Date: March 18th, 2020
Reference: Ebell et al. Accuracy of Biomarkers for the Diagnosis of Adult Community-Acquired Pneumonia: A Meta-analysis. AEM March 2020
Guest Skeptic: Dr. Chris Bond is an emergency medicine physician and assistant Professor at the University of Calgary. He is also an avid FOAM supporter/producer through various online outlets including TheSGEM.
Disclaimer: This is Not an Episode on COVID19
Things are changing quickly with the COVID19 pandemic. Here are five basic things you can do to help flatten the curve as of this blogpost:
- Wash your hands well and often (at least 20 seconds with soap and water)
- Try not to touch your face
- Physically isolate yourself from large gatherings but stay socially connected electronically
- Cough into your elbow or use a tissue, throw the tissue out and go to #1
- Disinfect objects or surfaces with a regular household cleaning wipe or spray
If you are unsure of what to do or for more information, here are five websites to get up-to-date information about COVID19:
- Centre for Disease Control and Prevention
- Health Canada
- Public Health Ontario
- World Health Organization
- Food and Drug Administration
Case: A 47-year-old healthy, non-smoker, presents to the emergency department (ED) with a productive cough, fever and says it has been difficult to breathe for the past four days. He appears well, with a temperature of 38.7 Celsius, heart rate of 90 beats per minute, respiratory rate of 20 breaths per minute and room air oxygen saturation of 91%. On auscultation you hear some fine crackles at the bases. You wonder if there is value in ordering any bloodwork, particularly a biomarker such as C-reactive protein (CRP), procalcitonin (PCT) or a complete blood count for white blood cell count (WBC) in addition to doing a chest x-ray (CXR).
Background: Community-acquired pneumonia (CAP) is a significant source of morbidity and mortality in adults (1,2). We have covered this issue a couple of times on the SGEM. One episode looked at β-Lactam monotherapy vs. β-Lactam plus macrolide combination therapy in adult patients admitted to hospital with moderately severe CAP (SGEM#120). This study supported the combination therapy in these patients.
More recently, we looked at the question of whether steroids improve morbidity and mortality in patients admitted to hospital with CAP (SGEM#216). The bottom line was that corticosteroids appear to improve mortality and/or morbidity in patients admitted to hospital with CAP.
There is evidence that an accurate diagnosis of CAP may lead to earlier treatment while avoiding unnecessary antibiotics for patients who do not have CAP. Pervious research has demonstrated that individual signs and symptoms have limited accuracy in the diagnosis of CAP. The diagnosis of CAP is usually based on an abnormal chest x-ray in a patient with signs and symptoms of a lower respiratory tract infection (3,4).
White blood cell count (WBC), C-reactive protein (CRP), and procalcitonin are biomarkers associated with an increased likelihood of CAP. There are also clinical prediction rules that include CRP for the diagnosis of CAP (5,6).
Procalcitonin is another potential biomarker that may help in the diagnosis of bacterial pneumonia (7). Guidelines such as the National Institute for Health and Care Excellence (NICE) recommend the use of CRP at the point of care to reduce inappropriate antibiotic when diagnosing CAP (8) These various biomarkers are readily available in the ED setting in the US, as well as in the primary care setting in other countries in Europe.
The study we are reviewing on this SGEM episode performs an updated systematic review and meta-analysis (SRMA) of the diagnostic accuracy of biomarkers for CAP.
Clinical Question: What is the accuracy of biomarkers for the diagnosis of community acquired pneumonia?
Reference: Ebell et al. Accuracy of Biomarkers for the Diagnosis of Adult Community-Acquired Pneumonia: A Meta-analysis. AEM March 2020
- Population: Adult patients presenting with symptoms of acute respiratory infection and patients with clinically suspected pneumonia based on physician order of a chest radiograph, reporting sufficient information to calculate sensitivity and specificity for the diagnosis of CAP for at least one biomarker.
