Discussion
During the SARS-Cov2 pandemic there have been numerous reports (case report, case series) in literatures of chilblain like lesions. In our clinical practice we come into contact with about 1-2 cases of chilblain/year, mainly in cold months. The increased demand for medical visits for these skin manifestations, associated to mild temperatures observed in those months in Southern Italy and the high diffusion of SARS Cov-2 infection, led us to hypothesize a possible correlation with it.
We valued 9 cases of children who presented chilblain like lesions, since March to April 2020 during the outbreak of COVID-19. We performed first level tests, all negative except for D-dimer weakly increased in three of our patients. D-dimer is a marker of activation of coagulation and fibrinolysis and it provides a rapid evaluation of thrombotic activity. Its level correlated to coagulopathy have been described as prognostic factors in the evolution of SARS-CoV2 infection, especially in more severe patients. Zhang’s study developed a triage, testing D-dimer levels at the admission, on the first and third day to predict survival in a cohort of patients and to evaluate management and follow up. The result was that a regulatory level of D-dimer at the presentation is highly predictive for survival11L, Yan X, Fan Q, Liu H, Liu X, Liu Z, Zhang Z. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost. 2020 Jun;18(6):1324-1329. doi: 10.1111/jth.14859. PMID: 32306492; PMCID: PMC7264730.. This is useful to highlight, as in our case, the D-dimer of our patients was weak is increased, a condition perfectly correlated with the mild symptoms of SARS-CoV2 putative infection presented. We have also done autoimmunity tests, three out of nine had a ANA positivity (speckled pattern): two with a title of 1:160, one 1:320 not confirmed at a subsequent check after two months; another one with 1:5120 (speckled pattern) and she also had FR positivity and ENA SS-A positivity. Four out of nine had aPL positivity (IgM). The findings of the high title positivity of the ANA, ENA and the FR, in patient n 7, help us make a diagnosis of connectivity also for the similar symptomatology presented already in one occasion a year earlier. However, we cannot rule out that a possible SARS-CoV2 infection acted as a trigger. In other patients with ANA positivity, we can say that either it is a completely occasional finding, or more likely that this increase was caused by a recent viral infection (SARS-CoV2?). Acute viral, bacterial or parasitic infections may in fact induce antinuclear antibody and antiphospholipid antibodies positivity. This condition is transient and disappear within 2 or 3 months like in our patients22Berlin T, Zandman-Goddard G, Blank M, et al. Autoantibodies in nonautoimmune individuals during infections. Ann N Y Acad Sci . 2007;1108:584-593. doi:10.1196/annals.1422.061. It is important to underline that the chilblain-like manifestations in our patients healed spontaneously without any treatment. The results of our study are homogeneous describing the negativity of the oropharyngeal swab and serological tests, carried out respectively after about 30 days and 60 days from the appearance of the systemic manifestations probably related to SARS-Cov2 infection (Table 1). A lack of seroconversion is hypothesized in asymptomatic or pauci-symptomatic subjects who had SARS-CoV2 infection. Zhang et al. showed that in a cohort of patients divided into three groups according to the severity of the symptoms, (severe, mild and asymptomatic): 100% of the serious patients had shown seroconversion, only 1 out 5 asymptomatic cases generated specific antibody responses for SARS-CoV-233Zhang Yongchen, Han Shen, Xinning Wang, Xudong Shi, Yang Li, Jiawei Yan, Yuxin Chen & Bing Gu (2020) Different longitudinal patterns of nucleic acid and serology testing results based on disease severity of COVID-19 patients, Emerging Microbes & Infections, 9:1, 833-836, DOI: 10.1080/22221751.2020.1756699. The case of our family is emblematic: two parents presented striking symptoms of SARS-Cov2 infection, very high fever and difficulty in breathing, and three positive swabs; the father had positive serology with very high IgG, such as to have allowed the donation of plasma for therapeutic purposes, and the mother instead, surprisingly,negative. Sons who came to our observation, both with chilblain, presented mild respiratory symptoms and they were negative for both swabs and IgG serology, while in one of the two cases, the IgM were borderline. Despite the negativities of diagnostic test for SARS-CoV2, we are still convinced that there is a correlation between this infection and the development of chilblain-like lesions, as described in numerous reports. A group of Italian Dermatologists described 63 patients with chilblain like lesions, primarily adolescents. Swab for Sars-Cov2 infection was performed in 11 patients and resulted positive in 2 cases; serology was available in 6 cases and it was positive in the 2 patients with positive swab2. Also a study among 375 cutaneous manifestations in suspected SARS-Cov2 patients in Spain, 71 (19%) presented with “pseudo-chilblains”. Only one of the 71 patients had previous history of chilblain; 29 (41%) had SARS-CoV-2 confirmed3. Recalcati et al described from Lombardy, 14 cases including 11 children (average age 14 years) and 3 young adults (average age 29 years) with chilblain-like eruptions. No systemic symptoms were reported, except a mild itch in 3 cases. Nasopharyngeal swab for SARS-CoV-2 gave negative results5. In a report of 19 adolescent patients with a clinical diagnosis of chilblain-like lesions nasopharyngeal swab and IgG serology for SARS-CoV-2 nucleocapsid protein were negative. Importantly, IgA serology for S1 domain of SARS-CoV-2 spike protein was positive in 6 patients and borderline in 3 patients44El Hachem M, Diociaiuti A, Concato C, et al. A clinical, histopathological and laboratory study of 19 consecutive Italian paediatric patients with chilblain-like lesions: lights and shadows on the relationship with COVID-19 infection [published online ahead of print, 2020 May 31]. J Eur Acad Dermatol Venereol. 2020;10.1111/jdv.16682. doi:10.1111/jdv.16682. The understanding of the immuno-pathogenetic mechanisms of interaction between the SARS-CoV2 infection and childrens is very intriguing but current knowledge does not seem to be sufficient. Why some of the children who come into contact with the SARS-CoV2 do not develop striking respiratory symptoms but present chilblain like lesions with negativity on diagnostic tests?
Matricardi et al developed the first model of interaction between the human immune system and SARS-CoV-2, as an attempt to produce a synthesis of what is known today55Matricardi PM, Dal Negro RW, Nisini R. The first, holistic immunological model of COVID-19: implications for prevention, diagnosis, and public health measures [published online ahead of print, 2020 May 2]. Pediatr Allergy Immunol. 2020;10.1111/pai.13271. doi:10.1111/pai.13271. What emerges is that innate immunity represents the first line of defense against the new SARS-CoV-2 and this first comparison establishes the natural history of the pathology, or if the infection will effectively block in the upper airways, or if the virus manages to reach the lungs. Innate immunity is essential for controlling virus replication before an adaptive immune response is generated66Yu JC, Khodadadi H, Malik A, Davidson B, Salles ESL, Bhatia J, et al. Innate Immunity of Neonates and Infants. Front Immunol. 2018;9:1759. DOI:10.3389/fimmu.2018.01759.. Type I Interferones (IFN-I) are major components of the innate immune system and it represents critical antiviral molecules77Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (a/b) in immunity and autoimmunity. Annu Rev Immunol 2005;23:307-35.. It is hypothesized that the IFN-I response may induce microangiopathic changes, producing chilblains and lupus-like erythematous eruption.