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Review
. 2018 Nov;33(11):2009-2025.
doi: 10.1007/s00467-017-3783-4. Epub 2017 Sep 7.

Influenza-associated Thrombotic Microangiopathies

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Free PMC article
Review

Influenza-associated Thrombotic Microangiopathies

Martin Bitzan et al. Pediatr Nephrol. .
Free PMC article

Abstract

Thrombotic microangiopathy (TMA) refers to phenotypically similar disorders, including hemolytic uremic syndromes (HUS) and thrombotic thrombocytopenic purpura (TTP). This review explores the role of the influenza virus as trigger of HUS or TTP. We conducted a literature survey in PubMed and Google Scholar using HUS, TTP, TMA, and influenza as keywords, and extracted and analyzed reported epidemiological and clinical data. We identified 25 cases of influenza-associated TMA. Five additional cases were linked to influenza vaccination and analyzed separately. Influenza A was found in 83%, 10 out of 25 during the 2009 A(H1N1) pandemic. Two patients had bona fide TTP with ADAMTS13 activity <10%. Median age was 15 years (range 0.5-68 years), two thirds were male. Oligoanuria was documented in 81% and neurological involvement in 40% of patients. Serum C3 was reduced in 5 out of 14 patients (36%); Coombs test was negative in 7 out of 7 and elevated fibrin/fibrinogen degradation products were documented in 6 out of 8 patients. Pathogenic complement gene mutations were found in 7 out of 8 patients tested (C3, MCP, or MCP combined with CFB or clusterin). Twenty out of 24 patients recovered completely, but 3 died (12%). Ten of the surviving patients underwent plasma exchange (PLEX) therapy, 5 plasma infusions. Influenza-mediated HUS or TTP is rare. A sizable proportion of tested patients demonstrated mutations associated with alternative pathway of complement dysregulation that was uncovered by this infection. Further research is warranted targeting the roles of viral neuraminidase, enhanced virus-induced complement activation and/or ADAMTS13 antibodies, and rational treatment approaches.

Keywords: ADAMTS13; Complement; Hemolytic uremic syndrome; Influenza vaccine; Neuraminidase; Plasma exchange; Thrombotic-thrombocytopenic purpura.

Conflict of interest statement

M. Bitzan served on Advisory Boards for Alexion Pharmaceuticals. The authors declare no other interests.

Figures

Fig. 1
Fig. 1
Seasonal distribution and influenza subtypes in patients with influenza-associated thrombotic microangiopathy (TMA). The occurrence of A(H1N1)-linked hemolytic uremic syndrome (HUS) coincides with the peak of the 2009 pandemic (weeks 40–51). In contrast, the expected peak of seasonal influenza A is during the first 3 months of the year [44]
Fig. 2
Fig. 2
Micrographs from a patient with influenza thrombotic microangiopathy in the kidney allograft (patient #1). a Glomerulus with thrombosis of a capillary loop (phosphotungstic acid hematoxylin stain). b Cross-section of arteriole: the wall shows splitting and edema; the lumen is occluded by a thrombus (hematoxylin–eosin stain). Thrombi consisted of fibrin in addition to packed erythrocytes and thrombocytes. Some thrombi merged with the arteriolar wall, which then showed fibrinoid necrosis (reproduced from Petersen and Olsen [37], used with permission)
Fig. 3
Fig. 3
Diagnostic algorithm for influenza HUS and related thrombotic microangiopathies. a Influenza (or parainfluenza) virus; b the detection in plasma of fibrin/fibrinogen degradation products (such as d-dimers), but full-blown disseminated intravascular coagulation is not common and does not preclude the diagnosis of HUS; c combined complement regulator or coagulation protein mutations (e.g., membrane cofactor protein [MCP] and complement factor H (CFH) or single nucleotide polymorphisms (SNPs) in promoter regions [71]. aHUS atypical HUS, CFB complement factor B, CRP C-reactive protein, FDP fibrin/fibrinogen degradation products, IPD invasive pneumococcal disease, LDH lactate dehydrogenase, pnHUS pneumococcal/neuraminidase HUS, PCR polymer chain reaction, TF antigen Thomsen–Friedenreich antigen (Galβ1-3GalNAcα1), TMA thrombotic microangiopathy, TTP thrombotic thrombocytopenic purpura

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