Chilblain-Like Lesions (CLL) Coinciding With the SARS-CoV-2 Pandemic in Children: A Systematic Review.

Chilblain-like lesions (CLL) coinciding with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection have been described in the literature. Available reviews of the literature suggest that CLL are associated with younger age, an equal sex ratio, negative testing for SARS-CoV-2, and mild to no extracutaneous manifestations (ECM) associated with COVID-19 infection. This systematic review aims to provide a summary of reports of CLL associated with the early SARS-CoV-2 pandemic in children to clarify the prevalence, clinical characteristics, and resolution outcomes of these skin findings. Sixty-nine studies, published between May 2020 and January 2022, met inclusion criteria and were summarized in this review, representing 1,119 cases of CLL. Available data showed a slight male predominance (591/1002, 59%). Mean age was 13 years, ranging from 0 to 18 years. Most cases had no ECM (682/978, 70%). Overall, 70/507 (14%) of patients tested positive for COVID-19 using PCR and/or serology. In the majority the clinical course was benign with 355/415 (86%) of cases resolving, and 97/269 (36%) resolving without any treatment. This comprehensive summary of pediatric CLL suggests these lesions are rarely associated with COVID-19 symptoms or test positivity.

[Skin and SARS-CoV-2 in pediatrics]. / Piel y SARS-CoV-2 en pediatría.

The clinical presentation, disease course, and outcome of SARS-CoV-2 infection in pediatrics differ from the presentation in adults. In a review by Hoang et al., the prevalence of dermatological manifestations was estimated in 0.25% of a total of 2,445 children with confirmed COVID-19. Similarly, the prevalence of skin manifestations was reported in 3% of 100 children in the Parri's study. A systematic review by Shah et al. analyzed 13 studies with 149 children who met eligibility criteria. The acral erythematous maculopapular lesion was the most common, as well as erythema multiforme, varicella rash, and presentations similar to Kawasaki disease. The duration of the skin lesion was one to two weeks in 43%. Skin biopsy of 18 cases complete superficial and deep perivascular and paracrine lymphocytic infiltrate and lymphocytic vasculitis were reported. RT-PCR was positive in 13.8 % of the cases. The serological markers of herpes simplex virus and parvovirus B19 analyzed were negative, except for Mycoplasma pneumoniae in two of 20 cases. The pathophysiological mechanism of skin lesions secondary to SARS-CoV-2 infection has not yet been explained; likely to be a combination of one or more complex mechanisms, direct skin damages induced by the virus, vasculitis-like reactions either indirect or secondary injuries as a consequence of a systemic inflammatory reaction. Publications from years 2019 to 2021 are reviewed in PubMed as the main search source, using key words.

La presentación clínica, curso de la enfermedad y resultado de la infección por SARS-CoV-2 en pediatría difieren de los observados en adultos. En una revisión de Hoang et al. se estimó que la prevalencia de las manifestaciones dermatológicas fue de 0.25 % de un total de 2445 niños con COVID-19 confirmada. Según Parri, se documentó 3 % en 100 niños. En la revisión sistemática de Shah et al.se analizaron 13 estudios que incluyeron 149 niños que cumplieron con los criterios de elegibilidad. La lesión maculopapular eritematosa acral fue la más común, también el eritema multiforme, el exantema de la varicela y las presentaciones similares a enfermedad de Kawasaki. La duración de las lesiones cutáneas fue de una a dos semanas en 43 %. La biopsia de piel de 18 casos reveló infiltrado linfocítico perivascular, infiltrado paracrino superficial y profundo y vasculitis linfocítica. La RT-PCR fue positiva en 13.8 %. Los marcadores serológicos analizados de virus de herpes simple y parvovirus B19 fueron negativos, y fueron positivos para Mycoplasma pneumoniae en dos de 20 casos. El mecanismo fisiopatológico de las lesiones en piel secundarias a infección por SARS-CoV-2 aún no se ha podido explicar; es probable que se trate de la combinación de uno o más mecanismos complejos, daños cutáneos directos inducidos por el virus, reacciones vasculíticas o lesiones indirectas o secundarias como consecuencia de una reacción inflamatoria sistemática. Se revisaron las publicaciones de 2019 a 2021 en PubMed como fuente principal de búsqueda, para lo cual se utilizaron palabras clave.

Cilostazol as a Treatment for COVID Toes: A Case Report.

