Evidence-based appraisal of two guidelines for the diagnosis of suspected, uncomplicated urinary tract infections in primary care: a diagnostic accuracy validation study.

OBJECTIVES: Given the lack of accurate rapid diagnostics for urinary tract infection (UTI) in women, many countries have developed guidelines aiming to support appropriate antibiotic prescribing, but some guidelines have not been validated. We performed a diagnostic accuracy validation study of two guidelines: Public Health England (GW-1263) and Scottish Intercollegiate Guidelines Network (SIGN160). METHODS: We used data from women with symptoms suggestive of uncomplicated UTI from a randomized controlled trial comparing urine collection devices. Symptom information was recorded via baseline questionnaire and primary care assessment. Women provided urine samples for dipstick testing and culture. We calculated the number within each risk category of diagnostic flowcharts who had positive/mixed growth/no significant growth urine culture. Results were presented as positive/negative predictive values, with 95% CIs. RESULTS: Of women aged under 65 years, 311/509 (61.1%, 95% CI 56.7%-65.3%) classified to the highest risk category (recommended to consider immediate antibiotic prescribing) and 80/199 (40.2%, 95% CI 33.4%-47.4%) classified to the lowest risk category (recommended to reassure that UTI is less likely) by the GW-1263 guideline (n = 810) had positive culture. For the SIGN160 guideline (n = 814), the proportion with positive culture ranged from 60/82 (73.2%, 95% CI 62.1%-82.1%) in those for whom immediate treatment was indicated to 33/76 (43.4%, 95% CI 32.3%-55.3%) in those recommended a self-care/waiting strategy. CONCLUSIONS: Clinicians should be aware of the potential for diagnostic error when using diagnostic guidelines for managing uncomplicated UTI and making antimicrobial prescribing decisions. Infection cannot be excluded on the basis of symptoms and dipstick testing alone.

Challenges and strategies for general practitioners diagnosing serious infections in older adults: a UK qualitative interview study.

BACKGROUND: Serious infections in older people are associated with unplanned hospital admissions and high mortality. Recognising the presence of a serious infection and making an accurate diagnosis are important challenges for General Practice. This study aimed to explore the issues UK GPs face when diagnosing serious infections in older patients. METHODS: Qualitative study using semi-structured interviews. 28 GPs from 27 practices were purposively sampled from across the UK to achieve maximum variation in terms of GP role, experience and practice population. Interviews began by asking participants to describe recent or memorable cases where they had assessed older patients with suspected serious infections. Additional questions from the topic guide were used to explore the challenges further. Interview transcripts were coded and analysed using a modified framework approach. RESULTS: Diagnosing serious infection in older adults was perceived to be challenging by participating GPs and the diagnosis was often uncertain. Contributing factors included patient complexity, atypical presentations, as well as a lack of knowledge of patients due to a loss in continuity. Diagnostic challenges were present at each stage of the patient assessment. Scoring systems were mainly used as communication tools. Investigations were sometimes used to resolve diagnostic uncertainty, but availability and speed of result limited their practical use. Clear safety-net plans shared with patients and their families helped GPs manage ongoing uncertainty. CONCLUSIONS: Diagnostic challenges are present throughout the assessment of an older adult with a serious infection in primary care. Supporting GPs to provide continuity of care may improve the recognition and developing point of care testing for use in community settings may reduce diagnostic uncertainty.

Development and validation of the Baseline Recurrence Risk in Cellulitis (BRRISC) score.

