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Rapid Responses: Rapid Responses published:
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There comes the role of Physician
- Raghu S Raju (26 June 2005)
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CRP helps to exclude pneumonia
- Rogier Hopstaken, Rogier Hopstaken, Jochen Cals, and Geert-Jan Dinant (29 June 2005)
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The additional value of C reactive protein is uncertain
- Victor van der Meer, Willem J.J. Assendelft (6 July 2005)
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A different look at the same data
- Joshua P. Metlay (7 July 2005)
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Shall we wait for the perfect test?
- Hasse Melbye, Ralph Gonzales (7 July 2005)
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Diagnostic tests and antibiotics
- Anne Marie Oudesluys-Murphy, Annemarie van Rossum (12 July 2005)
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statistical versus clinical importance
- Ueli Bollag (18 July 2005)
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Response to Metlay and Melbye
- Victor van der Meer, Willem J.J. Assendelft (19 July 2005)
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Role of CRP in neonatal infection diagnosis
- zakir Shariff (20 July 2005)
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No evidence of effect instead of evidence of no effect
- Marc Jonkers (30 July 2005)
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Ethnographic studies required
- R Kumar (12 August 2005)
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Raghu S Raju, Doctor University Hospital of Wales, Heath Park, Cardiff, CF 14 4XW
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I agree with the authors about the ambiguous role of CRP in diagnosing infections of the lower respiratory tract or any infection for that matter. More often than not, CRP is used as an alternative to clinical decision making to evaluate the importance of patients' symptoms and their overall clinical presentation. It would be universally accepted that much bigger studies with better matched criteria are needed to assess the above argument. But, thats where the role of clnicians, their experience and their knowledge and skills comes. An experienced physician with sound clinical knowledge can predict the importance of patients' symptoms better than either a CRP or an ESR. Competing interests: None declared |
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Rogier Hopstaken, general practitioner, researcher Eindhoven, The Netherlands, 5605 LT, Rogier Hopstaken, Jochen Cals, and Geert-Jan Dinant
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According to the results - but not the conclusions - of the systematic review of van der Meer et al. C reactive protein appears to be very helpful in discriminating pneumonia from acute bronchitis in adults with a lower respiratory tract infection presenting in general practice. The relation of CRP with an infiltrate on chest radiography (reference standard) showed an area under the curve of 0.80, and even 0.85 for the studies that fulfilled the Lijmer criteria. We know that the accuracy of symptoms and signs in discriminating pneumonia from acute bronchitis in a patient with LRTI is very poor in general practice.[1 2] Classical symptoms and signs of pneumonia, derived from hospital studies, are of limited value in everyday general practice, because of the lower incidence and smaller extent of disease found there. Reviewing the accuracy of CRP as an isolated marker of LRTI would be comparable to evaluating only one finding of physical examination (e.g. abnormality on auscultation). The accuracy of a single CRP test is not 100%, but at least it appears to be much stronger than all findings from history-taking and physical examination. These results may have important implications. GPs may, in particular, be able to rule out pneumonia more accurately and could thus safely withhold unnecessary antibiotic prescriptions when CRP test results are low (e.g., <20 mg/l). This important message is unfortunately not reflected in the conclusions of the authors. References 1. Melbye H, Straume B, Aasebo U, Dale K. Diagnosis of pneumonia in adults in general practice. Relative importance of typical symptoms and abnormal chest signs evaluated against a radiographic reference standard. Scand J Prim Health Care 1992;10(3):226-33. 2. Hopstaken RM, Muris JWM, Knottnerus JA, Kester ADM, Rinkens PELM, 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. Competing interests: None declared |
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Victor van der Meer, junior researcher Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands, Willem J.J. Assendelft
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Hopstaken et al. hold the view that C reactive protein (CRP) is very helpful in excluding pneumonia. However our results, when applied to primary care, do not support this opinion. Exclusion of a diagnosis requires a sensitive test. In the discussion of our paper we consider the data of Melbye et al.[1] (a point right on the summary ROC curve). Although we find a high negative predictive value of 98.6%, we must bear in mind that the pre-test probability of a negative diagnosis is 95%, which means that in a low-prevalence situation the additional value of CRP is negligible. On the other hand, due to frequently reported low rates of specificity (see figure 2 of our systematic review), the CRP test would result in a considerably high rate of false positive tests, which in daily practice will most likely lead to considerable incorrect prescriptions of antibiotics. Whether the added value of CRP, being an imperfect test, will outweigh the potential negative side-effect of extra prescription due to false-positive tests can only be shown in clinical trials, evaluating the use of a CRP test in addition to a clinical prediction rule. As yet these trials are not available. 1. Melbye H, Straume B, Aasebo U, Brox J. Laboratory tests for pneumonia in general practice: the diagnostic values depend on the duration of illness. Scand J Prim Health Care 1992;19:234-40. Competing interests: None declared |
