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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 1320-1325, (2002)
© 2002 American Thoracic Society

CRITICAL CARE PERSPECTIVE

Effect of Design-related Bias in Studies of Diagnostic Tests for Ventilator-associated Pneumonia

Sophie Michaud, Sadao Suzuki and Stephan Harbarth

Medical Faculty of the University of Sherbrooke, Sherbrooke, Quebec, Canada; Harvard School of Public Health, Boston, Massachusetts; and University of Geneva Hospitals, Geneva, Switzerland

Correspondence and requests for reprints should be addressed to Sophie Michaud, M.D., M.P.H., C.S.P.Q., F.R.C.P.(C)., Department of Microbiology and Infectious Diseases, Medical Faculty of the University of Sherbrooke, 3001, 12th Avenue North, Sherbrooke, PQ, J1H 5N4 Canada. E-mail: sophie.michaud{at}usherbrooke.ca

Numerous studies have evaluated the performance of bronchoscopic and nonbronchoscopic procedures for the diagnosis of ventilator-associated pneumonia (VAP) (1–4). Nevertheless, controversy persists about the optimal diagnostic strategy for VAP (5–10). In the absence of a gold standard, the true accuracy of the various diagnostic procedures for VAP remains unknown. Moreover, the interpretation of the sensitivity and specificity of any given sampling technique may be severely hampered by the distorting effect of previous antibiotic exposure on the yield of bacterial cultures. Therefore, comparing the diagnostic performance of these techniques is a complex task.

Despite the absence of a perfect gold standard, efforts have been made to standardize criteria for evaluating diagnostic techniques for VAP. As a result of an international consensus conference in 1992, a group of experts issued a set of criteria to guide investigators in selecting appropriate patients for clinical investigation of VAP (11). These patient selection criteria included new and persistent infiltrates, grossly purulent tracheobronchial secretions, a fever of more than 38.3°C, leukocytosis, and deterioration of gas exchange. The experts also established a working definition of VAP by which new diagnostic techniques should be compared (hereafter referred to as the diagnostic consensus criteria; see Table E1 in the online data supplement). Finally, they recommended the injection of 140 ml or more of saline when performing bronchoalveolar lavage (BAL) (12).

Using these guidelines, we performed a meta-analysis to evaluate how study design and previous antibiotic exposure influence the reported accuracy of protected specimen brush (PSB), BAL, endotracheal aspirates (EA), and intracellular organisms count (ICO) in mechanically ventilated, nonimmunocompromised adults with suspected VAP.

METHODS

Studies were identified through a MEDLINE search (English, French, and German; January 1979–September 1999) using combinations of these index terms: pneumonia, ventilation, protected specimen brush, bronchoalveolar lavage, endotracheal aspirate, intracellular organisms, bronchoscopy, diagnostic tests, and receiver operating characteristic (ROC) curve. We scanned the references of all retrieved articles, including reviews, editorials, abstracts, book chapters, and clinical studies.

We screened prospective studies evaluating at least one diagnostic procedure (quantitative cultures of PSB, BAL, or EA, or percentage of ICO) in mechanically ventilated, nonimmunocompromised adults with suspected VAP. We considered only studies reporting the sensitivity and specificity of the test(s) or from which we could reconstruct 2 x 2 contingency tables. The exclusion criteria were as follows: failure to mention clearly defined criteria for VAP, inclusion of community-acquired pneumonia or of nonintubated patients, restriction to patients without pneumonia or to immunocompromised hosts only, exclusive assessment of patient outcomes or of a test's reproducibility, or the use of quantitative culture results to exclude adult respiratory distress syndrome. To avoid any incorporation bias (13), we excluded studies using a positive quantitative culture of PSB, BAL, or protected BAL specimen as a valid diagnostic criterion for VAP. Patients with an uncertain diagnosis or with a pulmonary infection caused by Aspergillus spp., Mycobacterium tuberculosis, Legionella pneumophila, or Pneumocystis carinii were also excluded. The study selection and data extraction were accomplished independently by at least two readers, with adjudication by a third reader if disagreement occurred.