OBJECTIVES: Cellulitis is often treated with antibiotics for longer than recommended by guidelines. Prolonged therapy may reduce recurrence in certain patients, but it is not known which patients are at greatest risk. Our objective was to develop and temporally validate a risk prediction score to identify patients attending hospital with cellulitis at highest risk of recurrence. METHODS: We included UK adult patients with cellulitis attending hospital in an electronic health records (EHR) study to identify demographic, comorbid, physiological, and laboratory factors predicting recurrence (before death) within 90 days, using multivariable logistic regression with backwards elimination in complete cases. A points-based risk score integerised model coefficients for selected predictors. Performance was assessed using the C-index in development and temporal validation samples. RESULTS: The final model included 4938 patients treated for median 8 days (IQR 6-11); 8.8% (n = 436) experienced hospitalisation-associated recurrence. A risk score using eight variables (age, heart rate, urea, platelets, albumin, previous cellulitis, venous insufficiency, and liver disease) ranged from 0-15, with C-index = 0.65 (95%CI: 0.63-0.68). Categorising as low (score 0-1), medium (2-5) and high (6-15) risk, recurrence increased fourfold; 3.2% (95%CI: 2.3-4.4%), 9.7% (8.7-10.8%), and 16.6% (13.3-20.4%). Performance was maintained in the validation sample (C-index = 0.63 (95%CI: 0.58-0.67)). Among patients at high risk, four distinct clinical phenotypes were identified using hierarchical clustering 1) young, acutely unwell with liver disease; 2) comorbid with previous cellulitis and venous insufficiency; 3) chronic renal disease with severe renal impairment; and 4) acute severe illness, with substantial inflammatory responses. CONCLUSIONS: Risk of cellulitis recurrence varies markedly according to individual patient factors captured in the Baseline Recurrence Risk in Cellulitis (BRRISC) score. Further work is needed to optimise the score, considering baseline and treatment response variables not captured in EHR data, and establish the utility of risk-based approaches to guide optimal antibiotic duration.

Infections diagnosed in children and young people screened for malaria in UK emergency departments: a retrospective multi-centre study.

BACKGROUND: Data on imported infections in children and young people (CYP) are sparse. AIMS: To describe imported infections in CYP arriving from malaria-endemic areas and presenting to UK emergency departments (ED) who were screened for malaria. METHODS: This is a retrospective, multi-centre, observational study nested in a diagnostic accuracy study for malaria rapid diagnostic tests. Any CYP < 16 years presenting to a participating ED with a history of fever and travel to a malaria-endemic area between 1 January 2016 and 31 December 2017 and who had a malaria screen as a part of standard care were included. Geographical risk was calculated for the most common tropical infections. RESULTS: Of the 1414 CYP screened for malaria, 44.0% (n = 622) arrived from South Asia and 33.3% (n = 471) from sub-Saharan Africa. Half (50.0%) had infections common in both tropical and non-tropical settings such as viral upper respiratory tract infection (URTI); 21.0% of infections were coded as tropical if gastro-enteritis is included, with a total of 4.2% (60) cases of malaria. CYP diagnosed with malaria were 7.44 times more likely to have arrived from sub-Saharan Africa than from South Asia (OR 7.44, 3.78-16.41). CONCLUSION: A fifth of CYP presenting to participating UK EDs with fever and a history of travel to a malaria-endemic area and who were screened for malaria had a tropical infection if diarrhoea is included. A third of CYP had no diagnosis. CYP arriving from sub-Saharan Africa had the greatest risk of malaria.Abbreviations: CYP: children and young people; ED: emergency department; PERUKI: Paediatric Emergency Research in the UK and Ireland; RDT: rapid diagnostic test; VFR: visiting friends and relatives.

Urine tenofovir and dried blood spot tenofovir diphosphate concentrations and viraemia in people taking efavirenz and dolutegravir-based antiretroviral therapy.

