key: cord-0909589-l7mqh4y9 authors: Sadeghzadeh‐Bazargan, Afsaneh; Rezai, Mahdi; Najar Nobari, Niloufar; Mozafarpoor, Samaneh; Goodarzi, Azadeh title: Skin manifestations as potential symptoms of diffuse vascular injury in critical COVID‐19 patients date: 2021-06-15 journal: J Cutan Pathol DOI: 10.1111/cup.14059 sha: 331ccb335f74bdcc9088620e0609514a97e08459 doc_id: 909589 cord_uid: l7mqh4y9 As a respiratory viral infection caused by a novel coronavirus, COVID‐19 became rapidly pandemic within a few months. Despite the wide range of manifestations and organ involvement in COVID‐19 patients, the exact pathogenesis of severe and fatal types of COVID‐19 and causes involved with the individual base of the disease is not yet understood. Several studies have reported clinical, laboratory, and histopathological data in favor of vascular injury in multiple organs of critically ill patients with COVID‐19 as a result of hyperactive immune response, inflammation, and cytokine storm. Also, both clinical and histopathological evidence points to such vascular involvements in the skin. Given the ease of clinical examinations and skin biopsy and the lower risks of transmission of COVID‐19 to healthcare workers, the present review article was conducted to investigate the vascular skin manifestations of COVID‐19 patients clinically and/or histopathologically as helpful clues for better understanding the pathogenesis and predicting the prognosis of the disease, especially in severe cases. autoimmune bullous diseases as markers for underlying malignancies, drugs, and collagen vascular diseases. 6, 7 Moreover, cutaneous vascular lesions such as vasculitis or vasculopathic reaction may be seen because of the infections, drugs, rheumatologic disorders, genetic predisposition, coagulopathies, or internal malignancies. 8, 9 The majority of these conditions can be diagnosed by examining or the skin sampling of cutaneous lesions. Given the high transmission rate of COVID-19 as a global pandemic and its high prevalence among healthcare workers, heavy burden in most of the affected communities 10 They supported this hypothesis by reporting an increase in the dead space and the lack of response to the increase in pulmonary compliance in the patients with pulmonary involvement of COVID-19, which was not justified by ARDS alone. 17 According to the studies mentioned above or shown in Table 1 The Key findings: • Cutaneous lesions with a vascular component including chilblain-like lesions, retiform purpura, petechia, livedoreticularis, and skin necrosis are some of the most common and important manifestations of COVID-19 patients. • The most common findings in skin biopsy of these lesions are perivascular infiltration, vascular injury, and microthrombus formation. • Various mechanisms have been proposed for these manifestations, including direct virus damage or immune system reactions. • The relationship between the incidence of these lesions and the prognosis of COVID- 19 has not yet been definitively determined. Abbreviations: CBC, complete blood count; CBC-NL, complete blood count-normal level; DIC, disseminated intravascular coagulation; DIF, differential; FDP, fibrinogen degradation product; PT, prothrombin time; PTE, pulmonary thromboembolism; RBC, red blood cells; RT-PCR, reverse transcription polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. reaction in these patients and may be associated with deterioration of the disease course. Therefore, accurate identification of these manifestations and evaluation of the underlying causes of them may be helpful in the survival of these patients. These manifestations, according to reports so far, include petechia and purpura, chilblain-like lesions, acro-ischemia, necrosis, and livedo reticularis that all of which are indicative of a kind of vascular involvement such as coagulopathy and thrombotic thrombocytopenia, leukocytoclastic, lymphocytic, ANCA-associated or septic vasculitis and vasculopathy, complement-mediated vascular injury, cryoglobulinemia, antiphospholipid antibody syndrome, and vasoocclusion. 14, 15, 17, 18, 26 Some of these reactions are mild and transient while others are indicative of systemic reactions. Table 1 Both arterial and venous thrombotic events were reported in 31% of critically ill ICU patients with COVID-19 despite receiving thromboprophylaxis. 27 The wide range of central or peripheral nervous system involvements, including agitation, confusion, disorientation, headache, dizziness, seizure, acute cerebrovascular attacks, perfusion disorders, anosmia, dysgeusia, neuralgia, and neuropathy, reported in critically ill COVID-19 patients with a higher D-dimer levels than non-critical patients suggest cerebrovascular accidents in these patients. 28 Five COVID-19 patients aged below 50 years also presented with a large-vessel stroke. 29 Neurologic manifestations including this thrombotic event were also reported in association with the SARS and Middle East Respiratory Syndrome (MERS) outbreak with positive polymerase chain reaction (PCR) in cerebrospinal fluid analysis. [30] [31] [32] However, it was not positive for COVID in some studies. 33, 34 Other systemic features of COVID-19 patients include manifestations of kidney involvement, such as hematuria, proteinuria, and increased blood urea nitrogen and creatinine levels. Mortality is also higher in the patients with kidney involvement compared to the patients without evidence of kidney involvement. Despite the unclear mechanism of kidney injury in these patients, direct damage by the virus and immunological mechanisms have been reported as the potential causes. 2, 35, 36 Moreover, the viral inclusion bodies detected in the endothelial cells of the kidney in some COVID-19 patients suggest vascular mechanisms. 22 Acute kidney injury and tubular necrosis were also reported in some SARS and MERS patients. [37] [38] [39] Some studies proposed that the ventilation-perfusion mismatch in patients with COVID-19 can be related to microvascular injuries. It can be explained as severe and resistant hypoxia was observed in these patients while it is not usually seen in the case of typical ARDS with the same therapeutic intervention. So, vascular injury can be a proposed etiology in this disorder. 