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Autoimmune haemolytic anaemia (AIHA) is rare but described after the SARS-CoV- 2 Pfizer-BioNTech vaccine. We present a case of severe refractory warm AIHA after this vaccine, managed with emergency splenectomy and complement inhibition with eculizumab. A male in his teens with a history of liver transplant for biliary atresia (aged 2 years) and AIHA (aged 6 years) presented to his district general hospital with jaundice, dark urine, fatigue and chest discomfort 48 h after the first dose of SARS-CoV- 2 Pfizer-BioNTech vaccine (BNT162b2 mRNA). Investigations revealed haemoglobin (Hb) of 70 g/L and bilirubin of 98 mumol/L, which was treated as AIHA. The patient initially responded to prednisolone (1 mg/kg, 60 mg) but subsequently deteriorated and failed to respond to second-line rituximab (375 mg/m2) and two units of packed red blood cells (PRBC). By day 29 the patient had developed life-threatening anaemia culminating in a Hb of 35 g/L (after transfusion), lactate dehydrogenase (LD) of 1293 units/L and bilirubin of 228 mumol/L. This necessitated an immediate transfer to our tertiary centre for specialist support. Further investigations revealed a haptoglobin <0.1 g/L and direct antiglobulin test (DAT) strongly positive for IgG (4+) and negative for C3d. The peripheral blood film showed severe anaemia, nucleated red cells, anisocytosis and spherocytes with no autoagglutination, schistocytes or platelet clumps. Thrombocytopaenia (platelets 49 +/- 109/L) was present. Differentials were ruled out, such as paroxysmal nocturnal haemoglobinuria and heparin-induced thrombocytopaenia. HIV and hepatitis serology were negative, as were adenovirus, cytomegalovirus and Epstein-Barr virus PCR assays. A CT showed splenomegaly of 15.5 cm. Urinalysis found urobilinogen and bilirubin at high concentrations and negative urinary haemosiderin. Together, the investigations were consistent with warm AIHA. On day 29, four units of PRBC were transfused alongside 100 mg methylprednisolone and 1 g/kg IVIG. On day 30 the patient deteriorated despite the escalated treatment: Hb had only increased to 54 g/L, bilirubin was 200 mumol/L and LD was rising. Considering this life-threatening fulminant haemolysis, an emergency splenectomy was performed. This slowed haemolysis but did not completely ameliorate it: by day 33 the patient had received 15 units of PRBC. Thus, eculizumab, a terminal complement pathway inhibitor, was trialled to arrest intravascular haemolysis, alongside rituximab, repeat IVIG 1 g/kg, prednisolone 40 mg and tacrolimus 2 mg. This showed a favourable response, requiring less frequent transfusions and settling haemolysis. This case highlights the rare complication of warm AIHA with the SARS-CoV- 2 Pfizer-BioNTech vaccine, the use of emergency splenectomy for disease control, and the potential of eculizumab for refractory cases.
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Introduction: Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) characterized by dysregulated complement activation. Antibodies to factor H (anti-FH), a regulator of the alternative complement pathway, are a recognized cause of aHUS particularly in children. We present the case of an elderly patient who developed aHUS following COVID-19. Case Description: A 74-year-old male presented with weakness, petechial rash involving extremities and diarrhea for 2 weeks. Prior history included hepatitis C infection status-post treatment 2 years ago with associated cirrhosis. Three weeks ago, the patient had been diagnosed with COVID-19. His symptoms of sore throat, cough and fever had by now resolved. Initial investigations showed leukocytosis and AKI with an active urinary sediment and nephrotic range proteinuria (Fig 1). Hemoglobin and platelets were normal and a blood smear was negative for hemolysis. Imaging revealed small bowel enteritis suggestive of an infectious or vasculitic process. Infectious workup returned negative. Autoimmune serologies revealed a borderline positive ANA, low C3 and low-normal C4. Renal biopsy revealed diffuse endothelial injury with swollen endothelial cells, focal mesangiolysis and glomerular basement membrane duplication. Hence, pulse dose steroids were started and complement function panel sent. Soon after steroid initiation, the patient's renal function, leukocytosis and rash improved. Ultimately, complement testing returned positive for anti-FH. At follow-up, renal function had returned to baseline with continued steroid taper. Discussion(s): COVID-19 is associated with TMA likely due to endothelial toxicity or complement pathway dysregulation. Our patient had no prior history of renal or hematologic disease. Given the chronology of events, it is likely that COVID-19 triggered formation of anti-FH, in turn leading to development of aHUS in our patient.
