Executive summary of HTA journal title
Health Technol Assess 2009;13(19):1–96
Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study
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P Little,1* S Turner,1 K Rumsby,1 G Warner,2 M Moore,3 JA Lowes,4 H Smith,1,5 C Hawke,6 D Turner,7 GM Leydon,1 A Arscott1 and M Mullee1
1Community Clinical Sciences Division (CCS), University of Southampton, UK
2Nightingale Surgery, Greatwell Drive, Romsey, UK
3Three Swans Surgery, Rollestone Street, Salisbury, UK
4Southampton Health Protection Agency Laboratory, Southampton, UK
5Brighton Medical School, Brighton, UK (present address)
6School of Rural Health, University of Sydney, Australia
7Wessex Institute, University of Southampton, UK
- To estimate independent clinical and dipstick predictors of infection and develop clinical scores.
- To test the clinical scores in an independent sample.
- To understand the natural history of urinary tract infection (UTI) and its key determinants.
- To perform a randomised controlled trial comparing management using the clinical and dipstick score with commonly used alternative management strategies.
- To estimate the resource use associated with each management strategy and estimate cost-effectiveness.
- To understand women’s understanding of and concerns about the presentation and management of UTI, and particularly their responses to being asked to delay antibiotics.
Six studies were carried out:
- a validation development study for diagnostic clinical score and diagnostic dipstick score (training study)
- a validation study for scores developed in study 1 (testing study)
- an observational study of the natural history of UTI
- a randomised controlled trial of scores developed in study 1
- an economic analysis of the randomised controlled trial
- a qualitative study of patients in the randomised controlled trial.
The setting was primary care.
In total, 427 women aged 17–70 with suspected UTI participated in study 1; 434 participated in study 2; 843 participated in study 3; 309 participated in the randomised controlled trial; and 21 participated in the qualitative study.
Independent clinical and dipstick predictors were estimated for diagnosis based on the European urinalysis guidelines standards for bacteriuria.
Independent predictors of symptom severity and duration were estimated.
Randomised controlled trial
Patients were randomised to five basic management approaches:
- empirical antibiotics
- empirical delayed antibiotics (by 48 hours)
- target antibiotics based on a higher symptom score (two or more of urine cloudiness, smell, nocturia, dysuria)
- target antibiotics based on dipstick results (nitrite or both leucocytes and blood)
- target antibiotics based on receipt of a positive mid-stream specimen of urine (MSU) result.
Advice on self-care was also controlled by randomisation.
A total of 21 participants from the trial participated in a recorded semistructured interview, which was analysed using the constant comparative method.
NHS resource use was estimated using data in GP notes, and effectiveness was estimated by the number of days for which symptoms were rated as moderately bad by patients.
The validation development study
In total, 62.5% of women had confirmed UTI (i.e. symptoms suggestive of UTI and bacteriuria). Only nitrite, leucocyte esterase (+ or greater) and blood (haemolysed trace or greater) independently predicted diagnosis (multivariate odds ratios 6.36, 4.52 and 2.23 respectively). A dipstick rule – based on having nitrite or both leucocytes and blood – was moderately sensitive (77%) and specific (70%) [positive predictive value (PPV) 81%, negative predictive value (NPV) 65%]. Predictive values were improved by varying the cut-point: the NPV was 73% for all three dipstick results being negative, and the PPV was 92% for having nitrite and either blood or leucocyte esterase. A clinical rule – based on having two of urine cloudiness, offensive smell, reported moderately severe dysuria and moderately severe nocturia – was less sensitive (65%) (specificity 69%, PPV 77%, NPV 54%). The NPV was 71% for none of the four clinical features and the PPV was 84% for three or more features.
The validation testing study
In total, 66% of women had confirmed UTI. The predictive values of nitrite, leucocyte esterase (+ or greater) and blood (haemolysed trace or greater) were confirmed (independent multivariate odds ratios of 5.56, 3.49 and 2.12 respectively). The dipstick rule – based on the presence of nitrite or both leucocytes and blood – was moderately sensitive (75%) but less specific (66%) (PPV 81%, NPV 57%). Predictive values were improved by varying the cut-point: the NPV was 76% for all three dipstick results being negative, and the PPV was 92% for having nitrite and either blood or leucocyte esterase.
Urine offensive smell was not found to be predictive in this sample; for a clinical score using the remaining three predictive clinical features (urine cloudiness, dysuria and nocturia) the NPV was 67% for none of the features and the PPV was 82% for three features.
