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The Cochrane Database of Systematic Reviews logoLink to The Cochrane Database of Systematic Reviews
. 2022 Dec 19;2022(12):CD014521. doi: 10.1002/14651858.CD014521

C‐reactive protein, procalcitonin, and erythrocyte sedimentation rate for the diagnosis of lower urinary tract infection in older people

Soemeja Hidad 1,✉, Sacha D Kuil 1, Johan C Fischer 2, Caroline E Visser 1, Suzanne E Geerlings 3, Mariska MG Leeflang 4, Caroline Schneeberger 5
Editor: Cochrane Kidney and Transplant Group
PMCID: PMC9761663

Objectives

This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows:

Secondary objectives

  • To assess the influence of patient and study characteristics on the diagnostic accuracy of the index tests.

  • To assess the influence of different reference standards for UTI on the diagnostic accuracy of the index tests.

Background

Target condition being diagnosed

Over the past decades, urinary tract infections (UTIs) have been responsible for a large burden of disease worldwide accounting for 150 million cases every year (Harding 1994). UTIs are one of the most common infections in older people (Rowe 2013). The incidence ranges from 0.05 to 0.07 infections per person‐year (Jackson 2004) and increases substantially with increasing age (0.08 and 0.13 per person‐year in men and women over 85 years respectively) (Caljouw 2011). Accordingly, UTIs are responsible for a major part of hospitalisation in older people (Genao 2012; Rowe 2013).

Urinary tract infection

UTIs are bacterial infections caused by various ‘uropathogens’, mainly gram‐negative bacteria (e.g. Escherichia coli, Klebsiella spp. and Proteus spp.) (Flores‐Mireles 2015). Infections can occur in any part of the urinary tract and clinical signs and symptoms differ related to the site of infection: from the urethra to the kidneys. Lower UTIs involve infections of the bladder (cystitis) and/or urethra (urethritis), while upper UTIs involve the ureters or kidneys. Classically, lower UTIs present with specific lower urinary tract related symptoms, such as urgency, frequency, dysuria, and supra‐pubic pain (Rowe 2013). Whereas upper UTI are accompanied by systemic signs, such as fever and flank pain (Belyayeva 2021).

Diagnosing UTIs in older people is based on specific UTI symptoms, with or without positive urine tests according to current guidelines (NICE 2015; van Buul 2018; EAU 2020; SIGN 2020). Once diagnosed, UTIs can be treated with antibiotics which is found to be associated with reduced death rates (Gharbi 2019). Other benefits are symptom resolution and prevention of progression towards invasive disease, such as urosepsis.

Risk factors for urinary tract infection in older people

Previous UTI is found to be the main risk factor for UTI in older people (Hu 2004; Jackson 2004; Raz 2000). Additionally, immune senescence by the aging immune system is one of the multifactorial risk factors for developing UTI (Cortes‐Penfield 2017; Juthani‐Mehta 2010). Thereby, host‐specific characteristics increasing the risk of UTIs involve underlying comorbidities (for e.g. diabetes mellitus, obesity and immunodeficiency), the use of an indwelling catheter, and history of urine incontinence (Caljouw 2011).

Asymptomatic bacteriuria

Asymptomatic bacteriuria refers to the presence of at least 105 colony‐forming units/mL (CFU/mL) of bacteria in the urine without specific UTI symptoms, while asymptomatic pyuria refers to white blood cells in the urine without specific UTI symptoms (Rowe 2013). The prevalence of asymptomatic bacteriuria ranges from 25% to 50% in older women, and from 15% to 35% in long‐term care facilities (Nicolle 2001). Both asymptomatic pyuria and asymptomatic bacteriuria are common among older people and do not require antibiotic treatment, as treatment does not improve patient outcomes and may lead to adverse drug events (Nicolle 2019). The presence of asymptomatic bacteriuria and asymptomatic pyuria limits the use of urine tests that detects bacteria or leukocytes, as their presence does not equal an infection.

In older people, the complexity of UTI symptom recognition, the frequent occurrence of non‐specific symptoms, and the high prevalence of asymptomatic bacteriuria are the main drivers for diagnostic uncertainty and unnecessary antibiotic use. Presumed UTIs are one of the most common reasons for initiating antibiotic treatment (Butler 2017) and are estimated to be unnecessary in one third of all UTI prescriptions in older people (van Buul 2015). Likewise, in both primary and secondary care, over half of the empirically initiated antibiotic treatments for UTI in older people were considered unnecessary (McMurdo 2000; Nace 2014).

