Focal small bowel thrombotic microvascular injury in COVID-19 mediated by the lectin complement pathway masquerading as lupus enteritis

Abstract

The clinician needs to consider the overlapping pathophysiological mechanisms of SLE, APS and coronavirus disease 2019. DearEditor, The multiorgan and systemic manifestations of coronavirus disease 2019 (COVID-19) share features in common with SLE and APS. They are all associated with complement activation and microvascular injury, which can cause gastrointestinal symptoms creating a diagnostic challenge for the clinician. The severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) was identified in Wuhan, China as the aetiologic agent of a novel respiratory illness [1]. In addition to acute respiratory failure, extrapulmonary manifestations include haematologic abnormalities resulting in systemic coagulopathy manifest as pulmonary embolisms, deep vein thrombosis, microvascular injury and gastrointestinal abnormalities [1–3]. Histopathologic studies have shown microvascular injury in the heart, lungs, skin, kidney and small bowel [2, 4]. There is evidence this is in part driven by lectin pathway complement activation, with reports of deposition of C5b-9, C4d and mannose-binding lectin serine protease 2 (MASP2) in the microvasculature, which can produce a catastrophic microvascular injury syndrome [4]. Additionally, there are reports of aPL occurring in COVID-19 patients [5]. SLE is an autoimmune disease, characterized by immune dysregulation resulting in activation of the innate immune system with increased type 1 IFN, production of autoantibodies, generation of circulating immune complexes and episodic activation of the complement system. Lupus enteritis is a rare manifestation characterized clinically by abdominal pain, diarrhoea and vomiting, and radiographically by bowel wall oedema [6]. A subset of SLE patients develop aPL and are at risk for thrombotic events [7]. The occurrence of small-vessel occlusion is uncommon, but is a well-documented APS phenomenon that can occur in skin, liver, kidney and bowel [6, 7]. We report a case of a 27-year-old woman presenting with acute onset nausea, vomiting and non-bloody diarrhoea. Four years prior to admission she was diagnosed with SLE after developing immune thrombocytopenic purpura. Her SLE manifestations include malar rash, arthritis, ANA, anti-dsDNA, anti-Ro, persistently low C3 and C4, and a positive LA, which on subsequent testing was negative along with absent aCL and beta 2 glycoprotein antibodies. At physical exam on hospital day 1, she was afebrile, normotensive, with a heart rate 97 b.p.m., oxygenating 98%, with clear lungs, a diffusely tender abdomen without rebound and skin without rash. A nasopharyngeal swab analysed by PCR confirmed SARS-CoV-2 infection. Laboratory tests revealed C3 and C4 at her usual baseline levels at 74 and 4 mg/dl, respectively, and anti-dsDNA antibody of 161 IU/ml, slightly elevated compared with baseline. Her D-dimer increased from 2872 ng/ml on day 1 to 5446 ng/ml on day 3. aPL testing revealed newly present aCL IgG and IgM at 24.2 GPL and 21.4 MPL, respectively. CT of her abdomen showed diffuse small bowel oedema (Fig. 1A). On day 2, biopsies obtained during esophagogastroduodenoscopy revealed platelet/fibrin-rich thrombi in the microvasculature of her duodenal lamina propria and submucosa associated with ischaemic mucosal necrosis (Fig. 1B and C). The patient was treated with enoxaparin with concurrent decrease in her D-dimer level and resolution of her abdominal pain, diarrhoea and anorexia. Apixaban was initiated on hospital discharge. Radiographic and histology findings (A) CT abdomen with oedema of the small bowel wall. (B) Mucosal necrosis with microvascular thrombi and fibrin extravasation in lamina propria, consistent with thrombogenic vasculopathy (haematoxylin and eosin). (C) Occlusive luminal thrombi and mural fibrin (haematoxylin and eosin). (D–I) In situ deposition of components of complement activation, namely C3d, C4d, C5b-9 and MASP2, the latter a protein formed as a sequelae of the mannose-lectin binding activation were conducted on 4-μm sections procured from formalin-fixed paraffin-embedded tissue. Immunohistochemical assessment of SARS-CoV-2-associated envelope and spike glycoprotein was also conducted, as previously described [4]. (D) MASP2 staining, (E) C4d staining in thrombosed and (F) non-thrombosed capillaries and venules (diaminobenzidine), and (G) C5b-9 staining of (H) SARS-CoV-2 membrane and (I) spike glycoprotein throughout the microvasculature ( diaminobenzidine). MASP2: mannose-binding lectin serine protease 2 SARS-CoV-2: severe acute respiratory distress syndrome coronavirus 2. Scale bar = 100 μm. Histopathological analysis demonstrated a pauci-inflammatory thrombogenic vasculopathy with marked endothelial cell injury. The case differed from conventional small vessel lymphocytic or neutrophil-rich vasculitis of SLE due to lack of vasocentric inflammation (Fig. 1B and C). There was minimal endothelial staining for myxovirus resistance protein Apointing to lack of type I IFN a