < .001; 92.0%) versus 72.6% in patients 20 years and older, whereas hand involvement was significantly associated with patients aged 20 years and older (32.3%) compared with those older than 20 years of age (19.2%) (P = .048). older compared with 8.0% and 12.0%, respectively, in those younger than 20 years. RT-PCR evaluation was reported in 113 (60.4%) cases (Table 2) . (Table 3) . heparin gel, 5 topical clobetasol, 6 nitroglycerin gel, 7 topical triamcinolone, 6 topical clotrimazole, 6 nonspecific topical antibiotic, azithromycin, 8, 9 hydroxychloroquine, 8, 9 oral antihistamine, nonspecific oral corticosteroid, aspirin, 10 gabapentin, 10 enoxaparin, 7 heparin, 11 lowmolecular-weight heparin, 12 and tocilizumab. 8 This paper highlights four main points to help clarify the mechanism behind COVID toes: (i) the pediatric population was mainly affected; (ii) age under 20 years was a determining factor for topography, morphology, signs, symptoms, and RT-PCR positivity; (iii) sex was not a determining factor; and (iv) the histopathological findings were nonspecific. The age distribution of affected patients was one of the most striking aspects of this work. Pediatric patients were predominantly affected, but cases were reported across all age groups. A possible explanation for this phenomenon is based on robust type 1 interferon (IFN-1) production by the pediatric population. IFN-1 acts as a bridge between innate and adaptive immunity, and it plays direct roles in immunomodulation and the production of antiviral proteins. Higher production of IFN-1 in younger individuals is possibly asso- The IgM peak occurs around 5-12 days postinfection, while the IgG peak occurs 20 days after infection. 16 COVID-19-associated pernio-like lesions tend to be self-limited, regardless of the therapy adopted. Oral antihistamines can aid in pruritus relief. 17 Reports about topical and oral corticosteroids are controversial and subjective, having various degrees of relief or no effect. 6, 18 We emphasize that individualized treatment and monitoring are even more important when there is a lack of therapeutic evidence. This study has several limitations. Most of the studies were conducted on the European continent; therefore, care must be taken when generalizing these results. Race subgroups were not evaluated. Case reports have a low or very low evidence level, and many did not follow the methodological rigor of the Case Reports Guideline (CARE). Funnel plot evaluation showed substantial publication bias in some variables, indicated by asymmetry of the points. We acknowledge that some studies published in local non-indexed journals may not have been included in this study. In conclusion, COVID-19-associated pernio-like lesions mostly occur in the pediatric population. The topographic and morphological distribution tends to be different in pediatric and non-pediatric populations. Multifactorial aspects may be associated with the pathophysiology of these lesions. The histopathological patterns are nonspecific and may not help in diagnosis or therapeutic management. The absence of positivity in RT-PCR or serological tests does not rule out a possible association with COVID-19. There is no specific treatment for the lesions, which tend to be self-limited. The data that support the findings of this study are openly available Management of perniolike cutaneous manifestations in children during the outbreak of COVID-19 Chilblains-like dermatologic manifestation of COVID-19 diagnosed by serology via multidisciplinary virtual care SARS-CoV-2-related chilblains Therapy for probable COVID-19 associated erythema pernio-like lesions in pediatric age. Case report Pernio-like eruption associated with COVID-19 in skin of color Treatment of COVID-19 induced chilblains with topical nitroglycerin Necrotic acral lesions and lung failure in a fatal case of COVID-19 Chilblainlike lesions on feet and hands during the COVID-19 Pandemic Chilblain and acral purpuric lesions in spain during covid confinement: retrospective analysis of 12 cases Digital Ischemia in COVID-19 patients: case report Perniolike lesions and coagulopathy in a patient with COVID-19 infection Type I interferonopathies in pediatric rheumatology Stress, inflammation, and eicosanoids: an emerging perspective Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases Recent outbreak of chilblain-like lesions is not directly related to SARS-CoV-2 infection Exantema palmar por el nuevo coronavirus SARS-CoV-2 Histopathological study of a broad spectrum of skin dermatoses in patients affected or highly suspected of infection by COVID-19 in the Northern part of Italy: analysis of the many faces of the viral-induced skin diseases in previous and new reported case