Chilblain lupus erythematosus associated with systemic lupus erythematosus: A classic diagnosis in a current epidemiological context

Objectives: Chilblain lupus erythematosus (LE) is a rare chronic cutaneous lupus erythematosus (CCLE) characterized by the appearance of violaceous plaques in acral regions most exposed to cold. The isolated form affects middle-aged women, while the familial form manifests in early childhood and is associated with mutations in the TREX1 gene. Result(s): A 13-year-old adolescent, with no relevant family history, was referred in March 2021 for suspected chilblain-like lesions associated with COVID-19 infection. The patient presented with multiple violaceous papules on hands and feet. The lesions were slightly painful. Small hyperkeratotic papules were also observed on finger pads. Physical examination also revealed some aphthae affecting the lips. No other systemic symptoms were reported. A skin biopsy and blood tests were performed due to presumed chilblain LE with probable systemic involvement. Histology revealed basal vacuolar damage and intense perivascular and periadnexal lymphocytic inflammatory dermal infiltrate. Remarkably, mucin was noted among the collagen bundles. Leukopenia and positive ANA antibodies (titre 1:320) were detected. Complement levels were normal. SARS-CoV2 infection was ruled out. Skin lesions disappeared within 1 month under topical corticosteroids. Hydroxychloroquine was afterwards started by Rheumatology without recurrence of skin symptoms until last follow-up. Discussion(s): We present an uncommon case of an adolescent with systemic LE presenting as chilblain LE. Chilblain LE can be accompanied by other discoid CCLE. It can progress to systemic LE in up to 20% of patients, especially when concomitant CCLE is present. This rare presentation of CCLE should be differentiated from typical chilblain and other resembling lesions, such as SARS-CoV2-associated chilblain and acral purpuric lesions (COVID toes). The Mayo Clinic diagnostic criteria can be helpful, particularly in this last SARS-CoV2 outbreak scenario, when the reporting of similar skin lesions has been significant.

Dynamic and spatial transcriptional responses in COVID-19-related chilblains

"COVID-toes" are chilblains that occurred in patients who may have been exposed to SARS-CoV-2, but without COVID-19 symptoms and/or with negative PCR or serology. The literature suggests that chilblains are an unexpected consequence of a strong interferon-mediated antiviral response, but the underlying molecular mechanisms remain poorly understood. We thus sought to explore the physiopathology of COVID-related chilblains by using spatially and temporally resolved transcriptomics. We included 19 patients with COVID-toes, and performed a complete virological assessment to exclude SARS-CoV-2 infection including skin viral metagenomics. Some patients had clinical symptoms evoking viral infection, but none had COVID-19. Apart from low levels of non-conventional antiphospholipid antibodies, biological tests were unremarkable. We performed spatially resolved transcriptomics (Visium, 10X Genomics) in 3 patients at different timepoints and compared them with 1 vaccination-related chilblain. We observed a different transcriptional profile in COVID-toes compared with COVID-19 vaccine-related chilblains. IRF1, CXCL10, ISG15 and STAT1 were highly expressed in COVID-toes and their expression decreased over time, confirming an activation of interferon and JAK/STAT pathways that was absent in vaccine-related chilblains. The proportion of inflammatory cell types obtained by spatial deconvolution varied over time in COVID-toes. Migratory dendritic cells were present at early stages, while T lymphocytes populations increased later. Overall, this work explores the mechanisms of COVID-19-related chilblains using spatially and temporally resolved transcriptomics.Copyright © 2023

Cutaneous manifestations of COVID-19.

COVID - 19 can be accompanied by a variety of cutaneous abnormalities, which mainly include vascular lesions chilblain - like lesions, livedo reticularis, purpura, ecchymosis, acral cyanosis, gangrene, etcand inflammatory lesionsdiffuse erythema, morbilliform exanthem, acute urticaria, varicella- like exanthem, etc. Some types of skin lesions may be the first symptom or the only clinical manifestation of COVID-19.Copyright © 2022 Chinese Journal of Dermatology. All rights reserved.