OBJECTIVE: We aimed to determine whether urine tenofovir (TFV) and dried blood spot (DBS) tenofovir diphosphate (TFV-DP) concentrations are associated with concurrent HIV viraemia. DESIGN: Cross-sectional study among people with HIV (PWH) receiving tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy (ART). METHODS: We used dual tandem liquid chromatography and mass spectrometry to measure urine TFV and DBS TFV-DP concentrations, and evaluated their associations with concurrent viraemia at least 1000 copies/ml using logistic regression models. In exploratory analyses, we used receiver operating curves (ROCs) to estimate optimal urine TFV and DBS TFV-DP thresholds to predict concurrent viraemia. RESULTS: Among 124 participants, 68 (54.8%) were women, median age was 39 years [interquartile range (IQR) 34-45] and 74 (59.7%) were receiving efavirenz versus 50 (40.3%) receiving dolutegravir. Higher concentrations of urine TFV [1000 ng/ml increase, odds ratio (OR) 0.97 95% CI 0.94-0.99, P  = 0.005] and DBS TFV-DP (100 fmol/punch increase, OR 0.76, 95% CI 0.67-0.86, P  < 0.001) were associated with lower odds of viraemia. There was evidence that these associations were stronger among people receiving dolutegravir than among people receiving efavirenz (urine TFV, P  = 0.072; DBS TFV-DP, P  = 0.003). Nagelkerke pseudo- R2 for the DBS TFV-DP models was higher for the urine TFV models, demonstrating a stronger relationship between DBS TFV-DP and viraemia. Among people receiving dolutegravir, a DBS TFV-DP concentration of 483 fmol/punch had 88% sensitivity and 85% specificity to predict concurrent viraemia ≥1000 copies/ml. CONCLUSION: Among PWH receiving TDF-based ART, urine TFV concentrations, and in particular DBS TFV-DP concentrations, were strongly associated with concurrent viraemia, especially among people receiving dolutegravir.

Diagnostic accuracy of a point-of-care antigen test for SARS-CoV-2 and influenza in a primary care population (RAPTOR-C19).

OBJECTIVES: Limited evidence exists for the diagnostic performance of point-of-care tests for SARS-CoV-2 and influenza in community healthcare. We carried out a prospective diagnostic accuracy study of the LumiraDx™ SARS-CoV-2 and influenza A or B assay in primary care. METHODS: Total of 913 adults and children with symptoms of current SARS-CoV-2 infection were recruited from 18 UK primary care practices during a period when Omicron was the predominant COVID variant of concern (June 2022 to December 2022). Trained health care staff performed the index test, with diagnostic accuracy parameters estimated for SARS-CoV-2 and influenza against real-time reverse-transcription PCR (rtRT-PCR). RESULTS: 151/887 participants were SARS-CoV-2 rtRT-PCR positive, 109 positive for Influenza A, 6 for Influenza B. Index test sensitivity for SARS-CoV-2 was 80.8% (122 of the 151, 95% CI, 73.6-86.7%) and specificity 98.9% (728 of the 736, 95% CI, 97.9-99.5%). For influenza A, sensitivity was 61.5% (67 of the 109, 95% CI, 51.7-70.6%) and specificity 99.4% (771 of the 776, 95% CI, 98.5-99.8%). Sensitivity to detect SARS-CoV-2 and influenza dropped sharply at rtRT-PCR cycle thresholds (Ct) > 30. DISCUSSIONS: The LumiraDx™ SARS-CoV-2 and influenza A/B assay had moderate sensitivity for SARS-CoV-2 in symptomatic patients in primary care, with lower performance with high rtRT-PCR Ct. Negative results in this patient group cannot definitively rule out SARS-CoV-2 or influenza.

A Diagnostic Accuracy Study to Evaluate Standard Rapid Diagnostic Test (RDT) Alone to Safely Rule Out Imported Malaria in Children Presenting to UK Emergency Departments.

