Standing on the shoulders of Edward H. Kass
“Without minimising the great advance made by Kass in the diagnosis of UTI, it is none the less important to recognise its limitations.” Rosalind Maskell, 1989 [1].Infectious diseases and clinical microbiology are specialties littered with the names of those that went into the field before us. From Lemièrre to Lancefield, Pasteurella to the unabashed Elizabethkingia, we memorialise these people in our daily practice usually without a second thought. In the laboratory, many microbiology tests bear witness to individuals’ research and discoveries. From my first days in microbiology training in the urine section of the laboratory, one eponym that particularly caught my interest was the Kass criteria for significant bacteriuria, named after Edward Kass.“10-to-the-5th colony-forming-units-per-mill” was a mantra taught to trainees in microbiology for determining the significance of a quantitative urine culture. ‘Ten to the fifth’ was a kind of ‘magic number’: when most of microbiology seemed so qualitative and open to interpretation, this Kass criterion was enticingly quantitative. How did this number come to be a reference standard in urinary tract infection (UTI) for so many years; in laboratory methods, textbooks, exam questions, research and clinical practice? And what has been the impact of Kass’s research on the field of UTI?Edward Kass (1917–1990) was the son of Russian immigrants who grew up in New York. Despite obvious academic ability, financial hardships forced him to leave school at age 15. He worked multiple jobs and managed to fund his way, eventually, through community college, a PhD in Bacteriology, and finally medical school at the University of California. After qualifying he moved to Boston and rose through the ranks at Harvard Medical School. It was in his early days at Harvard in the 1950s that his interests turned to the urinary tract. He was motivated to do so after witnessing a young girl with UTI in great distress [2]. The focus of early research was pyelonephritis, frequently fatal in that era with the diagnosis often being made at autopsy [3]. The field of UTI research in the 1950s was a small arena with two or three key players, Kass being one of them. Kass and his contemporaries investigated whether quantitative culture of urine could be used as a diagnostic test for pyelonephritis, thus enabling a pre-mortem diagnosis and, potentially, treatment with newly available antibiotics. His seminal studies on bacteriuria determined the future path of research and diagnosis of UTI for decades to come.In his 1956 study [4], Kass compared the aerobic bacterial counts in urine (obtained midstream and via urethral catheterization) from asymptomatic and symptomatic female patients. The asymptomatic group consisted of 337 medical outpatients who were “chosen at random, using no criteria for selection other than they were not regarded, by those responsible for their care, as having active infections of the urinary tract” [4]. No further details on these asymptomatic controls are reported. Age, menopausal status, co-morbidities, reason for out-patient attendance and prior urological history are all important unknowns; such omissions in trial reporting were common in that era (although arguably this remains an issue, to some extent, today) [5]. Kass compared the control group’s urine bacterial counts to those obtained from a non-contemporaneous cohort of seventy-four women “in whom the diagnosis of pyelonephritis was made or suspected”. No details were presented on the clinical symptoms or signs that preceded the diagnosis of pyelonephritis being ‘made or suspected’, or indeed who had already made or suspected this diagnosis. Similarly to the asymptomatic controls, no details on age, menopausal status, co-morbidities, or urological history were provided. In addition to the lack of participant demographic data, several other methodological points are notable. There was no mention of patient consent for urinary catheterization to obtain a specimen. Adverse events were reported; “frank dysuria and true bacilluria” occurred after catheterization for specimen collection in “about 2 % of female patients studied”, with exact numbers not provided. In fact, raw numbers are scarce in the published study, with percentages and graphs used to summarise the findings. Kass’s key finding was that 95 % of the females in the pyelonephritis group had ≥100,000 (105) aerobic coliform bacteria per millilitre of urine. Although no raw data was presented, a graph presented that 6 % of the asymptomatic controls had bacteriuria above 105 CFU/mL, approximately 45 % of controls had zero bacteria cultured, and the remaining controls had colony counts between 10 and 10,000 (104) per millilitre [4].Kass’s findings were applauded by his peers in the field, with their commentaries published alongside his original article. J. P. Sanford (who also went on to become another Infectious Diseases household name with his Sanford Guide) congratulated Kass “on his excellent study”, before pointing out that he himself had already performed similar studies [4]. Interestingly Sanford countered that in his own studies, he had found 1000 to 10,000 (103–104) bacteria per millilitre to be significant for distinguishing infection from contamination. Rather than contest or debate these conflicting findings, Sanford was content to yield to Kass’s findings, finishing his commentary with “Actually, I think, on further study, his figures come closer” [4]. Along with Sanford, the medical profession as a whole accepted Kass’s findings; they embraced them wholly and went on to apply them liberally to patients outside of Kass’s original study population.The fact that Kass himself did not propose that his findings be used as diagnostic criteria for pyelonephritis, or any other UTI, is not as well-remembered as his ‘magic number’. Kass was quite clear when he wrote “a count of ≥105 bacteria per ml has been designated arbitrarily as the dividing line between true bacilliuria and contamination…obviously for individual clinical purposes a reinvestigation of counts higher than 100 may at times be useful” [4]. Despite this, within a decade, use of the ‘Kass criteria’ became widespread in laboratory and clinical practice, and was being applied to all patient groups, clinical scenarios and urine specimen types. The data gaps on the validity of this cut-off were vast: children, males, females with