Chilblain: a brief history of cold comfort remedies

Chilblain, also known as pernio, has gained publicity in recent years as a result of its association with 'COVID toes' during the COVID-19 pandemic. Long before this, chilblain had left its mark throughout history and literature. The word 'chilblain' has Anglo-Saxon roots. 'Chil' comes from Old English ciele meaning 'chill' or 'frost', while 'blain' comes from the Old English blegen meaning 'inflammatory swelling' or 'sore'. The two words were brought together in the 1540s. The choice of words somehow acknowledges that cold is the aetiological factor that brings on this painful swelling. The Victorian novel Jane Erye, written by Charlotte Bronte in 1847, described the physical hardships that children had to struggle with through the winter at Lowood, the charity school for poor and orphaned girls. Her work masterfully sculptured the essence of chilblain and its effects on the children. Multiple notable figures proposed various remedies to treat the bothersome symptoms of chilblains. Pedanius Dioscorides was a Greek physician and botanist whose monumental work De Materia Medica in the first century AD compiled a list of topical remedies for chilblains, including quince oil, fenugreek oil, frankincense gum, burnt figs in wax, a mixture of gentian, crab ashes and honey, burnt ass hooves, bear grease and decoction of turnip as a warm pack. To cure chilblains, Nicholas Culpeper, an English herbalist, advised grating horseradish and applying it as a mustard plaster. We now know grated horseradish root produces a powerful mustard oil that acts as a rubefacient, which irritates the skin and increases its blood flow. Dr Lewis Johns was a recognized medical officer in the field of medical electricity in charge of the Electrical Department of St Bartholomew's Hospital. He noted a reduced incidence of chilblains in children with poliomyelitis who were treated with a warm electric footbath in 1899. The beneficial effects most likely originated from the warm bath rather than the electricity itself. Sir Thomas Lewis, a British cardiologist, investigated skin responses to injury and vascular reactions of the skin to cold exposure. His careful observations and descriptions of chilblains published in the British Medical Journal in 1941 remain true to this day. Practices such as praying to the statue of St Benignus of Dijon with chilblains, wearing electric patent socks (invented in 1882) and using an electrical vacuum tube in 1922 had also made their way into the lives of sufferers as a potential cure. Despite the epidemiological study of chilblain in over 3000 servicewomen, carried out by the Auxiliary Territorial Service in the winter of 1942, no specific remedy was found. When it comes to chilblain, prevention is better than cure by keeping the hands and feet warm and dry and staying active, and chilblains usually resolve spontaneously within a few weeks.