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Joshua P. Metlay, Physician, Assistant Professor VA Medical Center and University of Pennsylvania School of Medicine, Philadelphia PA 19104
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In a recent systematic review of the diagnostic value of C reactive protein in infections of the lower respiratory tract [1], the authors concluded that the evidence does not support the introduction of C reactive protein as a rapid test to guide antibiotic prescriptions. I disagree with this conclusion for several reasons. First, the analysis of C reactive protein as a stand-alone diagnostic test for community-acquired pneumonia is misguided. It is known that individual signs and symptoms have poor operating characteristics as diagnostic tests, but in combination they are much more useful [2]. As an example, temperature has poor operating characteristics as a stand-alone diagnostic test for pneumonia but, still, clinicians include a consideration of temperature in the overall assessment of the probability of pneumonia because it provides incremental information. The more useful question is whether any new test provides incremental diagnostic information. Recent studies by Flanders et al and Hopstaken et al found that C-reactive protein was significantly associated with radiographic pneumonia independent of clinical criteria [3, 4]. Second, the data are presented in a somewhat misleading manner. Presenting the range of sensitivities (from 10% to 98%) and range of specificities (from 44% to 99%) in both the abstract and results suggests that estimates of the diagnostic accuracy of the test are all over the place and, by implication, worthless. But these wide ranges reflect the results you would observe when you analyze a test over a range of cut-off points. All tests will display a similar sensitivity-specificity trade- off. This in no way is an indictment of the test. Indeed, it is clear that at the lowest cut-off points for C reactive protein, sensitivity is typically quite high and at the high cut-off points, specificity is very high. So, if appropriately incorporated into diagnostic algorithms, the information can be useful across the range of values. No one would expect a single cut-off point to both rule in and rule out a diagnosis even though the authors present a single example applying a cut-off value of 20 and demonstrate that (not surprisingly) the positive predictive value is poor. Third, the absence of information on the reference standards used to define pneumonia or bacterial lower respiratory tract infections is a major limitation. Chest radiography is an imperfect gold standard for diagnosing community-acquired pneumonia [5] and, similarly, the microbiological tests used have limited sensitivity and specificity. Therefore, the concept of false positives and false negatives is problematic when the gold standard is tarnished. From a practical standpoint, the true gold standard in this setting should be whether C reactive protein measurement contributes to the correct identification of antibiotic responsive illnesses, and in that regard, the data are encouraging. A minor additional point, Figure 3 is mislabeled. An ROC curve plots sensitivity against 1-specificity. References 1. van der Meer V, Neven AK, van den Broek PJ, Assendelft WJ. Diagnostic value of C reactive protein in infections of the lower respiratory tract: systematic review. Bmj 2005; 331(7507): 26. 2. Metlay JP, Fine MJ. Testing strategies in the initial management of patients with community-acquired pneumonia. Ann Intern Med 2003; 138(2): 109-18. 3. Flanders SA, Stein J, Shochat G, et al. Performance of a bedside C- reactive protein test in the diagnosis of community-acquired pneumonia in adults with acute cough. Am J Med 2004; 116(8): 529-35. 4. 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(490): 358-64. 5. Syrjala H, Broas M, Suramo I, Ojala A, Lahde S. High-resolution computed tomography for the diagnosis of community-acquired pneumonia. Clin Infect Dis 1998; 27(2): 358-63. Competing interests: None declared |
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Hasse Melbye, Professor of General Practice University of Tromsö, 9037 Tromsö, Norway, Ralph Gonzales
