Abstract
Background: After excluding pulmonary embolism (PE) with an unlikely Wells-decision rule and a negative D-dimer test, the general practitioner still has to differentiate between clinically relevant and clinically non-relevant diseases accounting for the presented symptoms. A negative D-dimer test makes clinically relevant disease less likely. The C-reactive protein (CRP) test could be of additional value to make this differentiation.
Objectives: To assess whether an unlikely Wells-decision rule in combination with a negative point of care D-dimer test not only can safely exclude PE but also, in combination with a negative CRP-test, any other clinically relevant disease.
Methods: We used data of a prospective study including 598 primary care patients suspected of pulmonary embolism. We included all patients, referred to secondary care for reference testing, with an unlikely Wells-decision rule and a negative point of care D-dimer test. We included 191 patients and imputed the CRP-test results in 60 patients. Alternative diagnoses were divided in clinically relevant diseases and clinically non-relevant diseases. A ROC-curve was constructed to determine the optimal CRP-cut-off.
Results: The optimal CRP cut-off value appeared to be 10 mg/l. A total of 116 patients had a CRP < 10 mg/l of whom 12 patients (10%) had a clinically relevant disease. Two patients (2%) needed hospital admission. A total of 75 patients had a CRP ≥ 10 mg/l of whom 32 patients (43%) had a clinically relevant disease. Fifteen patients (20%) were admitted to hospital.
Conclusion: The CRP-test is enhancing diagnostic decision making in patients in whom the general practitioner excluded PE.
KEY MESSAGE:
In patients in whom the general practitioner excluded pulmonary embolism combining an unlikely Wells- decision rule and a negative D-dimer test, the CRP-test can further reduce the number of clinically relevant alternative diagnoses.
INTRODUCTION
In patients consulting their general practitioner (GP) with symptoms suggestive of pulmonary embolism (PE), such as sudden unexplained dyspnoea, deterioration of existing dyspnoea, pain on inspiration or unexplained cough symptoms, the GP can apply a diagnostic strategy using the Wells PE decision rule in combination with a point of care (POC) D-dimer test. The Wells clinical decision rule stratifies patients with suspected pulmonary embolism into patients with a high probability and patients with a low probability of having pulmonary embolism. The following seven variables and assigned scores (in brackets) are included in the rule: clinical symptoms of deep venous thrombosis (DVT) (3.0), alternative diagnosis less likely than PE (3.0), heart rate more than 100 beats per minute (1.5), immobilization (of more than three days) or surgery in the previous four weeks (1.5), previous DVT or PE (1.5), haemoptysis (1.0) and malignancy (1.0) (Citation1). Patients with either a likely result of the Wells-rule (score > 4) or a positive D-dimer test will be referred to secondary care for further diagnostic testing. In patients with an unlikely result of the Wells-rule (score ≤ 4) and a negative POC D-dimer test the GP can safely exclude PE (Citation2).
After excluding PE, the GP might still face a diagnostic challenge. Non-life threatening causes (e.g. musculoskeletal pain) of the symptoms are common, but clinically important disorders, some of which require appropriate treatment or referral, such as acute coronary syndrome or pneumonia must not be overlooked (Citation3). For GPs working in daily clinical practice, empirical data concerning diagnostic probabilities of patients presenting with acute dyspnoea or (pleuritic) chest pain are scarce (Citation4–7).
D-dimer levels are elevated in venous thrombo-embolism as well as in many other conditions and disorders. Some of these disorders could account for the presented symptoms of (pleuritic) chest pain, dyspnoea or cough. Elevated D-dimer concentrations have been reported in patients with acute coronary syndrome, heart failure and in patients with community acquired pneumonia (Citation8–15). Using D-dimer tests in excluding venous thrombo-embolism is an accepted method (Citation16,Citation17). A negative D-dimer test is also a useful tool to exclude acute aortic dissection safely, can be used to identify candidates at low risk for pneumonia complications, and might exclude other clinically important disorders as well (Citation18–20).
In the further diagnostic work-up of patients with an unlikely PE-decision rule, combined with a negative D-dimer test, the CRP-test could be of additional value in excluding other clinically important disorders. C-reactive protein (CRP) is an acute phase protein with levels quickly rising with inflammatory processes like pneumonia (Citation21). Both CRP-tests and D-dimer tests are available as point of care tests which make them feasible for usage in primary care.
In this study performed with primary care patients suspected of PE we assessed whether an unlikely Wells-clinical decision rule in combination with a negative D-dimer test not only could safely exclude PE but also, in combination with a negative CRP-test, any other clinically relevant disease.