BACKGROUND: Microscopy is the gold standard for malaria diagnosis but is dependent on trained personnel. Rapid diagnostic tests (RDTs) form the mainstay of diagnosis in endemic areas without access to high-quality microscopy. We aimed to evaluate whether RDT alone could rule out imported malaria in children presenting to UK emergency departments (EDs). METHODS: UK-based, multi-center, retrospective, diagnostic accuracy study. Included: any child <16 years presenting to ED with history of fever and travel to a malaria-endemic country, between 01/01/2016 and 31/12/2017. Diagnosis: microscopy for malarial parasites (clinical reference standard) and RDT (index test). UK Health Research Authority approval: 20/HRA/1341. RESULTS: There were 47 cases of malaria out of 1,414 eligible cases (prevalence 3.3%) in a cohort of children whose median age was 4 years (IQR 2-9), of whom 43% were female. Cases of Plasmodium falciparum totaled 36 (77%, prevalence 2.5%). The sensitivity of RDT alone to detect malaria infection due to any Plasmodium species was 93.6% (95% CI 82.5-98.7%), specificity 99.4% (95% CI 98.9-99.7%), positive predictive value 84.6% (95% CI 71.9-93.1%) and negative predictive value 99.8% (95% CI 99.4-100.0%). Sensitivity of RDT to detect P. falciparum infection was 100% (90.3-100%), specificity 98.8% (98.1-99.3%), positive predictive value 69.2% (54.9-81.2%, n = 46/52) and negative predictive value 100% (99.7-100%, n = 1,362/1,362). CONCLUSIONS: RDTs were 100% sensitive in detecting P. falciparum malaria. However, lower sensitivity for other malaria species and the rise of pfhrp2 and pfhrp3 (pfhrp2/3) gene deletions in the P. falciparum parasite mandate the continued use of microscopy for diagnosing malaria.

Evaluation of the diagnostic accuracy of two point-of-care tests for COVID-19 when used in symptomatic patients in community settings in the UK primary care COVID diagnostic accuracy platform trial (RAPTOR-C19).

BACKGROUND AND OBJECTIVE: Point-of-care lateral flow device antigen testing has been used extensively to identify individuals with active SARS-CoV-2 infection in the community. This study aimed to evaluate the diagnostic accuracy of two point-of-care tests (POCTs) for SARS-CoV-2 in routine community care. METHODS: Adults and children with symptoms consistent with suspected current COVID-19 infection were prospectively recruited from 19 UK general practices and two COVID-19 testing centres between October 2020 and October 2021. Participants were tested by trained healthcare workers using at least one of two index POCTs (Roche-branded SD Biosensor Standard™ Q SARS-CoV-2 Rapid Antigen Test and/or BD Veritor™ System for Rapid Detection of SARS-CoV-2). The reference standard was laboratory triplex reverse transcription quantitative PCR (RT-PCR) using a combined nasal/oropharyngeal swab. Diagnostic accuracy parameters were estimated, with 95% confidence intervals (CIs), overall, in relation to RT-PCR cycle threshold and in pre-specified subgroups. RESULTS: Of 663 participants included in the primary analysis, 39.2% (260/663, 95% CI 35.5% to 43.0%) had a positive RT-PCR result. The SD Biosensor POCT had sensitivity 84.0% (178/212, 78.3% to 88.6%) and specificity 98.5% (328/333, 96.5% to 99.5%), and the BD Veritor POCT had sensitivity 76.5% (127/166, 69.3% to 82.7%) and specificity 98.8% (249/252, 96.6% to 99.8%) compared with RT-PCR. Sensitivity of both devices dropped substantially at cycle thresholds ≥30 and in participants more than 7 days after onset of symptoms. CONCLUSIONS: Both POCTs assessed exceed the Medicines and Healthcare products Regulatory Agency target product profile's minimum acceptable specificity of 95%. Confidence intervals for both tests include the minimum acceptable sensitivity of 80%. In symptomatic patients, negative results on these two POCTs do not preclude the possibility of infection. Tests should not be expected to reliably detect disease more than a week after symptom onset, when viral load may be reduced. REGISTRATION: ISRCTN142269.

The comparative interrupted time series design for assessment of diagnostic impact: methodological considerations and an example using point-of-care C-reactive protein testing.