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One may dream about, and wait for, the perfect test for pneumonia, with a sensitivity and specificity close to 100%. The time to wait will probably be long. Even PCR, which can detect infinitesimally small numbers of microbes, does not distinguish between colonization and infection. Thus, in the current era, pneumonia is an anatomical diagnosis based on radiographic and clinical criteria. Pneumonia refers to infections due to a wide assortment of microbiological aetiologies, and the severity of pneumonia varies widely as a function of host and virulence factors. Several studies have clearly demonstrated that the clinical findings that doctors have relied on in their diagnosis of pneumonia, like crackles and coloured sputum, are of limited value.1-2 Although the most severe pneumonias usually, but not always, present with a classical clinical picture, the majority of pneumonias met in general practice are not clear cut. Even the best clinical prediction rules have positive posterior probabilities of only about 30 to 40 percent.3 New diagnostic measures are sorely needed. van der Meer and co-authors have clearly summarized our knowledge so far about the diagnostic characteristics of C-reactive protein (CRP).4 What surprises us is that, in spite of favourable test characteristics, which are far better than those of chest signs and symptoms, the authors do not support the use of the test. Of course, CRP is not the perfect pneumonia test. The CRP test only reflects the acute phase response, and must be interpreted within a clinical setting. The duration of illness has to be taken into account,5-6 and symptoms and signs are still crucial, albeit low specificity. A CRP value above 200 mg/l strongly predicts pneumonia in coughing adult patients, and no risk is usually taken by withholding antibiotics when the CRP value is normal (which is the case in the majority of coughing patients who have been ill more than a week). Although we still have a way to go to determine the optimal use and interpretation of the test, CRP testing has been shown to be associated with lower rates of antibiotic prescriptions,7 a feat not easily accomplished with educational interventions.8 Prospective evaluations of management algorithms that combine CRP with clinical criteria are needed to assess the impact of CRP testing on other outcomes of interest—such as duration of office visit, chest X-ray utilization and return office visits.9 We should not rely on, nor can we afford to wait for, the perfect test. 1. Diehr P, Wood RW, Bushyhead J, Krueger L, Wolcott B, Tompkins RK. Prediction of pneumonia in outpatients with acute cough--a statistical approach. J Chronic Dis 1984;37:215-25. 2. Hopstaken RM, Muris JW, Knottnerus JA, 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. 3. Metlay JP, Fine MJ. Testing strategies in the initial management of patients with community-acquired pneumonia. Ann Intern Med 2003;138:109 -18. 4. van der Meer V, Neven AK, van der Broek, Assendelft WJJ. Diagnostic value of C reactice protein in infections of the lower respiratory tract: a systematic review. BMJ 2005: 331 …….. 5. Melbye H, Hvidsten D, Holm A, Nordbo SA, Brox J. The course of C- reactive protein response in untreated upper respiratory tract infection.Br J Gen Pract 2004;54:653-8. 6. Melbye H, Straume B, Aasebo U, Dale K. Laboratory tests for pneumonia in general practice: the diagnostic values depend on the duration of illness. Scand J Prim Health Care 1992;10:234-40. 7. Andre M, Schwan A, Odenholt I, Swedish Study Group on Antibiotic Use. The use of CRP tests in patients with respiratory tract infections in primary care in Sweden can be questioned. Scand J Infect Dis 2004;36:192- 7. 8. Gonzales R, Sauaia A, Corbett KK, Maselli JH, Erbacher K, Leeman- Castillo BA et al. Antibiotic treatment of acute respiratory tract infections in the elderly: effect of a multidimensional educational intervention. J Am Geriatr Soc 2004;52:39-45. 9. Flanders SA, Stein J, Shochat G, Sellers K, Holland M, Maselli J et al. Performance of a bedside C-reactive protein test in the diagnosis of community-acquired pneumonia in adults with acute cough. Am J Med 2004;116:529-35. Competing interests: None declared |
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Anne Marie Oudesluys-Murphy, Paediatrician Leids Universitair Medisch Centrum, Albinusdreef 2, 2300 RC Leiden , The Netherlands, Annemarie van Rossum
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Dear Sir, We read the paper by van der Meer et al. with great interest (1). They assessed the value of C reactive protein (CRP) in detecting radiologically proven pneumonia and evaluated how well CRP can differentiate between bacterial and viral infections of the lower respiratory tract. They conclude that the current evidence does not support a wide introduction of CRP as a rapid test to guide prescription of antibiotics. We, also, have attempted to seek a reliable, sensitive and specific test to answer this question in children. We looked at the possibility that procalcitonin may provide the answer (2). Procalcitonin is a 116- aminoacid peptide and one of the precursors of calcitonin. Increases in procalcitonin occur more rapidly than increases in CRP. This rapid and specific induction of procalcitonin after an adequate stimulus and the high and reliable production of procalcitonin in patients with severe bacterial infections or sepsis suggest a pathophysiological function of procalcitonin in the acute immune response. In bacterial infections, procalcitonin levels increase from values in the picogram range to levels ranging from 1 to 1000ng/mL. In our review of the literature procalcitonin was found to be an excellent marker for severe bacterial infections in general. However, it was difficult to be clear about its value in lower respiratory tract infections in children. We included 6 studies on the use of procalcitonin as a marker of bacterial causes of lower respiratory infections. Three of these studies concluded that procalcitonin differentiates between bacterial and viral infections more effectively than CRP, white