Elevated UTI Biomarkers in Symptomatic Patients with Urine Microbial Densities of 10,000 CFU/mL Indicate a Lower Threshold for Diagnosing UTIs

Abstract

The literature lacks consensus on the minimum microbial density required for diagnosing urinary tract infections (UTIs). This study categorized the microbial densities of urine specimens from symptomatic UTI patients aged ≥ 60 years and correlated them with detected levels of the immune response biomarkers neutrophil gelatinase-associated lipocalin (NGAL), interleukin-8 (IL-8), and interleukin-1-beta (IL-1β). The objective was to identify the microbial densities associated with significant elevation of these biomarkers in order to determine an optimal threshold for diagnosing symptomatic UTIs. Biobanked midstream voided urine samples were analyzed for microbial identification and quantification using standard urine culture (SUC) and multiplex-polymerase chain reaction (M-PCR) testing, while NGAL, IL-8, and IL-1β levels were measured via enzyme-linked immunosorbent assay (ELISA). NGAL, IL-8, and IL-1β levels were all significantly elevated at microbial densities ≥ 10,000 cells/mL when measured via M-PCR (p < 0.0069) or equivalent colony-forming units (CFUs)/mL via SUC (p < 0.0104) compared to samples with no detectable microbes. With both PCR and SUC, a consensus of two or more elevated biomarkers correlated well with microbial densities > 10,000 cells/mL or CFU/mL, respectively. The association between ≥10,000 cells and CFU per mL with elevated biomarkers in symptomatic patients suggests that this lower threshold may be more suitable than 100,000 CFU/mL for diagnosing UTIs.

Emerging and Fastidious Uropathogens Were Detected by M-PCR with Similar Prevalence and Cell Density in Catheter and Midstream Voided Urine Indicating the Importance of These Microbes in Causing UTIs

“… 22 Our recent data on midstream voided specimens support the clinical validity of the ≥ 10,000 CFU/mL threshold. 23 We have also demonstrated that microbial densities reported as cells/mL by M-PCR are equivalent to CFU/mL reported by SUC. 24 …”

Evaluation of diagnostic accuracy of urine neutrophil gelatinase-associated lipocalin in patients with symptoms of urinary tract infections: a meta-analysis

“…Six studies were classified as having high risk of bias ( 36 , 38 – 40 , 43 , 49 ). Seven remaining studies had unclear risk of bias ( 37 , 45 , 51 , 52 , 54 – 56 ). Details on the rating of each risk of bias are shown in Figure 2 .…”

Comparison Shows that Multiplex Polymerase Chain Reaction Identifies Infection-associated Urinary Biomarker–positive Urinary Tract Infections That Are Missed by Standard Urine Culture

“…We compared the biomarker levels among specimens with no microorganisms detected by either M-PCR or SUC, with specimens that were M-PCR-positive/SUC-negative, M-PCR-negative/SUC-positive, and M-PCR-positive/SUC-positive. We evaluated two thresholds of microbe positivity: 100 000 cells/ml or CFUs/ml, which is traditionally considered diagnostically significant for UTIs in the USA, and 10 000 cells/ml or CFUs/ml, which has been suggested as more clinically relevant in recent clinical reviews and guidelines and in our own studies [20] , [22] , [23] . Since M-PCR has previously been demonstrated to be superior at detecting non– E. coli or polymicrobial infections [5] , [6] , [7] , [8] , [9] , we further examined cases where E. coli was detected, non– E. coli organisms were detected, and two or more microorganisms were detected in the same specimen (polymicrobial).…”

“…Analyses were performed according to two microbial density thresholds of positivity (10 000 cells/ml by M-PCR or colony forming units (CFUs)/ml by SUC, and 100 000 cells/ml or CFUs/ml). The 100 000 cells/ml or CFUs/ml threshold is traditionally considered diagnostically significant in the USA; however, clinical reviews and guidelines in addition to our data [20] , [21] have suggested a lower microbial density threshold of 10 000 cells/ml or CFUs/ml is clinically relevant [22] , [23] . Participant demographics and ICD-10-CM diagnostic code breakdown were described by summary statistics (eg, mean and standard deviation for continuous variables such as age and count, and percentage for categorical variables such as sex and ICD-10-CM codes).…”