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

Abstract

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.

Anti-factor H antibody and its role in atypical hemolytic uremic syndrome

“…Over the years, many therapies have been used to manage aHUS such as plasma exchange therapy, eculizumab, immunosuppressants like prednisone, cyclophosphamide, rituximab and eventually a renal transplant. According to a study conducted by Bagga and Khandelwal et al in 2019, plasma exchange therapy (PEX) along with immunosuppressants is the recommended treatment for aFH antibody associated aHUS (13). This study, however, did not show a significant change in renal outcomes through PEX use vs. without PEX is done using fresh frozen plasma as a replacement fluid.…”

“…Furthermore, data from the global aHUS registry reports the presence of aFH antibodies is 24% in all children with aHUS and 19% in adults diagnosed with aHUS ( 11 ). The deletion of CFHR1 gene can be seen in 5-10% of healthy individuals in the world ( 13 ). As this complement abnormality is common in aHUS patients, it is imperative to analyze its biological features.…”

“…More recently, Khandelwal et al. has shown infection with COVID-19 to be a potential trigger in the presentation of aHUS ( 13 ). During the second wave of the pandemic in India, five patients ages 4-13 years were found to have aFH antibody associated aHUS coinciding with a diagnosis of COVID-19.…”

“…Three of the five patients also showed a CFHR1 gene deletion on genetic testing. This suggests aFH associated aHUS patients were at an increased risk of suffering a relapse or recurrence after contracting COVID-19 infection, despite a long dormant course ( 13 ). While showing promising results, this paper is limited by its small patient population.…”

COVID-19 microthrombosis: unusually large VWF multimers are a platform for activation of the alternative complement pathway under cytokine storm

“…Subsequent investigations have confirmed that a low ADAMTS13/VWF ratio in patient plasma is associated with a high prothrombotic risk [ 11 – 13 ]. Indeed, these patients sometimes have a variety of autoimmune complications, such as immune thrombocytopenia (ITP) [ 72 ], Guillain–Barré syndrome [ 73 ], antiphospholipid syndrome (APS) [ 74 ], immune TTP [ 75 ], and more recently anti-factor H associated aHUS [ 76 ]. However, anti-PF4 antibody [ 77 , 78 ] rarely appears after SARS-CoV-2 vaccination.…”