Unnecessary antibiotic treatment can lead to adverse effects, including Clostridioides difficile infections and increasing antimicrobial resistance (Llor 2014). Currently, there are no appropriate tests available to differentiate between older people with UTIs and older people without UTIs. Measurement of inflammatory biomarkers may be helpful to improve antimicrobial prescriptions and discriminate between infection (UTI) and non‐infection (e.g. asymptomatic bacteriuria).

Index test(s)

We will evaluate the diagnostic accuracy of three biomarkers: C‐reactive protein (CRP), procalcitonin (PCT) and erythrocyte sedimentation rate (ESR) for diagnosing UTI in older people. Assays to measure these biomarkers are easy to perform, often by point‐of‐care systems (POCT) and yield rapid results which may support bedside decision‐making. In addition, biomarkers are widely used in many health care settings worldwide and generate objective test results. CRP and PCT have proven to be useful in guiding antibiotic therapy and reducing antibiotic use in respiratory tract infections, and monitoring of bacterial sepsis (Martinez‐Gonzalez 2020; Wirz 2018). With growing interest in the usefulness of potential biomarkers, it is necessary to systematically review existing literature on accuracy of these biomarkers.

C‐reactive protein

CRP is one of the acute‐phase proteins, produced by the liver in response to increased Interleukin‐6 (IL‐6) during inflammation. CRP levels can rapidly increase during bacterial infection or inflammation and elevated levels can be measured within four to six hours after infection (Sproston 2018). Diagnostic accuracy studies in primary care showed good performance for CRP as a predictor for pneumonia (van Vugt 2013).

Procalcitonin

PCT, a prohormone of calcitonin, is another acute‐phase protein and is produced by immune cells in various tissues (liver, lung, and intestine) in response to systemic inflammation (Meisner 2014). The use of PCT is recommended for the diagnosis and monitoring of sepsis and septic shock (Rhodes 2016).

Erythrocyte sedimentation rate

ESR is the rate of descending red blood cells in standardised Westergren tubes over time. The ESR is a non‐specific haematology test that increases in response to auto‐immune diseases, infections and malignancies. It is one of the most commonly used laboratory tests to detect or monitor inflammatory, infectious or malignant diseases. Shortly after infection (24 to 48 hours after infection), ESR levels increase and subsequently decrease when inflammatory cells are cleared from the site of infection (Markanday 2015).

Clinical pathway

In older people with suspected UTI, it is recommended to start with a clinical assessment including verification of UTI symptoms. Subsequently, a voided urine specimen is collected in older people with UTI symptoms to test for bacteriuria or leukocyturia. Depending on the setting, rapid urine tests such as leukocytes and nitrite by urine dipstick testing (on or off‐site) and/or urine culture testing can be performed. It is not recommended to use urine tests when specific UTI symptoms are lacking. However, due to the difficulties in symptom assessment in older people, urine testing is also frequently initiated in case of (solely) non‐specific symptoms.

Urine culture is a semi‐quantitative laboratory test that enables detection of bacteria from the urinary tract. When necessary, antimicrobial resistance patterns are obtained to guide antimicrobial therapy (Schmiemann 2010). The most commonly used threshold for urine culture positivity is > 105 CFU/mL (Rowe 2013) growth of a uropathogen. However, thresholds may differ based on clinical and specimen characteristics (Aspevall 2001).

Role of the index test

Three index tests (CRP, PCT or ESR) will be evaluated individually for their diagnostic accuracy to possibly assist in the clinical pathway of diagnosing UTI in older people. Based on the index test threshold values, results can be categorized as increased (positive), borderline or low (negative). The index test can be used as an add‐on test consecutive upon assessment of UTI specific signs and symptoms and (if performed) positive urine test(s), see Figure 1 (Bossuyt 2006).

1.

1

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Clinical pathway of UTI diagnoses in older people (≥ 65 years) and possible position for index test as an add‐on: after assessment of signs and symptoms and verification of UTI symptoms and an optional rapid urine test

We will consider index test results exceeding a certain threshold, as true positives, if participants were diagnosed by having UTI symptoms and a positive urine test. Whereas, we will consider index test results below the threshold, as true negatives, in the absence of UTI symptoms and a negative urine test. However, in clinical practice, those with small suspicion of UTI may not be assigned to urine collection and further testing (dipstick and/or culture) although this might happen in an research setting to establish true negatives and false negatives.

