A Van den Bruel

Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review

Objective To collate all available evidence on the diagnostic value of laboratory tests for the diagnosis of serious infections in febrile children in ambulatory settings. Design Systematic review. Data sources Electronic databases, reference tracking, and consultation with experts. Study selection Studies were selected on six criteria: design (studies of diagnostic accuracy or deriving prediction rules), participants (otherwise healthy children and adolescents aged 1 month to 18 years), setting (first contact ambulatory care), outcome (serious infection), features assessed (in first contact care), and data reported (sufficient to construct a 2×2 table). Data extraction Quality assessment was based on the quality assessment tool of diagnostic accuracy studies (QUADAS) criteria. Meta-analyses were done using the bivariate random effects method and hierarchical summary receiver operating characteristic curves for studies with multiple thresholds. Data synthesis None of the 14 studies identified were of high methodological quality and all were carried out in an emergency department or paediatric assessment unit. The prevalence of serious infections ranged from 4.5% to 29.3%. Tests were carried out for C reactive protein (five studies), procalcitonin (three), erythrocyte sedimentation rate (one), interleukins (two), white blood cell count (seven), absolute neutrophil count (two), band count (three), and left shift (one). The tests providing most diagnostic value were C reactive protein and procalcitonin. Bivariate random effects meta-analysis (five studies, 1379 children) for C reactive protein yielded a pooled positive likelihood ratio of 3.15 (95% confidence interval 2.67 to 3.71) and a pooled negative likelihood ratio of 0.33 (0.22 to 0.49). To rule in serious infection, cut-off levels of 2 ng/mL for procalcitonin (two studies, positive likelihood ratio 13.7, 7.4 to 25.3 and 3.6, 1.4 to 8.9) and 80 mg/L for C reactive protein (one study, positive likelihood ratio 8.4, 5.1 to 14.1) are recommended; lower cut-off values of 0.5 ng/mL for procalcitonin or 20 mg/L for C reactive protein are necessary to rule out serious infection. White blood cell indicators are less valuable than inflammatory markers for ruling in serious infection (positive likelihood ratio 0.87-2.43), and have no value for ruling out serious infection (negative likelihood ratio 0.61-1.14). The best performing clinical decision rule (recently validated in an independent dataset) combines testing for C reactive protein, procalcitonin, and urinalysis and has a positive likelihood ratio of 4.92 (3.26 to 7.43) and a negative likelihood ratio of 0.07 (0.02 to 0.27). Conclusion Measuring inflammatory markers in an emergency department setting can be diagnostically useful, but clinicians should apply different cut-off values depending on whether they are trying to rule in or rule out serious infection. Measuring white blood cell count is less useful for ruling in serious infection and not useful for ruling out serious infection. More rigorous studies are needed, including studies in primary care, to assess the value of laboratory tests alongside clinical diagnostic measurements, including vital signs.

Diagnostic accuracy of exercise stress testing for coronary artery disease: a systematic review and meta-analysis of prospective studies

Background:  Exercise stress testing offers a non‐invasive, less expensive way of risk stratification prior to coronary angiography, and a negative stress test may actually avoid angiography. However, previous meta‐analyses have not included all exercise test modalities, or patients without known Coronary artery disease (CAD).

Validity and reliability of measurement of capillary refill time in children: a systematic review