blood cell count or interleukin –6 in emergency department settings ( 3,4,5). Three other studies stated that measurement of procalcitonin is of little value in differentiating between bacterial and viral pneumonia (6,7,8). Results of studies on markers of infection depend on the accuracy of the aetiological diagnosis of lower respiratory infection. Diagnostic work-up varied between the studies, as was also noted by van der Meer et al (1). Also the use of antibiotics before enrolment into the studies could be a major confounding factor. However, studies on respiratory tract infections in adults show the value of procalcitonin measurements more clearly. A recent prospective, cluster-randomised, controlled, single- blinded intervention trial by Christ-Crain et al. found that procalcitonin guidance significantly reduced the use of antibiotics in adults with lower respiratory tract infections (9). In the procalcitonin group the proportion of patients with lower respiratory tract infections who received antibiotics was reduced by 47% compared with the standard group. It is clear from the study of van der Meer et al. (1) that CRP is not a suitable test to guide antibiotic prescription in lower respiratory infections. We suggest it may be worthwhile to consider the use of procalcitonin in these situations. References 1. van der Meer V, Neven AK, van den Broek J. Assendelft WJJ. Diagnostic value of C reactive protein in infections of the lower respiratory tract: systemic review. BMJ, doi:10.1136/bmj.38483.478183.EB 2. van Rossum AMC, Wulkan RW, Oudesluys-Murphy AM. Procalcitonin as an early marker of infection in neonates and children. Lancet Inf Dis 2004;4:620-30 3. Prat C, Dominguez J, Rodrigo C, et al. Procalcitonin, C-reactive protein and leukocyte count in children with lower respiratory tract infection. Pediatr Infect Dis J 2003;22: 963-68 4. Hatzistilianou M, Hitoglou S, Gougoustamou D, et al. Serum procalcitonin, adenosine deaminase and its isoenzymes in the aetiological diagnosis of pneumonia in children. Int J Immunopathol Pharmacol 2002; 15: 119-27 5. Moulin F, Raymond J, Lorrot M, et al. Procalcitonin in children admitted to hospital with community acquired pneumonia. Arch Dis Child 2001; 84: 332-36 6. Korppi M, Remes S, Heiskanen –Kosma T. Serum procalcitonin concentrations in bacterial pneumonia in children; a negative result in primary healthcare settings. Pediatr Pulmonol 2003; 35: 56-61 7. Korppi M, Remes S. Serum procalcitonin in pneumococcal pneumonia in children. Eur Respir J. 2001;17: 623-27 8. Toikka P, Irjala K, Juven T et al. Serum procalcitonin, C-reactive protein and interleukin-6 for distinguishing bacterial and viral pneumonia in children. Pediatr Infect Dis 2000; 19: 598-602 9. Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet 2004; 363: 600-7 Competing interests: None declared |
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Ueli Bollag, practitioner 3012 Berne, Switzerland
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Re: Victor van der Meer, et al. Diagnostic value of C reactive protein in infections of the lower respiratory tract: systematic review. BMJ 2005;331:26-29. C reactive protein (CRP) is used by the practitioner as a marker for infection and disease activity, and as a diagnostic adjunct. Patients who present with the typical symptoms and signs of lower respiratory tract infection are physically examined and a temptative diagnosis is established on the basis of the clinical findings, fever, cough, chest pain, and extrapulmonary symptoms (headache, malaise, myalgias, sore throat, gastrointestinal distress). The age and environmental history are also taken into consideration. Pneumonia can be diagnosed from clinical symptoms and signs. A CXR is not needed in many instances. CRP will be determined only when the clinical picture is not clear or when the doctor feels insecure or is urged to undertake additional investigations for non- medical reasons. Antibiotics will be prescribed or not according to the sum of all the above, but never routinely. Systematic reviews are in fashion. Searching the data-bases from different providers according to a predetermined list of subject headings and text words serves the investigator to dissect the articles which have been retrieved. Articles and material which do not fit all criteria are excluded from further analysis. Statistics usually are of a complex nature and cannot be grasped by the practitioner in full detail. The problem is compounded when researchers focus on the wrong questions. No sensible clinician will ever use the CRP to detect signs of pulmonary consolidation or infiltrates on CXR. Ueli Bollag, paediatric and general practitioner u.bollag@bluewin.ch Competing interests: None declared |
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Victor van der Meer, junior researcher Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands, Willem J.J. Assendelft