Alternative test(s)

Other urine markers (interleukin‐6, neutrophil gelatinase‐associated lipocalin (NGAL) and chemokines) have been proposed to diagnose UTI in adults, but these markers are beyond the scope of this review.

Rationale

The usefulness of biomarkers as reliable diagnostic method is an interesting research gap for many syndromes such as acute pyelonephritis and sepsis (Onyenekwu 2017; Shaikh 2020), this is also the case for lower UTI in older people. The combination of frequent attribution of non‐specific symptoms to UTIs and high prevalence of asymptomatic bacteriuria, results in inappropriate antibiotic use in presumed UTI, increasing antimicrobial resistance development (van Buul 2015). The lack of a diagnostic test and the imprecision of the clinical diagnosis, warrants an adequate diagnostic method to differentiate between older people with a UTI and older people without a UTI, resulting in improved antibiotic prescriptions.

Objectives

Primary objectives

To assess and compare the diagnostic accuracy (sensitivity, specificity, positive and negative predictive value) of CRP, PCT and ESR to diagnose UTIs in older people.

Secondary objectives

  • To assess the influence of patient and study characteristics on the diagnostic accuracy of the index tests.

  • To assess the influence of different reference standards for UTI on the diagnostic accuracy of the index tests.

Methods

Criteria for considering studies for this review

Types of studies

We will consider any published diagnostic accuracy study that compares CRP and/or PCT and/or ESR results to each other and separately. This may include cross‐sectional studies, cohort studies and randomised controlled trials (RCTs), which assessed sensitivity and specificity of the index test in diagnosing UTI. We will consider studies from every setting (e.g. primary care, long‐term care). In contrast, we are planning to exclude case‐control studies, as they possibly overestimate the effect measure because of the sampling strategy for this study design, which includes older people without the target condition of interest (controls) and older people with the target condition of interest (cases) (Rutjes 2005). Studies will be eligible for inclusion when sensitivity and specificity of the index test are reported, and/or the number of true positive, true negatives, false positives and false negatives.

Participants

We will include older people, in any setting, aged ≥ 65 years with UTI (presence of UTI symptoms with or without a positive urine culture). We will also include studies that enrolled older people as a subgroup, when we are able to extract data for this subgroup only. We will not exclude participants with urinary catheters or urinary abnormalities.

Index tests

Studies that determined the accuracy of one or more index tests (CRP, PCT or ESR) for UTI diagnosis in older people, will be considered, regardless of the manufacturers, type of test device (point‐of‐care test or central laboratory tests) and threshold values used.

Positive index test results for any of the three biomarkers is referred to as an index test result which exceeds a certain threshold for index test positivity. Negative index test results for any of the three biomarkers is referred to as an index test result which is below a certain threshold for index test negativity.

Target conditions

The target condition of interest is UTI (variously defined). UTI is defined by a positive urine culture and the presence of (specific and/or non‐specific) UTI symptoms. The absence of the target condition is defined by at least a negative urine culture result.

Reference standards

We will use a reference standard which includes (specific and/or non‐specific) UTI symptoms and a positive urine culture (Rowe 2013). Threshold for culture positivity may be defined in various ways.

Search methods for identification of studies

Electronic searches

We will search MEDLINE (OvidSP), EMBASE (OvidSP), and BIOSIS, and will request a search of the Cochrane Register of diagnostic test accuracy studies. We will also search ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform for ongoing trials.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

  1. Reference lists of review articles retrieved from searches of ARIF (Aggressive Research Intelligence Facility).

  2. Reference lists of relevant DTA studies

Data collection and analysis

Selection of studies

The search strategy described in Appendix 1, will be used to obtain titles and abstracts of studies that may be relevant to the review. Two authors (SH, SK) will independently screen titles and abstracts. They will independently assess retrieved abstracts, and if relevant the full text of these studies to determine which studies satisfy the inclusion criteria. Any disagreements will be resolved by discussion with a third author (CS).

