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Host-Pathogen Relationships among Escherichia coli Isolates Recovered from Men with Febrile Urinary Tract Infection

  1. James R. Johnson1,3,
  2. Flemming Scheutz5,
  3. Peter Ulleryd6,
  4. Michael A. Kuskowski2,4,
  5. Timothy T. O'Bryan1,3,a, and
  6. Torsten Sandberg6
  1. 1Mucosal and Vaccine Research Center, Minneapolis
  2. 2Geriatric Research, Education, and Clinical Center, Minneapolis Veterans Affairs Medical Center, Minneapolis
  3. 3Department of Medicine, University of Minnesota, Minneapolis
  4. 4Department of Psychiatry, University of Minnesota, Minneapolis
  5. 5International Escherichia coli and Klebsiella Center, World Health Organization, Statens Seruminstitut, Copenhagen, Denmark
  6. 6Departments of Infectious Diseases, University of GÖteborg, GÖteborg, Sweden
  1. Reprints or correspondence: Dr. James R. Johnson, Infectious Diseases (111F), Minneapolis VA Medical Center, 1 Veterans Dr., Minneapolis, MN 55417 (johns007{at}umn.edu).

  • ↵a Present affiliation: Gentra Systems, Minneapolis, Minnesota.

 
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Abstract

Background. Host-pathogen relationships in men with febrile urinary tract infection (FUTI) are poorly understood.

Methods. Phylogenetic background, extended virulence genotypes, and serotypes were determined for 70 Escherichia coli isolates recovered from urine samples obtained from men with FUTI for comparison with available data for 70 E. coli rectal isolates recovered from uninfected men. Bacterial traits were assessed in relation to underlying host characteristics (age, compromise status, and history of urinary tract infection) and acute manifestations (bacteremia, flank pain, and serum prostate-specific antigen [PSA] level).

Results. Compared with rectal isolates, FUTI isolates exhibited a significantly higher prevalence of virulence-associated phylogenetic groups, serotypes, and extraintestinal virulence genes. The latter included traditional prostatitis-associated traits (e.g., hemolysin and cytotoxic necrotizing factor), as well as unconventional traits, such as outer membrane protease T. These bacterial traits occurred largely independent of host age, urological compromise status, urinary tract infection history, and acute manifestations. However, certain traits were less prevalent in association with use of urinary tract instrumentation and significantly predicted elevated PSA levels.

Conclusions. Considerable virulence capability may be required for an E. coli strain to cause FUTI in men, regardless of whether most compromising conditions are present. Bacterial traits that promote prostatic invasion may be relevant for the pathogenesis of FUTI, even among men without classic manifestations of acute prostatitis.

Urinary tract infection (UTI) is a significant health problem for men as well as women [1]. In addition to acute cystitis and pyelonephritis, men experience acute and chronic prostatitis [1] and febrile UTI (FUTI). In cases of FUTI, systemic inflammatory manifestations accompany bacteriuria, together with signs or symptoms referable to the urinary tract [2].

Escherichia coli is the most common cause of UTI in men [1, 2]. To date, few studies have examined the virulence characteristics and clonal background of E. coli isolates recovered from men with UTI [3–12]. The available data indicate that such strains are similar in many respects to E. coli strains recovered from women and children with acute UTI. They derive predominantly from specific O (somatic antigen) serogroups, exhibit certain virulence-associated K (capsular) antigens and O:K:H (H, flagellar) serotypes, and possess many UTI-associated virulence factors. Compared with isolates recovered from women with pyelonephritis, E. coli isolates from men with prostatitis or FUTI exhibit a similar or slightly lower prevalence of P fimbriae (pap) and aerobactin (iuc) and a higher prevalence of hemolysin (hly,) cytotoxic necrotizing factor (cnf), F1C fimbriae (foc), and a siderophore receptor (iroN) [5, 6, 8–12]. Of the 3 P adhesin (papG) variants, allele III reportedly predominates in UTI in male subjects, whereas allele II may be less common [8, 9].

