Cutaneous Pathology of COVID-19 as a Window into Immunologic Mechanisms of Disease.

Many skin manifestations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection reflect activation of cutaneous and systemic immune responses involving effector pathways of both the innate and adaptive arms of the immune system. This article reviews evidence from the recent clinical and scientific literature that informs the current understanding of the consequences of coronavirus disease 2019 (COVID-19)-induced immune cell activation, as relevant to dermatology. Topics include the clinical consequences of autoantibody production in patients with COVID-19, immunologic evidence for chilblains as a manifestation of SARS-CoV-2 infection, and the relationship between type I interferons and COVID-19 disease severity.

Cutaneous Manifestations of COVID-19.

Patients with coronavirus disease 2019 (COVID-19) present with multisystem signs and symptoms, including dermatologic manifestations. The recent literature has revealed that dermatologic manifestations of COVID-19 often are early onset and provide helpful cues to a timely diagnosis. We compiled the relevant emerging literature regarding the dermatologic manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) so that physicians can be aware of the various clinical cutaneous presentations in this time of high incidence of COVID-19.

Chilblain-Like Lesions (CLL) Associated With COVID-19 ("COVID Toes"): A Systematic Review.

Reports of chilblain-like lesions (CLL) coinciding with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been described in the literature, but this phenomenon has not been critically summarized. The aim of this paper is to summarize reports of CLL coinciding with SARS-CoV-2 infection to clarify the prevalence, clinical relevance, and prognostic value of these lesions. A literature search was conducted using the Embase, Pubmed, and Scopus databases from December 2019 to June 16, 2020 using the search terms ("COVID-19" OR "coronavirus" OR "2019-nCoV" OR "SARS-CoV-2") AND ("chilblain-like" OR "COVID toes" OR "acral"). Papers that described skin changes in patients with suspected or confirmed COVID-19 were included. A total of 31 papers were summarized, representing 813 cases of CLL. Available data suggests an equal gender distribution, mean age of 21 years, and median age of 14 years. Mild extracutaneous symptoms were reported in 53% of cases and 47% were asymptomatic. CLL occurred an average of 16 days after extracutaneous symptoms. Patients with CLL were positive for SARS-CoV-2 in 15% of cases. Lesions were mainly described as asymptomatic and/or pruritic erythematous to violaceous acral macules and plaques. Partial or complete resolution occurred in 85% of cases in a mean of 13 days. The most common histologic findings were perivascular and perieccrine superficial and deep lymphocytic infiltrates. Although a causal relationship between CLL and SARS-CoV-2 has not been confirmed, the temporal association and 15% positive SARS-CoV-2 rate in affected individuals should not be ignored.

Pernio (Chilblains), SARS-CoV-2, and COVID Toes Unified Through Cutaneous and Systemic Mechanisms.

Pernio or chilblains is characterized by erythema and swelling at acral sites (eg, toes and fingers), typically triggered by cold exposure. Clinical and histopathologic features of pernio are well described, but the pathogenesis is not entirely understood; vasospasm and a type I interferon (IFN-I) immune response are likely involved. During the coronavirus disease 2019 (COVID-19) pandemic, dermatologists have observed an increase in pernio-like acral eruptions. Direct causality of pernio due to COVID-19 has not been established in many cases because of inconsistent testing methods (often negative results) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a form of COVID-19‒associated pernio (also called COVID toes) is probable because of increased occurrence, frequently in young patients with no cold exposure or a history of pernio, and reports of skin biopsies with positive SARS-CoV-2 immunohistochemistry. PubMed was searched between January 1, 2020, and December 31, 2020 for publications using the following keywords: pernio, chilblain, and acral COVID-19. On the basis of our review of the published literature, we speculate that several unifying cutaneous and systemic mechanisms may explain COVID-19‒associated pernio: (1) SARS-CoV-2 cell infection occurs through the cellular receptor angiotensin-converting enzyme 2 mediated by transmembrane protease serine 2, subsequently affecting the renin-angiotensin-aldosterone system with an increase in the vasoconstricting, pro-inflammatory, and prothrombotic angiotensin II pathway. (2) Severe acute respiratory syndrome coronavirus 2 cell infection triggers an immune response with robust IFN-I release in patients predisposed to COVID-19‒associated pernio. (3) Age and sex discrepancies correlated with COVID-19 severity and manifestations, including pernio as a sign of mild disease, are likely explained by age-related immune and vascular differences influenced by sex hormones and genetics, which affect susceptibility to viral cellular infection, the renin-angiotensin-aldosterone system balance, and the IFN-I response.