Data extraction and management

Data extraction will be carried out independently by two authors (SH, SK) using standardized data extraction forms for all studies meeting the inclusion criteria. The data extraction form will be tested prior to use. After reviewing the data extraction form on two included studies, the form will be finalized. Appendix 2 presents the data extraction form. Study authors will be contacted for clarification of unclear data and to obtain missing information if necessary. Studies that include participants that meet our inclusion criteria as a subgroup, will be reviewed and data extraction will only apply for those meeting the inclusion criteria. Studies not published in English or Dutch will be translated into English where possible. Where more than one publication of one study exists, reports will be grouped and the publication with the most complete data will be used in the analyses. Any discrepancy between published versions will be highlighted. Two‐by‐two tables will be constructed independently by each author from the data in the publication. Only studies for which two‐by‐two data are available (or can be reconstructed) will be included. Any disagreements between authors will be resolved by discussion with a third review author (CS). Two independent review authors (SH, SK) will enter the extracted data into a password‐protected spreadsheet, which includes the data extraction form.

Assessment of methodological quality

Two authors (SH, SK) will independently assess the methodological quality of each included study using a four‐domain tool (patient selection, the index test, the reference standard, and flow/timing) adapted from QUADAS‐2 and QUADAS‐C, see Appendix 2 (Whiting 2011; Yang 2021). We will apply QUADAS‐ 2 signalling questions to each study and report results in the graphical form. We will apply QUADAS‐C signalling questions to studies that compared at least two different index tests to each other. We will refine the tools until a satisfactory inter‐rater agreement is achieved. We will summarize the methodological quality assessment in tables for each study. For QUADAS‐2, signalling questions will be judged as ‘yes’ when items are appropriately addressed, and ‘no’ when not appropriately addressed. When there is no sufficient information available, this is judged as unclear. A sensitivity analysis will be performed to evaluate the effect of excluding studies that have a high level of concern about either bias or applicability.

Statistical analysis and data synthesis

Our diagnostic accuracy review includes several index tests which can provide continuous values with a broad range. Data extracted from studies will be entered into the Review Manager 5.4 (RevMan 2020). Each index test will be evaluated individually. Different threshold values for CRP, PCT and ESR may be used in the primary studies and therefore we will use the threshold as reported in the included studies for analysis. This will allow us to describe how sensitivity and specificity of different included studies will trade‐off when threshold values vary. When all included studies have used the same threshold value (e.g. 5 mg/L for CRP), the bivariate random‐effects model will be used to perform overall meta‐analysis at that cut‐off. Otherwise, the HSROC model will be used (Leeflang 2013). We will use SAS NLMIXED for the meta‐analyses but when insufficient data is available for meta‐analysis, findings will be descriptively summarised.

The reference standard of included studies can be defined in various ways, including at least UTI symptoms and a positive urine culture. We will dichotomise the outcome (UTI or no UTI), following the included study’s definition. When sufficient data is available, our primary analysis includes the estimate sensitivity and specificity for CRP, PCT and ESR separately.

Our primary analysis is to estimate sensitivity and specificity for CRP, PCT and ESR separately in diagnosing UTI in older people. We will extract and/or construct two‐by‐two tables (two level diagnosis: above and below threshold) or three‐by‐three (three level diagnosis: above, borderline and below threshold) tables from the included studies based on how index test results are categorised by primary authors from included studies. For meta‐analysis, three‐by‐three tables will be reduced to two‐by‐two tables. Borderline index test results will be handled in a sensitivity analysis by treating them as positive or negative test result. Thereafter this data will be used to calculate sensitivity and specificity for each study individually including a 95% confidence interval (CI) around the summary estimate of sensitivity. The results from included studies will be summarised and presented in a summary of findings table. In addition, a forest plot and summary receiving operating curve (SROC) will be plotted.

Comparisons between tests will be made by including test type as a covariate in the meta‐regression analyses. These analyses will include both studies that evaluated only one test and studies that evaluated multiple tests. If a study has used more than one index test to their study population (e.g. both CRP and PCT measured in the same participant simultaneously), these index tests are directly compared to each other, which makes the comparison less susceptible to confounding (Hayen 2010; Takwoingi 2013). If we find four or more studies directly comparing two index tests, we will analyse those separately in a sensitivity analysis.

Investigations of heterogeneity

Sources of heterogeneity in diagnostic performance will be investigated across included studies when sufficient data are provided. The following factors will be included as covariates in the meta‐regression models:

  • Institutionalised older people (yes/no)

  • Type of assay (POCT or laboratory)

  • Hospitalised older people (yes/no)

  • Dipstick test (yes/no)

  • Reference standard

Sensitivity analyses

We will explore the risk of bias, whether studies with a high risk of bias provide different results compared to studies with a low risk of bias. We will prioritise studies that have a high risk of bias and/or applicability in the reference standard and/or patient selection domain. 
We will also explore the effect of direct comparisons between the different index tests as compared to an analysis combining direct and indirect comparison.