However, the available studies are limited by small sample sizes, limited ranges of virulence factors analyzed, a lack of consideration of phylogenetic group, comingling of data from men and women, and/or inattention to the host's compromise status and acute manifestations of infection [3–12]. Furthermore, the 2 studies that did address the host's compromise status concluded divergently that it either does not affect the prevalence of virulence factors [5] or is associated with an increased prevalence of papG allele III [9]. Therefore, we characterized E. coli isolates from 70 men with FUTI for E. coli phylogenetic group, a broad range of virulence factors, and O:K:H serotypes. We compared these results with published data for rectal isolates recovered from uninfected men and explored associations among bacterial traits, host characteristics, and acute manifestations.

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Patients and Methods

Subjects. The 70 men with FUTI due to E. coli were prospectively enrolled during the period of March 1993 through December 1996 at Sahlgrenska University Hospital (GÖteborg, Sweden) [2, 13]. The University of GÖteborg Research Ethics Committee approved the study protocol. The experimentation guidelines of the authors' institutions were followed in the conduct of clinical research. All participants provided informed consent. Inclusion criteria included fever (temperature, ⩾38.0°C), ⩾1 symptom or sign referable to the urinary tract (frequency, dysuria, flank pain, or costovertebral angle tenderness), and an E. coli count of ⩾104 cfu/mL in a midstream urine specimen. Patients with an indwelling urinary catheter in place were excluded.

At hospital admission, data on current signs and symptoms, the history of previous UTI and genitourinary disorders, and the presence of concomitant diseases were recorded. Pretherapy urine and blood samples were obtained for culture. Serum prostate-specific antigen (PSA) levels—which, in most men with FUTI, are elevated acutely and normalize with therapy [2]—were measured by monoclonal fluoro-immunoassay (normal PSA level, ⩽4.0 ng/mL). Uroflowmetry, digital rectal examination, and postvoid residual urine measurement were done at the time of study entry and 3 months later. Cysto-urethroscopy was performed 3 months after enrollment, as was upper urinary tract imaging [13].

Among the 70 subjects, 8 had slight prostatic tenderness, but none had classical acute prostatitis. All had community-onset symptoms and were hospitalized for ⩾1 day. All had an elevated serum C-reactive protein level (median, 135 mg/L; range, 15–420 mg/L).

Serotyping. O, K, and H antigens were detected using standard methods [14]. Ten UTI-associated O antigens (O1, O2, O4, O6, O7, O8, O16, O18ac, O25, and O75) were classified as “O-UTI antigens” [15, 16], 6 UTI-associated K antigens (K1, K2, K3, K5, K12, and K13) were classified as “K-UTI antigens” [15], and 12 pyelonephritis-associated O:K:H serotypes (O1:K1:H7, O2:K1:H4, O4:K5:H5, O4:K12:H1, O4:K12:H5, O6:K2:H1, O6:K5:H1, O7:K1:H1, O16:K1:H6, O18ac:K1:H7, O18ac:K5:H-, and O18ac:K5:H7) were classified as “O:K:H-pyelo serotypes” [15, 16]. Isolates exhibiting an O:K:H-pyelo serotype except for an absent K or H antigen were analyzed with that serotype [15].

Phylogenetic analysis and virulence genotyping. E. coli phylogenetic group (A, B1, B2, or D) was determined by PCR [17]. Isolates were tested for 35 extraintestinal virulence factors (including 3 papG alleles) and, if pap positive, for 13 papA alleles, with use of PCR and dot-blot-based assays [18–21]. Tests were performed in duplicate, with appropriate positive and negative controls. The virulence factor score was the number of virulence factors detected, accounting for multiple detection of the pap, sfa/foc, and kps operons. Extended virulence factor profiles were used to construct a similarity dendrogram in accordance with the unweighted pair-group method.

Rectal sample control group. Published data for 70 rectal isolates from uninfected male inpatients (Minneapolis Veterans Affairs Medical Center, Minnesota) from 1996 to 1999, which had been generated using the same methods as those used for the FUTI isolates [22], were analyzed.