METHODS
Design and methodology
General design. We analysed data from a prospective cohort study including 598 primary care patients suspected of PE. This study, executed in the Netherlands between 1 July 2007 and 31 December 2010, evaluated a diagnostic strategy consisting of the Wells PE-rule and a point of care D-dimer test. The characteristics of the study are described in detail elsewhere (Citation2).
Primary care. Consecutive adults (≥ 18 years) in whom the GP suspected PE were included. The GP obtained written informed consent and documented systematically information on the patient's history and physical examination. The GP calculated the score of the Wells-rule and performed a qualitative point of care D-dimer test (Clearview Simplify, Inverness Medical, Bedford, UK). Regardless of the outcome of the Wells PE-rule and D-dimer test, we asked GPs to refer all patients to secondary care for reference testing.
Secondary care. In secondary care, doctors were asked to carry out the diagnostic procedures at their own discretion based on local hospital guidelines and independent of the results from primary care. During three months of follow-up we asked GPs to document the final diagnosis of every patient. Medical information was retrieved from the GP about the investigations done to establish a diagnosis, including hospital discharge letters.
Additional data for this study. Data on alternative diagnosis and CRP-values were retrieved from the hospital discharge letter or from the three months follow-up form filled out by the GP. For the present analysis we included all patients with a Wells decision rule-score ≤ 4 and a negative D-dimer test.
Alternative diagnoses
Alternative diagnoses were divided in three categories:
Clinically relevant objective disease (CROD): disease diagnosed by a doctor and confirmed with one of the following methods: (a) Pneumonia: infiltrate on chest radiograph or CT-scan (Citation22); (b) Pneumothorax: visceral pleural line on the chest radiograph; (c) Pleuritis: a pleural friction rub with auscultation and/or pleural effusion on the chest radiograph (Citation23); (d) Pericarditis: a pericardial rub with auscultation and/or pericardial effusion with echocardiography and/or typical electrocardiography changes; (e) Atelectasis: as diagnosed on the chest radiograph; (f) Heart failure: increased natriuretic peptides (BNP or NT-proBNP) and abnormalities with echocardiography as seen in heart failure (Citation24); (g) Asthma/COPD: (i) Newly diagnosed: on the basis of patient history and physical examination and/or lung function test and prescribed bronchodilator or corticosteroid medication; (ii) Exacerbation: deterioration in symptoms in known asthma/COPD-patient and deterioration in lung function or change in medication (oral corticosteroids, inhalation Beta2-agonists or antibiotics) (Citation25); (h) Lung cancer: confirmed with histopathology; (i) Other clinical relevant diseases: as assessed by the study-investigators.
Clinically relevant subjective disease (CRSD): (a) Disease diagnosed by a doctor but not confirmed with any of the above methods; (b) A diagnosis of respiratory tract infection treated with antibiotics but without an infiltrate on the chest radiograph was included in this category.
Non-clinically relevant diagnosis: Any diagnosis made by a doctor but not included in the above list and not leading to any treatment other than supportive care (i.e. pain-killing in case of musculoskeletal chest pain).
Two investigators (MK and WL) assessed both three-month follow-up forms and hospital discharge letters and assigned patients to one of the three above categories without knowledge of the CRP-results. In case of disagreement a third investigator (HvW) was involved and disagreements were resolved by discussion. The primary outcome of the study was the prevalence of clinically relevant disease, both objective and subjective.
Statistical analysis
Missing values. Missing values for the Wells rule items were observed in one patient. Missing values for the D-dimer test result were observed in eight patients (4.1%). We also were confronted with missing values for the CRP-test result in 60 of 191 study-patients (31%) due to the fact that the CRP-test was ordered at the discretion of the attending doctor in secondary care. Lack of data seldom occurs completely at random. Deleting subjects with a missing value does not only lead to a loss of statistical power but also to biased results. Comparing patients with and without CRP-results showed significantly more CRP-results in hospital-admitted patients (). Imputing missing values is generally preferred to complete case analysis (Citation26,Citation27). We imputed missing values for the Wells-rule items, D-dimer test and the CRP-test using multiple imputation techniques (Citation28). Imputation techniques are based on the correlation between each variable with missing values and all other variables as estimated from the set of complete subjects.
Table 1. Comparison of study-patients with and without missing information on CRP-test results.