Paediatric Aps - Children Are Not Just Small Adults

Introduction/Background: Antiphospholipid syndrome (APS) is a rare autoimmune multisystem disease characterised by thrombosis and pregnancy morbidity in the presence of persistently elevated titres of: lupus anticoagulant, anticardiolipin and/or anti-glycoprotein 1. It may be primary (occurring alone) or secondary (in combination with another disease, most commonly systemic lupus erythematosus (SLE)). Recent publications highlighted clinical criteria limitations for children and raised awareness of the burden and prevalence of non-criteria manifestations in this population. This case report adds further weight to the need to raise multi-specialty awareness of non-criteria manifestations to aid recognition and treatment of this rare condition with potentially severe sequelae. Description/Method: 13-year-old female with SLE diagnosed aged 8 in India with bilateral optic neuritis occurring two months later. ANA positive at diagnosis with low complement and thrombocytopenia. Treated with prednisolone and hydroxychloroquine. Patient moved to the UK aged 9;initial abnormal bloods: mildly positive ANA (ENA negative), thrombocytopenia, strong lupus anticoagulant. As serology not strongly suggestive and optic neuritis rare in lupus diagnosis questioned. Ophthalmology review confirmed bilateral optic atrophy without evidence of previous vasculitis. There was debate whether the postretinal demyelination was due to antiphospholipid syndrome or a primary demyelinating condition. Hydroxychloroquine stopped and azathioprine started. Following normal neurology investigations (brain, spine MRI/MRV/MRA) concluded if patient developed new APSrelated symptoms or worsening visual evoked potentials anticoagulation would be discussed. Patient remained stable over four years with chronic thrombocytopenia and ESR persistently elevated. Azathioprine changed to Mycophenolate mofetil (MMF) due to side effects. Routine medication monitoring bloods in 2022 showed ESR 97, CRP 78, Platelets 61. Review identified vasculitic rash on soles of both feet with palpable nodules and normal pulses. Further investigation confirmed antiphospholipid antibody triple positivity. Aspirin commenced, hydroxychloroquine restarted, MMF dose increased and rituximab administered. Left foot rash settled but right progressed with toe discolouration and numbness. Skin biopsy considered but not performed due to skin integrity concerns. Foot pulses remained present and normal. Bilateral lower limb doppler reported as normal;increased symptoms resulted in CT angiogram which revealed bilateral non-occlusive popliteal thrombus and left pulmonary embolus. Subsequent echocardiogram was normal. Patient was anticoagulated with low molecular weight heparin followed by warfarin. Vascular surgical team advocated medical management and patient received seven infusions of Iloprost followed by Sildenafil. She achieved near total resolution of skin changes to toes with only minimal loss of skin over tip of right great toe. Patient will now require long-termanticoagulation. Discussion/Results: APS was considered in initial differential diagnosis but patient did not meet current clinical criteria as no past evidence of thrombosis. Lupus anticoagulant was consistently strongly positive and anticardiolipin repeatedly negative. As anti-B2 glycoprotein 1 antibody is not routinely tested and must be verbally requested, it was only checked once (negative) prior to discovery of triple positivity. ANA reported as strongly positive at time of SLE diagnosis but reviewing original notes from India titre was 1:100 and therefore not highly convincing. ENA negative and complement and white cell count normal on repeat testing since. Therefore, it is probable that this patient has primary APS as opposed to secondary APS in association with SLE. However, it is possible that this patient may develop more symptoms of SLE over time. When this patient presented with foot rash there were high numbers of children presenting with varying severity of painful, itchy toes coined 'covid toes' due to suspected lin to SARS-CoV-2 infection. Patient had exposure history, and COVID antibody serology was difficult to interpret due to recent vaccination. Dermatology found appearance to be consistent with 'covid toes' and advised supportive treatment. The triple APS antibody positivity result provided probable aetiology. Providing evidence of thrombus was problematic with false reassurance from apparently normal lower limb arterial doppler when actually popliteal arteries were not checked in view of the presence of normal flow proximally at the groin and distally in the feet. This case highlights the need to continue to search for thrombus in presence of high titres antiphospholipid antibodies and particularly in the case of triple positivity as although patient presented with colour change to toes, she was entirely asymptomatic from her PE and her left foot improved spontaneously despite a left popliteal thrombus also being present. Key learning points/Conclusion: Non-criteria manifestation of thrombocytopenia (occurs in 25% paediatric APS patients) was present throughout and patient had past history of haematuria (a recognised renal non-criteria manifestation). A paediatric specific APS criteria including these may have resulted in earlier detection of triple antiphospholipid antibody positivity and thus earlier treatment escalation and possible avoidance of thrombus. It has been reported that a high proportion of children with positive antiphospholipid antibodies don't develop a thrombus. However, it is interesting that our patient was entirely asymptomatic from her pulmonary embolus which was an incidental finding on her CT angiogram. This prompts a discussion about how much imaging should be performed in those with high levels of persistent positive antiphospholipid antibodies. Rituximab resulted in normalisation of platelet count and ESR for the first time since initial presentation. Anticardiolipin antibodies normalised, lupus anticoagulant decreased from strong to moderate and anti- B2 glycoprotein levels decreased but remained positive. Rituximab is a recognised treatment for catastrophic antiphospholipid syndrome (CAPS) but not routinely used in APS. The consistently raised ESR in an apparently clinically well patient is a reminder to continue to search for causes of inflammation. As the CRP was largely in normal range, this demonstrates the unique value of the ESR. In view of anti-B2 glycoprotein 1 antibody requiring to be verbally requested, discussions are ongoing with the laboratory department regarding the possibility of electronic request and a comment with recommendation to check other two antiphospholipid antibodies following one positive antibody result. As a result of this case, a plan will be put in place to ensure annual screening of antiphospholipid antibodies in all juvenile SLE patients in our care. It is hoped that this case report promotes discussion amongst the paediatric rheumatology community regarding further research required for development of paediatric specific APS criteria and management.

COVID-19 Dermatological Manifestations in Children

This article describes various COVID-19 dermatological manifestations that can develop in children. Their incidence and clinical features are described. Сhilblain-like lesions were considered as the most typical in children population after coronavirus infection. Description of skin manifestations in multisystem inflammatory syndrome in children is also presented, issues of laboratory diagnosis are covered as well.