Statistical methods. Comparisons of proportions, including elderly age (⩾65 years) and elevated PSA level (>4.0 ng/mL), were tested using Fisher's exact test (unpaired) or McNemar's test (paired). Comparisons involving absolute age, PSA levels, or virulence factor scores were tested using the Mann-Whitney U test. Host compromise status variables included 4 conditions that possibly predispose persons to UTI and that occurred in ⩾5 subjects each (i.e., recent instrumentation, increased postvoid residual, renal cortical scarring, and diabetes mellitus), plus a composite “any compromise” variable (table 1). Prior UTI history was analyzed as “any previous UTI” and “previous FUTI.” Multiple variables were assessed as predictors of categorical outcomes by stepwise multivariable logistic regression analysis. The significance threshold was P ⩽.01, with a P value of >.01 and ⩽.05 considered to be suggestive of significance.

Table 1
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Table 1

Underlying host characteristics among 70 men with febrile urinary tract infection (UTI).

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Results

Underlying host characteristics and acute manifestations of infection. Of the 70 men with FUTI, approximately one-third were elderly, one-half had previously experienced ⩾1 UTI episode, and one-half had ⩾1 underlying condition that possibly predisposed them to UTI (table 1). Initial PSA levels ranged from 0.5 to 120 ng/mL (median, 12.0 ng/mL) among the 66 assessable subjects and were elevated (>4.0 ng/mL) in 53 (80%). Flank pain and/or tenderness occurred in 22 subjects (31%), who tended to be younger than other subjects (median age, 49 years [range, 29–83 years] vs. 61 years [range, 18–86 years]; P =.03). Bacteremia was detected in 11 (16%) of the 68 assessable subjects, always with a strain corresponding with the patient's urine isolate (data not shown). Bacteremic subjects were somewhat older than nonbacteremic subjects (median age, 69 years [range, 48–83 years] vs. 55 years [range, 18-86 years]; P =.025).

Molecular characteristics of urine isolates. The 70 E. coli FUTI isolates were overwhelmingly from phylogenetic group B2 (91%), followed by groups B1 (4%), A (3%), and D (1.4%). All virulence factors sought except papG allele I, afa/dra, bmaE, and gafD were detected in ⩾1 isolate each, in proportions ranging from 7% (papG allele II and III combination) to 99% (fimH) (table 2). Aggregate virulence factor scores ranged from 1 to 14 (median, 10). Among the 70 isolates, the various papA alleles were detected, in order of decreasing prevalence, as follows: F10 (26%), F12 (16%), F48 (13%), F11 (11%), F7-1 and F14 (10% each), F16 (9%), F13 (6%), F7-2 (4%), F9 and F15 (3% each), and F8 (1.4%). Some isolates exhibited multiple alleles.

Table 2
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Table 2

Prevalence of virulence factors among 70 Escherichia coli urine isolates recovered from men with febrile urinary tract infection and 70 E. coli rectal isolates from uninfected male veterans.

Comparison with rectal isolates. Compared with FUTI isolates, the 70 reference rectal isolates were significantly less likely to derive from phylogenetic group B2 (53% vs. 91%; P <.001). They also exhibited a significantly lower prevalence of 15 of the 29 detected virulence factors (table 2) and of 3 papA alleles, including F10 (9% vs. 26%; P =.01), F12 (0% vs. 16%; P =.001), and F48 (0% vs. 13%; P =.003). Accordingly, their virulence factor scores were much lower (median, 4.5 [range, 0-12] vs. 10 [range, 1–14]; P <.001). In a stepwise multivariable logistic regression model that included as candidate predictor variables phylogenetic group B2 and those virulence factors that exhibited a significant univariate association with urine status, 2 virulence factors—ompT (OR, 6.52; 95% CI, 3.44–13.59; P <.001) and hlyD (OR, 2.53; 95% CI, 1.33–4.96; P =.003)—emerged as significant predictors of FUTI, eclipsing group B2 and the other virulence factors.

