Respiratory tract infections (RTIs) in primary care: narrative review of C reactive protein (CRP) point-of-care testing (POCT) and antibacterial use in patients who present with symptoms of RTI.

Antimicrobial resistance (AMR) continues to be a global problem and continues to be addressed through national strategies to improve diagnostics, develop new antimicrobials and promote antimicrobial stewardship. Patients who attend general (ambulatory) practice with symptoms of respiratory tract infections (RTIs) are invariably assessed by some sort of clinical decision rule (CDR). However, CDRs rely on a cluster of non-specific clinical observations. A narrative review of the literature was undertaken to ascertain the value of C reactive protein (CRP) point-of-care testing (POCT) to guide antibacterial prescribing in adult patients presenting to general practitioner (GP) practices with symptoms of RTI. Studies that were included were Cochrane reviews, systematic reviews, randomised controlled trials, cluster randomised trials, controlled before and after studies, cohort studies and economic evaluations. An overwhelming number of studies demonstrated that the use of CRP tests in patients presenting with RTI symptoms reduces index antibacterial prescribing. GPs and patients report a good acceptability for a CRP POCT and economic evaluations show cost-effectiveness of CRP POCT over existing RTI management in primary care. POCTs increase diagnostic precision for GPs in the better management of patients with RTI. With the rapid development of artificial intelligence, patients will expect greater precision in diagnosing and managing their illnesses. Adopting systems that markedly reduce antibiotic consumption is a no-brainer for governments that are struggling to address the rise in AMR.

Economic considerations support C-reactive protein testing alongside malaria rapid diagnostic tests to guide antimicrobial therapy for patients with febrile illness in settings with low malaria endemicity.

Malaria is no longer a common cause of febrile illness in many regions of the tropics. In part, this success is a result of improved access to accurate diagnosis and effective anti-malarial treatment, including in many hard-to-reach rural areas. However, in these settings, management of other causes of febrile illness remains challenging. Health systems are often weak and other than malaria rapid tests no other diagnostics are available. With millions of deaths occurring annually due to treatable bacterial infections and the ever increasing spread of antimicrobial resistance, improvement in the management of febrile illness is a global public health priority. Whilst numerous promising point-of-care diagnostics are in the pipeline, substantial progress can be made in the interim with existing tools: C-reactive protein (CRP) is a highly sensitive and moderately specific biomarker of bacterial infection and has been in clinical use for these purposes for decades, with dozens of low-cost devices commercially available. This paper takes a health-economics approach to consider the possible advantages of CRP point-of-care tests alongside rapid diagnostic tests for malaria, potentially in a single multiplex device, to guide antimicrobial therapy for patients with febrile illness. Three rudimentary assessments of the costs and benefits of this approach all indicate that this is likely to be cost-effective when considering the incremental costs of the CRP tests as compared with either (i) the improved health outcomes for patients with bacterial illnesses; (ii) the costs of antimicrobial resistance averted; or (iii) the economic benefits of better management of remaining malaria cases and shorter malaria elimination campaigns in areas of low transmission. While CRP-guided antibiotic therapy alone cannot resolve all challenges associated with management of febrile illness in remote tropical settings, in the short-term a multiplexed CRP and malaria RDT could be highly cost-effective and utilize the well-established funding and distribution systems already in place for malaria RDTs. These findings should spark further interest amongst industry, academics and policy-makers in the development and deployment of such diagnostics, and discussion on their geographically appropriate use.

Socio-economic inequalities in C-reactive protein levels: Evidence from longitudinal studies in England and Indonesia.

OBJECTIVE: The levels of health enjoyed by individuals vary according to socio-economic status, and inflammation has been proposed as one pathway through which socio-economic status influences health in high-income countries. However, little is known regarding the social determinants of inflammation in low- and middle-income countries. This study investigated the association between socio-economic status and C-reactive protein (CRP) in England and Indonesia. METHODS: This study used data from 4923 respondents aged 50+ in the English Longitudinal Study of Ageing and from 1812 respondents from the Indonesian Family Life Survey at baseline. The sources of information on individuals' education attainment, wealth, CRP and other covariates were ELSA Waves 2, 4 and 6, and IFLS Waves 4 and 5. Linear mixed models were performed to identify the longitudinal relationships between socio-economic status and CRP, and joint models were used to deal with bias in longitudinal ageing surveys due to attrition. RESULTS: Respondents with high school education (ß = -0.036, p < 0.01) or college degree or higher (ß = -0.127, p < 0.01) in England had lower CRP levels. Being wealthy is correlated with lower CRP levels in England (middle: ß = -0.073, p < 0.01; wealthiest: ß = -0.133, p < 0.01). Being wealthy and having higher education were related with higher level of CRP in Indonesia. However, those significant relationships vanished when health behaviour and health status were included in the analysis. CONCLUSIONS: The relationships between socio-economic status and CRP proved to be different in England and Indonesia. Encouraging healthy lifestyles among older adults with low socio-economic status may be the main focus of efforts toward healthy ageing in England and other developed countries. However, in Indonesia and other developing countries, attention is also required to older adults in wealthier socio-economic groups.

