Systematic Review of Individual Patient Data COVID-19 Infection and Vaccination-Associated Thrombotic Microangiopathy

Introduction: Sporadic cases of atypical hemolytic uremic syndrome (aHUS) have been described in the literature in association with COVID-19 infection and vaccination in adults and pediatric patients. The exact mechanisms underlying COVID-19-associated thrombotic microangiopathies (TMAs) remain incompletely understood. Herein, we present a detailed meta-analysis of the clinical characteristics, outcomes, and management strategies of COVID-19-associated aHUS and thrombotic thrombocytopenic purpura (TTP).

Methods: This study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses updated guidelines. PubMed was utilized for searching for case reports and series. Adverse outcome at last follow-up was defined as estimated glomerular filtration rate < 30 ml/min per 1.73 m² (patients with aHUS), no remission with therapy, or patient death. Data were analyzed using Wilcoxon rank and Chi-square tests.

Results: Our analysis cohort included 118 studies reporting on 170 patients. These included 84 cases of aHUS and 86 cases of TTP resulting from COVID-19 infection (n = 92) or vaccination (n = 78). Significantly more cases of aHUS were reported after infection (n = 65) than immunization (n = 19), compared to TTP, where the reverse was true (n = 27 and n = 59, respectively; P < 0.001). In patients with aHUS with stage 3 acute kidney injury (AKI), requirement of kidney replacement therapy (KRT) was seen in three-fourths of the cohort for a median of 15. In patients with TTP, severe COVID-19 infection (P = 0.04) predicted nonremission or death at last follow-up. Administration of i.v., rituximab and caplacizumab were protective (P = 0.03 and P = 0.06, respectively). Immune TTP (iTTP) was reported more often than HUS following mRNA vaccines (81% vs. 58%; P = 0.06).

Conclusion: COVID-19 infection and vaccination are a potential trigger for onset or relapse of aHUS and TTP, especially in patients who are not on maintenance complement inhibitors or immunosuppression.