Assessment of reporting bias

No assessment of reporting bias will be carried out as this is not conclusively recommended in diagnostic test accuracy (DTA) reviews (Macaskill 2010).

Acknowledgements

We would like to thank Tess Cooper, Ruth L Mitchell and Narelle Willis from Cochrane Kidney and Transplant for assisting the authors with the search strategy and to complete this protocol. We would also like to thank the peer reviewers for their time and comments.

Appendices

Appendix 1. Electronic search strategies

Databases Search terms
MEDLINE

  1. Procalcitonin/

  2. procalcitonin.tw.

  3. pro‐calcitonin.tw.

  4. (calcitonin adj2 precursor*).tw.

  5. PCT.tw.

  6. or/1‐5

  7. C‐Reactive Protein/

  8. c‐reactive protein.tw.

  9. creactive protein.tw.

  10. CRP.tw.

  11. hsCRP.tw.

  12. or/7‐11

  13. Blood Sedimentation/

  14. erythrocyte sedimentation rate*.tw.

  15. blood sedimentation rate*.tw.

  16. ESR.tw.

  17. or/13‐16

  18. or/6,12,17

  19. Urinary Tract Infections/

  20. urin* tract infection*.tw.

  21. urin* infection*.tw.

  22. (UTI or UTIs).tw.

  23. genitourinary tract infection*.tw.

  24. Bacteriuria/

  25. bacteriuria.tw.

  26. Pyuria/

  27. pyuria.tw.

  28. exp Cystitis/

  29. cystitis.tw.

  30. candiduria.tw.

  31. urosepsis.tw.

  32. or/19‐31

  33. and/18,32
EMBASE

  1. Procalcitonin/

  2. procalcitonin.tw.

  3. pro‐calcitonin.tw.

  4. (calcitonin adj2 precursor*).tw.

  5. PCT.tw.

  6. or/1‐5

  7. C Reactive Protein/

  8. c‐reactive protein.tw.

  9. creactive protein.tw.

  10. CRP.tw.

  11. hsCRP.tw.

  12. or/5‐11

  13. erythrocyte sedimentation rate/

  14. erythrocyte sedimentation rate*.tw.

  15. blood sedimentation rate*.tw.

  16. ESR.tw.

  17. or/13‐16

  18. or/6,12,17

  19. Urinary Tract Infection/

  20. urinary tract infection*.tw.

  21. urin* infection*.tw.

  22. (UTI or UTIs).tw.

  23. genitourinary tract infection*.tw.

  24. Bacteriuria/

  25. bacteriuria.tw.

  26. Pyuria/

  27. pyuria.tw.

  28. Cystitis/

  29. cystitis.tw.

  30. Candiduria/

  31. candiduria.tw.

  32. Urosepsis/

  33. urosepsis.tw.

  34. or/19‐33

  35. and/18,34
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Appendix 2. Standardised data extraction form for each study

Study First author, year publication
Type of study Journal article, abstract only or unpublished study
Setting ‐ Primary care: outpatient or inpatient
‐ OR long‐term care facilities: psychogeriatric, revalidation or somatic ward
Participants ‐ Inclusion and exclusion criteria
‐ Sample size (number)
‐ Age distribution
‐ Antibiotic use before index test (yes/no)
Study design ‐ Prospective or retrospective
‐ Single‐centre or multi‐centre
‐ Sample (consecutive, random, or unclear)
Reference standard ‐ Clinical diagnosis by having symptoms related to UTI (yes/no)
‐ Culture confirmed (yes/no)
‐ Dipstick performed (yes/no)
‐ Other
Index test ‐ CRP, PCT or ESR measurement
‐ POCT or laboratory test
‐ Specimen type (venous capillary or whole blood serum or plasma)
‐ Threshold values
‐ Threshold definitions
‐ Time interval between index test and reference standard
‐ Manufacturer of index test used
Results ‐ Total of true positives, true negatives, false positives, and false negatives (number)
‐ Sensitivity of index test (%)
‐ Specificity of index test (%)
‐ Missing data (number)
Notes Anything else of relevance
Footnotes
CRP: C‐reactive protein; ESR: erythrocyte sedimentation rate PCT: procalcitonin; POCT: point of care test
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Appendix 3. QUADAS‐2

Domain 1: Patient selection

Was a consecutive or random sample of patients enrolled?

