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 new, integrated model is evolving, which may include short-term therapeutic
complement blockade, particularly where genetic or functional APC dysregulation is suspected, in addition to bacterial elimination and, potentially,
neuraminidase neutralization.