The methodologic features of each study were assessed by comparing the patient selection and diagnostic criteria to the consensus recommendations. We sought to construct four contingency tables for each test: (1) all patients aggregated, (2) patients with no antibiotic therapy for 24 hours or more before respiratory sampling (no antibiotics), (3) patients with prior antibiotic therapy started more than 48 hours before respiratory sampling (former antibiotics), and (4) patients with antibiotic therapy either started or changed 48 hours or more before respiratory sampling (recent antibiotics). Whenever possible, we used a test positivity threshold of 103 cfu/ml for PSB, 104 cfu/ml for BAL, 105 cfu/ml for EA, and 5% for the ICO count.

The diagnostic accuracy of each test was assessed using summary ROC curves (14). An ROC curve graphically represents the true-positive rate (sensitivity) and the false-positive rate (1-specificity) of a diagnostic test when the threshold is varied. Similarly, in a summary ROC curve, each point (true-positive rate, false-positive rate) represents a single study using a specific diagnostic threshold.

Q* value is a summary measure of a test's discriminative ability and represents the intersection between the summary ROC curve and the line sensitivity = specificity, which slopes from the left superior corner to the right inferior corner (14, 15). The greater the Q* value, the more discriminative is the test: a Q* value of 1.0 indicates a perfect test, and a Q* value of 0.5 indicates a nondiscriminative test.

We constructed summary ROC curves and calculated Q* values for each test using unweighted models (15). To evaluate the heterogeneity among the studies, Q* values were calculated for different subgroups, based on patient selection criteria, diagnostic criteria, BAL volume, and previous antibiotic exposure. Q* values were also calculated for studies using histopathologic procedures (biopsy or autopsy) that were in agreement with the diagnostic consensus criteria, as they theoretically represent the best studies in terms of gold standard. Q* values of statistically independent studies were compared in the light of their standard errors. All statistical tests were two tailed, and calculations were done using SAS version 6.12.

RESULTS

We identified 177 relevant articles from the literature search; 129 studies were selected, of which 103 were excluded (see Table E2 in the online data supplement). Thus, 26 studies were used to evaluate the following diagnostic procedures: quantitative cultures of PSB, 21 studies (1,016 suspected episodes of VAP); quantitative cultures of BAL, 17 studies (855 episodes); percentage of ICO, 10 studies (477 episodes); and quantitative cultures of EA, seven studies (308 episodes).

Overview of the Methodologic Characteristics of the Studies
The characteristics of the studies are summarized in Table 1 . Fifteen studies satisfied the patient selection criteria proposed by the consensus statement. Six studies included only patients who died while on mechanical ventilation (16–21), and two studies included a control group of noninfected patients (22, 23). Nineteen studies did not meet the diagnostic criteria proposed by the consensus statement; this was mainly due to a delay of more than 3 days between the diagnostic and the histopathologic procedures or to the use, as a valid diagnostic criterion, of a clinical suspicion of VAP followed by a favorable clinical evolution after antibiotic therapy. Only one study satisfied both the patient selection and diagnostic consensus criteria (24). Finally, only 6 of 19 studies used a minimum of 140 ml of saline for BAL.


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  		TABLE 1. Descriptive summary of the included studies

 
Assessment of Antibiotic Exposure
Table E3 (online data supplement) summarizes the antibiotic exposure data of each study for all patients aggregated and for the three antibiotic exposure groups described in the METHODS section. Six studies did not provide detailed patient-level information about antibiotic exposure (21, 25–29). Nine studies did not specify the timing of the antibiotic therapy relative to respiratory sampling (16, 17, 20, 22, 24, 30–33).

