Harriet Downing

The diagnosis of urinary tract infections in young children (DUTY): Protocol for a diagnostic and prospective observational study to derive and validate a clinical algorithm for the diagnosis of UTI in children presenting to primary care with an acute illness

BackgroundUrinary tract infection (UTI) is common in children, and may cause serious illness and recurrent symptoms. However, obtaining a urine sample from young children in primary care is challenging and not feasible for large numbers. Evidence regarding the predictive value of symptoms, signs and urinalysis for UTI in young children is urgently needed to help primary care clinicians better identify children who should be investigated for UTI. This paper describes the protocol for the Diagnosis of Urinary Tract infection in Young children (DUTY) study. The overall study aim is to derive and validate a cost-effective clinical algorithm for the diagnosis of UTI in children presenting to primary care acutely unwell.Methods/designDUTY is a multicentre, diagnostic and prospective observational study aiming to recruit at least 7,000 children aged before their fifth birthday, being assessed in primary care for any acute, non-traumatic, illness of ≤ 28 days duration. Urine samples will be obtained from eligible consented children, and data collected on medical history and presenting symptoms and signs. Urine samples will be dipstick tested in general practice and sent for microbiological analysis. All children with culture positive urines and a random sample of children with urine culture results in other, non-positive categories will be followed up to record symptom duration and healthcare resource use. A diagnostic algorithm will be constructed and validated and an economic evaluation conducted.The primary outcome will be a validated diagnostic algorithm using a reference standard of a pure/predominant growth of at least >103, but usually >105 CFU/mL of one, but no more than two uropathogens.We will use logistic regression to identify the clinical predictors (i.e. demographic, medical history, presenting signs and symptoms and urine dipstick analysis results) most strongly associated with a positive urine culture result. We will then use economic evaluation to compare the cost effectiveness of the candidate prediction rules.DiscussionThis study will provide novel, clinically important information on the diagnostic features of childhood UTI and the cost effectiveness of a validated prediction rule, to help primary care clinicians improve the efficiency of their diagnostic strategy for UTI in young children.

Improving the Diagnosis and Treatment of Urinary Tract Infection in Young Children in Primary Care: Results from the DUTY Prospective Diagnostic Cohort Study

PURPOSE Up to 50% of urinary tract infections (UTIs) in young children are missed in primary care. Urine culture is essential for diagnosis, but urine collection is often difficult. Our aim was to derive and internally validate a 2-step clinical rule using (1) symptoms and signs to select children for urine collection; and (2) symptoms, signs, and dipstick testing to guide antibiotic treatment. METHODS We recruited acutely unwell children aged under 5 years from 233 primary care sites across England and Wales. Index tests were parent-reported symptoms, clinician-reported signs, urine dipstick results, and clinician opinion of UTI likelihood (clinical diagnosis before dipstick and culture). The reference standard was microbiologically confirmed UTI cultured from a clean-catch urine sample. We calculated sensitivity, specificity, and area under the receiver operator characteristic (AUROC) curve of coefficient-based (graded severity) and points-based (dichotomized) symptom/sign logistic regression models, and we then internally validated the AUROC using bootstrapping. RESULTS Three thousand thirty-six children provided urine samples, and culture results were available for 2,740 (90%). Of these results, 60 (2.2%) were positive: the clinical diagnosis was 46.6% sensitive, with an AUROC of 0.77. Previous UTI, increasing pain/crying on passing urine, increasingly smelly urine, absence of severe cough, increasing clinician impression of severe illness, abdominal tenderness on examination, and normal findings on ear examination were associated with UTI. The validated coefficient- and points-based model AUROCs were 0.87 and 0.86, respectively, increasing to 0.90 and 0.90, respectively, by adding dipstick nitrites, leukocytes, and blood. CONCLUSIONS A clinical rule based on symptoms and signs is superior to clinician diagnosis and performs well for identifying young children for noninvasive urine sampling. Dipstick results add further diagnostic value for empiric antibiotic treatment.