Diagnostic parameters. A receiver operating characteristic (ROC) curve of the CRP-test was constructed and the optimal cut-off value of the CRP-test was determined. We calculated the sensitivity, the specificity, the negative predictive value and the positive predictive value of the CRP-test for clinically relevant disease in patients with an unlikely Wells-rule and a negative D-dimer test.
Statistical testing. Corresponding 95% confidence intervals were calculated using Confidence Interval Analysis (CIA, version 1.0; Gardner MJ). For statistical differences we used the Chi-square-test for dichotomous variables and the independent samples t-test for continuous variables. All statistical analyses were done using the Statistical Package for the Social Sciences Software (version 18; SPSS, Chicago, IL, USA).
RESULTS
We included 272 patients with a Wells-score ≤ 4 and a negative qualitative Simplify-D-dimer test. A total of 79 patients (29%) were not referred for reference testing to secondary care and were excluded from further analysis. In two patients, not diagnosed with pulmonary embolism, the final diagnosis was missing, leaving 191 patients for the current analysis (: Flow-chart). Mean age of the study population was 45 years and 70% were female. (: Characteristics of study participants). With the constructed ROC-curve we determined the optimal cut-off value of the CRP-test which appeared to be 10 mg/l ().
Figure 1. Flow-chart.
Figure 2. ROC-curve of the CRP-test.
Table 2. Characteristics of study participants (n = 191).
Alternative diagnoses
Doctors in secondary care diagnosed 44 of the 191 patients (23%) with a clinically relevant disease including four patients with pulmonary embolism (failure of the negative Wells PE-rule/negative D-dimer test-strategy). In 116 of 191 patients (61%) the CRP-value was below 10 mg/l. Twelve (10%) of those 116 patients had a clinically relevant disease, including one patient with pulmonary embolism (). Two of these 12 patients needed admission to hospital (2%, one patient with Kahler's disease (multiple myeloma), one patient with pulmonary embolism). From the remaining 75 patients with a CRP ≥ 10 mg/l, 32 patients had a clinically relevant disease (43%) of whom 15 (20%) were admitted to hospital ().
Table 3. Disease and CRP in study-patients (n = 191).
Table 4. Clinically relevant disease and hospital admission.
Diagnostic performance of the CRP-test
Sensitivity and specificity of the CRP test in patients with an unlikely Wells-rule and a negative point-of-care Simplify D-dimer test for any clinically relevant disease (including pulmonary embolism) was 73% (95% CI: 57–85%) and 71% (95% CI: 63–78%), respectively. The negative predictive value was 90% (95% CI: 84–95%), the positive predictive value 43% (95% CI: 31–55%) ().
Table 5. Clinically relevant disease (CRD) and CRP-value.
DISCUSSION
Main findings
In patients suspected of pulmonary embolism the general practitioner can safely exclude PE with an unlikely Wells pulmonary embolism decision rule (score ≤ 4) and a negative D-Dimer test (Citation2). However after excluding PE the question remains whether the patient is suffering from any other clinically relevant disease. In this secondary analysis of data from a large prospective study performed in primary care, we determined the negative predictive value of a strategy using the Wells rule and a point of care D-Dimer test, followed by a CRP-test for excluding any clinically relevant alternative disease (Citation2). Secondary care doctors diagnosed 12 of the 116 CRP-negative-patients (10%) with clinically relevant disease as opposed to 32 of the 75 CRP-positive-patients (43%). Moreover, just two of the 12 CRP-negative patients with a clinically relevant disease needed admission to the hospital as opposed to 15 of the 32 CRP-positive patients with a clinically relevant disease.
Limitations
Firstly, in secondary care reference testing was based on routine clinical practice. Not all patients underwent the same reference testing, leading to differential verification. Moreover, results will be influenced by incorporation bias which means that the index test (CRP-test) is part of the reference standard (Citation29). Doctors working in secondary care were not blinded for results of the CRP-test and in fact made use of the CRP-test in diagnosing or refuting a clinically relevant disease. Lijmer et al demonstrated that both differential verification and incorporation bias can affect (often overestimate) the diagnostic performance of an index test (Citation30).
Secondly, as this was not a management study and the study relied on local hospital guidelines the CRP-test was ordered at the discretion of the attending doctor and only performed in a selected group of patients. As a result the CRP-test results were missing in about one third of study patients. We imputed these values according to methodological guidelines. In comparing patients with known CRP-results and patients with imputed CRP-results, we could not detect significant differences in prevalence of clinically relevant disease ().