Global Comparison of the Tests and Subgroup Analyses
Table 2 (see expanded version of the this in Table E4 of the online data supplement) displays the crude Q* value for each test, as well as for each analyzed subgroup. Overall, PSB had the highest Q* value (0.85), followed by ICO (0.79), BAL (0.72), and EA (0.71). Nevertheless, subgroup analyses of methodologic characteristics revealed substantial heterogeneity among the studies. For each test, the Q* values were systematically lower in studies not fulfilling the consensus criteria on patient selection and, inversely, systematically higher in studies not meeting the consensus diagnostic criteria. Finally, the performance of BAL was significantly lower in studies using a saline volume inferior to 140 ml (p = 0.023).


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  		TABLE 2. Crude and subgroup analyses of the performance of diagnostic tests for ventilator-associated pneumonia*

 
Analysis of antibiotic exposure suggested heterogeneity among the patients as well. There was a systematic difference between the Q* values of the no-antibiotics and the recent-antibiotics groups and that, for each of the four diagnostic tests. In the no-antibiotics group, PSB had the highest Q* value (0.87), followed by ICO (0.79), BAL (0.78), and EA (0.71). In contrast, in the recent-antibiotics group, Q* values ranged between 0.65 and 0.71 for all tests, and no procedure appeared superior to the others. Finally, among patients having received antibiotics before respiratory sampling, the performance of diagnostic tests was generally better in the former-antibiotics group than in the recent-antibiotics group.

Stratified Analyses
After stratification, diagnostic criteria had no effect on the Q* values for PSB, BAL, and ICO in studies not satisfying the patient selection consensus criteria (Table 3A) (see Table E5A in the online data supplement). Furthermore, a BAL volume inferior to 140 ml was still associated with a significantly lower Q* value in studies meeting the consensus criteria on patient selection (p = 0.003; Table 3B) (see Table E5B in the online data supplement).


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  		TABLE 3. Stratified analyses

 
When comparing the performance of diagnostic tests in studies in agreement with the patient selection consensus criteria (see Figure E1 in the online data supplement), PSB, BAL (using a BAL volume of 140 ml or more), and ICO all seemed of comparable and high accuracy (Q* = 0.92–0.94), in contrast with the performance of EA, which appeared much lower (Q* = 0.72).

Postmortem Studies
In total, seven studies used histopathologic procedures consistent with the diagnostic consensus criteria (i.e., procedures types 1 and 2 in Table 1). All studies but one (24) included patients who died while on mechanical ventilation (in whom pneumonia was not necessarily suspected), and only one study (24) used a BAL volume of 140 ml or more. In these studies, Q* values were comparably low for all three tests: PSB (Q* = 0.75), BAL (Q* = 0.62), and ICO (Q* = 0.79) (see Table E6 in the online data supplement).

DISCUSSION

The literature contains a large number of potential biases in the evaluation of diagnostic tests; however, quantification and understanding of the effect of design-related bias in studies of diagnostic tests can bring important insights about the conditions yielding the best diagnostic effectiveness. Our meta-analysis suggests that patient selection criteria, BAL volume, and previous antibiotic exposure may have a substantial effect on the reported accuracy of diagnostic tests for VAP. These findings might explain, at least in part, the variation in the performance of diagnostic tests observed among studies published over the last 20 years. More importantly, such information can be key for clinical decisions and for the design, reporting practice, and critical appraisal of future studies.

Patient selection criteria appeared to have the most important effect on the measurement of a test's performance. Q* values were systematically lower in studies not satisfying the patient selection criteria issued by the consensus statement, even after stratifying on diagnostic criteria or BAL volume. This suggests the presence of a spectrum bias, which is due to differences between the population in which a test's performance is measured and the population in which it will be used. Most of the studies not satisfying the patient selection consensus criteria included patients with no clinical suspicion of VAP. This might have caused an increase of false-positive test results and thereby lower Q* values.

Insufficient fluid volume for BAL constitutes another source of misclassification bias. Q* values were significantly lower in studies using less than 140 ml of saline, supporting the recommendation of the consensus statement. An inadequately obtained specimen might result in a false-negative culture, thereby underestimating the accuracy of BAL for diagnosing VAP.