Childhood urinary tract infection in primary care: a prospective observational study of prevalence, diagnosis, treatment, and recovery

BACKGROUND The prevalence of targeted and serendipitous treatment for, and associated recovery from, urinary tract infection (UTI) in pre-school children is unknown. AIM To determine the frequency and suspicion of UTI in children who are acutely ill, along with details of antibiotic prescribing, its appropriateness, and whether that appropriateness impacted on symptom improvement and recovery. DESIGN AND SETTING Prospective observational cohort study in primary care sites in urban and rural areas in England and Wales. METHOD Systematic urine sampling from children aged <5 years presenting in primary care with acute illness with culture in NHS laboratories. RESULTS Of 6079 childrens urine samples, 339 (5.6%) met laboratory criteria for UTI and 162 (47.9%) were prescribed antibiotics at the initial consultation. In total, 576/7101 (8.1%) children were suspected of having a UTI prior to urine sampling, including 107 of the 338 with a UTI (clinician sensitivity 31.7%). Children with a laboratory-diagnosed UTI were more likely to be prescribed antibiotics when UTI was clinically suspected than when it was not (86.0% versus 30.3%, P<0.001). Of 231 children with unsuspected UTI, 70 (30.3%) received serendipitous antibiotics (that is, antibiotics prescribed for a different reason). Overall, 176 (52.1%) children with confirmed UTI did not receive any initial antibiotic. Organism sensitivity to the prescribed antibiotic was higher when UTI was suspected than when treated serendipitously (77.1% versus 26.0%; P<0.001). Children with UTI prescribed appropriate antibiotics at the initial consultation improved a little sooner than those with a UTI who were not prescribed appropriate antibiotics initially (3.5 days versus 4.0 days; P = 0.005). CONCLUSION Over half of children with UTI on culture were not prescribed antibiotics at first presentation. Serendipitous UTI treatment was relatively common, but often inappropriate to the organisms sensitivity. Methods for improved targeting of antibiotic treatment in children who are acutely unwell are urgently needed.

Empiric antibiotic treatment for urinary tract infection in preschool children: susceptibilities of urine sample isolates

BACKGROUND Antibiotic treatment recommendations based on susceptibility data from routinely submitted urine samples may be biased because of variation in sampling, laboratory procedures and inclusion of repeat samples, leading to uncertainty about empirical treatment. OBJECTIVE To describe and compare susceptibilities of Escherichia coli cultured from routinely submitted samples, with E. coli causing urinary tract infection (UTI) from a cohort of systematically sampled, acutely unwell children. METHODS Susceptibilities of 1458 E. coli isolates submitted during the course of routine primary care for children <5 years (routine care samples), compared to susceptibilities of 79 E. coli isolates causing UTI from 5107 children <5 years presenting to primary care with an acute illness [systematic sampling: the Diagnosis of Urinary Tract infection in Young children (DUTY) cohort]. RESULTS The percentage of E. coli sensitive to antibiotics cultured from routinely submitted samples were as follows: amoxicillin 45.1% (95% confidence interval: 42.5-47.7%); co-amoxiclav using the lower systemic break point (BP) 86.6% (84.7-88.3%); cephalexin 95.1% (93.9-96.1%); trimethoprim 74.0% (71.7-76.2%) and nitrofurantoin 98.2% (97.4-98.8%). The percentage of E. coli sensitive to antibiotics cultured from systematically sampled DUTY urines considered to be positive for UTI were as follows: amoxicillin 50.6% (39.8-61.4%); co-amoxiclav using the systemic BP 83.5% (73.9-90.1%); co-amoxiclav using the urinary BP 94.9% (87.7-98.4%); cephalexin 98.7% (93.2-99.8%); trimethoprim 70.9% (60.1-80.0%); nitrofurantoin 100% (95.3-100.0%) and ciprofloxacin 96.2% (89.4-98.7%). CONCLUSION Escherichia coli susceptibilities from routine and systematically obtained samples were similar. Most UTIs in preschool children remain susceptible to nitrofurantoin, co-amoxiclav and cephalexin.

Investigating the effectiveness and cost-effectiveness of FITNET-NHS (Fatigue In Teenagers on the interNET in the NHS) compared to Activity Management to treat paediatric chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME): protocol for a randomised controlled trial