- Exclusions: Studies of dyspnea or sepsis rather than suspected CAP. Studies limited to patients with chronic lung disease, patients in skilled nursing facilities, or immunosuppressed/HIV patients. Ventilator or hospital acquired pneumonia. Studies of the diagnosis of a specific pathogen (i.e. mycoplasma or legionella). Studies that did not use a cohort design (i.e. recruited patients with known CAP and healthy controls).
- Intervention: C-reactive protein (CRP), procalcitonin or white blood cell (WBC) count
- Comparison: Chest imaging with CXR or CT scan
- Outcome: Diagnosis accuracy of biomarkers for pneumonia
This is an SGEMHOP episode which means we have the lead author on the show. Dr. Mark Ebell is a Family Physician and Professor at the University of Georgia in Athens. He is a co-founder of POEMs, editor-in-chief of Essential Evidence, deputy editor of American Family Physician, and co-host of the podcast Primary Care Update.
Authors’ Conclusions: Biomarkers can be useful for the diagnosis of community-acquired pneumonia. The cutoff chosen will determine whether the test is most useful for ruling out pneumonia (CRP < 10 or 20 mg/L) or for ruling in pneumonia (e.g., CRP > 50 or 100 mg/L). CRP is the most accurate of the three studied biomarkers that are currently being used to assist in the diagnosis of community acquired pneumonia. We note that CRP is inexpensive and readily available in many settings and may be easily integrated into the clinical workflow for diagnosis of community acquired pneumonia in appropriate patients.
Quality Checklist for Therapeutic Systematic Reviews:
- The clinical question is sensible and answerable. Yes
- The search for studies was detailed and exhaustive. Yes
- The primary studies were of high methodological quality. Yes
- The methodological quality of primary studies were assessed for bias. Yes
- The assessment of studies were reproducible. Yes
- The outcomes were clinically relevant. Yes
- There was low heterogeneity for estimates of sensitivity or specificity. No
- There was low statistical heterogeneity for the primary outcomes. No
- The treatment effect was large enough and precise enough to be clinically significant. Yes
Key Results: They screened 829 studies and found 14 that met inclusion and exclusion criteria with a total number of 6,599 patients. The study time periods ranged from 1986 to 2016, with 12 studies being performed in Europe, and one in each of the United States and Chile. Half of the studies were performed in ED patients and the other half in primary care settings.
CRP was studied in 13 of the 14 studies, PCT in seven and leukocytosis in five. One study used the combination of CRP and PCT.
Eight studies were felt to be at low risk of bias using the QUADAS-2 tool while six studies were felt to be at moderate risk of bias. None of the studies appeared to have been industry funded.
Key Result: Diagnostic accuracy for community acquired pneumonia was greatest with CRP.
All of these biomarkers have a threshold effect, meaning that sensitivity increases as specificity decreases. As a result, summary estimates of sensitivity, specificity and likelihood ratio are shown for different cutoffs for each test.
- Primary Outcome: Diagnostic accuracy of community acquired pneumonia
- C-Reactive Protein: A CRP cutoff of 10 mg/L had the highest sensitivity at 90% and lowest negative likelihood ratio of 0.27. CRP > 20 mg/L CRP > 50 mg/L and CRP > 100 mg/L had positive likelihood ratios of 2.08, 3.68 and 5.79 respectively, with poor negative likelihood ratios.
- Procalcitonin: PCT > 0.25 mcg/L and PCT > 0.50 mcg/L had good positive likelihood ratios (5.43 and 8.25 respectively), negative likelihood ratios were worse than for CRP
- Leukocytosis: This was defined as a white blood cell count (WBC) > 9.5 to 10.5 x 10^9 cells/L had modest accuracy (LR+ 3.15, LR- 0.54) with good homogeneity around this estimate.
We asked Mark five questions to get a greater understand of his publication. Listen to the SGEMHOP podcast to hear all of his answers.
1) External Validity: Less than 1/3 of patients came from the ED setting. This limits the application of these results to this clinical setting. The NICE guideline recommends the use of CRP in the primary care setting, presumably as a point of care test to help decide whether or not to order a CXR. Is this a rational use of resources in an ED setting where a CXR could be done as the initial test?