Cutaneous manifestations of COVID-19.

The severe acute respiratory syndrome coronavirus two (SARS-CoV-2), which causes the 2019 coronavirus disease (COVID-19), has infected patients worldwide. Physicians have increasingly identified cutaneous findings as a significant clinical manifestation of COVID-19. In this review, we describe the clinical presentation, onset, duration, associated symptoms, treatment, and outcome of cutaneous manifestations thus far reported to be related to COVID-19. We have included data from 63 studies and subdivided reported cutaneous manifestations into the categories of viral exanthem, urticarial, vesicular, chilblains/chilblains-like, non-chilblains vasculopathy-related, pityriasis rosea-like, erythema multiforme-like, Kawasaki/Kawasaki-like disease, and others. Physicians should be aware of the known common cutaneous manifestations of COVID-19 and future research is required to better understand the pathophysiology and prognosis of each COVID-19-related skin manifestation.

Familial chilblain lupus due to a novel mutation in TREX1 associated with Aicardi-Goutie'res syndrome.

BACKGROUND: Familial chilblain lupus (FCL) is a rare, chronic form of cutaneous lupus erythematosus, which is characterized by painful bluish-red inflammatory cutaneous lesions in acral locations. Mutations in TREX1, SAMHD1 and STING have been described in FCL patients. Less than 10 TREX1 mutation positive FCL families have been described in the literature. CASE PRESENTATION: Genetic study was performed in a large, nonconsanguineous Chinese family with 13 members over 4 generations affected by chilblain lupus. Whole exome sequencing was performed for the index patient. Significant variant detection was subsequently validated by resequencing using Sanger sequencing in the index patient and other family members. A novel pathogenic mutation TREX1 p.Asp18His was iditified in the index patient. The mutation was present in affected individuals and was absent in non-affected individuals in the familiy. CONCLUSIONS: We present a four-generation Chinese family with FCL caused by a novel heterozygous mutation TREX1 p.Asp18His, which had been reported in a patient with Aicardi-Goutie'res syndrome. This is the first reported Chinese family with FCL based on mutation in TREX1.

Familial Chilblain Lupus - What Can We Learn from Type I Interferonopathies?

PURPOSE OF REVIEW: Familial chilblain lupus belongs to the group of type I interferonopathies and is characterized by typical skin manifestations and acral ischaemia. This review aims to give an overview of clinical signs and the pathophysiological mechanisms. RECENT FINDINGS: There are several mutations that can lead to this autosomal dominant disease. Most frequent is a mutation of the gene for TREX-1. However, as well cases of families with mutations in the SAMHD1 gene and, recently, with one for the gene that codes for the protein stimulator of interferon genes have been described. These genes are involved in the process of the detection of intracellular DNA, and their mutation results in an increased production of type I interferons and their gene products, resulting in auto-inflammation and auto-immunity. JAK inhibitors have been successfully used to treat this disorder. Familial chilblain is a rare disorder with very distinct clinical signs. Its pathophysiological mechanism gives insight into the process of interferon-induced inflammation in auto-immune diseases.

Vasospasm Is a Consistent Finding in Pernio (Chilblains) and a Possible Clue to Pathogenesis.

BACKGROUND/AIMS: Pernio (chilblains) is an inflammatory condition classically characterized by localized erythema and swelling of acral sites upon exposure to cool and damp conditions. We sought to determine whether cold-induced vasospasm has a role in the development of pernio. METHODS: We retrospectively reviewed 5 patients with pernio who were seen at our institution between January 1, 2000 and December 31, 2011, and had undergone a noninvasive arterial vascular study of the upper extremities that corresponded to a site of clinical involvement of pernio and who had also undergone vasospastic testing and ice water immersion as part of the noninvasive arterial vascular study protocol. RESULTS: Vascular testing in all patients (mean age 37.8 years; 4 women) demonstrated vasospasm with ice water immersion. CONCLUSION: Our findings suggest that vasospasm likely has a role in the pathophysiology of pernio and may also provide a rationale for the pharmacological treatment of vasospasm in patients with pernio.