BACKGROUND: In diagnostic evaluation, it is necessary to assess the clinical impact of a new diagnostic as well as its diagnostic accuracy. The comparative interrupted time series design has been proposed as a quasi-experimental approach to evaluating interventions. We show how it can be used in the design of a study to evaluate a point-of-care diagnostic test for C-reactive protein in out-of-hours primary care services, to guide antibiotic prescribing among patients presenting with possible respiratory tract infection. This study consisted of a retrospective phase that used routinely collected monthly antibiotic prescribing data from different study sites, and a prospective phase in which antibiotic prescribing rates were monitored after the C-reactive protein diagnostic was introduced at some of the sites. METHODS: Of 8 study sites, 3 were assigned to receive the diagnostic and 5 were assigned as controls. We obtained retrospective monthly time series of respiratory tract targeted antibiotic prescriptions at each site. Separate ARIMA models at each site were used these to forecast monthly prescription counts that would be expected in the prospective phase, using simulation to obtain a set of 1-year predictions alongside their standard errors. We show how these forecasts can be combined to test for a change in prescription rates after introduction of the diagnostic and estimate power to detect this change. RESULTS: Fitted time series models at each site were stationary and showed second-order annual seasonality, with a clear December peak in prescriptions, although the timing and extent of the peak varied between sites and between years. Mean one-year predictions of antibiotic prescribing rates based on the retrospective time series analysis differed between sites assigned to receive the diagnostic and those assigned to control. Adjusting for the trend in the retrospective time series at each site removed these differences. CONCLUSIONS: Quasi-experimental designs such as comparative interrupted time series can be used in diagnostic evaluation to estimate effect sizes before conducting a full randomised controlled trial or if a randomised trial is infeasible. In multi-site studies, existing retrospective data should be used to adjust for underlying differences between sites to make outcome data from different sites comparable, when possible.

The Impact of Point-of-Care Blood C-Reactive Protein Testing on Prescribing Antibiotics in Out-of-Hours Primary Care: A Mixed Methods Evaluation.

Improving prescribing antibiotics appropriately for respiratory infections in primary care is an antimicrobial stewardship priority. There is limited evidence to support interventions to reduce prescribing antibiotics in out-of-hours (OOH) primary care. Herein, we report a service innovation where point-of-care C-Reactive Protein (CRP) machines were introduced to three out-of-hours primary care clinical bases in England from August 2018-December 2019, which were compared with four control bases that did not have point-of-care CRP testing. We undertook a mixed-method evaluation, including a comparative interrupted time series analysis to compare monthly antibiotic prescription rates between bases with CRP machines and those without, an analysis of the number of and reasons for the tests performed, and qualitative interviews with clinicians. Antibiotic prescription rates declined during follow-up, but with no clear difference between the two groups of out-of-hours practices. A single base contributed 217 of the 248 CRP tests performed. Clinicians reported that the tests supported decision making and communication about not prescribing antibiotics, where having 'objective' numbers were helpful in navigating non-prescribing decisions and highlighted the challenges of training a fluctuant staff group and practical concerns about using the CRP machine. Service improvements to reduce prescribing antibiotics in out-of-hours primary care need to be developed with an understanding of the needs and context of this service.

Pre-analytical error for three point of care venous blood testing platforms in acute ambulatory settings: A mixed methods service evaluation.