A dendrogram based on extended virulence profiles revealed 102 unique pathotypes among the 140 isolates, of which 89 (87%) included only 1 isolate each, and 13 (13%) included 2–17 isolates each. Two major clusters each accounted for approximately one-half of the population. Urine and rectal isolates segregated significantly by cluster, with cluster 1 (n = 71) comprising primarily urine isolates (72%) and cluster 2 (n = 69) comprising primarily rectal isolates (72%; P <.001). Additional segregation was apparent within each cluster, with minority group isolates within either cluster being significantly more likely to be placed closest to another same-source isolate than to an alternate-source isolate (P <.001). The 13 multiple-isolate pathotypes differed considerably in virulence factor content according to cluster (1 vs. 2) and source group (table 3).

Table 3
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Table 3

Virulence factor profiles of 13 multiply represented pathotypes among 70 Escherichia coli urine isolates from men with febrile urinary tract infection and 70 E. coli rectal isolates recovered from uninfected male veterans.

Phylogenetic distribution of virulence factors. Among the FUTI isolates, most virulence factors were concentrated within phylogenetic group B2. The virulence factors that were significantly more prevalent among group B2 isolates included papA/C/EF/G, hlyD, fyuA, kpsM II, ompT, and malX (table 4). Similar suggestive trends involved sfa/foc, cnf1, and iutA (table 4). Consequently, median aggregate virulence factor scores were much higher in group B2 (10; range, 7–14; P <.001) than in group A (1.5; range, 1-2; P =.001), group B1 (6; range, 2-8; P =.003), or group D (4 [there was 1 isolate only]).

Table 4
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Table 4

Phylogenetically distributed virulence factors among 70 Escherichia coli isolates recovered from men with febrile urinary tract infection.

Virulence factors and phylogenetic group versus host characteristics. Of the 8 dichotomous host variables analyzed, 3 (recent instrumentation, prior febrile UTI, and old age) were significantly associated with bacterial characteristics (table 5). Recent instrumentation was positively associated with group B1 (P =.001), negatively associated with phylogenetic group B2 and malX (P =.01 for both), and exhibited a suggestive trend away from fyuA (P =.047). Previous FUTI was positively associated with group B1 (P =.01) and exhibited a suggestive trend away from kpsM II (P =.04). Age of ⩾65 years was positively associated with kpsM II (P =.01). Although none of the remaining 5 host variables exhibited a significant association with any bacterial trait, suggestive trends were noted for “any compromise” (negative for group B2 and malX) and diabetes mellitus (positive for ibeA) (table 5).

Table 5
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Table 5

Prevalence of bacterial traits in relation to host characteristics among 70 Escherichia coli isolates recovered from men with febrile urinary tract infection (UTI).

As for continuous variables, phylogenetic group B1 and the papG allele II and III combination were associated with a lower absolute age, and kpsM II was associated with a higher absolute age (table 6). Somewhat lower median virulence factor scores were associated with recent instrumentation (8 [range, 2-11] vs. 10 [range, 1–14]; P =.026), and higher scores were associated with diabetes mellitus (11 [range, 10–14] vs. 10 [range, 1-13]; P =.02), but this did not vary with other types of host compromise, age, or UTI history (data not shown).

Table 6
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Table 6

Association of host age with bacterial traits among 70 Escherichia coli isolates recovered from men with febrile urinary tract infection.

Serological characteristics of FUTI isolates. Overall, 17 different O antigens, 10 different K antigens, and 50 different O:K:H serotypes were detected (table 4). Of the 70 isolates, 77% expressed O-UTI antigens, 49% expressed K-UTI antigens, and 29% expressed O:K:H-pyelo serotypes (table 7).

Table 7
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Table 7

Serotypes detected among 70 Escherichia coli isolates from men with febrile urinary tract infection.

