Complement depletion and Coombs positivity in pneumococcal hemolytic uremic syndrome (pnHUS). Case series and plea to revisit an old pathogenetic concept

• Published in: International journal of medical microbiology 2018-12, Vol.308 (8), p.1096-1104
• Main Authors: Bitzan, Martin, AlKandari, Omar, Whittemore, Blair, Yin, Xiao-ling
• Format: Article
• Language: English
• Subjects: Acute kidney injury; Complement C3 - metabolism; Coombs Test; Empyema, Pleural - blood; Empyema, Pleural - complications; Empyema, Pleural - metabolism; Empyema, Pleural - urine; Fatal Outcome; Female; Hemolytic-Uremic Syndrome - blood; Hemolytic-Uremic Syndrome - complications; Hemolytic-Uremic Syndrome - metabolism; Hemolytic-Uremic Syndrome - urine; Humans; Hypocomplementemia; Infant; Intravenous immunoglobulin; Male; Neuraminidase; Plasma - metabolism; Pneumonia, Pneumococcal - blood; Pneumonia, Pneumococcal - complications; Pneumonia, Pneumococcal - metabolism; Pneumonia, Pneumococcal - urine; Pseudomonas aeruginosa - isolation & purification; Pseudomonas aeruginosa - pathogenicity; Pseudomonas Infections - blood; Pseudomonas Infections - complications; Pseudomonas Infections - metabolism; Pseudomonas Infections - urine; Renal Dialysis; Retrospective Studies; Sepsis - blood; Sepsis - complications; Sepsis - metabolism; Sepsis - microbiology; Streptococcus pneumoniae; Streptococcus pneumoniae - isolation & purification; Streptococcus pneumoniae - pathogenicity; T antigen
• ISSN: 1438-4221; 1618-0607
• DOI: 10.1016/j.ijmm.2018.08.007

Hemolytic uremic syndrome is a rare complication of invasive pneumococcal infection (pnHUS). Its pathogenesis is poorly understood, and treatment remains controversial. The emerging role of complement in various forms of HUS warrants a new look at this “old” disease. We performed a retrospective analysis of clinical and laboratory features of three sequential cases of pnHUS since 2008 associated with pneumonia/pleural empyema, two due to Streptococcus pneumoniae serotype 19 A. Profound depletion of complement C3 (and less of C4) was observed in two patients. One patient was Coombs test positive. Her red blood cells (RBCs) strongly agglutinated with blood group compatible donor serum at 0 °C, but not at 37 °C. All three patients were treated with hemodialysis, concentrated RBCs, and platelets. Patient 2 received frozen plasma for hepatic failure with coagulation factor depletion. Intravenous immunoglobulin infusion, intended to neutralize pneumococcal neuraminidase in patient 3, was associated with rapid normalization of platelets and cessation of hemolysis. Two patients recovered without sequelae or disease recurrence. Patient 2 died within 2½ days of admission due to complicating Pseudomonas aeruginosa sepsis and multiorgan failure. Our observations suggest that pnHUS can be associated with dramatic, transient complement consumption early in the course of the disease, probably via the alternative pathway. A critical review of the literature and the reported cases argue against the postulated pathological role of preformed antibodies against the neuraminidase-exposed Thomsen-Friedenreich neoantigen (T antigen) in pnHUS. The improved understanding of complement regulation and bacterial strategies of complement evasion allows to propose a testable, new pathogenetic model of pnHUS. This model shifts emphasis from the action of natural anti-T antibodies toward impaired Complement Factor H (CFH) binding and function on desialylated membranes. Removal of neuraminic acid residues converts (protected) self to non-self surfaces that supports membrane attack complex (MAC) assembly. Complement activation is potentially exacerbated by decreased CFH availability following tight CFH binding to pneumococcal evasion proteins and/or by the presence of genetic variants of complement regulator proteins. Detailed clinical and experimental investigations are warranted to better understand the role of unregulated complement activation in pnHUS. Instead of avoidance of plasma, a