Febrile Urinary Tract Infection: P fimbriae, Innate Host Response and Bacteremia

Abstract: Urinary tract infections (UTI) are among the most common human infections, and febrile UTI with bacteremia the most severe form. The relation between bacteria and host decides disease severity. The dominating uropathogen is Escherichia coli (E. coli). P fimbriae are the virulence factor of E. coli most clearly associated to severe disease. P fimbriated E. coli predominated in bacteremic febrile UTI in both women and men, and carried papDNA sequences of papGIA2 and prsGJ96 adhesin type in both bacteremic and nonbacteremic patients. papGIA2 + E. coli were the major uropathogens in women of all ages, and the major cause of bacteremia in women. prsGJ96 + E. coli were common uropathogens in men, and associated with urinary tract abnormalities. papGIA2+ isolates was the only cause of bacteremia in healthy patients. Bacteremia in patients with host compromise was caused by a mixture of papGIA2+, prsGJ96+ or pap negative isolates. The results emphasise the strong influence of host factors on the selection of uropathogenic E. coli. Febrile UTI was accompanied by a broad and diverse local chemokine response with both CXC and CC chemokines, and by both local and systemic IL-6 responses, as measured in urine and serum. The responses showed therapy-related kinetics. The response magnitudes were associated to bacteremia and disease severity, and influenced by gender and general health. papGIA2+ E. coli were associated to pyelonephritis symptoms, high incidence of bacteremia, and high fever, CRP and higher CCL2/MCP-1 response. Febrile UTI patients with prsGJ96+ isolates had instead more focal symptoms from the lower urinary tract. Systemic IL-6 responses occurred regardless of bacteremia, suggesting that locally produced IL-6 trigger systemic responses. Urine CXCL8/IL-8 was found in all patients and may be used as a marker for UTI, and urine CCL2/MCP-1 for disease severity, correlating to kidney involvement and bacteremia. The results characterise papGIA2+ E. coli as the most virulent strains, with invasive abilities and causing bacteremia, kidney involvement and intense host responses. Seven days of adequate antibiotic therapy was shown to be effective and safe in hospitalised patients with community-acquired febrile UTI, regardless of gender, compromising conditions or bacteremia, and with no difference in clinical and bacteriological outcome compared to 14 days of therapy. Patients with persistence of the original uropathogen developed early clinical infection, whereas all super- or reinfections with gram-positive bacteria were asymptomatic. Bacteremic patients with compromising conditions might need closer observations or longer therapy until further studies. Women had a worse secondary outcome, with lower clinical and bacteriological cure rates, which probably reflect the natural course of UTI in women.