Comparing the cost-effectiveness of four novel risk markers for screening asymptomatic individuals to prevent cardiovascular disease (CVD) in the US population.

BACKGROUND: High sensitivity CRP (hsCRP), coronary artery calcification on CT (CT calcium), carotid artery intima media thickness on ultrasound (cIMT) and ankle-brachial index (ABI) improve prediction of cardiovascular disease (CVD) risk, but the benefit of screening with these novel risk markers in the U.S. population is unclear. METHODS AND RESULTS: A microsimulation model evaluating lifelong cost-effectiveness for individuals aged 40-85 at intermediate risk of CVD, using 2003-2004 NHANES-III (N=3736), Framingham Heart Study, U.S. Vital Statistics, meta-analyses of independent predictive effects of the four novel risk markers and treatment effects was constructed. Using both an intention-to-treat (assumes adherence <100% and incorporates disutility from taking daily medications) and an as-treated (100% adherence and no disutility) analysis, quality adjusted life years (QALYs), lifetime costs (2014 US $), and incremental cost-effectiveness ratios (ICER in $/QALY gained) of screening with hsCRP, CT coronary calcium, cIMT and ABI were established compared with current practice, full adherence to current guidelines, and ubiquitous statin therapy. In the intention-to-treat analysis in men, screening with CT calcium was cost effective ($32,900/QALY) compared with current practice. In women, screening with hsCRP was cost effective ($32,467/QALY). In the as-treated analysis, statin therapy was both more effective and less costly than all other strategies for both men and women. CONCLUSIONS: When a substantial disutility from taking daily medication is assumed, screening men with CT coronary calcium is likely to be cost-effective whereas screening with hsCRP has value in women. The individual perceived disutility for taking daily medication should play a key role in the decision.

Cost-effectiveness of point-of-care C-reactive protein tests for respiratory tract infection in primary care in England.

INTRODUCTION: Despite recommendations that general practitioners (GPs) delay antibiotic prescribing for respiratory tract infections (RTIs), antibiotic prescriptions in primary care in England increased by 4.1% from 2010 to 2013. C-reactive protein (CRP) point-of-care tests (POCT), for example, the Afinion™ Analyzer (Alere Ltd, Stockport, UK) device, are widely used in several countries in the European Union. Studies suggest that CRP POCT use, either alone or in combination with communication training, reduces antibiotic prescribing and improves quality of life for patients presenting with RTI symptoms. The aim of this study is to evaluate the cost-effectiveness of CRP POCT for RTIs in primary care in England over 3 years for three different strategies of care compared to standard practice. METHODS: An economic evaluation was carried out to compare the costs and benefits of three different strategies of CRP testing (GP plus CRP; practice nurse plus CRP; and GP plus CRP and communication training) for patients with RTI symptoms as defined by National Institute for Health and Care Excellence guideline CG69, compared with current standard GP practice without CRP testing. Analysis consisted of a decision tree and Markov model to describe the quality-adjusted life years (QALYs) and cost per 100 patients, together with the number of antibiotic prescriptions and RTIs for each group. RESULTS: Compared with current standard practice, the GP plus CRP and practice nurse plus CRP test strategies result in increased QALYs and reduced costs, while the GP plus CRP testing and communication training strategy is associated with increased costs and reduced QALYs. Additionally, all three CRP arms led to fewer antibiotic prescriptions and infections over 3 years. CONCLUSION: The additional cost per patient of the CRP test is outweighed by the associated cost savings and QALY increment associated with a reduction in infections in the long term.

Clinical relevance of procalcitonin and C-reactive protein as infection markers in renal impairment: a cross-sectional study.

INTRODUCTION: Although the clinical application of procalcitonin (PCT) as an infection marker in patients with impaired renal function (estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m(2)) has been increasing recently, it is unclear whether PCT is more accurate than C-reactive protein (CRP). We investigated the clinical value of CRP and PCT based on renal function. METHODS: From November 2008 to July 2011, a total of 493 patients who simultaneously underwent CRP and PCT tests were enrolled. The area under the receiver operating characteristic (ROC) curve and characteristics of both markers were analyzed according to infection severity and renal function. RESULTS: In patients with impaired renal function, the area under the ROC curve was 0.876 for CRP and 0.876 for PCT. In patients with infection, CRP levels differed depending on whether the infection was localized, septic, or severely septic, whereas PCT levels were higher in patients with severe sepsis or septic shock. In patients without infection, CRP did not correlate with eGFR, while PCT was negatively correlated with eGFR. CONCLUSION: This study demonstrates that CRP is accurate for predicting infection in patients with impaired renal function. The study suggests that in spite of its higher cost, PCT is not superior to CRP as an infection marker in terms of diagnostic value.