Background Most guidelines recommend the use of capillary refill time (CRT) as part of the routine assessment of unwell children, but there is little consensus on the optimum method of measurement and cut-off time. Methods We searched Medline (from 1948), Embase (from 1980) and CINAHL (from 1991) to June 2014 to identify studies with information on the normal range of CRT in healthy children, the validity of CRT compared with reference standard measures of haemodynamic status, reliability and factors influencing measurement of CRT, such as body site, pressing time and temperature. Findings We included 21 studies on 1915 children. Four studies provided information on the relationship between CRT and measures of cardiovascular status, 13 provided data on the normal range of CRT, 7 provided data on reliability and 10 assessed the effect of various confounding factors. In children over 7 days of age, the upper limit of normal CRT is approximately 2 s when measured on a finger, and 4 s when measured on the chest or foot, irrespective of whether the child is feverish or not. Longer pressing times and ambient temperature outside 20°C–25°C are associated with longer CRT. Evidence suggests that the use of stopwatches reduces variability between observers. Interpretation We recommend use of the following standardised CRT method of measurement: press on the finger for 5 s using moderate pressure at an ambient temperature of 20°C–25°C. A capillary refill time of 3 s or more should be considered abnormal.

The diagnostic value of capillary refill time for detecting serious illness in children: A systematic review and meta-analysis

Importance Capillary refill time (CRT) is widely recommended as part of the routine assessment of unwell children. Objective To determine the diagnostic value of capillary refill time for a range of serious outcomes in children. Methods We searched Medline, Embase and CINAHL from inception to June 2014. We included studies that measured both capillary refill time and a relevant clinical outcome such as mortality, dehydration, meningitis, or other serious illnesses in children aged up to 18 years of age. We screened 1,265 references, of which 24 papers were included in this review. Where sufficient studies were available, we conducted meta-analysis and constructed hierarchical summary ROC curves. Results Meta-analysis on the relationship between capillary refill time and mortality resulted in sensitivity of 34.6% (95% CI 23.9 to 47.1%), specificity 92.3% (88.6 to 94.8%), positive likelihood ratio 4.49 (3.06 to 6.57), and negative likelihood ratio 0.71 (0.60 to 0.84). Studies of children attending Emergency Departments with vomiting and diarrhea showed that capillary refill time had specificity of 89 to 94% for identifying 5% dehydration, but sensitivity ranged from 0 to 94%. This level of heterogeneity precluded formal meta-analysis of this outcome. Meta-analysis was not possible for other outcomes due to insufficient data, but we found consistently high specificity for a range of outcomes including meningitis, sepsis, admission to hospital, hypoxia, severity of illness and dengue. Conclusions Our results show that capillary refill time is a specific sign, indicating that it can be used as a “red-flag”: children with prolonged capillary refill time have a four-fold risk of dying compared to children with normal capillary refill time. The low sensitivity means that a normal capillary refill time should not reassure clinicians.

Common evidence gaps in point-of-care diagnostic test evaluation: a review of horizon scan reports

Objective Since 2008, the Oxford Diagnostic Horizon Scan Programme has been identifying and summarising evidence on new and emerging diagnostic technologies relevant to primary care. We used these reports to determine the sequence and timing of evidence for new point-of-care diagnostic tests and to identify common evidence gaps in this process. Design Systematic overview of diagnostic horizon scan reports. Primary outcome measures We obtained the primary studies referenced in each horizon scan report (n=40) and extracted details of the study size, clinical setting and design characteristics. In particular, we assessed whether each study evaluated test accuracy, test impact or cost-effectiveness. The evidence for each point-of-care test was mapped against the Horvath framework for diagnostic test evaluation. Results We extracted data from 500 primary studies. Most diagnostic technologies underwent clinical performance (ie, ability to detect a clinical condition) assessment (71.2%), with very few progressing to comparative clinical effectiveness (10.0%) and a cost-effectiveness evaluation (8.6%), even in the more established and frequently reported clinical domains, such as cardiovascular disease. The median time to complete an evaluation cycle was 9 years (IQR 5.5–12.5 years). The sequence of evidence generation was typically haphazard and some diagnostic tests appear to be implemented in routine care without completing essential evaluation stages such as clinical effectiveness. Conclusions Evidence generation for new point-of-care diagnostic tests is slow and tends to focus on accuracy, and overlooks other test attributes such as impact, implementation and cost-effectiveness. Evaluation of this dynamic cycle and feeding back data from clinical effectiveness to refine analytical and clinical performance are key to improve the efficiency of point-of-care diagnostic test development and impact on clinically relevant outcomes. While the ‘road map’ for the steps needed to generate evidence are reasonably well delineated, we provide evidence on the complexity, length and variability of the actual process that many diagnostic technologies undergo.