We noticed considerable heterogeneity among the diagnostic criteria used in the studies. In the context of an imperfect gold standard for VAP, several misclassification biases might have occurred in either direction. In the subgroup analyses, Q* values were systematically higher in studies not satisfying the diagnostic consensus criteria; however, this effect disappeared in the stratified analyses, suggesting the presence of confounding by patient selection criteria.

Because there is no accepted "gold standard" for diagnosing VAP (9), we based our meta-analysis on the assumption that the diagnostic consensus criteria are currently the best reference standard available for clinical practice; however, some authors have suggested that the combination of both histology and microbiology might represent the most reasonable reference for validating diagnostic methods (34). We thus performed a subgroup analysis among postmortem studies, which showed comparably low Q* values for PSB, BAL, and ICO. Although they theoretically represent the best studies in terms of gold standard, most of these studies did not meet the patient selection consensus criteria nor used a BAL volume of 140 ml or more, which were two factors previously shown to have a major impact on Q* values. Therefore, these postmortem studies do not necessarily reflect the real accuracy of the diagnostic tests for VAP.

Finally, the subgroup analyses identified previous antibiotic exposure as an effect modifier on the performance of diagnostic tests for VAP. Q* values were substantially lower in patients having recently received antibiotics for any diagnostic procedure. In contrast, current antibiotic therapy introduced for reasons unrelated to the suspected VAP did not affect the diagnostic yield of most tests. These results must be interpreted with caution, as the presence of residual bias and/or confounding cannot be excluded. Because many studies did not specify the timing of antibiotic therapy relative to respiratory sampling, some patients with antibiotic therapy started more than 48 hours before the diagnostic procedure might have been erroneously classified in the recent-antibiotics group. To evaluate the direction of this possible bias, we pooled the recent and former antibiotics groups and recalculated the Q* value for each test. The resulting Q* values (PSB, 0.74; BAL, 0.76; and ICO, 0.84) were systematically higher than those of the recent-antibiotics group. This suggests that misclassification of patients with former antibiotic therapy within the recent-antibiotics group could lead to an overestimation of the Q* values in the latter category. Therefore, in patients having recently received antibiotics, the real test's performance could be even lower than what we found.

Souweine and colleagues (35) recommended the use of lower diagnostic thresholds in patients who have recently been started on new antibiotic therapy; unfortunately, we were unable to validate this recommendation as many studies did not provide patient-level data on antibiotic exposure. Some studies, however, suggest that using a lower threshold to define a positive PSB or BAL in such a setting may be inaccurate because follow-up cultures can be completely negative in 28% of true cases of VAP after only 12 hours of treatment (36) and in 65% after 48 hours (9, 37, 38). Among the remaining positive cases, the procedure can miss up to 50% of the species involved, and this trend increases in later samples. Similar results were obtained in quantitative cultures of samples of pulmonary tissue recovered immediately postmortem (17, 19). These data point to the need to obtain respiratory samples well before the introduction of the antibiotic (9, 39); otherwise, the quantitative thresholds lose their discriminatory value.

A recent meta-analysis (40) comparing the diagnostic value of PSB, BAL, and ICO suggested that prior administration of antibiotics markedly decreases the accuracy of PSB, but not of BAL; therefore, the authors recommended the use of BAL, rather than PSB, for patients receiving antibiotic therapy. However, the meta-analysis did not distinguish between previous antibiotic therapy unrelated to suspected VAP and antibiotic treatment started within the last 48 hours before respiratory sampling. Any reference standard was considered adequate for the diagnosis of VAP, and no quantitative evaluation of the heterogeneity among the studies was performed. Our results do not support these earlier findings, although our primary goal was not to provide the reader with a definitive statement about the accuracy of the different tests. Nevertheless, we showed that bias, confounding, and effect modification can dramatically influence the diagnostic performance of the examined tests and should be taken into account when pooling the results of different studies.