The observational study of the natural history of urinary tract infection
Women in this study were nested in studies 1 and 2. A total of 684 women provided symptom information and 511 had both laboratory results and complete diaries. Symptoms rated by the patient as a moderately bad problem or worse lasted an average of 3.25 days for infections sensitive to antibiotics. After adjusting for other predictors, when compared with sensitive infections, resistant infections lasted 56% longer [95% confidence interval (CI) 22–99%, p < 0.001], those with no antibiotic treatment 62% longer (95% CI 13–131%, p = 0.008) and those associated with urethral syndrome 33% longer (95% CI 14–56%, p < 0.001). Symptom duration was shorter if the doctor was perceived to be positive about diagnosis and prognosis and longer with frequent somatic symptoms, a previous history of cystitis, urinary frequency and more severe symptoms at baseline. Infections with no antibiotic treatment and also antibiotic-resistant infections were also associated with more severe frequency and dysuria symptoms after presentation.
The randomised trial
In total, 66% of the MSU group had laboratory-confirmed UTI – i.e. similar to the validation and observational studies. There were differences in antibiotic use between antibiotic management groups (immediate antibiotics 97%, MSU 81%, dipstick 80%, symptom score 90%, delayed antibiotics 77%, likelihood ratio test p = 0.011) and also in the use of MSUs at the initial consultation (23%, 89%, 36%, 33% and 15% respectively, p < 0.001), but little difference in symptomatic outcomes. Women suffered 3.5 days of moderately bad symptoms if they took antibiotics immediately. Those commencing antibiotics after 48 hours subsequently reconsulted less (hazard ratio 0.57, 95% CI 0.36–0.89) but also suffered a 37% longer duration of symptoms (95% CI 11–68%, p = 0.003), mainly in the MSU group (70% longer duration; other groups ≤ 21% longer duration). Advice to use bicarbonate or cranberry juice had no effect on any outcome.
The economic analysis
The MSU group was more costly over a period of 1 month but not over a period of 1 year. There were modest non-significant differences in the estimates of effectiveness. To allow for the uncertainty of estimates we estimated cost-effectiveness acceptability curves for the strategies, which suggest that if a day of moderately bad symptoms is given a low value, i.e. less than approximately £10, then immediate antibiotics is likely to be the most cost-effective strategy. For values over £10 the dipstick strategy becomes the most likely to be cost-effective. Because of the uncertainty we can never be more than 70% certain that the dipstick strategy is the most cost-effective.
The qualitative study
Several important features associated with women’s health-seeking behaviour and their experiences of consulting for a UTI were identified, as well as their general attitudes towards and understanding of UTI, its aetiology and treatment. A fear of spread to the kidneys and the appearance of blood in the urine were two organic symptoms that particularly triggered worry and, in turn, seeking help. The generalised impact of symptoms on vocational and leisure activities was considerable and women expressed these as important triggers for seeking help. When patients are asked to delay taking antibiotic medication, i.e. they are essentially asked to ‘wait some more’, the sometimes protracted, uncomfortable and worrying journey that people have taken from ‘person to patient’ needs to be acknowledged. Some patients who had negative experiences of delay indicated that they had not felt validated in their expressions of bodily change and were threatened by such delay because, it seemed, the rationale for not taking the antibiotics was unclear.
A clinical score is of limited value in increasing diagnostic precision, and dipstick results modestly improve diagnostic precision, but both of these diagnostic strategies have poor NPVs; they should not be used to rule out infection. Being positive about the diagnosis and natural history for patients with suspected UTI may help symptom resolution, and doctors can provide useful information on the natural history for patients (patients with a past history and those with high somatisation and severe baseline symptoms will have more severe symptoms lasting longer than 3 days). Immediate antibiotics targeted using dipsticks with a delayed prescription as backup or an empirical delayed prescription both achieve similar symptom control to immediate antibiotics and reduce antibiotic use. Dipsticks are likely to be cost-effective if the value of saving a day of moderately bad symptoms is valued at £10 or more, but caution is required given the considerable uncertainty surrounding the estimates. If women are asked to delay taking antibiotics, great care is needed in both acknowledging the triggers to consult and particular worries and explaining the rationale for not using antibiotics immediately.
Implications for practice
Although all of the strategies trialled are acceptable, to both achieve good symptom control and reduce antibiotic use clinicians should probably either offer a 48-hour delayed antibiotic prescription to be used at the patient’s discretion or target antibiotic treatment by dipsticks (positive nitrite or positive leucocytes and blood) with the offer of a delayed prescription if dipstick results are negative.
Suggestions for research
Trials are needed of alternative diagnostic approaches (e.g. microscopy, dipsticks combined with dipslides). Further research is needed to estimate quality of life and model cost-effectiveness of the different strategies. More research is needed into the use of alternatives/complements to antibiotics (e.g. herbal medicines).
Little P, Turner S, Rumsby K, Warner G, Moore M, Lowes JA, et al. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study. Health Technol Assess 2009;13(19).
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