BackgroundPaediatric chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a relatively common and disabling condition. The National Institute for Health and Clinical Excellence (NICE) recommends Cognitive Behavioural Therapy (CBT) as a treatment option for paediatric CFS/ME because there is good evidence that it is effective. Despite this, most young people in the UK are unable to access local specialist CBT for CFS/ME. A randomised controlled trial (RCT) showed FITNET was effective in the Netherlands but we do not know if it is effective in the National Health Service (NHS) or if it is cost-effective. This trial will investigate whether FITNET-NHS is clinically effective and cost-effective in the NHS.MethodsSeven hundred and thirty-four paediatric patients (aged 11–17 years) with CFS/ ME will be randomised (1:1) to receive either FITNET-NHS (online CBT) or Activity Management (delivered via video call). The internal pilot study will use integrated qualitative methods to examine the feasibility of recruitment and the acceptability of treatment. The full trial will assess whether FITNET-NHS is clinically effective and cost-effective. The primary outcome is disability at 6 months, measured using the SF-36-PFS (Physical Function Scale) questionnaire. Cost-effectiveness is measured via cost-utility analysis from an NHS perspective. Secondary subgroup analysis will investigate the effectiveness of FITNET-NHS in those with co-morbid mood disorders.DiscussionIf FITNET-NHS is found to be feasible and acceptable (internal pilot) and effective and cost-effective (full trial), its provision by the NHS has the potential to deliver substantial health gains for the large number of young people suffering from CFS/ME but unable to access treatment because there is no local specialist service. This trial will provide further evidence evaluating the delivery of online CBT to young people with chronic conditions.Trial registrationISRCTN registry, registration number: ISRCTN18020851. Registered on 4 August 2016.

Effect of Oral Prednisolone on Symptom Duration and Severity in Nonasthmatic Adults With Acute Lower Respiratory Tract Infection: A Randomized Clinical Trial

Importance Acute lower respiratory tract infection is common and often treated inappropriately in primary care with antibiotics. Corticosteroids are increasingly used but without sufficient evidence. Objective To assess the effects of oral corticosteroids for acute lower respiratory tract infection in adults without asthma. Design, Setting, and Participants Multicenter, placebo-controlled, randomized trial (July 2013 to final follow-up October 2014) conducted in 54 family practices in England among 401 adults with acute cough and at least 1 lower respiratory tract symptom not requiring immediate antibiotic treatment and with no history of chronic pulmonary disease or use of asthma medication in the past 5 years. Interventions Two 20-mg prednisolone tablets (n = 199) or matched placebo (n = 202) once daily for 5 days. Main Outcomes and Measures The primary outcomes were duration of moderately bad or worse cough (0 to 28 days; minimal clinically important difference, 3.79 days) and mean severity of symptoms on days 2 to 4 (scored from 0 [not affected] to 6 [as bad as it could be]; minimal clinically important difference, 1.66 units). Secondary outcomes were duration and severity of acute lower respiratory tract infection symptoms, duration of abnormal peak flow, antibiotic use, and adverse events. Results Among 401 randomized patients, 2 withdrew immediately after randomization, and 1 duplicate patient was identified. Among the 398 patients with baseline data (mean age, 47 [SD, 16.0] years; 63% women; 17% smokers; 77% phlegm; 70% shortness of breath; 47% wheezing; 46% chest pain; 42% abnormal peak flow), 334 (84%) provided cough duration and 369 (93%) symptom severity data. Median cough duration was 5 days (interquartile range [IQR], 3-8 days) in the prednisolone group and 5 days (IQR, 3-10 days) in the placebo group (adjusted hazard ratio, 1.11; 95% CI, 0.89-1.39; P = .36 at an &agr; = .05). Mean symptom severity was 1.99 points in the prednisolone group and 2.16 points in the placebo group (adjusted difference, −0.20; 95% CI, −0.40 to 0.00; P = .05 at an &agr; = .001). No significant treatment effects were observed for duration or severity of other acute lower respiratory tract infection symptoms, duration of abnormal peak flow, antibiotic use, or nonserious adverse events. There were no serious adverse events. Conclusions and Relevance Oral corticosteroids should not be used for acute lower respiratory tract infection symptoms in adults without asthma because they do not reduce symptom duration or severity. Trial Registration ISRCTN.com Identifier: ISRCTN57309858

Comparison of microbiological diagnosis of urinary tract infection in young children by routine health service laboratories and a research laboratory: diagnostic cohort study

