key: cord-0936338-s6u0ylri
authors: Sil, Abheek; Chakraborty, Uddalak; Chandra, Atanu; Biswas, Surajit Kumar
title: COVID-19 associated symmetrical peripheral gangrene: A case series
date: 2021-11-27
journal: Diabetes Metab Syndr
DOI: 10.1016/j.dsx.2021.102356
sha: 5cd30726e764015a5c66993310aad01bdbd0de17
doc_id: 936338
cord_uid: s6u0ylri

BACKGROUND AND AIMS: The novel coronavirus disease (COVID-19) caused by SARS-CoV-2 has turned the world topsy-turvy since its onset in 2019. The thromboinflammatory complications of this disease are common in critically ill patients and associated with poor prognosis. Symmetrical peripheral gangrene (SPG) is characterized by symmetrical distal gangrene in absence of any large vessel occlusion or vasculitis and it is usually associated with critical illness. Our aim was to report the clinical profile and outcome of patients diagnosed with SPG associated with COVID-19. To the best of our knowledge, no such similar cases have been reported till date. METHODS: In this case series, we have discussed the clinical presentation, laboratory parameters and outcome in a series of two patients of SPG associated with COVID-19 and also compared those findings. Due to paucity of data, we also reviewed the literature on this under-diagnosed and rarely reported condition and association. RESULTS: Two consecutive patients (both males, age range: 37–42 years, mean: 39.5 years) were admitted with the diagnosis of COVID-19 associated SPG. Both patients had clinical and laboratory evidence of disseminated intravascular coagulation (DIC). Leucopenia was noted in both patients. Despite vigorous therapy, both patients succumbed to their illness within a fortnight of admission. CONCLUSION: SPG in the background of COVID-19 portends a fatal outcome. Physicians should be aware of its grim prognosis.

Since its emergence, COVID-19 has baffled the world with its protean manifestations. Apart from the characteristic respiratory ailment, COVID-19 has wreaked havoc with its notorious thromboinflammatory complications, which are common in critically ill patients and associated with dismal prognosis. 1, 2 From the cutaneous perspective, livedoid and necrotic eruptions were commonly observed finding in patients with more severe occlusive vascular disease. 3 Symmetrical peripheral gangrene (SPG) is one such dreaded complication leading to symmetrical distal gangrene in absence of any large vessel occlusion or vasculitis. It is a cutaneous harbinger of critical illness and is characterized by a triad of shock, disseminated intravascular coagulation, and depletion of natural anticoagulants. 4 Few reports in literature have mentioned dry gangrene in non-vasculopathic patients with severe COVID-19, possibly attributable to consumption coagulopathy and shock. 5 This article encompasses two cases of SPG associated with COVID-19 and provides a comprehensive review of this under-recognized entity associated with critical illness.

This case series describes the clinico-demographic profiles and outcomes of two consecutive patients diagnosed with COVID-19 associated SPG. Written informed consent (from patients or their family members) and adequate ethical clearance were obtained. Data regarding demography, symptoms, clinical presentation, time course and evolution of disease, past medical history, comorbidities, vascular risk factors, addictions, drug/toxin exposure, and family history were obtained. The patients underwent thorough clinical examination and routine laboratory workup. Relevant investigations like estimation of fibrin degradation products, d-dimer assay, J o u r n a l P r e -p r o o f anti-nuclear antibodies, anti-phospholipid antibody screening, skin biopsy, and radiological assessment (High resolution computed tomography thorax, Doppler ultrasound) were also performed to rule out any cause. Data was compiled on MS Excel platform. Confirmation of COVID-19 was through positive reverse transcription-polymerase chain reaction (RT-PCR) for SARS-CoV-2 from oropharyngeal and nasopharyngeal swab. Symmetrical peripheral gangrene was defined as "symmetrical irreversible ischemic damage of two or more sites in the absence of any large vessel occlusion or vasculitis". 6 Given the rarity of this presentation and its association with COVID-19, we further reviewed the literature on PubMed and Medline databases using Medical Subject Headings (MeSH) terms "Symmetrical peripheral gangrene" or "SPG" and "COVID-19" or "SARS-Cov-2".

A 37-year-old immunocompetent male, without any prior comorbidity, presented to the emergency room with high grade fever, cough and dyspnea for last 10 days. Over the past week, he experienced progressive altered sensorium associated with blackish discoloration of skin involving the extremities. No history of any substance abuse or any regular medication was elicited. On admission, he was febrile (39.6 0 C), pale, hypoxic (maintaining an oxygen saturation of 89% on room air), and hypotensive (blood pressure: 89/50 mm Hg) with tachycardia (pulse rate-128/min). Cutaneous examination revealed symmetrically distributed blackish discoloration of hands and feet, with a sharp line of demarcation at the ankles and proximal phalanges. for SARS-CoV-2 from oropharyngeal and nasopharyngeal swab turned out to be positive.

Laboratory investigations revealed thrombocytopenia (56x10 9 /l), elevated prothrombin time (21.96s), prolonged activated partial thromboplastin time (58.9 s) along with elevated fibrin degradation products (171mg/l, normal <10mg/l) and D-dimer levels (11562 ng/ml; normal <500ng/ml). High resolution computed tomography (HRCT) thorax revealed multiple patchy and confluent areas of ground glass opacities and septal thickening involving all the lobes of both lungs (CT severity score 20/25). (Figure 3a ) Skin biopsy showed microthrombi in small vessels without any evidence of vasculitis or vasculopathy. Blood culture was non-contributory.