Arterial Thrombosis as a Presentation of Systemic Lupus Erythematosusin a Young Child

Introduction: Systemic lupus erythematosus (SLE) is a rare diagnosis in children and can present with nonspecific symptoms. Similarly, arterial thromboses in children without risk factors is also rare. Together, they present a diagnostic challenge which may lead to a delay in proper management. Our objective is to emphasize the importance of having high suspicion for SLE in children, especially when presenting with arterial thrombosis. Case Description: Our patient is a 6-year-old female who presented with a 3-week history of severe right foot pain with a 1-week history of discoloration in the same foot. She sought care multiple times prior to presentation. She initially received the diagnosis of “COVID toes” despite a negative COVID PCR. Prior to presentation, she developed fevers, worsening foot pain, increasing discoloration, decreased oral intake, weight loss, and fatigue. Further lab work showed acute kidney injury, elevated inflammatory markers, and coagulopathy. She was also found to have elevated troponins and QTc prolongation. Additionally, a lower extremity Doppler demonstrated an acute partially occluding thrombus in her right popliteal artery. She was transferred to the pediatric intensive care unit (PICU) and started on a heparin infusion. An Echocardiogram with bubble study showed no interatrial shunting. Thrombolysis was considered but held due to concerns regarding thrombus chronicity. COVID-19 PCR and antibodies were negative, so Infectious Disease team determined this was unlikely related to an acute or remote COVID-19 infection or multisystem inflammatory syndrome in children (MIS-C). Her hemoglobin and platelets began to downtrend and Coombs was positive, raising concern for autoimmune hemolytic anemia. Autoimmune and coagulopathy work-up was significant for positive ANA titer, low complement levels and elevated anticardiolipin, anti-dsDNA, anti-Smith, anti-chromatin, and anti-RNP antibodies. She also had a chest X-ray that showed small non-infectious pleural and pericardial effusions suggestive of serositis. The constellation of these findings eventually led to the diagnosis of SLE. Discussion: There have been several cases of thrombotic or thromboembolic events reported in pediatric patients with SLE, with a majority being venous related events. Only two reports involving cerebral arteries have been published. For several of these patients, thrombosis was the presenting symptoms of their disease. In our literature review, we did not find any cases of arterial thrombosis outside the central nervous system related to SLE. Conclusion: Arterial thrombosis can be a presenting symptom for SLE in children. Despite being a rare presentation, rheumatologic diseases such as SLE should always be considered to prevent a delay in diagnosis and management. In our case, our patient experienced a notable delay in care due to a misdiagnosis related to the COVID-19 pandemic. While it is extremely important to consider sequelae of COVID-19, we would like to emphasize the importance of ensuring consideration of other diagnoses as well.

COVID-19 manifestations in the skin

Skin changes are seen in up to 20% of patients with COVID-19 and vary widely in presentation. The most common include maculopapular eruptions, 'COVID toes', urticaria and most concerningly vaso- occlusive rashes, such as livedo reticularis and retiform purpura. Some of these skin signs are indicators of disease progression or severity.

COVID-19 cutaneous manifestations in children and adolescents: a systematic review

Objective: The aim of this study was to evaluate the coronavirus disease 2019 (COVID-19) cutaneous manifestations described in pediatric patients and discuss their relevance for early diagnosis. Data source: The study consisted of a systematic review of original articles indexed in PubMed and Embase databases, as well as gray literature articles found through Google Scholar. A search strategy, based on PICO (Patient, Intervention, Comparison, Outcome) Tool, with the terms "child," "infant," "childhood," "adolescents," "teenagers," "COVID-19," "SARS-CoV-2," and "skin manifestations," was performed to optimize the findings. The study did not restrict any article regarding language. Data synthesis: Out of the 310 articles that initially met the inclusion criteria, 35 were selected for review, totalizing 369 patients. The most common COVID-19 cutaneous manifestations in children and adolescents were Chilblain-like lesions, presented in 67.5% of the cases, followed by erythema multiforme-like (31.7%) and varicella-like lesions (0.8%). The Chilblain-like lesions appeared 7.6 days (95%CI 7.4-7.8) after the viral infection and lasted for 17.5 days (95%CI 16.5-18.5), erythema multiformelike lesions appeared in 9.5 days (95%CI 9-10) and lasted for 10.3 days (95%CI 9.1-11.5), and varicella-like lesions appeared in 12.3 days (95%CI 4-20.6) and lasted for 7 days. Conclusions: Knowledge of the different skin manifestations in children and adolescents with COVID-19 is essential for an early diagnosis and, consequently, the possibility of promptly care adoption as well as to interrupt the new coronavirus transmission chains in the current pandemic context.