2) Point Estimates and 95% Confidence Intervals: There have been some conventional cut offs for likelihood ratios. None of the positive likelihood ratios were >10 to confidently rule in pneumonia and none of the negative likelihood rations were <0.1 to confidently rule out pneumonia. There were generally wide confidence intervals around the point estimates.
3) Post-Hoc Cut Offs: It is not clear in some of the studies used a post-hoc cutoff. We have discussed this before on the SGEM of potentially overfitting the data. How do you think this could affect your results and the interpretation?
4) Imperfect Gold Standard Bias (Copper Standard Bias):The biomarkers were compared to CXR in 13 of the 14 studies. We know that CXRs is less accurate in diagnosing CAP than a CT scan. How do you think that could have impacted the results?
5) Clinically Significant: A positive CXR does not mean a patient has a bacterial pneumonia. Prescribing antibiotics to patient with a viral pneumonia is unlikely to have a patient-oriented outcome (POO). Do you think this disease-oriented outcome (DOO) and not a POO is a problem?
Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree that biomarkers “can” be useful for diagnosis of CAP in the outpatient setting but are skeptical of their impact on the diagnosis of ED patients.
SGEM Bottom Line: Do not rely only upon a biomarker in the emergency department to rule in or rule out community acquired pneumonia.
Case Resolution: You order CXR which is reported by the radiologist as a “right lower lobe infiltrated consistent with early pneumonia, clinical correlation required”. You prescribe the antibiotic doxcycline and provide appropriate follow-up and discharge instructions.
Clinical Application: We are not going to use these biomarkers routinely to make the diagnosis of community acquired pneumonia in the emergency department.
What Do I Tell My Patient? It looks like you have a pneumonia in the base of your right lung on the CXR. Here is a prescription for an antibiotic. If it is a bacterial pneumonia the medicine should work. If it is a viral pneumonia the antibiotic is unlikely to help. Follow-up with your family physician next week. Return to the emergency department if you develop a rash, get increasing shortness of breath or are worried.
Keener Kontest: Last weeks’ winner was Dr. Kirby Black and EM physician from Oneida NY. They knew five possible reasons as to why Michael Jackson wore a mask in public: For anonymity, for infectious risk mitigation, to hide displeasure with complexion and facial plastic surgery, for anxiety and sense of personal breathing space and for continuity- started wearing for an above reason then liked how it was part of his style.
SGEMHOP: Now it is your turn SGEMers. What do you think of this episode on the diagnostic accuracy of biomarkers for community acquired pneumonia? Tweet your comments using #SGEMHOP. What questions do you have for Mark and his team? Ask them on the SGEM blog. The best social media feedback will be published in AEM.
Also, don’t forget those of you who are subscribers to Academic Emergency Medicine can head over to the AEM home page to get CME credit for this podcast and article. We will put the process on the SGEM blog:
- Go to the Wiley Health Learning website
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- Search for Academic Emergency Medicine – “March”
- Complete the five questions and submit your answers
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REMEMBER TO BE SKEPTICAL OF ANYTHING YOU LEARN, EVEN IF YOU HEARD IT ON THE SKEPTICS’ GUIDE TO EMERGENCY MEDICINE.
- Broulette et al. The incidence rate and economic burden of community-acquired pneumonia in a working-age population. Am Heal Drug Benefits 2013;6:494–50.
- Centers for Disease Control and Prevention. National Center for Health Statistics: Pneumonia. Available at: https://www.cdc.gov/nchs/fastats/pneumonia.htm. Accessed September 30, 2019.
- Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA 1997;278: 1440–5
- Mandell et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44 (Suppl 2):S27–72.
- Hopstaken et al. 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 Pr 2003;53:358–64.
- van Vugt et al. Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: diagnostic study. BMJ 2013; 346:f2450.
- Self et al. Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia. Clin Infect Dis 2017;65:183–90.
- National Institute for Health and Care Excellence. Pneumonia in Adults: Diagnosis and Management – NICE Guideline. London: Royal College of Physicians.