Serotype versus phylogenetic group, virulence factors, and host status. Certain serotypes and O antigens accompanied specific virulence factor profiles (table 3). All 3 serological categories (i.e., O-UTI antigens, K-UTI antigens, and O:K:H-pyelo serotypes) were positively associated with multiple virulence factors (table 8) and increased aggregate virulence factor scores (table 9). Notably, virulence factor scores of <6 were confined to isolates lacking O-UTI antigens (25% vs. 0%; P =.002), and scores of <8 occurred only among strains lacking K-UTI antigens (17% vs. 0%; P =.025) and O:K:H-pyelo serotypes (12% vs. 0%; P >.10). Additionally, both O-UTI antigens and K-UTI antigens were associated with phylogenetic group B2 (table 7). Nonetheless, no serological category exhibited even a suggestive trend involving the host's compromise status, UTI history, or age.

Table 8
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Table 8

Prevalence of bacterial traits in relation to serotype among 70 Escherichia coli isolates recovered from men with febrile urinary tract infection (UTI).

Table 9
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Table 9

Virulence factor score in relation to antigen status among 70 Escherichia coli isolates recovered from men with febrile urinary tract infection (UTI).

Bacterial traits versus acute manifestations. Comparisons of bacterial traits with acute manifestations showed that only K-UTI antigens exhibited even a suggestive trend with flank pain, which was present in only 21% of subjects with a K-UTI-positive organism but in 44% of other subjects (P =.03). Group B2 and malX exhibited trends involving supra-normal PSA levels, which occurred among 84% of subjects with isolates possessing these traits, compared with 40% of others (P =.048). Likewise, group B2 and several B2-linked traits were significantly or suggestively associated with higher absolute PSA levels, with median levels being 13.0 ng/mL if the trait was present and 1.4–4.8 ng/mL (varying by trait) if not present (P =.006, for group B2 and malX; P =.015, for fyuA; P =.03, for kpsM II; and P =.04, for ompT). No bacterial trait exhibited even a suggestive trend involving bacteremia.

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Discussion

Our phylogenetic and pathotypic analysis of E. coli isolates recovered from men with FUTI, the largest and most extensive to date, showed that, compared with rectal isolates, such strains are richly endowed with diverse extraintestinal virulence factors and derive from virulence-associated clonal and phylogenetic groups, largely (but not entirely) independent of host compromise status. This supports the hypothesis that men are naturally highly resistant to FUTI, such that considerable virulence capability is required for an E. coli strain to cause FUTI even in the presence of most of the predisposing conditions analyzed.

Many virulence factors exhibited strong statistical associations with FUTI. This newly implicates several little studied but high-prevalence virulence factors—notably, iha, fyuA, and ompT—as possible contributors to the pathogenesis of FUTI in men. Conceivably, these traits (or others linked to them) might serve as useful targets for future preventive interventions. Of note, in the multivariable analysis, phylogenetic group dropped out as a significant predictor once ompT and hlyD had entered the model. This suggests that known virulence factors are more important in determining a strain's ability to cause FUTI than is either phylogenetic background or the as-yet-undefined virulence factors that may be associated with phylogenetic background. Interestingly, ompT was also the virulence factor most closely associated with bacteremia in a recent comparison of bloodstream versus rectal E. coli isolates among male veterans [22]. Thus, ompT deserves experimental assessment for a direct virulence role.

The above findings contrast with the results of the comparisons of the FUTI isolates with underlying host status and acute manifestations. Here, the strongest and most numerous associations involved, not specific virulence factors, but phylogenetic groups B2 (high virulence) and B1 (low virulence) [18, 23, 24], plus malX, a group B2-associated marker with no suspected virulence role. This suggests that, among E. coli strains with sufficient virulence to cause FUTI in men, unrecognized traits associated with these markers may contribute more directly to host-pathogen interactions than do most of the virulence factors we analyzed. Identification of such traits will be an important future goal.

The few significant associations that did emerge of bacterial traits with specific categories of host compromise (especially recent urinary tract instrumentation) and acute manifestations (especially elevated PSA levels) were interesting. They suggest that these bacterial traits, or associated properties, assist in overcoming the particular host defense mechanisms that were breached and/or contribute to the particular acute manifestations. Notably, most of these associations followed the expected pattern (e.g., a decreased prevalence of a virulence factor among compromised hosts). They also tended to cluster consistently around certain bacterial traits, host characteristics, and acute manifestations. Moreover, many exhibited quite low P values. These considerations support their validity.