Possible reflex sympathetic dystrophy secondary to 'COVID toes'

A 51-year-old woman presented acutely to dermatology with an 8-week history of painful, purple discolouration of her toes, which started on her left foot but progressed to involve all of her toes. She was noted to have a positive COVID-19 polymerase chain reaction test after her symptoms began. There was some superficial ulceration of two of her toes. The episode lasted for 5 weeks;however, after 6 weeks her toes had flared again. No triggers were indentified;in particular, her symptoms were not related to the cold. There were no other rashes. She has a past medical history of endometriosis and gout. She takes desogestrel and allopurinol, which she had been on for 2 years. Vasculitis screen was negative. She was treated initially with clobetasol propionate and nifedipine. On follow-up 6 weeks later, the patient reported hypersensitivity of her toes, with severe pain reported from socks rubbing against her toes. The toes had normal appearances and cool peripheries. We suspect that the increased sensitivity and pain is a reflex sympathetic response secondary to 'COVID toes' and have treated with it gabapentin. It is thought that reflex sympathetic dystrophy occurs because inflammation causes damage to the nerves;however, the exact mechanism behind reflex sympathetic dystrophy is yet to be elucidated.

Sarcoid-like immune reaction following COVID-19 infection presenting with COVID toes and dactylitis

A 21-year-old woman presented with a 5-month history of swollen, painful, purple discolouration of her toes and fingers, which began 6 weeks after COVID-19 infection. This was refractory to ibuprofen and clobetasol 0.05% w/w ointment. She reported no other associated symptoms. On examination she had erythematous mottling of the tips of the toes and nail folds of the right foot and sausage-shaped deformities of the left second and fourth toes, consistent with dactylitis. Her blood work-up for COVID toes revealed a raised serum angiotensin- converting enzyme (ACE) level (64 U L-1) with no other abnormalities. Her chest X-ray was unremarkable. Plain radiographs of the feet showed soft tissue swelling and lacelike bony appearances with discrete areas of lucency, particularly affecting the middle phalanx of the left second toe. This pattern has been described in sarcoid arthropathy. Magnetic resonance imaging of the left foot demonstrated features of inflammatory arthropathy, including subarticular bone marrow oedema, periarticular soft tissue oedema and flexor tendon tenosynovitis. The findings were consistent with COVID toes;however, some features of the dactylitis extended beyond the expected presentation of a vascular manifestation of COVID-19. She displayed overlap features seen in sarcoid-related pathologies, including raised ACE levels and a lace-like bony appearance. We believe this to be a sarcoid-like immune reaction to COVID-19 presenting with COVID toes and dactylitis. A sarcoid-like immune reaction to COVID-19 with granulomatous skin lesions rather than dactylitis has been reported. Viral infections are a documented trigger for sarcoid- like immune reactions. This case suggests that COVID-19 can trigger sarcoid-like immune reactions, albeit with a more discrete presentation.

Juvenile dermatomyositis: Five new cases during the SARS-Cov2 pandemic

Objectives: To describe the clinical and laboratory characteristics of pediatric patients diagnosed with dermatomyosis during the COVID pandemic. Method: Description of the clinical and laboratory findings in patients under 15 years of age, who were admitted at our hospital with signs and symptoms suggestive of dermatomyositis, from March 2020 until November 2021. Results: Five patients, three boys and two girls, aged between 8 and 13 years, were diagnosed with juvenile dermatomyositis (JDM). The most frequent symptom was asthenia. Heliotrope erythema, malar rash, periungual erythema, and papules on elbows and knees were present in all cases. Three of our patients had perniosis on their toes. Four patients presented lesions in the oral mucosa, such as geographic tongue or gingivitis. The time between the onset of symptoms and the first visit with the pediatrician ranged from 1 to 6 months. In all cases, GOT/GPT enzymes, and aldolase were elevated at diagnosis, and the SARS-CoV-2 PCR was negative. Two patients had anti-TIF1 antibodies, and two had anti-MDA5 antibodies. In one girl, no specific autoantibodies for JDM were detected. Magnetic resonance imaging showed muscle oedema in all patients. All cases are in remission after systemic treatment with steroids, methotrexate or immunoglobulins. Discussion: JDM is a severe disease of childhood. Our cases did not present symptoms suggestive of COVID and the PCR for SARS-CoV-2 was negative on admission in all of them, but the presence of perniosis on the toes of three patients could correspond to “COVID toes,” and be a late manifestation of an asymptomatic or oligosymptomatic infection of SARS-CoV-2. It has been suggested that SARS-CoV-2 infection could trigger the development of JDM, possibly through the induction of IFNα. Long-term follow-up is necessary to establish a relationship between the prognosis of specific autoantibodies, the involvement of acral and mucosal areas, and the possible relation with COVID.