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SESSION TITLE: Unique Inflammatory and Autoimmune Complications of COVID-19 Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: ANCA-associated vasculitis (AAV) is a systemic disease that causes inflammation of small vessels in various organs, such as the lungs, kidneys, and nervous system. We report a case of AAV following SARS-CoV-2 infection. CASE PRESENTATION: A 64-year-old female from Albania with no known medical history, presented with intermittent low-grade hemoptysis and fever for 1 week prior to admission. She had chills, myalgias, fatigue, and poor appetite 6 weeks prior. On arrival, she was febrile (101F), and hypoxic (Spo2 92% on 3L O2). Labs were significant for anemia [Hb 6.8 g/dl], acute kidney injury (AKI) [Cr 2.5 mg/dl]. She was found to be Positive for Sars-CoV-2 by PCR. Chest X-Ray showed patchy bilateral airspace opacities with peripheral and lower lobe predominance, concerning for atypical pneumonia (Fig 1). Urinalysis was significant for proteinuria (2+) and hematuria (2+). CT (Computed Tomography) thorax showed extensive bilateral airspace disease (dense consolidations and ground-glass opacities) favoring multifocal infection and mediastinal lymphadenopathy(Fig 2). Due to the chronicity of her symptoms and atypical imaging for viral pneumonia, other diagnoses were explored including bacterial superinfection, Tuberculosis, and autoimmune disease. Sputum studies were negative for infections including Acid Fast Bacilli. Workup revealed elevated Antimyeloperoxidase antibodies (MPO) and positive COVID-19 Ig G. She was started on methylprednisolone 1g for AAV. Renal biopsy revealed pauci-immune glomerulonephritis with features of cellular crescent consistent with microscopic polyangiitis (Fig 3). Follow-up CT chest showed improved airspace abnormalities and mediastinal lymphadenopathy. After induction therapy with Rituximab was initiated, she continued to recover and was discharged home. DISCUSSION: The pathogenesis of AAV is believed to be an aberrant pathogenic autoimmune response that follows an initial insult which can include infections. SARS-CoV-2 has been associated with the emergence of autoimmune diseases in susceptible patients(1). The proposed mechanism is linked to elevated levels of circulating neutrophil extracellular traps (NETs) observed in covid infection. These NETS are covered with proteins including neutrophilic enzymes which can activate complement pathways causing tissue destruction and vasculitis. The diagnosis of new-onset AAV can be challenging in COVID-19 patients as symptoms and clinical manifestations of both diseases can overlap. AAV should be considered strongly in patients who are currently infected or have been infected with SARS-CoV-2 and present with atypical or non-resolving pneumonia and other organ involvement such as AKI to avoid permanent organ damage. CONCLUSIONS: The presence of non-resolving or atypical pneumonia and AKI in a patient with SARS-CoV-2 should prompt evaluation of immunological markers to assess or rule out AAV for early diagnosis and treatment. Reference #1: Caso F, Costa L, Ruscitti P, Navarini L, Del Puente A, Giacomelli R, Scarpa R. Could Sars-coronavirus-2 trigger autoimmune and/or autoinflammatory mechanisms in genetically predisposed subjects? Autoimmun Rev. 2020;19(5):102524. doi: 10.1016/j.autrev.2020.102524 DISCLOSURES: No relevant relationships by Tarik Al-Bermani No relevant relationships by Anant Jain No relevant relationships by Ian Kaplan No relevant relationships by Alina Kifayat No relevant relationships by Lisa Paul
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BACKGROUND AND AIMS: Haemolytic uremic syndrome (HUS) is a rare disease characterized by macroangiopathic haemolytic anaemia, thrombocytopaenia and severe AKI, belonging to the thrombotic microangiopathies (TMAs). It is divided into typical and atypical HUS: the first one occurs most frequently in children within the first 5 years of life and it is associated with Shiga-like toxin producing Escherichia coli infection;the second one (aHUS) is less common (10%) and it is due to complement abnormalities with coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs or pregnancy. There is an increasing interest in SARS-CoV-2 infection as new trigger for complement activation. Nine cases of aHUS were recently associated with COVID-19, most of them occurring within 1 month from the infection. Available data suggest that SARS-CoV-2 is a potential trigger for aHUS: it can induce an over inflammatory state and to activate coagulation and complement pathway. Likewise, mRNA-based vaccines against COVID-19 inducing the expression of SARS-CoV-2 spike protein to stimulate immune recognition and antibody response could be a suitable trigger for HUS. METHOD: We report the case of a 17-year-old woman, who presented at our emergency department with fever, dyspnoea, acute kidney injury AKI III with anuria, hypertension, severe anaemia, no diarrhoea, severe thrombocytopaenia and myocarditis, about 2 weeks after the first administration of SARS-CoV-2 vaccine (Comirnaty) and recent exposition to SARS-CoV-2 positive individual. SARS-CoV-2 nasal PCR swab was negative (as well as