Elevated serum PSA levels that resolve with antimicrobial therapy occur with overt acute prostatitis [25–27] and subclinical chronic prostatitis [28, 29]. In the latter situation, the degree of PSA level elevation is proportional to histopathological intensity of prostatic inflammation [29]. Thus, the observed associations of disproportionately elevated PSA levels with group B2 and B2-linked traits suggest that the causative E. coli strains possess an enhanced ability to invade the prostate and/or to produce tissue injury once within the prostate. Likewise, identification of hlyD as a multivariate predictor of FUTI status, the known association of hly with acute prostatitis [6–8, 10, 12], and the finding of acutely elevated serum PSA levels in 80% of study subjects suggest that FUTI in men usually involves the prostate gland. Therefore, virulence factors relevant to acute prostatitis may also contribute to FUTI.

Somewhat surprisingly, UTI-associated serological categories were not associated with underlying host status, despite strong associations with other bacterial traits that were so associated. This conflicts with previous findings from a more highly compromised mixed-sex urosepsis population [15]. It suggests that, in the present population, the serological markers were too removed from the primary bacterial factors, or captured the wrong mix of traits, to yield significant associations with host compromise. Similar considerations may explain the serotypes' minimal associations with acute manifestations.

Bacteremia was significantly associated with older age, as previously noted also among women with UTI [30, 31]. This may reflect unrecognized age-related host defense defects or delayed diagnosis among elderly persons. In contrast, bacteremia was not associated with any of the bacterial characteristics studied. This conflicts with evidence associating pap with bacteremia among women with acute pyelonephritis [31] and suggests that, among men with FUTI, the virulence factors studied are not major determinants of bloodstream invasion or survival.

Strengths of the study include the extensive battery of bacterial traits analyzed, a well-characterized patient sample, and inclusion of rectal samples as controls. Additionally, comparisons of virulence genotypes, phylogenetic groups, and serotypes with underlying host characteristics and acute manifestations provided perspectives absent from most previous similar studies. Limitations include the urine isolates' origin from a single institution and their acquisition during a limited time interval, whereas the rectal isolates represented a different locale and a slightly different time interval. Sample size limited statistical power, and multiple comparisons increased the probability of type I errors. To guard against spurious conclusions, we adjusted the criterion for statistical significance and considered the consistency and biological plausibility of observed associations.

In summary, in comparison with reference rectal isolates, E. coli urine isolates recovered from men with FUTI were richly endowed with diverse extraintestinal virulence factors and derived from virulence-associated clonal and phylogenetic groups, largely independent of underlying host status. This suggests that, regardless of most of the predisposing conditions studied, considerable virulence is required for an E. coli strain to cause FUTI in a man. The nearly universal presence of elevated PSA levels suggests that bacterial traits responsible for invasion and infection of the prostate may be relevant for the pathogenesis of FUTI, even among men without classic manifestations of acute prostatitis.

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Acknowledgments

Ann Emery helped prepare the manuscript.

Financial support. This material is based on work supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs (J.R.J.); National Institutes of Health (grant DK-47504; to J.R.J.); National Research Initiative Competitive Grants Program/US Department of Agriculture (grant 00-35212-9408; to J.R.J.); the Scandinavian Society for Anitmicrobial Chemotherapy (T.S.); and the Medical Society of GÖteborg (P.U.).

Potential conflicts of interest. J.R.J. has received grant support and/or honoraria from Bayer, Wyeth-Ayerst, Ortho-McNeil, Merck, and Rochester Medical Group. T.S. has received grant support and/or honoraria from AstraZeneca, Aventis Pharma, Bayer, Bristol-Myers Squibb, and Schering-Plough. P.U. has received grant support and/or honoraria from AstraZeneca and Bayer. All other authors: no conflicts.

  • Received September 9, 2004.
  • Accepted November 4, 2004.
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  1. Clin Infect Dis. (2005) 40 (6): 813-822. doi: 10.1086/428048
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