COVID-19 as a potential trigger of complement-mediated atypical HUS

El-Sissy, Carine; Saldman, Antonin; Zanetta, Gilbert; Vieira-Martins, Paula; Poulain, Coralie; Cauchois, R.; Kaplanski, Gilles; Venetz, Jean-Pierre; Bobot, Mickaël; Dobosziewicz, H.; Daniel, Laurent; Koubi, Marie; Sadallah, Salima; Rotman, Samuel; Mousson, Christiane; Pascual, Manuel; Frémeaux‐Bacchi, Véronique; Fakhouri, Fádi

doi:10.1182/blood.2021012752

Cited by 21 publications

(25 citation statements)

References 22 publications

(34 reference statements)

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“…Once the complement cascade is activated beyond a critical threshold, C3b formation and deposition occur on the vascular endothelium, which leads to further complement activation through the alternative pathway self-amplifying loop, culminating in microangiopathic injury and thrombosis. Reports from large cohorts show that atypical HUS onset or relapse are often triggered by bacterial and viral infections ( Fang et al, 2008 ; Noris et al, 2010 ) , as well as the occurrence of HUS in COVID-19 patients ( El Sissy et al, 2021 ; Mat et al, 2021 ), and present data corroborate the hypothesis that SARS-CoV-2 triggers the development of renal TMA through activation of the complement alternative pathway.…”

Section: Discussionsupporting

confidence: 87%

Case Report: Tackling Complement Hyperactivation With Eculizumab in Atypical Hemolytic Uremic Syndrome Triggered by COVID-19

et al. 2022

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Hemolytic uremic syndrome (HUS) is a rare life-threatening disease of unrestrained complement system dysregulation, microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure in genetically predisposed individuals. In this report, we describe two cases of SARS-CoV-2–associated HUS treated with eculizumab, a C5-blocking monoclonal antibody reported to be remarkably effective in the treatment of HUS. Detailed biochemical and genetic complement system analysis is reported, and the prompt clinical response after C5 pharmacological blockade is documented. Our report provides the rationale and supports the use of terminal complement pathway inhibition for the treatment of SARS-CoV-2–associated HUS.

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Section: Discussionsupporting

confidence: 87%

Case Report: Tackling Complement Hyperactivation With Eculizumab in Atypical Hemolytic Uremic Syndrome Triggered by COVID-19

et al. 2022

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“…The review of the literature showed a total of 9 patients with HUS associated with COVID-19 infection ( Table 5 ) ( 56 – 59 ). Eight subjects developed an atypical HUS and 1 a typical HUS with bloody diarrhea in the preceding days and confirmed E. coli infection.…”

Section: Resultsmentioning

confidence: 99%

“…Eight subjects developed an atypical HUS and 1 a typical HUS with bloody diarrhea in the preceding days and confirmed E. coli infection. Interestingly, most patients had mild or asymptomatic COVID-19 infection, whilst HUS presented with severe haemolytic anemia and acute kidney injury requiring transfusions, hemodialysis, and the C5 inhibitor eculizumab in 7 cases ( 56 – 59 ). All HUS flares occurred within 1 month from COVID-19 infection, mostly concomitantly, and all resolved.…”

Section: Resultsmentioning

confidence: 99%

Complement Mediated Hemolytic Anemias in the COVID-19 Era: Case Series and Review of the Literature

et al. 2021

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The complex pathophysiologic interplay between SARS-CoV-2 infection and complement activation is the subject of active investigation. It is clinically mirrored by the occurrence of exacerbations of complement mediated diseases during COVID-19 infection. These include complement-mediated hemolytic anemias such as paroxysmal nocturnal hemoglobinuria (PNH), autoimmune hemolytic anemia (AIHA), particularly cold agglutinin disease (CAD), and hemolytic uremic syndrome (HUS). All these conditions may benefit from complement inhibitors that are also under study for COVID-19 disease. Hemolytic exacerbations in these conditions may occur upon several triggers including infections and vaccines and may require transfusions, treatment with complement inhibitors and/or immunosuppressors (i.e., steroids and rituximab for AIHA), and result in thrombotic complications. In this manuscript we describe four patients (2 with PNH and 2 with CAD) who experienced hemolytic flares after either COVID-19 infection or SARS-Cov2 vaccine and provide a review of the most recent literature. We report that most episodes occurred within the first 10 days after COVID-19 infection/vaccination and suggest laboratory monitoring (Hb and LDH levels) in that period. Moreover, in our experience and in the literature, hemolytic exacerbations occurring during COVID-19 infection were more severe, required greater therapeutic intervention, and carried more complications including fatalities, as compared to those developing after SARS-CoV-2 vaccine, suggesting the importance of vaccinating this patient population. Patient education remains pivotal to promptly recognize signs/symptoms of hemolytic flares and to refer to medical attention. Treatment choice should be based on the severity of the hemolytic exacerbation as well as of that of COVID-19 infection. Therapies include transfusions, complement inhibitor initiation/additional dose in the case of PNH, steroids/rituximab in patients with CAD and warm type AIHA, plasma exchange, hemodialysis and complement inhibitor in the case of atypical HUS. Finally, anti-thrombotic prophylaxis should be always considered in these settings, provided safe platelet counts.