successive ones) and she was immediately admitted to paediatric intensive care unit and treated with transfusions and haemodialysis. Laboratory exams suggested a thrombotic microangiopathy with normal ADAMTS-13 activity and no E. coli infection. She underwent a renal biopsy that confirmed our hypothesis of aHUS: wrinkled capillaries, subendothelial expansion, mesangiolysis and rare thrombi in capillaries lumen. Arterioles had intimal proliferation with mucoid oedema who gave rise to onionskin like lesion that obliterates lumens. One glomerulus showed extracapillary proliferation (crescent), and there was interstitial lymphomonocytic inflammatory infiltration in the nearby. Also signs of acute tubular injury and atrophy were reported. Positive stain to fibrinogen in the arterioles at immunohistology was noted. She immediately performed genetic exams for aHUS-related complement mutations and she started immunosuppression with corticosteroids and eculizumab infusions. After 2 months of eculizumab, she was still oliguric, requiring renal replacement therapy. Genetic analysis showed no mutations. Therefore, she was examined for other genetic causes of thrombotic microangiopathies. RESULTS: Finally, came to light that she had high levels of homocysteine, and she was diagnosed with secondary HUS associated with cobalamin C deficiency, which manifests with methylmalonic aciduria and homocystinuria due to a recessive mutation in the MMACHC gene, causing a cobalamin C type deficiency, which is the common functional variant of vitamin B12. After metabolic therapy with hydroxocobalamin, she gradually recovered diuresis and partially renal function without need for replacement therapy. CONCLUSION: Reports from immunization programs show as myocarditis and thrombotic thrombocytopaenia are considered among main serious complications caused by COVID-19 vaccines, representing 12.6 cases per million doses and 0.73 cases per 100 000, respectively. This interesting case probably supports data about the role of mRNA-based anti- SARS-CoV-2 vaccines like a precipitant factor for TMAs. Moreover, our patient turned out to be an extremely rare case of HUS secondary to cobalamin C deficiency, that is generally diagnosed in early infancy and show typically neurological symptoms (absent in our case). Probably, the mRNA-based vaccine acted like 'a second hit', but existing predisposition should always be investigated including also the les frequent forms. (Table Presented).
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Background: Coronavirus disease-19 (COVID-19) is an acute respiratory illness caused by the SARS-COV-2 virus. Patients with COVID-19 infection can present with thrombosis in the setting of inflammation (thromboinflammation), presumably from endothelial dysfunction, or “endotheliopathy”. Yu et al demonstrated in vitro that the spike protein subunit of SARS-COV2 acts as a potent activator of the alternative complement pathway (AP), one of three complement pathways within the innate immune system. Satyam et alreported the deposition of complement components on lung tissue of patients who succumbed to COVID-19, consistent with activation of classical and alternate pathways. These studies suggest complement dysregulation potentially causing endotheliopathy in COVID-19 patients. Thrombomodulin (TM) is an endothelial glycoprotein that plays two crucial roles in maintaining a healthy endothelium - as a natural anticoagulant and a negative regulator of complement. TM shed into the circulation due to endothelial injury can be measured in the plasma as soluble TM (sTM). Goshua et al showed elevated sTM in an adult cohort of patients with COVID-19. However, it is yet to be demonstrated if there is any correlation between endothelial injury and AP activation in COVID-19, or if either play a role in clinical outcome in the pediatric population. Objective: To 1) assess endothelial injury and AP activation in a cohort of critically ill pediatric patients with COVID-19 by measuring sTM and Ba (an AP activation product);2) determine the correlation between endothelial injury and AP activation;and 3) analyze the utility of sTM and Ba in predicting pediatric clinical outcomes. Methods: We collected plasma samples of patients admitted to the Pediatric Intensive Care Unit and found to be positive for SARS-CoV-2 between Dec 2, 2020 and Jan 22, 2021 at Texas Children's Hospital. For controls, we collected plasma samples from pediatric patients undergoing preoperative clearance, all at their baseline state of health. sTM levels and Ba levels were measured in plasma samples using commercially available TM and Ba ELISA kits. sTM greater than 7.6 ng/ml (based on the assay range in adults) and Ba greater than 1080 ng/ml (based on data from adult healthy controls) were considered elevated. Data regarding demographics, length of ICU stay, clinical indicators of end organ damage- mechanical ventilation, dialysis, use of vasopressors, ECMO, mortality were obtained retrospectively via chart review. Inclusion criteria included all patients with a positive SARS-COV2 PCR admitted to the ICU. Exclusion criteria was age greater than 21 years, pregnant female, patients with known inflammatory or complement-mediated