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Metlay raises some methodological issues regarding our review (1, 2). He states that we can’t conclude on heterogeneity of sensitivities and specificities based on the ROC-curve, since this curve represents various cut-off points of C reactive protein. However, as shown in figure 2, we have also aggregated the data for every single cut-off point. This figure shows that also for separate cut-off points the sensitivity and specificity differ widely between the reported studies. In our discussion paragraph we chose an example with a cut-off point from a study with a favourable sensitivity and sensitivity . However, even this cut-off point does not provide satisfying diagnostic information. Although presentation of a high cut-off point would result in better positive predictive values (at the cost of the negative predictive value), we can unfortunately not yet determine the optimal cut-off point for use in clinical practice. With regard to the reference standards, Metlay considers the absence of information a major limitation. In our review we chose a chest radiograph as a reference standard, because this is at present still considered the reference standard in international guidelines. (3) The limitations of microbiological work-up are evident. This reference standard should, however, not be regarded as a gold standard. Our results reflect the poor association of C reactive protein with the outcomes of this other diagnostic tool. Finally, the strenght of a systematic review is that is summarizes all available evidence, taking into account the methodological quality of the studies. On the basis of the currently available studies we still conclude that the diagnostic value of C reactive protein in lower respiratory tract infection is limited. This doesn’t mean that we should wait for the perfect test, as remarked by professor Melbye (4). However, we should also not feel obliged to use a test which additional value is uncertain. 1. Metlay JP. A different look at the same data http://bmj.bmjjournals.com/cgi/eletters/331/7507/26#111570 2. Van der Meer V, Knuistingh Neven A, Van den Broek PJ, Assendelft WJJ. Diagnostic value of C reactive protein in infections of the lower respiratory tract: systematic review. BMJ 2005;331:26-9. 3. BTS Standards of Care Committee. BTS guidelines for the management of community acquired pneumonia in adults. Thorax 2001;56(Suppl IV):iv1–64. 4. Melbye H, Gonzales R. Shall we wait for the perfect test? http://bmj.bmjjournals.com/cgi/eletters/331/7507/26#111611 Competing interests: None declared |
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zakir Shariff, SHO, Plastic Surgery, Preston. PR2 9HT
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Sir, It was interesting to note that CRP was not very sensitive in prediction or absence of lower respiratory tract infection. There was an interesting study done in neonates infection which showed Serial CRP levels are useful in the diagnostic evaluation of neonates with suspected infection. Two CRP levels <1 mg/dL obtained 24 hours apart, 8 to 48 hours after presentation, indicate that bacterial infection is unlikely. I think CRP could be used as a method of exclusion, rather than a sole predector of infection Ref: 1.William E. Benitz, Michael Y. Han, Ashima Madan, and Pramela Ramachandra:Serial Serum C-Reactive Protein Levels in the Diagnosis of Neonatal Infection, PEDIATRICS Vol. 102 No. 4 October 1998, p. e41 Competing interests: None declared |
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Marc Jonkers, pediatrician Amphia Hospital Breda 4819EV The Netherlands
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A clinician can use C-reactive proteïne as a diagnostic tool in a strategy to increase certainty on the presence or absence of pneumonia. Victor van der Meer et.al. asked themselves if there is evidence in literature that CRP is an accurate tool. In a systematic review and meta- analysis way they try to deterimine accuracy cut-off points for CRP. They conclude that methodological quality of the individual studies is generaly poor. Combined with the heterogeneity between the studies (fig. 2) we must be very careful to draw conclusions to answer the primary question on the accuracy of CRP. The authors rightly conclude there is insufficient evidence in literature to support this strategy. From here it can be confusing to readers and apparently also the editor who writes "what this study adds". It is important to realise that here is an essential and subtle difference between what we call “no evidence of effect and the evidence of no effect”. So the evidence is insufficient not jet the strategy of using CRP. That means that we must not stop using (serial) CRP in patients suspected to have pneumonia but we have to generate high quality diagnostic research on this subject. Competing interests: None declared |
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R Kumar, Paediatrics Preston, UK PR2
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I find CRP levels have more uses in clinical decision-making than the obviously binary ie. "CRP high, therefore bacterial, therefore I must start antibiotics" vs. "CRP low, therefore viral, therefore I will withhold antibiotics". Quantitative research studies unfortunately tend to favour this sort of binary outcome, single goal-of-testing paradigm. As an example, in young infants with a pyrexial illness, it is often not possible to initially identify the focus of infection: pharyngitis, pneumonia, meningitis and urinary tract infection may all present similarly. When I see a markedly raised CRP without obvious focus, I will request more invasive or specialised tests to look for the source of infection. I think there is a need for qualitative research or audit, looking at how CRP is actually used in clinical practice, who it is requested in and why, who it is not, did it affect management, etc. This will be required particularly if we are considering introducing new tests such as serum procalcitonin. Competing interests: CRP levels influence my clinical decision-making. |
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