PAEDIATRIC COVID TOES AND THE RECOMMENDED CARE MANAGEMENT

Aim To define COVID toes and fingers in paediatrics, and to explain the aetiology, the assessment and investigation management, the diagnosis, the clinical presentation and the care management including the use of oral nifedipine in this newly found disease during the COVID-19 pandemic. In addition, we will illustrate the process using the multi-disciplinary approach to prepare the Paediatric COVID toes guideline in our Trust, and to cite some examples of the related patient cases seen in our hospital as well as to summarise the total number of patient cases seen to date. Method To carry out a literature search to find out the latest related articles and clinical studies, and to summarise the findings to prepare for the drafting of the clinical guideline. This guideline was initially prepared by the medical team and was then reviewed using multi-disciplinary team (MDT) approach including the paediatric pharmacists and the consultation from the tertiary paediatric centre. We also summarised the number of paediatric patient cases that were seen in our Trust and categorised them into different age groups, ethics background, and referral systems. Results A number of related articles were found after the literature search. The first draft of the Paediatric COVID-toes guideline was prepared in March 2021 and it was then reviewed by the MDT in the Paediatric Clinical Guideline Group of our Trust. The paediatric pharmacist expressed her comments including the drug of choice such as oral nifedipine, the dosages below and above 2 years of age, the evidence to support the dosage recommendations, the different formulations available in the market for oral nifedipine such as oral suspension, capsule, tablet and modified-released (MR) tablet, recommended effective method for oral administration, side effects profile, monitoring such as blood pressure, patient counselling and education, and provision of patient leaflet and video-link to aid patient compliance. Conclusion The final version of the Paediatric COVID toes guideline was prepared by the multi-disciplinary team in July, 2021, and it was uploaded in the Trust intranet in August 2021. In view of the literature search, there is limited evidence to support the use of oral nifedipine under 2 years of age for this indication. In our guideline, we recommend the dose of nifedipine to be 2.5-10 mg 2-4 times a day for children age 2 to 17 years old, starting with low doses at night and increase gradually by closely monitoring blood pressure and other side effects. The use of oral nifedipine is unlicensed for this indication in children. In our guideline, we recommend the use of oral MR nifedipine tablet after the consultation with the tertiary centre. Oral suspension is not routinely used. During counselling session, the pharmacist will advise the parent/carer to crush and dissolve the MR tablet in water and give appropriate dose accordingly. To date, 15 patients diagnosed with this disease were seen in our clinic. They are mainly referred to the clinic via the Accident and Emergency Department. The patient ages are all above 8 years old and they are mainly of Asian ethical background.