During the Coronavirus Disease 2019 (COVID-19) pandemic, skin lesions resembling those seen in pernio (chilblains) have been observed in patients with COVID-19 infection. The term "COVID toes" has been used when there is toe involvement. We describe the case of a fully vaccinated, 56-year-old woman with no prior diagnosis of COVID-19 who developed pernio-like lesions many months after being vaccinated. Her skin lesions resolved after treatment with cilostazol, suggesting that this medication may be a viable treatment for pernio in the setting of COVID-19 infection.

"COVID toes": A true viral phenomenon or a diagnosis without a leg to stand on?

"COVID toes" is the colloquial name of chilblain-like lesions thought to be a sequela of COVID-19 infection. Over two years and approximately 300 publications later, this association remains controversial. Here, we summarize key clinical, serological, biological, histological, and immunological evidence that supports and rejects this relationship and discuss alternate theories underlying the pathogenesis of chilblain-like lesions.

Vaccine Toes Are the New COVID Toes.

Introduction: Pernio-like lesions were reported as dermatologic manifestations of COVID-19 as early as May of 2020. Since mRNA COVID-19 vaccines were introduced in December 2020, 9 reports of vaccine-associated pernio-like lesions have been presented in the medical literature. Case Presentation: A male in his 60s developed pernio-like lesions on the bilateral toes approximately 1 week after receiving the second dose of the Pfizer-BioNTech COVID-19 mRNA vaccine. His symptoms resolved in 6 weeks. Conclusion: The rising number of reports of pernio-like lesions associated with COVID-19 vaccination underlines the importance of the pathophysiological state of the vaccinated patient and how it relates to dermatological manifestations. Pernio-like lesions are thought to represent a robust host immune antiviral response related to production of interferon-1 in the setting of primary infection; incidences occurring after vaccination further support this theory. Unfortunately, media-generated reports of such reactions have the potential to inflame distrust and fear of the vaccine among the general public. Given the previous media interest in reporting pernio-like lesions with primary COVID-19 infection, it is reasonable to expect overrepresentation of pernio-like lesions with vaccination. There appears to be a general increase in patient distrust of evidence-based medicine and thus "COVID toes" represent an important intersection at which the clinician can capture the patient's trust by providing education and counseling.

Histopathology of persistent long COVID toe: A case report.

During the 2020 coronavirus (SARS-CoV-2) pandemic, several cutaneous lesions were identified, including pseudo-chilblain, vesicular, urticarial, maculopapular, and livedo/necrosis. A 59-year-old obese man with probable COVID-19 developed painful cyanosis with histopathologic capillary thrombosis of toes, and the cyanosis persisted for nearly 22 months. Shortly after initial exposure to family members with documented SARS-CoV-2, he developed upper respiratory symptoms, yet his anti-SARS-CoV-2 antibody and nasal swab RT-PCR tests were repeatedly negative. Two family members were hospitalized and one of them succumbed with documented SARS-CoV-2 pneumonia within 10 days of exposure. Biopsy specimen of the distal toe 16 weeks after initial exposure showed papillary dermal capillary thrombosis with endothelial swelling, telangiectasia, and peri-eccrine lymphocytic infiltrates resembling pernio. Overall, this is the first case of biopsy specimen of "long COVID toe" following presumed SARS-CoV-2 exposure, with a demonstration of thrombotic vasculopathy, toe cyanosis, and pernio-like pathology.

A systematic review on mucocutaneous presentations after COVID-19 vaccination and expert recommendations about vaccination of important immune-mediated dermatologic disorders.

With dermatologic side effects being fairly prevalent following vaccination against COVID-19, and the multitude of studies aiming to report and analyze these adverse events, the need for an extensive investigation on previous studies seemed urgent, in order to provide a thorough body of information about these post-COVID-19 immunization mucocutaneous reactions. To achieve this goal, a comprehensive electronic search was performed through the international databases including Medline (PubMed), Scopus, Cochrane, Web of science, and Google scholar on July 12, 2021, and all articles regarding mucocutaneous manifestations and considerations after COVID-19 vaccine administration were retrieved using the following keywords: COVID-19 vaccine, dermatology considerations and mucocutaneous manifestations. A total of 917 records were retrieved and a final number of 180 articles were included in data extraction. Mild, moderate, severe and potentially life-threatening adverse events have been reported following immunization with COVID vaccines, through case reports, case series, observational studies, randomized clinical trials, and further recommendations and consensus position papers regarding vaccination. In this systematic review, we categorized these results in detail into five elaborate tables, making what we believe to be an extensively informative, unprecedented set of data on this topic. Based on our findings, in the viewpoint of the pros and cons of vaccination, mucocutaneous adverse events were mostly non-significant, self-limiting reactions, and for the more uncommon moderate to severe reactions, guidelines and consensus position papers could be of great importance to provide those at higher risks and those with specific worries of flare-ups or inefficient immunization, with sufficient recommendations to safely schedule their vaccine doses, or avoid vaccination if they have the discussed contra-indications.