Thirdly, 79 patients were excluded from our study because the GP did not refer those patients for reference testing in secondary care. In those 79 patients GPs diagnosed 13 out of 71 patients (18%) with a clinically relevant disease, admitted no patient to the hospital, and in eight patients the final diagnosis was missing. Those eight patients had no venous thrombo-embolism in three months follow-up. Obviously, the GP felt confident after history and physical examination (if necessary with additional laboratory, chest X-ray or ECG) to take care of the patient in primary care. Although selection bias seems obvious the prevalence of clinically relevant disease in those patients (18%) and study patients (23%) was comparable.
Previous literature
A secondary care-study in patients suspected of PE showed that non-specific chest-pain is the most frequent alternative diagnosis (63%). Other patients had a variety of diagnoses of which bronchopneumonia was the most frequent (6%). Angina pectoris was diagnosed in only 2% of the patients (Citation3). In our study-population no patients were diagnosed with acute coronary syndrome. An elevated CRP-level is associated strongly with pneumonia (Citation22). We observed that all 16 patients diagnosed with pneumonia had elevated CRP-levels (mean CRP 91 mg/l, range: 19–224 mg/l). Strikingly three out of four patients diagnosed with pulmonary embolism (failure of the PE-strategy) had a positive CRP-test (mean CRP 18 mg/l, range: 4–33 mg/l). Two studies both evaluating the diagnostic value of a standard CRP-test at a cut-off level of 5 mg/l in excluding pulmonary embolism demonstrated a relatively modest sensitivity of 84% not allowing a safe exclusion of PE and a sensitivity of 95.7%, potentially useful for excluding PE, respectively (Citation31,Citation32).
Implications
After the exclusion of PE using a negative Wells-CDR and a negative D-dimer test the patient could still be suffering from a clinically relevant alternative disease. In 116 patients with CRP < 10 mg/l only 12 patients (10%) were diagnosed with clinically relevant disease of whom just two needed admission to hospital. The general practitioner might be able to further manage the patient with the use of a (point of care) CRP-test to reduce the risk of having a clinically relevant alternative disease in patients with a CRP < 10 mg/l. Future research on excluding PE should examine the additional value of the CRP-test in a prospective diagnostic study in primary care, preferably using both a point of care D-dimer test and a point of care CRP-test, thereby making this strategy applicable to primary care.
Conclusion
The CRP-test may be useful in excluding clinically relevant disease in patients in whom the general practitioner excluded PE.
FUNDING
The study was funded by the Dutch Heart Foundation (project number No. 2006B237). The funding source had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES
- Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: Increasing the models utility with the SimpliRED D-dimer. Thromb Haemost. 2000; 83:416–20.
- Geersing GJ, Erkens PM, Lucassen WA, Buller HR, Cate HT, Hoes AW, et al. Safe exclusion of pulmonary embolism using the Wells rule and qualitative D-dimer testing in primary care: Prospective cohort study. Br Med J. 2012;345:e6564.
- Bernard BS, Bounameaux H, Perneger T, Perrier A. Suspicion of pulmonary embolism in outpatients: Nonspecific chest pain is the most frequent alternative diagnosis. J Intern Med. 2004;256: 153–60.
- Charles J, Ng A, Britt H. Presentations of shortness of breath in Australian general practice. Aust Fam Physician 2005;34: 520–1.
- Bosner S, Becker A, Haasenritter J, Abu HM, Keller H, Sonnichsen AC, et al. Chest pain in primary care: Epidemiology and pre-work-up probabilities. Eur J Gen Pract. 2009;15:141–6.
- Klinkman MS, Stevens D, Gorenflo DW. Episodes of care for chest pain: A preliminary report from MIRNET. Michigan Research Network. J Fam Pract. 1994;38:345–52.
- Ruigomez A, Rodriguez LA, Wallander MA, Johansson S, Jones R. Chest pain in general practice: Incidence, comorbidity and mortality. Fam Pract. 2006;23:167–74.
- Querol-Ribelles JM, Tenias JM, Grau E, Querol-Borras JM, Climent JL, Gomez E, et al. Plasma d-dimer levels correlate with outcomes in patients with community-acquired pneumonia. Chest 2004;126:1087–92.
- Castro DJ, Perez-Rodriguez E, Montaner L, Flores J, Nuevo GD. Diagnostic value of D dimer in pulmonary embolism and pneumonia. Respiration 2001;68:371–5.
- Guneysel O, Pirmit S, Karakurt S. Plasma d-dimer levels increase with the severity of community acquired pneumonia. Tuberk Toraks 2004;52:341–7.