COVID-19 PERNIOSIS, A DIFFERENTIAL DIAGNOSIS TO CONSIDER IN ADOLESCENT PATIENTS PRESENTING WITH CHILBLAIN-LIKE LESIONS

Background/Aims Chilblain-like lesions (perniosis) have been reported frequently during COVID-19 pandemic in children and adolescents with no history of exposure to cold temperatures or underlying autoimmune conditions. Patients with these skin changes reported mild COVID-19 symptoms or previous contact with confirmed COVID-19 cases before they became symptomatic. In the majority of cases, a causal relationship between SARS-CoV-2 infection and chilblain-like lesion has not been proven. Methods Retrospective review of patients with chilblain-like lesions, possibly secondary to SARS-CoV-2 infection, presenting to a tertiary Adolescent Rheumatology service between January and August 2021. Results We identified five, male, adolescent patients (mean age, 16 years old) who presented with new onset of chilblain-like lesions affecting fingers, toes and heels in December 2020, which coincided with the peak of second wave of COVID-19 infection. One month prior to skin changes occurrence, 3 out of 5 patients experienced mild respiratory COVID-19-like symptoms and the rest of the patients were asymptomatic but were in contact with COVID-19 positive cases following outbreaks in schools. 1 of 3 symptomatic patients had a positive COVID-19 PCR test prior to skin manifestations. 2 out of 4 patients with heel lesions had deep, full thickness skin loss heel ulcers and 2 of 5 patients had superficially ulcerated lesions on a finger and toes, respectively, resulting in inability to attend school. None of the patients had any other symptoms or signs to suggest an underlying autoimmune connective tissue disorder. Demographics, clinical features and serological data are summarised in Table 1. One patient underwent a biopsy of heel ulcer which was histologically consistent with perniosis. In two patients (40%) chilblain like lesions resolved spontaneously within 2 months. Three patients (60%), with progressive ulcerated lesions, required various combinations of treatments with aspirin, calcium channel blockers (nifedipine), topical or oral steroids and hydroxychloroquine with complete resolution of symptoms within 6 months. Conclusion Chilblain-like lesions, including heel involvement associated with mildly symptomatic COVID-19 infection, have been reported before. Our mini-case series raises awareness of ulcerating chilblain like lesions possibly secondary to COVID-19 in adolescent patients, which require early recognition and instigation of treatment leading to better patient's outcomes.

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.

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.

SARS-CoV-2 infection, hypercoagulability and hereditary thrombophilia factors

Coronavirus disease (COVID-19) is a potentially fatal infectious disease caused by the SARS-CoV-2 virus, a virus of zoonotic origin (1). It has been observed that clinical manifestations of SARS-CoV-2 infection range from asymptomatic disease to severe viral pneumonia accompanied by severe respiratory failure and may result in death (2). The most common initial symptoms of COVID-19 disease are fever, cough, and fatigue. Transmission primarily occurs through direct contact or droplets spread from an infected person (1). The binding of a receptor expressed by host cells is the first step of viral infection. Lung epithelial cells are thought to be the primary target of the virus. Most of the used drugs are drugs used in the treatment of other diseases, and their effectiveness in the treatment of COVID-19 is still at the research level. Specific anti-infection drugs are under development for potential treatment in humans (1). Veklury (Remdesivir) is the first treatment for COVID-19 to receive FDA approval. It is used in adults and pediatric patients [12 years and older and at least 40 kilograms] for the treatment of COVID-19 requiring hospitalization (3). The treatment of COVID-19 in our country is carried out by the recommendations of the Ministry of Health's Guide 'COVID-19 (SARS-CoV-2 infection)' prepared by the recommendations of the Coronavirus Science Council and updated by the developments (4). All of the drugs recommended in the manual are used under the approval of the Ministry of Health within the framework of non-indication drug use. In this pandemic, where new waves are constantly coming, scientists have succeeded in developing a large number of COVID-19 vaccine types in a short time as a result of intensive studies. The mRNA-based Pfizer-BioNTech COVID-19 vaccine is the first FDA-approved vaccine [23.08.2021] (5). The information about the COVID-19 disease, which is spreading rapidly around the world, is increasing with new researches day by day. Thrombophilia is a hypercoagulable condition that predisposes patients to thrombosis. It is a multifactorial condition that can result from genetic factors, acquired factors, or a combination of both. The prothrombin gene (F2), factor V Leiden (F5), and PAI-1 are important biomarkers of thrombophilia. Patients with multiple gene defects have a high risk of thrombosis (6). It is known that thromboembolic events can develop in patients with COVID-19 and the incidence of death increases accordingly. Studies have shown that VTE can be induced in patients with COVID-19 and severe pneumonia, and the incidence of VTE in COVID-19 patients hospitalized in the intensive care unit due to severe pneumonia has been reported to be high (7). The risk of thrombosis and arterial and venous thromboembolic complications seen in 30% of hospitalized subjects due to Novel Coronavirus pneumonia has been reported in many studies, which can be explained by the prolonged inflammatory response, decreased physical activity during infection, and reduced oxygen levels in the circulation (6). Thrombotic and microangiopathic effects of the SARS-CoV-2 virus have been reported in COVID-19 patients (8). Circulatory disorders in the toes of COVID-19 patients are also reported as 'Covid toe (acro ischemia)' (9). Although it is reported that the disease progresses more severely in the elderly, patients with sub-diseases, and smoking history, it is also observed that the clinical course is severe and patient losses are experienced in young patients who do not have any underlying disease. The mechanisms of the development of thromboembolic events are the binding of the virus to the ACE-2 receptor and/or direct endothelial damage, activation of inflammatory and microthrombotic pathways as a result of endothelial damage by complement activation as in sepsis, and stasis due to hospitalization and immobility (10). DIC clinic may develop in patients with severe clinical course. The pathophysiology of DIC is reported to be complex and multifactorial, involving the interaction between the hemostatic system and components of the innate immune response to the infecting pathogen (11). However, there is no comprehensive research on inherited thrombophilia factors that may affect the hemostatic system. Severe clinical course in young patients, a similar clinical course in individuals from the same family even though they are in different cities, elderly patients recovering from the clinic safely and being discharged, VTE in different locations in COVID-19 patients, microangiopathic thrombus, etc. monitoring of the findings, the use of anticoagulants due to their positive contributions in treatment are included in the observations in this process. In the light of all this information, it is aimed to examine and reveal the possible relationship between the genetic variations evaluated in the thrombophilia panel and COVID-19 and presented with the literature data findings and recent studies. Gralinski et al. suggested that PAI-1 plays a protective role against infection in the viral pathogenesis studies of SARS-coronavirus disease (12). In another study, no statistically significant difference in thrombophilia polymorphic biomarkers between the severely ill COVID-19 group and the healthy population was found (6). Various studies that will provide new information on the subject are also actively continuing. In conclusion, thrombosis is frequently seen in severe COVID-19 patients. Essentially, the determination of the thrombophilia profile can assist in determining bleeding risk, mortality, ARDS incidence, and admission to the ICU. Latent genetic risk factors for thrombotic events may affect the outcome of COVID-19. Therefore, the identification of these factors may be useful for understanding the various COVID-19 outcomes and assessing COVID-19 patients' risk of thrombosis, severe disease, and vaccination policies.