The comprehensive diagnostic study: a new solution to old problems?

Diagnostic labeling is one of the key elements of clinical care. The diagnostic label is used to explain symptoms, initiate appropriate treatment, or provide prognostic information [1]. Choosing the correct diagnostic label based on the available diagnostic information can be challenging. Especially in primary care, which is the first contact setting for an unselected patient population, the clinician is left to choose from a large list of diagnostic possibilities. A patient presenting with chest pain may suffer from an acute coronary syndrome, hyperventilation, esophagitis, muscle pain, or pulmonary embolism [2]. This is contrary to many diagnostic accuracy studies in which one or more index tests are evaluated for their ability to diagnose one specific target condition [3]. The results of such studies therefore apply to only a very small piece of the diagnostic puzzle. In a reaction to this, Donner-Banzhoff et al. propose what they call a new design, in which patients are recruited based on a specific finding or symptom and classified into multiple diagnostic categories. Although appealing and seemingly more relevant to routine care because it is aligned to the logic of real clinical practice, we think this design is neither new nor solving the problem. We fully agree with the authors that recruiting patients based on presenting symptoms or certain findings leads to clinically more relevant estimates of diagnostic accuracy. Empirical evidence has shown that recruiting patients based on referral for the index test rather than on clinical symptoms significantly affects estimates of diagnostic accuracy [4]. Consequently, authors are advised to report whether recruitment was based on presenting symptoms, as per Standards for Reporting of Diagnostic Accuracy reporting guidelines for diagnostic accuracy studies (item 4) [5]. As such, we believe that the importance of symptomguided recruitment of patients in diagnostic accuracy studies is sufficiently clear, and many such studies have been performed in the past, including studies recruiting patients

Point-of-care testing for coeliac disease: primary care diagnostic technology update

#### Clinical Question In primary care patients with suspected coeliac disease, what is the accuracy and utility of point-of-care (POC) testing for coeliac disease compared to standard practice? Coeliac disease is a malabsorption syndrome precipitated by gluten ingestion, and characterised by inflammation of the small intestine. Serological tests for IgA anti-tissue transglutaminase antibody (tTGA) and anti-endomysial antibody (EMA) have high sensitivity and specificity for coeliac disease.1,2 In patients with IgA deficiency, the IgG class of the tTGA and EMA tests are recommended. Anti-gliadin antibodies are no longer used for the detection of coeliac disease, except in children younger than 18 months.2 Conventional serological tests are performed in central laboratories, whereas the point-of-care (POC) test can be performed in practice or at home. Both the POC and conventional serological tests require patients to be on a normal gluten-containing diet at the time of testing, since IgA-tTGA titres diminish on a gluten-free diet. Two POC devices available on the market were identified. ### Biocard Coeliac Test Kit (Ani Biotech, Finland; UK Distributor: BHR Pharmaceuticals Ltd) There are two versions of the test, a home test and a professional test; a ‘total IgA measuring system’ is included in the professional kit. The Biocard requires a drop of whole blood (finger-prick) and provides results within 10 minutes. Anti-tTG IgA antibodies bind to antigen in the test strip to form a visible line. A positive test result shows two lines, while only one line appears if the test is negative. If there is no line, IgA deficiency should be suspected. ### Stick CD1 and CD2 (Operon SA, Zaragoza, Spain) Both are one-step tests detecting IgA, IgG, and IgM antibodies against human tTG; and the CD2 test also detects anti-gliadin antibodies. The tests use serum instead of whole blood, which limits …

Predictors of pneumonia in lower respiratory tract infections: 3C prospective cough complication cohort study.