17,40 In some patients with severe COVID-19, histopathological examinations suggested vascular involvements such as endothelial injury, fibrinoid necrosis, microvascular thrombosis, red blood cell (RBC) extravasation, leukocytoclasia, infiltration of the inflammatory cells, including the neutrophils, monocytes, and lymphocytes, and complement deposition in the vessel walls of the skin, heart, kidney, and lung biopsies; however, there are conflicting results about the detection of SARS-COV-2 particles in these involved tissue, except for lung involvement. 17, 41 In the autopsy of three patients with COVID, obvious endothelitis has been reported in various organs such as the lung, heart, kidney, liver, and intestines. Viral inclusion bodies were also detected in the endothelial cells of some involved organs, such as the kidneys. It has been proposed that this widespread endothelial involvement is caused by inflammatory cells recruitment because of direct virus stimulation or immune system response and induces generalized endothelial dysfunction, pro-coagulation state, microcirculation disturbance, and ischemia, respectively. 22 tors production, which can finally lead to multiorgan damage. [43] [44] [45] Systemic vasculitis has different types such as leukocytoclastic, lymphocytic, ANCA-associated, complement-mediated, cryoglobulinemia, septic, and so on, and various causes such as autoimmune connective tissue diseases, malignancies, drugs, and infections. 9, 18 A study on pathological changes in different organs in SARS infection found the main targets of virus to include the lungs, the immune system, and systemic small vessels. Moreover, histopathological examinations found systemic vasculitis to include edema, localized fibrinoid necrosis and infiltration of monocytes, lymphocytes and plasma cells into vessel walls in the heart, the lung, the liver, the kidney, the adrenal glands, the stroma of striated muscles, and thrombosis in small veins. 46 Maybe, these pathological changes in favor of vasculitis are also present in COVID- 19. 47 Infections and immunization are important factors in the pathogenesis of acute hemorrhagic edema of infancy as an abnormal form of cutaneous small vessel vasculitis, which usually affects children aged 4 to 24 months. Infection with human coronavirus NL63 comorbid with recurrent rash was reported in a child. 48 2. Vaso-occlusion: After the stimulation of the immune system and the production of pro-inflammatory cytokines, some infections increase thrombin production and cause anticoagulant pathway dysfunction. The thrombin released during the process also increases inflammation. This damaged cycle progresses to microthrombosis, diffuse intravascular coagulation, and multiorgan failure. Increased immune responses and cytokine storms were found to cause thrombotic disorders in critically ill COVID-19 patients. This hypothesis was confirmed with the observation of high D-dimer levels in most of these patients. 3, 10, 49 F I G U R E 1 Acral pernio/chilblain-like lesions F I G U R E 2 A,B, Diffuse vascular injury The expression polymorphisms of the genes involved in complement or coagulation pathway scan increase vulnerability to vascular thrombotic events; for instance, a mutation in the complement regulatory gene causes uncontrolled complement activation and lethal thrombotic events in catastrophic antiphospholipid syndrome. 50, 51 The vascular deposition of the complement also plays a critical role in many thrombotic syndromes, and infections can activate the complement cascade. [52] [53] [54] As discussed earlier, complement deposition in the vessel walls of the lung and skin has been reported in some SARS-COV-2 patients. 17 Thrombocytopenia, prolonged prothrombin time and partial thromboplastin time, and elevated serum levels of D-dimer, and antiphospholipid antibodies (anticardiolipin antibody, anti B2 glycoprotein) were derived from the laboratory data of three critical COVID-19 patients with clinically significant coagulopathy (bilateral lower limbs and digital ischemia of the hand and multiple cerebral infarcts). It is recommended that further studies be conducted to confirm certain pathological roles of these antibodies in COVID-19 patients. 26 Cutaneous manifestations are in favor of vascular injuries, vasculitis, and vasculopathies in the majority of critically ill COVID-19 patients. There were also reports on the role of antithrombotic and anti-inflammatory agents in treating COVID-19. 55, 56 The present review was therefore performed to summarize evidence for these features in the skin and internal organs and discuss its relevance and ultimately decide on the possibility of skin involvements for reflecting events in visceral tissues. In contagious infections, the simplest way of tissue sampling can be vital in limiting the transmission of the disease to healthcare workers. 55, 56, [74] [75] [76] The authors of this study have concentrated on various aspects of COVID-19, especially dermatologic concerns. [77] [78] [79] [80] [81] [82] [83] We believe that vascular injuries may be one of the key pathomechanisms of COVID-19 in various vital organs; awareness of dermatologic manifestation may offer an approach to earlier diagnosis and more rapid therapeutic approaches toward similar systemic events. Various types of vascular injuries of skin in our own tertiary center and in patients were admitted by COVID-19 infection (Figures 1-6) . Because of certain condition of these patients, we were not able to histopalogically evaluate these vascular injuries that were obviously a COVID-related dermatologic manifestation. We would like to show our gratitude to the Rasool Akram Medical Complex Clinical Research Development Center (RCRDC) for its technical and editorial assists. This study did not receive any funding. 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