Lack of association between pandemic chilblains and SARS-CoV-2 infection.

An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral infection. Direct evidence of this relationship has been limited, however, as most cases do not have molecular evidence of prior SARS-CoV-2 infection with PCR or antibodies. We enrolled a cohort of 23 patients who were diagnosed and managed as having SARS-CoV-2-associated skin eruptions (including 21 pandemic chilblains [PC]) during the first wave of the pandemic in Connecticut. Antibody responses were determined through endpoint titration enzyme-linked immunosorbent assay and serum epitope repertoire analysis. T cell responses to SARS-CoV-2 were assessed by T cell receptor sequencing and in vitro SARS-CoV-2 antigen-specific peptide stimulation assays. Immunohistochemical and PCR studies of PC biopsies and tissue microarrays for evidence of SARS-CoV-2 were performed. Among patients diagnosed and managed as "covid toes" during the pandemic, we find a percentage of prior SARS-CoV-2 infection (9.5%) that approximates background seroprevalence (8.5%) at the time. Immunohistochemistry studies suggest that SARS-CoV-2 staining in PC biopsies may not be from SARS-CoV-2. Our results do not support SARS-CoV-2 as the causative agent of pandemic chilblains; however, our study does not exclude the possibility of SARS-CoV-2 seronegative abortive infections.

Evolution of incidence of chilblain-like lesions in children during the first year of COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has brought innumerable reports of chilblains. The relation between pernio-like acral eruptions and COVID-19 has not been fully elucidated because most reported cases have occurred in patients with negative microbiological tests for SARS-CoV-2. METHODS: A retrospective study of 49 cases of chilblains seen during the first year of the pandemic in a children's hospital in Madrid, Spain. The incidence of these skin lesions was correlated with the number of COVID-19 admissions and environmental temperatures. Patients were separated into two groups depending on the day of onset (strict lockdown period vs. outside the lockdown period). RESULTS: Most chilblains cases presented during the first and third waves of the pandemic, paralleling the number of COVID-19 admissions. The first wave coincided with a strict lockdown, and the third wave coincided with the lowest ambient seasonal temperatures of the year. Systemic symptoms preceding chilblains were more frequent in the first wave (45.8% vs. 8.0%, p = .002), as was the co-occurrence with erythema multiforme-like lesions (16.7% vs. 0%, p = .033). Laboratory test and skin biopsies were performed more frequently in the first wave (75.0% vs. 12.0%, p < .001; and 25.0% vs. 0%, p = .007; respectively). Five patients developed recurrent cutaneous symptoms. CONCLUSIONS: An increased incidence of chilblains coincided not only with the two major waves of the pandemic, but also with the strict lockdown period in the first wave and low seasonal temperatures during the third wave. Both increased sedentary behaviors and cold environmental temperatures may have played an additive role in the development of COVID-19-related chilblains.

Chilblains during lockdown are associated with household exposure to SARS-CoV-2: a multicentre case-control study.