Familial chilblain lupus due to a novel mutation in the exonuclease III domain of 3' repair exonuclease 1 (TREX1).

IMPORTANCE: Familial chilblain lupus is a rare, autosomal dominant form of lupus erythematosus characterized by cold-induced inflammatory lesions at acral locations presenting in early childhood. Familial chilblain lupus is usually caused by a mutation in TREX1 (3' repair exonuclease 1). OBSERVATIONS: We report on a family with dominant chilblain lupus segregating a novel TREX1 mutation (c.585C>G; H195Q) within the highly conserved exonuclease (Exo) III domain. Affected family members experienced cold-induced chilblain lesions of varying degrees, ranging from bluish-red infiltrations to mutilating necrotic ulcerations. In addition, all patients showed signs of systemic disease, such as arthritis, lymphopenia, or antinuclear antibodies. An increased expression of myxovirus resistance protein A in the skin and induction of interferon-stimulated genes in peripheral blood cells demonstrated activation of type I interferon. CONCLUSIONS AND RELEVANCE: This case further implicates type I interferon-dependent innate immune activation in the pathogenesis of TREX1-associated familial chilblain lupus. Unlike previously reported TREX1 mutations, which affect the Exo I or Exo II domains, the mutation presented here alters the Exo III domain, suggesting a particular role of mutations within the catalytic Exo domains in the pathogenesis of familial chilblain lupus. The high prevalence of extracutaneous manifestations, along with activation of type I interferon, underlines the systemic nature of familial chilblain lupus.

Demographical, laboratory and associated findings in patients with perniosis.

BACKGROUND: Perniosis is a cold-induced inflammatory disorder of the acral areas. The objective of this study was to investigate the demographic characteristics, associated factors, clinical and laboratory findings in patients with perniosis and to compare those findings between patients who had recurrent and acute disease. METHODS: Thirty-four patients with perniosis were investigated retrospectively for age, gender, occupation, smoking and diet histories, associated diseases, family history of perniosis, precipitating factors, the month of onset and the duration of perniosis, the distribution of the lesions and the results of laboratory investigations. RESULTS: Fifteen patients were male and 19 were female. The ages of the patients ranged from 15 to 57 years. Thirteen patients were working as sales people, which was the most common occupation. Sixteen patients were smokers. While 25 of the patients had encountered perniosis for the first time, in 9 of the patients, there were recurrent lesions. Diseases other than perniosis were recorded in 6 of the patients. The laboratory tests revealed mild leukopenia in 2, antinuclear antibody (ANA) positivity in 3, mild rise in albumin level in serum protein electrophoresis in 1 patient. ANA positivity was significantly higher in patients with recurrent disease. CONCLUSION: Perniosis was more common in women and below 40 years. We found no significant laboratory findings except ANA positivity in patients with recurrent perniosis.

[Hypothermia, chilblain and frostbite].

Many factors such as the environmental conditions (temperature and humidity etc.), a nutritional status, the degree of fatigue, a moisturizing state of the body, clothes, the sensitivity to coldness are involved in an outbreak of hypothermia. Children, aged persons and the presence of an underlying disease are also risk factors related to the occurrence of hypothermia. The dysfunction of the respiratory system, the circulatory system and the central nervous system is caused by a decrease in body temperature. Finally, death is brought about at 25 degrees C of body temperature or lower. Frostbite develops when tissue is exposed to -4 degrees C of coldness or lower. The extent of injury is determined by the magnitude of coldness.

Major cluster of chilblain cases in a cold dry Western Australian winter.

AIM: Primary chilblains are an idiopathic cold-induced vasculopathy affecting the soft tissues of the hands and feet. Secondary chilblains occur in different forms of vasculitis and chronic autoimmune connective tissue disorders. Idiopathic chilblains are rarely reported in children and may generate significant anxiety to doctors and patients. We describe a cluster of idiopathic chilblains encountered over the winter of 2010 in Perth, Western Australia. METHODS: This is a retrospective review of patients identified from a prospectively compiled database of all new cases seen in our department. Data on history, examination, investigations, prescribed treatments and outcomes were collected. RESULTS: Thirty-two patients with isolated idiopathic chilblains were included, including 20 females and 12 males with a median age at onset of 13.5 years. Lesions were papular with signs of peripheral vasoconstriction causing acrocyanosis, and uncomfortable due to pain and/or pruritis in most. Thickening of the small joints was common where lesions involved these areas. Ulceration of lesions also occurred in some. One patient required hospitalisation for secondary bacterial infection. Most received some form of treatment including non-steroidal anti-inflammatory drugs, prednisolone or nifedipine. Most patients improved spontaneously with warmer weather or responded to cold protection advice. All had resolved completely by late spring (November). CONCLUSION: Our cluster of chilblains was associated with an unusually cold winter in Perth 2010. It is the largest series reported in the literature, suggesting that chilblains may be more common than previously thought. Chilblains are almost always benign in nature and patients are systemically well and usually need no further investigation and only symptomatic treatment. Prompt recognition can avoid excessive investigation and anxiety, allowing appropriate simple advice and treatment.