disorders. Statistical analysis: For sTM and Ba levels between control and COVID-19 patients, mean +/- standard deviation was calculated and significance determined with an unpaired t-test. Fischer exact test, Wilcoxon rank sum and Pearson product-moment correlation tests were used for statistical analysis of clinical outcomes as appropriate. A p-value <0.05 was considered statistically significant. Results: A total of 38 control patients and 33 COVID-19 patients were enrolled. Ba and sTM levels were both significantly higher in the COVID-19 pediatric patients compared to the controls (Fig. 1). Within the COVID-19 patient cohort, 61% (n=20) had elevated sTM and 42% (n=14) had elevated Ba levels. There was a moderately positive correlation between sTM and plasma Ba levels in the COVID-19 cohort (Fig. 2). Within the COVID-19 patients' cohort, though higher Ba levels were not associated with an increased rate of intubation, they were associated with an increased duration of mechanical ventilation (p=.039) for those intubated (Table 1). Elevated sTM was associated with increased vasopressor use (p=.011). Although other clinical outcome variables did not reach statistical significance likely owing to small numbers, overall trend indicated worse outcomes in patients with elevated sTM. Conclusions: Our findings are consistent with the hypothesi that SARS-COV-2 activates AP and causes endothelial injury in children. The positive correlation between sTM and Ba suggest interplay between inflammation, coagulation and endotheliopathy supporting thromboinflammation in COVID-19. Higher sTM and Ba levels indicated worse clinical outcomes in children, but larger studies are needed to confirm our findings. [Formula presented] Disclosures: Sartain: Alexon Pharamaceuticals: Membership on an entity's Board of Directors or advisory committees.
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BACKGROUND. COVID-19 is a prothrombotic disease, characterized by endotheliopathy, hypercoagulability, and thromboembolic complications. We hypothesized that the pathogenesis of thromboembolism associated with COVID-19 might differ from thromboembolism in patients without COVID-19. In this study, we sought to evaluate the proteomic signatures of plasma from patients with venous thromboembolism with and without COVID-19. METHODS. Between December 17, 2020 and February 25, 2021 blood was collected from 48 hospitalized patients. Of these 24 had a confirmed diagnosis of COVID-19 infection (COVID+) and radiologic confirmation of arterial or venous thromboembolism (TE+);17 had COVID-19 infection with absence of arterial thrombosis clinically and absence of venous thromboembolism on lower extremity Doppler ultrasound or chest CT angiography (COVID+/TE-), while 7 were arterial or venous thromboembolism in the absence of COVID-19 (COVID-/TE+). Blood was collected in sodium citrate tubes and centrifuged at 4000 rpm for 20 minutes, with resulting plasma supernatant used for protein profiling performed at Eve Technologies (Calgary, Alberta, Canada). Institutional Review Board approval was obtained for this study. Statistical analysis was performed using GraphPad Prism (v9.1, GraphPad Software, San Diego, CA) and R (v4, R Core Team). P values <0.05 were considered statistically significant. A heatmap was generated using Heatmapper (heatmapper.ca) to represent the concentrations of proteins. RESULTS. The median age was 63 years;overall 25 (52%) were men (13 [54%] among COVID+/TE+, 11 [65%] among COVID+/TE-, and 1 [14%] among COVID-/TE+). In COVID-19 patients who developed thromboembolic events, several proteins associated with inflammation, complement activation, and hemostasis were present at higher levels than in non-COVID-19 patients who developed thromboembolic events (Fig. 1). These included complement factors C2 and C5a, pentraxin-3 (PTX-3), lipocalin-2 (LCN2), resistin (RETN), platelet endothelial cell adhesion molecule-1 (Pecam1), serum amyloid A (SAA), and tissue factor (TF). The heatmap indicates relative protein levels detected in each subject (columns) for proteins (rows) that had statistically significant differences between groups (Fig. 2). Heatmap revealed relatively lower levels of all proteins in patients with thromboembolism without COVID-19 and relatively higher levels of proteins in patients with COVID-19, and especially in ICU patients with COVID-19 and thromboembolism. CONCLUSIONS. Thromboembolic complications in patients with COVID-19 are associated with increased levels of various proteins involved in complement activation and immunothrombotic cascades, compared to thrombotic events in the absence of COVID-19. Activation of the classical complement pathway as evidenced by a relative increase in complement factor C2 may lead to increased TF activation, reflecting more substantial endothelial damage in COVID-19 patients. Higher levels of Pecam1, SAA, LCN2, and RETN all point to increased endotheliopathy, inflammation, and tissue damage in COVID-19 compared to non-COVID-19 thrombosis. These findings may offer insights into novel therapeutic strategies to treat immunothrombotic complications of COVID-19. [Formula presented] Disclosures: No relevant conflicts of interest to declare.