Clinical, Laboratory, and Interferon-Alpha Response Characteristics of Patients With Chilblain-like Lesions During the COVID-19 Pandemic

Abstract

Importance: Chilblain-like lesions have been reported during the coronavirus 2019 (COVID-19) pandemic. The pathophysiology of such manifestations remains largely unknown.

Objective: To perform a systematic clinical, histologic, and biologic assessment in a cohort of patients with chilblain-like lesions occurring during the COVID-19 pandemic.

Design, setting, and participants: In this prospective case series carried out with a COVID-19 multidisciplinary consultation group at the University Hospital of Nice, France, 40 consecutive patients presenting with chilblain-like lesions were included.

Main outcomes and measures: Patients underwent a thorough general and dermatologic examination, including skin biopsies, vascular investigations, biologic analyses, interferon-alpha (IFN-α) stimulation and detection, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) and serologic analysis.

Results: Overall, 40 consecutive patients with chilblain-like lesions were included. Most patients were young, with a median (range) age of 22 (12-67) years; 19 were male and 21 were female. The clinical presentation was highly reproducible with chilblain-like lesions mostly on the toes. Bullous and necrotic evolution was observed in 11 patients. Acrocyanosis or cold toes were reported in 19 (47.5%) cases. Criteria compatible with COVID-19 cases were noted in 11 (27.5%) within 6 weeks prior to the eruption. The real-time PCR (rt-PCR) testing results were negative in all cases. Overall, SARS-CoV-2 serology results were positive in 12 patients (30%). D-dimer concentration levels were elevated in 24 (60.0%) cases. Cryoglobulinemia and parvovirus B19 serologic results were negative for all tested patients. The major histologic findings were features of lymphocytic inflammation and vascular damage with thickening of venule walls and pericyte hyperplasia. A significant increase of IFN-α production after in vitro stimulation was observed in the chilblain population compared with patients with mild-severe acute COVID-19.

Conclusions and relevance: Taken together, our results suggest that chilblain-like lesions observed during the COVID-19 pandemic represent manifestations of a viral-induced type I interferonopathy.

Trial registration: ClinicalTrials.gov Identifier: NCT04344119.

Figure 1.. Clinical and Histologic Presentation of Chilblain-like Lesions

A, Red-to-violaceous purpuric lesions on the toes. Note the bullous and necrotic evolution. B, Red-to-violaceous papules with marked bullous evolution. C, Dense superficial and deep lymphocytic inflammation with perivascular and peri-eccrine arrangement (hematoxylin-eosin stain). D, Interface dermatitis extending to the intra-epidermis portion of acrosyringium (hematoxylin-eosin stain).

Figure 2.. Comparison of IFN-α Response in Chilblain Population With Ambulatory and Hospitalized Mild or Severe Cases of Coronavirus Disease 2019 (COVID-19)

A. Interferon alpha (IFN-α) levels after stimulation in the population with chilblains compared with patients with ambulatory or hospitalized mild or severe forms of COVID-19. Results are shown for all the patients tested. The dots represent the level detected for each patient and the bar represents the median. Chilblains: n = 25; median (range) age, 32 (16-38) years; mean (range) IFN-α levels, 751 (224-1468) pg/mL; ambulatory: n = 10; median (range) age, 41 (16-73); mean (range) IFN-α levels, 262 (95.5-1015) pg/mL; hospitalized mild or severe: n = 58; median (range) age: 64 (22-89) years; mean (range) IFN-α levels, 9.8 (1.6-84.9) pg/mL. B. Results when population was paired by age. The dots represent the level of IFN-α detected for each patient and the bar represents the median. Chilblains: n = 25; median (range) age, 32 (16-38) years; mean (range) IFN-α levels, 751 (224-1468) pg/mL; ambulatory: n = 10; median (range) age, 41 (16-73) years; mean (range) IFN-α levels, 262 (95.5-1015) pg/mL; hospitalized mild or severe: n; = 7; median (range) age: 42 (22-47) years; mean (range) IFN-α levels, 89.2 (4.9-777) pg/mL.