cystitis, pregnancy. Despite these gaps, and fuelled by the development of agar well-suited to uropathogen isolation, the Kass criteria had been almost universally adopted by the late 1960s as the reference standard for UTI diagnosis in medical laboratories. Urine culture became cheap and accessible, and with a criterion that made interpretation clear-cut, no wonder it was (and still is) such a temptingly popular test to order.As the decades passed, new data emerged challenging the validity of applying the Kass criteria to all patients with all possible UTIs. Rosalind Maskell, Walter Stamm and Thomas Hooton (amongst others) demonstrated convincingly and repeatedly that much lower colony counts, and organisms aside from aerobic coliforms, were clinically relevant and were being missed by the misapplication of the Kass criteria [[6], [7], [8]]. A diagnosis of ‘the urethral syndrome’ was created to describe females with classic cystitis symptoms but negative urine cultures; this ‘syndrome’ was studied extensively by Walter Stamm in the United States and Rosalind Maskell in the United Kingdom in the 1980s. Both independently concluded that ‘the urethral syndrome’ was, in fact, a result of the improper use of the Kass criteria to divide women with the same clinical syndrome arbitrarily into ‘infection’ and ‘not infection’. Stamm summarised this false dichotomy succinctly in his 1980 paper when he wrote “women with acute cystitis and the acute urethral syndrome due to coliforms have the same disease; they differ only in that their quantitative culture results fall on different sides of the 105 colonies/ml standard” [9]. Women diagnosed with the urethral syndrome were usually not treated with antibiotics, with many suffering from recurrent, chronic and debilitating symptoms as a result. Maskell set up a clinic especially for women with these symptoms and studied their symptomatology and microbiology meticulously. In 1989 she highlighted the patient harm that may be done by applying the Kass criteria incorrectly, writing “All these patients, whether men or women, whose urine is wrongly reported to be free of pathogens, are liable to have their symptoms attributed to psychological causes” [1]. Maskell was concerned at patients being given diagnoses such as interstitial cystitis or abacterial prostatitis purely based on the misapplication of the Kass criteria. Such concerns still persist amongst patients, as well as clinicians [10].In addition to individual patient impact, the status of the Kass criteria has impacted clinical trials in UTI immeasurably. Inclusion and exclusion criteria into trials, for example on the efficacy of new drugs and new diagnostic tests for UTI have long hinged on the Kass criteria. The FDA guidance documents on developing drugs for urinary tract infections still classifies the microbiological definition of a ‘true pathogen’ being one that grows to ≥105 cfu/mL, and defines microbiological success as growth of <103 cfu/mL [11]. These definitions are identical for uncomplicated UTI in females and complicated UTI (which currently encompasses a large spectrum of infective urological diagnoses thrown into one regulatory bucket) [12].The study of asymptomatic bacteriuria in pregnancy is a particular area where the Kass criteria have had potential untold impact. Being almost the only clinical scenario where some asymptomatic patients may benefit from antibiotics, the decision to prescribe still rests to this day on whether the culture result falls the ‘right’ side of 105 cfu/mL. Modern-day, well-conducted studies that critically re-evaluate the concept of asymptomatic bacteriuria in pregnancy and the potential benefits (and/or harms) of antibiotics in this context are sorely needed if both perinatal outcomes and antimicrobial stewardship are to improve.Research funding for UTI diagnostics was hard to come by for many decades; why spend money researching when a ‘gold standard’ already exists? Urinary diagnostics are only recently experiencing a much-needed renaissance, with rising antimicrobial resistance (AMR) finally forcing a light on the importance of rapid and accurate diagnosis in UTI. While this regulatory and clinically dogmatic backdrop complicates the landscape for diagnostics developers, perhaps there can be some optimism, with Astrego’s microfluidic technology for rapid UTI diagnosis being award the Longitude Prize for AMR in 2024 [13].E.H. Kass is rightly remembered as a giant in his field. A founding father of the Infectious Diseases Society of America, his research changed the future direction of infectious diseases and clinical microbiology. Kass’s contributions to women’s health research were wider than UTI, with notable discoveries in the pathogenesis of tampon-associated toxic shock syndrome [14]. However it is the Kass criteria for significant bacteriuria that remain his most-remembered legacy. His original studies were well-conducted for their time, but their findings were used as the foundation for a diagnostic and research house-of-cards. Perhaps it is now time - nearly 70 years on - to let go of the ‘magic number’, and instead acknowledge the considerable uncertainties that still exist in the diagnosis of UTI. Hopefully then, the space for new scientific curiosity will open wider and advances will again be made.CRediT authorship contribution statementAmelia Joseph: Writing – review & editing, Writing – original draft, Data curation, Conceptualization.Declaration of competing interestThe authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Amelia Joseph reports a relationship with Global Access Diagnostics Ltd that includes: consulting or advisory. Amelia Joseph reports a relationship with Serosep Limited that includes: speaking and lecture fees. Amelia Joseph reports a relationship with GSK that includes: consulting or advisory. Amelia Joseph reports a relationship with Advanz Pharma Services UK Limited that includes: consulting or advisory. Amelia Joseph reports a relationship with Eumedica Pharma Ltd that includes: consulting or advisory. Amelia Joseph reports a relationship with Pfizer that includes: consulting or advisory. Amelia Joseph reports a relationship with bioMérieux Inc that includes: speaking and lecture fees. Amelia Joseph is an Associate Editor for this journal and was not involved in the editorial review or the decision to publish this article.FundingThis commentary did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.