Current analytical strategies for C-reactive protein quantification in blood.

The measurement of serum C-reactive protein (CRP) levels has been given particular interest as a marker of inflammation associated with cardiovascular diseases. CRP belongs to the pentraxin family of proteins and the routine clinical analysis of CRP in blood samples is used as an important factor in primary prevention programmes together with causative and predisposing factors. This review focuses on the most representative methodologies and strategies for CRP detection and quantification that have been recently proposed, as well as reviewing those that are currently being developed for the specific, sensitive, inexpensive and high-throughput blood analysis of this protein.

[CRP in the management of bacterial infections in emergency]. / Utilité du dosage de la CRP pour la prise en charge des infections bactériennes aux urgences.

OBJECTIVES: To assess the interest of measuring CRP in emergency for diagnosing bacterial infections and making decisions about antibiotics and to compare its practical usefulness with clinicians' conclusions. METHODS: Systematic CRP measurements in 80 consecutive patients admitted to emergency ward with possible bacterial infection. RESULTS: were not transmitted to the physician in charge. Patients' files were analyzed retrospectively in two phases. In phase 1, two senior physicians assessed the diagnosis and need for antibiotics on the basis of the admission (emergency unit) files. In phase 2, a panel of experts examined the complete files (including discharge notes) to determine the likelihood of infection (obvious or probable, unlikely or excluded) and appropriateness of emergency antibiotics. Their recommendations were used as the standard, against which the usefulness of the laboratory indicators (including CRP) and decisions of the emergency physicians were assessed. ROC curves were used to determine threshold values for CRP and body temperature. We then calculated the sensitivity, positive predictive value and negative predictive value of these cutoffs and compared them with those for the phase 1 clinician recommendations. RESULTS: The study included 76 patients (mean age: 74 years): 28 presented obvious or possible infections and 21 required emergency antibiotic therapy. Mean leukocyte values did not differ between groups. For diagnosis, the threshold value of CRP was 85 mg/L and of body temperature 37.8 degrees C; for prescribing antibiotics, the values were 130 mg/L and 38 degrees C, respectively. The sensitivity, specificity, negative and positive predictive values of CRP were, respectively, 79, 81, 76, and 83% for diagnosis of bacterial infection and 71, 71, 48 and 87% for prescription of an emergency antibiotic. These values were lower than those of clinician's conclusions. CONCLUSION: Because of the variability in the thresholds used in its interpretation, the lack of specificity, and its poor predictive value for treatment decisions, CRP is of little interest in the diagnosis and treatment of patients with bacterial infections in intensive care. The cost generated by this examination is therefore not justified.

Medical-economical aspects of high sensitivity C-reactive protein assay for the prediction of coronary heart disease. An analysis in Germany and Italy.

BACKGROUND: Elevated plasma concentrations of C-reactive protein (CRP) are associated with increased cardiovascular risk. We studied the cost-effectiveness of CRP determination in primary and secondary prevention settings in two European countries: Germany and Italy. METHODS: Using a decision analytic model we evaluated the costs and consequences of testing or not testing using a high sensitivity (hs)-CRP assay. In a primary prevention model we analyzed a hypothetical cohort of 300000 apparently healthy men divided into three age groups (35-44, 45-54 and 55-64 years). Individuals with CRP levels > 3 mg/l were administered either aspirin or statins according to lipid levels. The cohort was followed for 5 years. In the secondary prevention model hs-CRP testing was evaluated in a cohort of 10000 patients with total cholesterol levels < 4.52 mmol/l and a history of myocardial infarction or unstable angina. The two strategies tested were: 1) administer pravastatin only to those with high CRP values, and 2) treat all patients. The analysis was performed from the societal perspective. Event rates were obtained from epidemiological studies and clinical trials. RESULTS: In the primary prevention model, strategies including testing showed, for men aged 45 years and older, cost-effectiveness ratios between each life year saved (LYS) and cost savings in Germany equal to 10217euro and between each LYS and savings in Italy equal to 16950euro In the age group 35-44 years, therapy with aspirin showed cost-effectiveness ratios of 5318euro and 11203euro per LYS in Germany and in Italy respectively. The widespread use of statins showed an unfavorable cost-effectiveness profile: 44630euro per LYS in Germany and 36270euro per LYS in Italy. In the secondary prevention model, hs-testing for CRP can reduce the cost-effectiveness of pravastatin from 16400 to 6830euro per quality adjusted life year gained. Sensitivity analysis performed on the variables test price and costs of cardiovascular events resulted in minimal changes of the cost-effectiveness ratios. CONCLUSIONS: Both in the primary and the secondary prevention settings, hs-testing for CRP can better target individuals at higher risk, thus improving outcomes and resulting in a more cost-effective strategy.