Objectives To compare the validity of diagnosis of urinary tract infection (UTI) through urine culture between samples processed in routine health service laboratories and those processed in a research laboratory. Population and methods We conducted a prospective diagnostic cohort study in 4808 acutely ill children aged <5 years attending UK primary health care. UTI, defined as pure/predominant growth ≥105 CFU/mL of a uropathogen (the reference standard), was diagnosed at routine health service laboratories and a central research laboratory by culture of urine samples. We calculated areas under the receiver-operator curve (AUC) for UTI predicted by pre-specified symptoms, signs and dipstick test results (the “index test”), separately according to whether samples were obtained by clean catch or nappy (diaper) pads. Results 251 (5.2%) and 88 (1.8%) children were classified as UTI positive by health service and research laboratories respectively. Agreement between laboratories was moderate (kappa = 0.36; 95% confidence interval [CI] 0.29, 0.43), and better for clean catch (0.54; 0.45, 0.63) than nappy pad samples (0.20; 0.12, 0.28). In clean catch samples, the AUC was lower for health service laboratories (AUC = 0.75; 95% CI 0.69, 0.80) than the research laboratory (0.86; 0.79, 0.92). Values of AUC were lower in nappy pad samples (0.65 [0.61, 0.70] and 0.79 [0.70, 0.88] for health service and research laboratory positivity, respectively) than clean catch samples. Conclusions The agreement of microbiological diagnosis of UTI comparing routine health service laboratories with a research laboratory was moderate for clean catch samples and poor for nappy pad samples and reliability is lower for nappy pad than for clean catch samples. Positive results from the research laboratory appear more likely to reflect real UTIs than those from routine health service laboratories, many of which (particularly from nappy pad samples) could be due to contamination. Health service laboratories should consider adopting procedures used in the research laboratory for paediatric urine samples. Primary care clinicians should try to obtain clean catch samples, even in very young children.

ARE ORAL STEROIDS EFFECTIVE IN TREATING THE SYMPTOMS OF ACUTE LOWER RESPIRATORY TRACT INFECTION IN NON-ASTHMATIC ADULTS? THE ORAL STEROIDS FOR ACUTE COUGH (OSAC) PLACEBO-CONTROLLED RANDOMISED TRIAL

Background The majority of UK adults experience at least one lower respiratory tract infection (LRTI, or acute bronchitis) a year. Despite an absence of evidence in this patient group, some GPs prescribe inhaled or oral corticosteroids. OSAC sought to demonstrate ‘proof of concept’ symptomatic effectiveness of a moderate dose of oral corticosteroid for adults without asthma or COPD with acute LRTI. Methods OSAC was a double blind, placebo controlled RCT set in GP practices in England, powered to investigate if oral prednisolone reduces the duration of moderately bad or worse cough and/or the severity of its associated symptoms, when compared to placebo, by at least 20%. Adults (≥18 years) with acute (≤28 days) cough, for whom same-day antibiotics were not clinically indicated, and without asthma or COPD, received 40 mg oral prednisolone or matched placebo for 5 days. Symptom diaries, completed for up to 28 days, measured two primary outcomes: the duration of moderately bad or worse cough; and the average severity of all symptoms on days 2 to 4 on a scale of 0–6. We sought to demonstrate a minimum clinically important reduction of 20% in each outcome. Results 398 participants were randomised to either prednisolone or placebo tablets (198 and 200 respectively) from 54 UK primary care sites. Attrition was lower than expected, giving over 85% power for the two primary outcomes. Data were analysed on an intention-to-treat basis. The median duration of moderately bad or worse cough was 5 days in both groups (IQRs 2–8 and 3–8 for prednisolone and placebo respectively). Adjusting for trial centre and baseline characteristics, this gave a hazard ratio of 1.11 (95% CI 0.89 to 1.39, p = 0.35). Symptom severity was lower in the prednisolone group (mean 1.99 vs 2.16), adjusted difference -0.090 (-0.212 to 0.003, p = 0.152). Conclusions We found no evidence that a moderately high dose of oral corticosteroid reduced either duration of moderately bad (or worse) cough, or symptom severity at days 2 to 4 in adults without asthma or COPD with LRTI not requiring immediate antibiotic treatment. Lower dose oral or high dose inhaled corticosteroids are also unlikely to be beneficial.

Recruitment to diagnosis of urinary tract infections in young children (DUTY) study: an evaluation of the successful methods used in a primary care, prospective cohort study

DUTY is a prospective cohort study to derive a clinical algorithm for diagnosis of urinary tract infections in acutely unwell children in primary care. It provides an example of successful recruitment to a complex paediatric study, requiring the collection of a urine sample from young, unwell children. The aim is to describe and evaluate factors that contributed to its success from a study management and recruiter perspective.