The capillaroscopic findings in idiopathic pernio: is it a microvascular disease?

OBJECTIVES: Pernio is a disorder that affects the unprotected skin regions of individuals who are exposed to nonfreezing, damp cold. We aimed to examine nailfold capillaries by video capillaroscopy and evaluate the vascular involvement in patients with idiopathic pernio. METHODS: Fifty-three patients with idiopathic pernio (male/female ratio 35:18, mean age 25 ± 9 years) and 38 age- and sex-matched healthy volunteers (male/female ratio 30:8, mean age 24 ± 4 years) were included in the study. Forty-seven of the 53 patients and all the healthy volunteers were evaluated by nailfold video capillaroscopy. RESULTS: In the patient group, the mean capillary diameter and the mean apical capillary diameter were 56 ± 15 and 24 ± 7 µm, respectively. In the control group, the mean capillary diameter and the mean apical capillary diameter were 37 ± 8 and 15 ± 4 µm, respectively (both p < 0.001). Both of these differences were independent of the disease activity, smoking, and the number of pernio episodes. There were no architectural derangements, avascular areas, or hemorrhages. CONCLUSIONS: In the present study, increased nailfold capillary diameter and increased apical capillary diameter were found in patients with pernio regardless of the disease activity. These findings suggest organic damage of the microcirculation.

Thermotherapy: a novel possible treatment strategy of chronic rhinosinusitis based on the chilblain-like alteration in the early pathophysiology.

Chronic rhinosinusitis (CRS) is one of the most common inflammatory diseases affecting large number of patients globally. The pathogenesis of CRS is still unclear and the treatment is unsatisfied. Clinical data provide the evidence that the chilblain-like alteration occurs in the early pathophysiology of CRS. We hypothesize that thermotherapy may offer a novel possible treatment strategy of chronic rhinosinusitis. In this article, we discuss the possibility of the chilblain-like alteration in the early pathophysiology and a therapeutic role of thermotherapy.

Nonfreezing cold-induced injuries.

Non-freezing cold injury (NFCI) is the Cinderella of thermal injuries and is a clinical syndrome that occurs when tissues are exposed to cold temperatures close to freezing point for sustained periods. NFCI is insidious in onset, often difficult to recognize and problematic to treat, and yet the condition accounts for significant morbidity in both military and civilians who work in cold conditions. Consequently recognition of those at risk, limiting their exposure and the appropriate and timely use of suitable protective equipment are essential steps in trying to reduce the impact of the condition. This review addresses the issues surrounding NFCI.

Chilblain lupus erythematosus--a review of literature.

Chilblain lupus erythematosus (CHLE) is a rare, chronic form of cutaneous lupus erythematosus. Sporadic cases and two families with autosomal dominant-inherited CHLE have been reported. In familial CHLE, two missense mutations in TREX1 encoding the 3'-5' repair exonuclease 1 were described in affected individuals. The pathogenesis of sporadic CHLE remains unknown. Up to 20% of patients develop systemic lupus erythematosus (SLE). An association with anorexia is discussed. In many cases, there is good response to symptomatic therapy. SLE therapeutics have good effects on SLE-typical symptoms but not on chilblains themselves. This article reviews the clinical presentation, pathogenesis, diagnosis and treatment of CHLE. As an index patient with unique features, we report a 13-year-old boy developing CHLE after anorexia nervosa. Sequencing of TREX1 was normal. With psychotherapeutic support for anorexia and after antibiotic therapy, topical steroids, physical warming and calcium channel blockers, the patient experienced significant relief. Improvement of phalangeal perfusion was demonstrated by angio-MRI.