Yes If it is stated that study participants are randomly or consecutively enrolled (e.g. if a study reports that 'all patients' were included', then we assume that enrolment was consecutively)
No If neither of the above conditions is met
Unclear If there is not sufficient information regarding sampling to answer yes or no
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Was a case‐control avoided?

This question is irrelevant as we do not include case‐control studies, and the answer to this question will be ‘yes’ in all cases.

Did the study avoid inappropriate inclusion?

Yes When inclusion and exclusion criteria were explicitly stated and participants were only excluded based on the mentioned exclusion criteria (e.g. missing values should have been handled as missing values and not excluded from analysis)
No If study authors did not meet their inclusion and exclusion criteria (e.g. when participants with missing values were excluded from analysis)
Unclear If there is no or not enough information to answer yes or no; or if no inclusion or exclusion criteria were reported
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Guidelines for assessing risk of bias

Risk of bias sample selection will be categorized as ‘low’ when all signalling questions from domain 1 are answered with ‘yes’.

Risk of bias sample selection will be categorized as ‘high’ when at least one signalling question from domain 1 is answered with ‘no’.

Risk of bias sample selection will be categorized as ‘unclear’ when insufficient information is reported for domain 1 to answer signalling questions.

Is there concern that the included patients do not match the review question?

Yes If included patients give a high concern of not matching the review question (e.g. when participants have other infections at time of inclusion)
No If included patients give a low concern of not matching the review question
Unclear If there is not enough information to answer the question above with yes or no
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Domain 2: Index tests

Were the index test results interpreted without knowledge of the results of the reference standard? Please answer for CRP, PCT and or ESR separately when necessary

Yes If the staff that performed the index test were unaware of the results of the reference standard and blinding was explicitly stated
No If the staff that performed the index test were aware of the results of the reference standard and/or blinding was not explicitly stated
Unclear If there is not enough information to answer this question
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If a threshold was used, was it pre‐specified? Please answer for CRP, PCT and or ESR separately when necessary

Yes If a pre‐specified threshold has been stated for test positivity in the index test
No If no pre‐specified threshold has been stated for test positivity in the index test (e.g. when studied aimed to determine optimal thresholds or when thresholds reported were data driven)
Unclear If there is not enough information to answer this question
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Guidelines for assessing risk of bias

Risk of bias introduced by index test will be categorized as ‘low’ when both signalling questions are answered with ‘yes’.

Risk of bias introduced by index test will be categorized as ‘high’ when one or both signalling questions are answered with ‘no’.

Risk of bias introduced by index test will be categorized as ‘unclear’ when insufficient information is reported to answer signalling question.

Is there concern that the index test, its conduct, or interpretation differ from the review question?

Index test accuracy can be influenced by factors, such as non‐adherence to manufacturer's protocol, different underlying techniques, and interpretation of test results. Therefore, adherence to manufacturer's protocol is essential.

The used index test should be briefly described, reporting the manufacturers' name and clearly stating that the index test was performed following manufacturers protocol. If a non‐standardized test is used, the following details must be provided

  • Name of the manufacturer of index text

  • Name of manufacturer

  • Instrument used

  • Type of specimen

  • Type of test (laboratory or POCT)

  • Type of specimen tube

Asses as high concern regarding applicability for the index test if it is not explicitly stated which system was used; or when not clearly stated that manufacturers' protocol was followed.

Asses as low concern regarding applicability for the index test if above conditions are met.

Asses as unclear concern regarding applicability for the index test when there is insufficient information available regarding the conditions described above.

Domain 3: Reference standard

Is the reference standard likely to correctly classify the target condition?

Yes UTI diagnosis based on at least assessment of UTI symptoms and based on positive urine culture
No If a study includes a urine culture solely or symptom assessment solely or when a completely different reference standard such as urine microscopy or dip slide is used
Unclear If there is not enough information to answer the question above
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Were the reference standard results interpreted without knowledge of the results of the index test?