Examination of other organ systems was unremarkable. Evaluation for other infective, cardiovascular, malignant, autoimmune, drug, or miscellaneous cause was normal. A final diagnosis of SPG associated with COVID-19 was established. He was managed conservatively [intravenous meropenem at the dose of 1gm thrice a day, enoxaparin 60 mcg twice a day through subcutaneous route and intravenous methyl-prednisolone at the dose of 100 mg/day along with other supportive measures] in the intensive care unit; however, despite our best efforts the patient succumbed to severe acute respiratory distress syndrome after 12 days of hospitalization.

A 42-year-old gentleman presented with a complaint of fever for last 12 days. Fever was initially low grade and intermittent, but over last 5 days it became high grade and continuous. There was also a dry cough since the onset of febrile illness. He was feeling short of breath on minimal activity over last three days. He complained of slightly painful blackish discoloration of the skin involving the toes for last 4-5 days. Notably, he did not have any hemoptysis, chest pain, J o u r n a l P r e -p r o o f orthopnea, diarrhea and loss of smell or taste sensation. The patient did not give any history of diabetes or hypertension; no substance abuse or use of any regular medication was elicited.

On admission, he was febrile (37.8 0 C) with tachycardia (pulse rate: 110/min). His blood pressure was 104/60 mmHg and respiratory rate 30/minute. Pulse oximetry revealed oxygen saturation of 84% on room air. Cutaneous examination revealed dry gangrene with areas of ulceration involving the toes of both feet. All the peripheral pulses were palpable. There was no clinical evidence of cardiovascular ailment. On auscultation of the chest, crackles and wheezes were audible bilaterally, most predominantly over the lung bases. Examination of other systems was unremarkable.

RT-PCR for SARS-CoV-2 from oropharyngeal and nasopharyngeal swab came positive. patients in a systematic review. 7 It is well established that severe COVID-19 associated with cytokine storm is a harbinger of dysregulated coagulation homeostasis leading to thromboinflammation and consumption coagulopathy, subsequently increasing mortality and morbidity. Although the exact mechanism of COVID-19 induced thrombosis remains elusive, increased activation of thrombocytes with coagulation cascade and decreased fibrinolysis deserve mention. Direct endothelial damage mediated by SARS-CoV-2 with subsequent exposure of collagen may lead to platelet adhesion and aggregation, followed by subsequent activation of coagulation cascade coupled with abnormal fibrinolysis. 8, 9 The cytokine storm triggered by SARS-CoV-2 mediated by IL-6, interferon-gamma, and IL-2 aggravates the prothrombotic state and facilitates hypercoagulability. 10 Moreover, the alternative and the lectin pathways of the complement system adds additional fuel to the fire, facilitating thrombosis. 11 Microvascular and macrovascular thrombosis in COVID-19 have been reported worldwide and correlates well with severity of ailment.

SPG is a rare entity harboring significant morbidity characterized by symmetrical irreversible ischemic damage of two or more sites in the absence of any large vessel occlusion or vasculitis. 6 A wide spectrum of infective and non-infective etiologies have been attributed to cause SPG, although the pathogenesis is debatable. Disseminated intravascular coagulation J o u r n a l P r e -p r o o f (DIC) with microcirculatory occlusion is usually contributory. Schwartzman reaction, endotoxin, platelet plugging in peripheral vasculature due to hypercoagulable vasospasm and DIC are the probable pathomechanisms involved in SPG. 12 DIC contributes to the final common pathway in majority cases of SPG. Bacterial, viral, protozoal agents are common offenders aside the noninfective causes like myocardial infarction, hypovolemic/septic shock, lymphoreticular malignancies, pulmonary embolism, and vasopressors. Pain in the extremities followed by fever with or without constitutional symptoms in presence of cold, pale, cyanotic acral parts of the body is the usual presentation, which may progress to a frank dry gangrene if not reversed. The gangrene is usually symmetric, may progress proximally from distal sites, often associated with mummification and may lead to auto-amputation. SPG is not associated with any compromise of the distal pulses, however features of shock may predominate in some cases. 13 Coagulation abnormalities and thrombotic manifestations have been increasingly reported in patients with moderate to severe COVID-19 pandemic. Multisystem inflammation and thromboinflammation has provided new insights to the management of this pandemic. Purpura fulminans (PF) is one such manifestation, characterized by rapidly progressive cutaneous necrosis and hemorrhage attributable to vascular thrombosis and DIC, which have been reported in literature in association with COVID-19. 14 Majority of patients of SPG may have preceding PF in different parts of the body. However, notable causes of acral gangrene namely thrombangitis obliterans, atherosclerotic plaque, thomboemboli, vasculitis must be ruled out to establish a diagnosis of SPG. DIC has been reported to lead to development of dry gangrene in patients with severe COVID-19. 15 Limitation: Our series is limited by a small sample size. Large scale pooled data from multiple centers would further advance our knowledge on this association. We could not perform estimation of anticoagulant proteins due to institutional non-availability. Further, post-mortem examinations of these patients were not conducted.

To conclude, we would like to draw attention of physicians to this unique clinical entity (SPG) 

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