key: cord-1017434-4dnj742q authors: Cordoro, Kelly M.; Reynolds, Sean D.; Wattier, Rachel; McCalmont, Timothy H. title: Clustered Cases of Acral Perniosis: Clinical Features, Histopathology and Relationship to COVID‐19 date: 2020-05-12 journal: Pediatr Dermatol DOI: 10.1111/pde.14227 sha: bfbc493f793a4fc99951dbf7f2dc2393adf4b27d doc_id: 1017434 cord_uid: 4dnj742q BACKGROUND/OBJECTIVES: There has been a recent marked increase in pediatric and adult patients presenting with purpuric acral lesions concerning for ischemia, thrombosis and necrosis in COVID‐19 prevalent regions worldwide. The clinical and histopathological features and relationship to COVID‐19 have not been well described. The objective of this case series is to describe the clinical features and determine the histopathologic findings and clinical implications of the clusters of acral perniosis cases identified in pediatric patients. METHODS: We describe 6 otherwise healthy adolescents – 3 siblings per family from 2 unrelated families – presented within a 48‐hour period in April, 2020, with acral perniosis‐like lesions in the context of over 30 similar patients who were evaluated within the same week. RESULTS: Affected patients had mild symptoms of viral upper respiratory infection (URI) or contact with symptomatic persons 1‐2 weeks preceding the rash. They all presented with red to violaceous macules and dusky, purpuric plaques scattered on the mid and distal aspects of the toes. Skin biopsies performed on each of the 6 patients demonstrated near identical histopathologic findings to those of idiopathic perniosis, with a lymphocytic inflammatory infiltrate without evidence of thromboembolism or immune complex vasculitis. While SARS‐CoV‐2 polymerase chain reaction was negative, testing was performed 1‐2 weeks after URI symptoms or sick contact exposure. CONCLUSION: We offer a clinical approach to evaluation of patients with this presentation and discuss the possibility that these skin findings represent a convalescent‐phase cutaneous reaction to SARS‐CoV‐2 infection. This article is protected by copyright. All rights reserved early April, our center saw a sharp uptick in pediatric patients with itchy, tender acral lesions. The temporal relationship between suggestive viral symptoms in affected patients and/or close contacts and the appearance of the lesions suggest a relationship to SARS-CoV-2 infection. A report detailing acro-ischemia in the context of acquired hypercoagulable states in critically ill COVID-19 patients from Wuhan describes cyanosis, bullae and gangrene of the digits. Four of these patients developed disseminated intravascular coagulation (DIC) and five died. 2 In addition, adult patients with COVID-19 with coagulopathy, antiphospholipid antibodies, and multiple infarcts have been described. 3 Whether a relationship exists between the severe adult inpatient cases and systemically healthy pediatric patients with acral purpura is unknown. We present a detailed investigation of the clinical and histopathological features of 6 healthy adolescent outpatients presenting with acral purpura amidst the COVID-10 pandemic. We offer an approach to evaluation, discuss the likelihood that these skin findings represent a convalescent-phase cutaneous reaction to SARS-CoV-2 infection, and offer evidence that pediatric cases are distinct from the severe ischemic and thrombotic cases in adults. We report 6 patients-3 siblings per family from 2 unrelated families -who presented to our tertiary referral academic children's hospital in Northern California within a 48-hour period in early April 2020. The patients ranged in age from 12-17 years; 5 were male, 1 female. All were healthy with no significant past medical history nor family history of inflammatory, autoimmune genetic or coagulopathic conditions. Provisional diagnoses prior to dermatology evaluation included postinfectious vasculitis, perniosis, coagulopathy and septic emboli. There were striking similarities to their history and presentation. Two siblings from one family reported rhinorrhea, congestion, sore throat and subjective fevers one week prior to the onset of skin lesions. There were no symptoms This article is protected by copyright. All rights reserved nasopharynx and oropharynx swabs; COVID-19 IgM and IgG antibodies were negative; however, there are concerns regarding the validity of serologic testing (discussed below). Histopathologic Findings (Figure 2) We obtained two biopsies of lesional skin from all six patients for conventional and direct immunofluorescence (DIF) microscopy. Routine sections demonstrated a superficial and deep lymphocytic infiltrate that also abuts the junctional zone, where vacuolar change and purpura were noted. There was hemorrhagic parakeratosis in the stratum corneum. The dermal infiltrate was tightly perivascular and also perieccrine, and intramural lymphocytes ('lymphocytic vasculitis') were present in the thin muscular walls of small vessels. There was no evidence of thrombosis in the vessels. Direct immunofluorescence was negative for immunoreactant deposition in all cases. Overall, the histopathologic findings were nearly identical in all patients and to those seen in perniosis. The cases reported herein describe the clinical presentation, laboratory evaluation and histopathologic This article is protected by copyright. All rights reserved Clinical Implications and Relevance to the COVID-19 Pandemic While clusters of perniosis cases have been reported in Australia 7 and parts of China 8 during unusually cold periods, perniosis has also clustered in association with viral and bacterial infection including Mycoplasma. 7 Cold agglutinins and cryoglobulins produced in response to viral infection have been hypothesized as a cause of post-infectious perniosis. 