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“…Both patients showed satisfactory response to therapy with eculizumab. Atypical HUS triggered by mild SARS-CoV-2 infection was reported in 2 adults, each with a pathogenic variant in CFI and an at-risk CFH-H3 haplotype, who were additionally found to have anti-FH antibodies [ 15 ]. A homozygous CFHR1 deletion was not found in these patients, in contrast to its characteristic association with anti-FH antibodies in 71.4–92.3% and 88.2% patients in Caucasian [ 21 ] and Indian [ 3 ] cohorts, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…While several autoimmune diseases such as immune thrombocytopenic purpura, thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia, and systemic lupus erythematosus have been associated with SARS-CoV-2 infection [ 14 ], the association of anti-FH associated aHUS has rarely been reported. In a recent report of 5 adults with SARS-CoV-2 triggered aHUS, genetic variations were found in all patients tested; additionally, anti-FH autoantibodies were detected with pathogenic CFI variant and CFH-H3 at-risk polymorphism in 2 patients [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Anti-factor H antibody associated hemolytic uremic syndrome following SARS-CoV-2 infection

et al. 2022

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Background The pathogenesis of autoantibody generation in anti-factor H (FH) antibody associated atypical hemolytic uremic syndrome (aHUS) is unknown and is perhaps triggered by an infectious or environmental agent. We observed an unusual increase of patients with anti-FH antibody associated aHUS coinciding with the second pandemic wave in New Delhi and suspected that SARS-CoV-2 infection might be a potential trigger. Methods We screened for SARS-CoV-2 infection using reverse transcriptase polymerase chain reaction (RT-PCR) and serology in 13 consecutive patients with anti-FH antibody associated aHUS during the past year in New Delhi. Results We report 5 patients, 4–13 years old, who presented with a febrile illness without respiratory symptoms during the second pandemic wave. Of these, 3 patients presented with a relapse 25–85 months following the initial episode of aHUS. SARS-CoV-2 was detected by RT-PCR in 1 patient and by serology in 4 patients (median titer 47.1 cut-off index). Patients had high titers of anti-FH antibodies (median 2,300 AU/ml). Genetic studies, done in 3 of the 5 patients, showed homozygous CFHR1 deletion without other significant genetic abnormalities. Specific management comprised plasma exchanges and oral prednisolone, combined with either cyclophosphamide or mycophenolate mofetil. At median follow-up of 3.3 months, the estimated glomerular filtration rate in 4 patients ranged from 62 to 110 ml/min/1.73 m 2 ; one patient was dialysis-dependent. Conclusion Increased vigilance is required during the pandemic, especially in patients with anti-FH associated aHUS, who might relapse despite quiescent disease for a prolonged period. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information. Supplementary Information The online version contains supplementary material available at 10.1007/s00467-021-05390-4.

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COVID-19 as a potential trigger of complement-mediated atypical HUS

Cited by 21 publications

References 22 publications

Case Report: Tackling Complement Hyperactivation With Eculizumab in Atypical Hemolytic Uremic Syndrome Triggered by COVID-19

Case Report: Tackling Complement Hyperactivation With Eculizumab in Atypical Hemolytic Uremic Syndrome Triggered by COVID-19

Complement Mediated Hemolytic Anemias in the COVID-19 Era: Case Series and Review of the Literature

Anti-factor H antibody associated hemolytic uremic syndrome following SARS-CoV-2 infection

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