The impact of the diagnostic strategy on the clinical outcome of patients with suspected VAP remains a controversial issue (10). Among the four randomized trials recently published (41–44), three Spanish studies could not find any difference with regard to mortality and morbidity when either invasive (PSB and/or BAL) or noninvasive (EA) techniques were used to diagnose VAP. In contrast, a multicenter French study (43) found a bronchoscopic strategy, including quantitative cultures of PSB and/or BAL, to be superior compared with a clinical strategy using qualitative EA in terms of 14-day mortality, morbidity, and use of antimicrobial treatment. Although our study did not aim to resolve this very important question, the identification of the conditions yielding the best diagnostic effectiveness may help in the design of future outcome studies.

Based on our results, we make the following recommendations:

  1. Studies on diagnostic tests for VAP should be performed on patients with clinical suspicion of pneumonia (see PATIENT SELECTION CONSENSUS CRITERIA).
  2. The diagnostic consensus criteria represent the best reference standard currently available for clinical practice; however, studies evaluating the accuracy of diagnostic tests should not include the test results as part of the definition of pneumonia.
  3. A BAL volume of 140 ml or more should be used to obtain a higher diagnostic yield.
  4. The performance of diagnostic tests is lower in patients who have been recently started on new antibiotic therapy. Pulmonary secretions therefore need to be obtained before new antibiotics are administered.
  5. Studies should provide detailed patient-level information on the type, duration, and timing of antibiotic therapy relative to respiratory sampling.
  6. More high-quality studies are needed to evaluate the performance of quantitative cultures of EA to diagnose VAP.
  7. Finally, clinicians should be aware of the possible consequences of biases, confounding, and effect modification on the measured accuracy of diagnostic tests.

Previous Presentations
This was presented in part at the 4th Decennial International Conference on Nosocomial and Healthcare-associated Infections, March 5–9, 2000, Atlanta, GA (abstract P-M2-40), and at the 11th Annual Scientific Meeting of the Society for Healthcare Epidemiology of America, April 1–3, 2001, Toronto, Canada (abstract 75).

Acknowledgments

The authors thank Dr. Bertrand Souweine for critically reading a previous version of the manuscript and Dr. Jacques Lacroix for providing additional patient-level information obtained from several authors.

FOOTNOTES

This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Received in original form February 20, 2002; accepted in final form September 9, 2002

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Diagnosis of Ventilator-Associated Pneumonia: Focus on Nonbronchoscopic Techniques (Nonbronchoscopic Bronchoalveolar Lavage, Including Mini-BAL, Blinded Protected Specimen Brush, and Blinded Bronchial Sampling) and Endotracheal Aspirates.
J Intensive Care Med, January 1, 2006; 21(1): 17 - 21.
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 Am. J. Respir. Crit. Care Med.Home page
Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare-associated Pneumonia
Am. J. Respir. Crit. Care Med., February 15, 2005; 171(4): 388 - 416.
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 Am. J. Respir. Crit. Care Med.Home page
D. E. Ost, C. S. Hall, G. Joseph, C. Ginocchio, S. Condon, E. Kao, M. LaRusso, R. Itzla, and A. M. Fein
Decision Analysis of Antibiotic and Diagnostic Strategies in Ventilator-associated Pneumonia
Am. J. Respir. Crit. Care Med., November 1, 2003; 168(9): 1060 - 1067.
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 Am. J. Respir. Crit. Care Med.Home page
M. J. Tobin
Writing a Review Article for AJRCCM
Am. J. Respir. Crit. Care Med., October 1, 2003; 168(7): 732 - 734.
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 Am. J. Respir. Crit. Care Med.Home page
P. Eggimann, S. Harbarth, B. Ricou, S. Hugonnet, K. Ferriere, P. Suter, and D. Pittet
Acute Respiratory Distress Syndrome after Bacteremic Sepsis Does Not Increase Mortality
Am. J. Respir. Crit. Care Med., May 1, 2003; 167(9): 1210 - 1214.
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M. J. Tobin
Critical Care Medicine in AJRCCM 2002
Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 294 - 305.
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