9 Laboratory evaluation and histopathology of our cases did not show evidence of cryproteinemia or other coagulopathy and suggest the etiology is inflammatory but not thromboembolic. Evidence from Wuhan and early US investigations in children suggest that a majority of COVID-19 infected children are mildly symptomatic. 10 Effective innate immune responses to viral infection rely on type I interferons (IFNs) which activate the JAK-STAT signaling pathway leading to the expression of genes that block viral replication and dissemination. 11 Interestingly, patients with Type I Interferonopathies have similar immune signaling and develop perniosis-type lesions. 12, 13 It is possible that healthy children have a robust initial IFN-1 immune response to infection that produces transient cold-like symptoms (as described in our patients) or no symptoms at all, and which may both protect from progressive infection and precipitate inflammatory perniosis. It seems unlikely that the perniosis observed in healthy outpatients has a direct relationship to the severe coagulopathy, ischemic necrosis and infarcts observed in critically ill adult patients with COVID-19 infection. 2 To date, widespread SARS-CoV-2 testing has not been performed on healthy pediatric outpatients and therefore the timing of the infection relative to onset of perniosis is unclear. The timeline of our cases suggests that acral perniosis may represent a response to subclinical infection or a convalescent-phase reaction. Given the uncertain relationship to SARS-CoV-2 and the as-yet unclear natural history of these cases, patients who are otherwise well and systemically asymptomatic could be watched closely and offered conservative care measures. Those who are febrile, have severe, diffuse or necrotic skin lesions or systemic symptoms should undergo comprehensive laboratory evaluation including coagulation panels and possibly skin biopsy to clarify the diagnosis and direct management. Patients This article is protected by copyright. All rights reserved presenting with acral perniosis should be tested for COVID-19 with PCR and antibodies if available given the clinical and epidemiologic implications. Of note, 24 additional cases evaluated in the Bay Area last week were in adolescent patients aged 10 to 19 years. 13 of 24 of these have been tested with upper respiratory PCR and all have been SARS-CoV-2 negative. Lack of positive testing has presented obstacles to defining the precise relationship between acral perniosis and SARS-CoV-2 infection. It is important to note limitations in testing for COVID-19, particularly later in the course of illness. False negative PCR testing has been reported from multiple upper respiratory sites and false negative rates may be higher in minimally symptomatic persons. 14 Viral detection in the upper respiratory tract is highest in the pre-symptomatic and early symptomatic phases of infection and declines before day 5 of respiratory symptoms. 15, 16 Antibody testing for COVID-19 is very newly developed at this time. It is unclear what the ideal timing of testing should be, and concerns have arisen about clinical validity and reproducibility of the current commercially available tests. 17 It is also possible that recent cases of acral perniosis are unrelated to SARS-CoV-2 infection directly and instead represent a temporally associated epiphenomenon that is not yet fully understood. Some have hypothesized that acral perniosis is quarantine-related due to prolonged barefoot exposure to cool indoors. Assessment of a large sample size over time will clarify the demographics, range of clinical features and severity, association with COVID-19 (as antibody testing becomes more reliable and widely available) and provide data for risk stratification in terms of evaluation, management and clinical course. The Pediatric Dermatology Research Alliance COVID-19 Response Task Force has developed a registry to rapidly collect and analyze cases towards a better understanding of this phenomenon 18 . Acute Acro-Ischemia in the child in the time of COVID-19. Mazzotta F., Troccoli T. Dermatologia Pediatrica, Bari, with acknowledgement to "Amici DermPed Forum and doctors Francesca Baisi and Laura D'Aloisio who sent the clinical case images via WhatsApp Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19 CA Monthly Weather Forecast -weather.com. The Weather Channel Clinical characteristics, etiologic associations, laboratory findings, treatment, and proposal of diagnostic criteria of pernio (chilblains) in a series of 104 patients at Mayo Clinic Vasospasm Is a Consistent Finding in Pernio (Chilblains) and a Possible Clue to Pathogenesis Accepted Article This article is protected by copyright. All rights reserved Major cluster of chilblain cases in a cold dry Western Australian winter. J Paediatr Child Health A cluster of chilblains in Hong Kong. Hong Kong medical journal Childhood pernio and cryoproteins Coronavirus Disease 2019 in Children -United States Regulation of type I interferon responses Familial Chilblain Lupus -What Can We Learn from Type I Interferonopathies? Coronavirus (COVID-19) infectioninduced chilblains: a case report with histopathological findings Evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and monitoring the viral shedding of 2019-nCoV infections Virological assessment of Accepted Article This article is protected by copyright. All rights reserved hospitalized patients with COVID-2019 SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients The Promise and Peril of Antibody Testing for COVID-19 Acknowledgements: The authors would like to thank Drs. Amy Gilliam and Ilona Frieden for their critical review of this manuscript.