Yes If the staff that performed the reference test were unaware of the results of the index test and vice versa and blinding was explicitly stated
No If the staff that performed the reference standard were aware of the results of the index test and vice versa and/or blinding was not explicitly stated
Unclear If there is not enough information to answer the question above
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Guidelines for assessing risk of bias

Risk of bias introduced by reference standard will be categorized as ‘low’ when all signalling questions in domain 3 are answered with ‘yes’.

Risk of bias introduced by reference standard will be categorized as ‘high’ when all signalling questions in domain 3 are answered with ‘no’.

Risk of bias introduced by reference standard will be categorized as ‘unclear’ when insufficient information is reported in domain 3, to answer signalling question.

Is there concern that the target condition as defined by the reference standard does not match the review question?

The used reference standard to identify the target condition, should be briefly described in sufficient detail. Information regarding, used laboratory tests e.g. urine culture agar plate types and thresholds for test positivity should be described.

Assess as high concerns regarding applicability introduced by reference standard if no information regarding the reference standard is given; or when information on the reference standard, such as threshold for test positivity, is lacking.

Assess as low concerns regarding applicability introduced by reference standard if all the information is given, this includes at least: test positivity threshold.

Assess as unclear concerns regarding applicability when there is insufficient information available regarding the used reference standard by included studies.

Domain 4. Flow and timing

Did all the participants receive the same reference standard?

Yes If all included participants diagnosed with UTI, were diagnosed by the reference standard as reported by primary study authors from the included study (e.g. when reference standard includes both UTI symptom assessment and urine culture result, this means that all participants included should have received this reference standard)
No If only part of the included participants was diagnosed with UTI by the reference standard as reported by primary study authors from the included study
Unclear If there is not enough information to answer the above
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Were all participants included in the analysis?

Yes If the analysis has been carried out based on all the UTI episodes in the study population
No If not all UTI episodes are included for analysis from the study population
Unclear If there is not enough information to answer the above
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Was there an appropriate interval between index test and reference standard?

Urine and blood samples collected on the same day, are within the appropriate time interval between index test and reference standard.

Yes If included studies explicitly stated that there was < 24 hours between collection of the samples for the index test and reference standard
No If there was > 24 hours between the collection of samples for the index test and reference standard
Unclear If there is not enough information to answer the above
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Guidelines for assessing risk of bias

Risk of bias introduced by flow and timing (participant) will be categorized as ‘low’ when all the above signalling questions regarding to flow and timing are answered ‘yes’.

Risk of bias introduced by flow and timing (participant) will be categorized as ‘high’ when any of the above signalling questions regarding to flow and timing are answered ‘no’.

Risk of bias introduced by flow and timing (participant) will be categorized as ‘unclear’ when insufficient information is reported to answer any one of the four signalling questions.

QUADAS‐C

QUADAS‐C signalling question will be used if we identify studies that compared at least two different index tests to each other.

Contributions of authors

  • Conceived the review: CS

  • Wrote draft of protocol: SH, SK

  • Comment and input to protocol: SG, JF, CV, ML, CS

  • Study selection: SH, SK

  • Data management in Rev Man: SH, SK

  • Carry out analysis in Rev Man: SH, SK

  • Interpret analysis: SH, SK, ML

  • Draft review: SH

  • Comment on draft review: SG, JF, CV, ML, CS

  • Update the review: SH

Sources of support

Internal sources

  • Amsterdam University Medical Centers, Netherlands

    SH, SDK, JCF, CEV, SEG, MMGL receive salary for their work at the Amsterdam University Medical Centers

External sources

  • No sources of support provided

Declarations of interest

  • Soemeja Hidad: no relevant interests were disclosed

  • Sacha D Kuil: Specific diagnostics (Gift), Avant medical (Gift), ZonMw grant (Dutch Government Funding Agency for Health Research and Development (grant number: 541001003).

  • Johan C Fischer: no relevant interests were disclosed

  • Caroline E Visser: no relevant interests were disclosed

  • Suzanne E Geerlings: no relevant interests were disclosed

  • Mariska MG Leeflang: no relevant interests were disclosed

  • Caroline Schneeberger: ZonMw grant (Dutch government funding agency for health research and development, (grant number 541001003) paid to her institution for conducting a study on the use of point‐of‐care tests in Dutch nursing home residents in diagnosing urinary tract infections. Sacha Kuil was paid from this grant. Caroline Schneeberger, Johan Fischer, Sacha Kuil and Soemeja Hidad were involved in this study.

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References

Additional references

Aspevall 2001

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