COVID-19 in children: A case series

BACKGROUND: The COVID-19 pandemic has had an overwhelming impact worldwide. Studies on pediatric populations remain limited, as the burden of disease in pediatric patients appears to be low at this time. OBJECTIVES: To further describe clinical characteristics and severity of disease of confirmed pediatric COVID-19 patients seen and evaluated in a community-based hospital. DESIGN/METHODS: A retrospective chart review of positive COVID-19 patients = 18 years seen in COVID clinic or in the Emergency Department (ED) between April and December 2020 was performed. The results of nasopharyngeal swabs were confirmed using real-time reverse-transcription-polymerase chain reaction (RT-PCR) assays. A descriptive analysis of illness severity, performed via Excel 2019, was based on clinical presentation, laboratory data, and chest X-ray imaging. The categories of illness severity were: asymptomatic, mild, moderate, severe or critical. RESULTS: A total of 53 positive COVID-19 patients were enrolled in this study, which consisted of 24 (45.3%) males and 29 (54.7%) females. The median age was 7.5 years (2.4-12.8). The majority of patients presented with mild symptoms (64.2%), with fever and cough being the main symptoms in 20 (37.7%) and 16 (30.2%) cases, respectively. Other symptoms included sore throat (15.1%), diarrhea (13.2%), headache (9.4%), runny nose (7.5%) and abdominal pain (7.5%). The remaining patients (35.8%) were asymptomatic. Of note, one patient (1.9%) presented with COVID toes requiring referral to a tertiary centre, and one (1.9%) was diagnosed with acute appendicitis. A history of contact with a confirmed COVID-19-positive family member was present in 43 (81.1%) patients, and 6 (11.3%) reported a history of recent travel. Laboratory tests were performed in 7 (13.2%) patients, and chest X-rays were performed in 9 (17%). There were no abnormalities detected in either, other than an elevated CRP seen in one patient with appendicitis. Two (3.8%) patients were admitted, including the patient with appendicitis who developed a perforation and was later transferred to a tertiary care centre to undergo an appendectomy. The majority of patients (96.2%) were discharged home. CONCLUSION: All patients either presented with mild symptoms or were asymptomatic. Fever and cough were the most common presenting symptoms. Due to this, the vast majority of patients were discharged home. The infection in the majority of patients could be traced to a positive family contact. Our findings are consistent with what has been observed previously in our centre as well as worldwide.