- Arslan S, Ugurlu S, Bulut G, Akkurt I. The association between plasma D-dimer levels and community-acquired pneumonia. Clinics (Sao Paulo) 2010;65:593–7.
- Jug B, Vene N, Salobir BG, Sebestjen M, Sabovic M, Keber I. Procoagulant state in heart failure with preserved left ventricular ejection fraction. Int Heart J. 2009;50:591–600.
- Tokita Y, Kusama Y, Kodani E, Tadera T, Nakagomi A, Atarashi H, et al. Utility of rapid D-dimer measurement for screening of acute cardiovascular disease in the emergency setting. J Cardiol. 2009;53:334–40.
- Bayes-Genis A, Mateo J, Santalo M, Oliver A, Guindo J, Badimon L, et al. D-Dimer is an early diagnostic marker of coronary ischemia in patients with chest pain. Am Heart J. 2000; 140:379–84.
- Kruskal JB, Commerford PJ, Franks JJ, Kirsch RE. Fibrin and fibrinogen-related antigens in patients with stable and unstable coronary artery disease. N Engl J Med. 1987;317:1361–5.
- Di Nisio NM, Squizzato A, Rutjes AW, Buller HR, Zwinderman AH, Bossuyt PM. Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: A systematic review. J Thromb Haemost. 2007;5:296–304.
- Righini M, Perrier A, De MP, Bounameaux H. D-Dimer for venous thromboembolism diagnosis: 20 years later. J Thromb Haemost. 2008;6:1059–71.
- Shimony A, Filion KB, Mottillo S, Dourian T, Eisenberg MJ. Meta-analysis of usefulness of D-dimer to diagnose acute aortic dissection. Am J Cardiol. 2011;107:1227–34.
- Snijders D, Schoorl M, Schoorl M, Bartels PC, van der Werf TS, Boersma WG. D-dimer levels in assessing severity and clinical outcome in patients with community-acquired pneumonia. A secondary analysis of a randomised clinical trial. Eur J Intern Med. 2012;23:436–41.
- Chalmers JD, Singanayagam A, Scally C, Hill AT. Admission D-dimer can identify low-risk patients with community-acquired pneumonia. Ann Emerg Med. 2009;53:633–8.
- Cals JW, Schot MJ, de Jong SA, Dinant GJ, Hopstaken RM. Point-of-care C-reactive protein testing and antibiotic prescribing for respiratory tract infections: A randomized controlled trial. Ann Fam Med. 2010;8:124–33.
- Hopstaken RM, Muris JW, Knottnerus JA, Kester AD, Rinkens PE, Dinant GJ. Contributions of symptoms, signs, erythrocyte sedimentation rate, and C-reactive protein to a diagnosis of pneumonia in acute lower respiratory tract infection. Br J Gen Pract. 2003;53:358–64.
- Kass SM, Williams PM, Reamy BV. Pleurisy. Am Fam Physician 2007;75:1357–64.
- Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008;29:2388–442.
- Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An official American Thoracic Society/ European Respiratory Society statement: Asthma control and exacerbations: Standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180:59–99.
- Janssen KJ, Donders AR, Harrell FE, Jr, Vergouwe Y, Chen Q, Grobbee DE, et al. Missing covariate data in medical research: to impute is better than to ignore. J Clin Epidemiol. 2010;63:721–7.
- Donders AR, van der Heijden GJ, Stijnen T, Moons KG. Review: A gentle introduction to imputation of missing values. J Clin Epidemiol. 2006;59:1087–91.
- Rubin DB, Schenker N. Multiple imputation in health-care databases: An overview and some applications. Stat Med. 1991; 10:585–98.
- Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al. QUADAS-2: A revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155:529–36.
- Lijmer JG, Mol BW, Heisterkamp S, Bonsel GJ, Prins MH, van der Meulen JH, et al. Empirical evidence of design-related bias in studies of diagnostic tests. J Am Med Assoc. 1999;282: 1061–6.
- Aujesky D, Hayoz D, Yersin B, Perrier A, Barghouth G, Schnyder P, et al. Exclusion of pulmonary embolism using C-reactive protein and D-dimer. A prospective comparison. Thromb Haemost. 2003; 90:1198–203.
- Steeghs N, Goekoop RJ, Niessen RW, Jonkers GJ, Dik H, Huisman MV. C-reactive protein and D-dimer with clinical probability score in the exclusion of pulmonary embolism. Br J Haematol. 2005;130:614–9.