The aim was to aid diagnosis of pneumonia in those presenting with lower respiratory tract symptoms in routine primary care. A cohort of 28 883 adult patients with acute cough attributed to lower respiratory tract infections (LRTIs) was recruited from 5222 UK practices in 2009–13. Symptoms, signs and treatment were recorded at presentation and subsequent events followed-up for 30 days by chart review. The predictive value of patient characteristics, presenting symptoms and clinical findings for the diagnosis of pneumonia in the first 7 days was established. Of the 720 out of 28 883 (2.5.%) radiographed within 1 week of the index consultation, 115 (16.0%; 0.40% of 28 883) were assigned a definite or probable pneumonia diagnosis. The significant independent predictors of radiograph-confirmed pneumonia were temperature >37.8°C (RR 2.6; 95% CI 1.5–4.8), crackles on auscultation (RR 1.8; 1.1–3.0), oxygen saturation <95% (RR 1.7; 1.0–3.1) and pulse >100·min–1 (RR 1.9; 1.1–3.2). Most patients with pneumonia (99/115, 86.1%) exhibited at least one of these four clinical signs; the positive predictive value of having at least one of these signs was 20.2% (95% CI 17.3–23.1). In routine practice, radiograph-confirmed pneumonia as a short-term complication of LRTI is very uncommon (one in 270). Pulse oximetry may aid the diagnosis of pneumonia in this setting. Pulse oximetry probably has a role in the diagnosis of pneumonia in the community http://ow.ly/QpWc30fVM2j

Response to Donner-Banzhoff

We would like to thank Donner-Banzhoff et al. for their thoughtful and careful response to our commentary. We are convinced that we share a common goal, which is to provide clinicians with reliable scientific information that will help them achieve the best possible outcome for their patients. Any study design that is able to contribute to this goal is to be welcomed. Further specification of the comprehensive diagnostic study and application of the concept to

CRP-test alleen bij acuut zieke kinderen met hoger risico

SamenvattingInleiding Een CRP-sneltest via een vingerprik zou de huisarts kunnen helpen bij het uitsluiten van een ernstige infectie bij kinderen. Wij onderzochten of we de sneltest bij alle kinderen moeten aanbieden of alleen bij kinderen met klinische risicofactoren.Methode We voerden een clustergerandomiseerd onderzoek uit onder acuut zieke kinderen die zich aanmeldden bij 133 huisartsen in 78 huisartspraktijken in België (3147 ziekte-episodes). We randomiseerden praktijken om een CRP-sneltest uit te voeren bij alle kinderen of alleen bij kinderen met klinische risicofactoren (kortademigheid, temperatuur ≥ 40 °C, diarree bij kinderen tussen 12 tot 30 maanden of een niet-pluisgevoel van de arts). De uitkomstmaat was ziekenhuisopname met een ernstige infectie binnen vijf dagen.Resultaten Als kinderen een CRP-test krijgen op basis van klinische risicofactoren, is zo’n test slechts nodig bij 20% van de kinderen. Er was tussen de twee onderzoeksgroepen geen verschil in het aantal kinderen met een ernstige infectie dat de huisartsen dadelijk naar het ziekenhuis verwezen (0,16% versus 0,14%, p = 0,88), of misten bij het eerste contact (0,29% versus 0,14%, p = 0,35). Elf kinderen hadden een ernstige infectie, van hen hadden er zes een CRP van minder dan 20 mg/L. Slechts een kind met een CRP < 5 mg/L had een ziekte die een opname rechtvaardigde.Conclusie De CRP-sneltest is alleen nuttig bij kinderen met klinische risicofactoren. Een CRP < 5 mg/L sluit een ernstige infectie uit en kan de huisarts helpen om onnodige verwijzingen te vermijden. Het klinische oordeel van de arts blijft essentieel, zelfs als een lage CRP-waarde een ernstige infectie lijkt uit te sluiten.