INTRODUCTION: Point of care blood testing to aid diagnosis is becoming increasingly common in acute ambulatory settings and enables timely investigation of a range of diagnostic markers. However, this testing allows scope for errors in the pre-analytical phase, which depends on the operator handling and transferring specimens correctly. The extent and nature of these pre-analytical errors in clinical settings has not been widely reported. METHODS: We carried out a convergent parallel mixed-methods service evaluation to investigate pre-analytical errors leading to a machine error reports in a large acute hospital trust in the UK. The quantitative component comprised a retrospective analysis of all recorded error codes from Abbott Point of Care i-STAT 1, i-STAT Alinity and Abbott Rapid Diagnostics Afinion devices to summarise the error frequencies and reasons for error, focusing on those attributable to the operator. The qualitative component included a prospective ethnographic study and a secondary analysis of an existing ethnographic dataset, based in hospital-based ambulatory care and community ambulatory care respectively. RESULTS: The i-STAT had the highest usage (113,266 tests, January 2016-December 2018). As a percentage of all tests attempted, its device-recorded overall error rate was 6.8% (95% confidence interval 6.6% to 6.9%), and in the period when reliable data could be obtained, the operator-attributable error rate was 2.3% (2.2% to 2.4%). Staff identified that the most difficult step was the filling of cartridges, but that this could be improved through practice, with a perception that cartridge wastage through errors was rare. CONCLUSIONS: In the observed settings, the rate of errors attributable to operators of the primary point of care device was less than 1 in 40. In some cases, errors may lead to a small increase in resource use or time required so adequate staff training is necessary to prevent adverse impact on patient care.

Frequencies and patterns of laboratory test requests from general practice: a service evaluation to inform point-of-care testing.

AIMS: The demand for test requests from general practice to laboratory services remains high. Tests performed at the point of care could reduce turnaround time and speed up clinical decision making. Replicating laboratory testing in the community would require panels of tests to be performed simultaneously, which is now approaching technological feasibility. We assessed frequencies and combinations of test requests from community settings to inform the potential future development of multiplex point-of-care panels. METHODS: We assessed all laboratory test requests made from general practice in Oxfordshire, UK, from January 2014 to March 2017. We summarised test request frequency overall and in combination, using heatmaps and hierarchical cluster analysis. Results are also presented by age/sex subgroups. We further assessed patterns of tests requested within 7 and 14 days after an initial test request. RESULTS: 11 763 473 test requests were made for 413 073 individuals (28% age >65). Of more than 500 test types, 62 were requested at least 5000 times, most commonly renal function tests (approximately 296 000/year), full blood count (278 000/year) and liver function tests (237 000/year). Cluster analysis additionally identified a clear grouping of tests commonly used to investigate anaemia. Follow-up test frequency was much lower than the frequency of multiple tests ordered at initial presentation. CONCLUSIONS: The current high volume of single and combination test requests highlights an opportunity for reliable multiplex point-of-care panels to cover a core set of frequently requested tests. The impact on test use of introducing such panels to general practice requires additional research.

Predicting clinical deterioration after initial assessment in out-of-hours primary care: a retrospective service evaluation.

BACKGROUND: Accurate assessment of the need for admission is challenging in out-of-hours (OOH) primary care. Understanding more about patient contacts where the decision to continue care in the community may have been incorrect could assist clinicians in assessing clinical risk. AIM: To define the population contacting OOH primary care who are at higher risk of re-presenting to this service and requiring urgent transfer to secondary care within 3 days of their initial contact. DESIGN AND SETTING: Retrospective service evaluation of 4 years of patient contacts with Oxfordshire OOH primary care. METHOD: Multivariable logistic regression was used to evaluate demographic and service delivery factors associated with increased risk of delayed escalation to secondary care. RESULTS: Almost 1% of 496 931 patients contacting OOH primary care required escalation to secondary care within 3 days. Of these, 68.5% were initially discharged with no follow-up or advice to contact their GP; 14.7% were initially referred to secondary care. The odds of requiring escalation were increased with age (odds ratio [OR] 1.010; 95% confidence interval [CI] = 1.009 to 1.011; P<0.001), more frequent prior use of the OOH service (OR 1.016; 95% CI = 1.010 to 1.021; P<0.001), and presenting during periods of low call volume (OR 0.880; 95% CI = 0.857 to 0.904; P<0.001). CONCLUSION: Older, prior users of the service, presenting at less busy times, are at greater risk of requiring secondary care referral from the OOH service within 3 days of their initial contact. These higher-risk patient groups might benefit from active follow-up by the OOH service.