OBJECTIVES: During the COVID-19 pandemic, numerous cases of chilblains have been reported. However, in most cases, RT-PCR or serology did not confirm SARS-CoV-2 infection. Hypotheses have been raised about an interferon-mediated immunological response to SARS-CoV-2, leading to effective clearance of the SARS-CoV-2 without the involvement of humoral immunity. Our objective was to explore the association between chilblains and exposure to SARS-CoV-2. METHODS: In this multicentre case-control study, cases were the 102 individuals referred to five referral hospitals for chilblains occurring during the first lockdown (March to May 2020). Controls were recruited from healthy volunteers' files held by the same hospitals. All members of their households were included, resulting in 77 case households (262 individuals) and 74 control households (230 individuals). Household exposure to SARS-CoV-2 during the first lockdown was categorized as high, intermediate or low, using a pre-established algorithm based on individual data on symptoms, high-risk contacts, activities outside the home and RT-PCR testing. Participants were offered a SARS-CoV-2 serological test. RESULTS: After adjustment for age, the association between chilblains and viral exposure was estimated at OR 3.3, 95% CI (1.4-7.3) for an intermediate household exposure, and 6.9 (2.5-19.5) for a high household exposure to SARS-CoV-2. Out of 57 case households tested, six (11%) had positive serology for SARS-CoV-2, whereas all control households tested (n = 50) were seronegative (p = 0.03). The effect of potential misclassification on exposure has been assessed in a bias analysis. DISCUSSION: This case-control study demonstrates the association between chilblains occurring during the lockdown and household exposure to SARS-CoV-2.

A Case of Longstanding Idiopathic Pernio/Chilblain Disease.

Pernio, also known as chilblains, presents as erythematous macules at sites of cold exposure, mainly in women. It is a diagnosis that is often overlooked, and when suspecting a patient with pernio, other conditions such as lupus nephritis and Raynaud's must be ruled out. A 46-year-old lady presented to the clinic with skin findings suggestive of pernio. She had erythematous macules on the dorsum of her hands, which appeared during cold weather and lasted for three weeks. She had been suffering with this condition for over 18 years and nothing has helped her condition, other than preventing cold exposure. There are limited treatment options for pernio, and current management includes using steroids, calcium-channel blockers and cold avoidance. Current research has suggested that pernio could also be linked to the severe acute respiratory syndrome coronavirus 2.

"COVID toes": A meta-analysis of case and observational studies on clinical, histopathological, and laboratory findings.

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.

Clinical and pathologic correlation of cutaneous COVID-19 vaccine reactions including V-REPP: A registry-based study.

BACKGROUND: Cutaneous reactions after COVID-19 vaccination have been commonly reported; however, histopathologic features and clinical correlations have not been well characterized. METHODS: We evaluated for a history of skin biopsy all reports of reactions associated with COVID-19 vaccination identified in an international registry. When histopathology reports were available, we categorized them by reaction patterns. RESULTS: Of 803 vaccine reactions reported, 58 (7%) cases had biopsy reports available for review. The most common histopathologic reaction pattern was spongiotic dermatitis, which clinically ranged from robust papules with overlying crust, to pityriasis rosea-like eruptions, to pink papules with fine scale. We propose the acronym "V-REPP" (vaccine-related eruption of papules and plaques) for this spectrum. Other clinical patterns included bullous pemphigoid-like (n = 12), dermal hypersensitivity (n = 4), herpes zoster (n = 4), lichen planus-like (n = 4), pernio (n = 3), urticarial (n = 2), neutrophilic dermatosis (n = 2), leukocytoclastic vasculitis (n = 2), morbilliform (n = 2), delayed large local reactions (n = 2), erythromelalgia (n = 1), and other (n = 5). LIMITATIONS: Cases in which histopathology was available represented a minority of registry entries. Analysis of registry data cannot measure incidence. CONCLUSION: Clinical and histopathologic correlation allowed for categorization of cutaneous reactions to the COVID-19 vaccine. We propose defining a subset of vaccine-related eruption of papules and plaques, as well as 12 other patterns, following COVID-19 vaccination.

Nail Manifestations in COVID-19: Insight into a Systemic Viral Disease.

Nail manifestations are 1 of the several extrapulmonary findings associated with COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nail changes, however, have been largely ignored and not yet summarized. This article is intended to increase awareness of nail manifestations of SARS-CoV-2, which occur weeks to months after acute infection and the periungual pernio-like changes may occur concomitantly with infection. An electronic search was carried out in PubMed (Medline), Science Direct, and Scopus databases. The following keywords and all of their possible combinations were used to identify studies: "SARS-CoV-2," "COVID-19," "Coronavirus," "2019-ncov," "nail," and "nails." Six case reports were included in this study. Manifestations identified included red half-moon sign, transverse orange nail lesions, Mees' lines, and Beau's lines. Though largely nonspecific, these findings can be recognized with the onset of symptom onset or as late as 16 weeks following the disease. Some of these findings are shared with other conditions associated with a proinflammatory state. Nail changes offer unique insight into the pathophysiologic basis for SARS-CoV-2 and they may serve as diagnostic clues.