POINT
Keep an open mind toward pneumonia. Our grandchildren will be interested and are likely to have as many differences of opinion regarding the disease as we have.
—Sir William Osler (1)
The best approach in establishing a diagnosis of ventilator-associated pneumonia (VAP) is quite controversial (2, 3). VAP contributes to excess morbidity, mortality, and costs, and these consequences have led to the designation of VAP as a quality performance monitor by the National Healthcare Safety Network (NHSN), the Institute for Healthcare Improvement, and the Joint Commission (4). Despite the importance of VAP, there is no universally accepted diagnostic approach.
The controversies surrounding VAP diagnosis are directly related to its clinicopathologic complexity. VAP represents inflammation of lung parenchyma following microaspiration of secretions that have accumulated around the ventilatory device. These secretions harbor significant concentrations of mixed bacterial microflora that may include health care-associated, multiply antimicrobial-resistant strains (5). Histopathologically, there is an inflammatory continuum along the airway from tracheobronchitis, to peribronchial pneumonitis, and eventually to progressive bronchopneumonia (6). The pneumonia may be multifocal and heterogeneous, a feature that complicates diagnosis (5).
Clinical findings are the result of the inflammation and include fever, leukocytosis or leukopenia, purulent secretions, and development of a new or persistent radiographic infiltrate. Unfortunately, these symptoms are not specific for pneumonia and may result from either noninfectious pulmonary conditions or infections at other anatomic sites. As a result, it is well accepted that using clinical features alone results in overdiagnosis of VAP, and microbiologic information is desirable (2, 7).
The newly proposed NHSN definitions of ventilator-associated events, including infections, attempt to integrate the complex clinical, histopathologic, and microbiologic features. In this new definition, VAP occurs in persons who had a device to assist or control respiration continuously through a tracheostomy or by endotracheal intubation within the 48-hour period before the onset of infection. VAP is deemed “possible” when microscopically purulent secretions are noted and “probable” when a quantitative culture of lower respiratory material is above a designated threshold as shown in Table 1 (8). However, the actual necessity and utility of such cultures, particularly on bronchoscopically obtained specimens, remain controversial.
Table 1.
Comparison of various sampling methods used for NHSN microbiologic thresholds
| Specimen |
Collectors |
Site(s) sampled |
Sample amt |
Diluent vol |
Dilution factor |
Quantitative thresholda
|
Semiquantitative equivalentb
|
Comment(s) |
| Lung tissue |
Trained physicians |
Lung parenchyma |
∼1.0 g |
∼1.0 ml |
1 |
≥104 g |
Few-moderate or 2-3+ |
Often obtained postmortem, is not representative of all patients |
| Bronchoscopicc protected specimen brushing |
Trained physicians |
Bronchioles |
0.001–0.01 ml |
1.0 ml |
1/100–1/1,000 |
≥103 ml |
Rare-few or 1-2+ |
Low-volume sampling restricts utility |
| Bronchoscopic bronchoalveolar lavage fluid |
Trained physicians |
Bronchioles and alveoli |
∼1 ml |
10–100 ml |
1/10–1/100 |
≥104 ml |
Few-moderate or 2-3+ |
Adequate volume for multiple analyses, including microscopy |
| Nonbronchoscopic protected specimen brushing |
Respiratory therapists or trained personnel |
Bronchioles |
0.001–0.01 ml |
1.0 ml |
1/100–1/1,000 |
≥103 ml |
Rare-few or 1-2+ |
Low-volume sampling restricts utility |
| Nonbronchoscopic bronchoalveolar lavage fluid |
Respiratory therapists or trained personnel |
Bronchioles and alveoli |
∼1 ml |
10–100 ml |
1/10–1/100 |
≥104 ml |
Few-moderate or 2-3+ |
Comparable to bronchoscopic alveolar lavage but often lower in lavaged volume |
| Endotracheal aspirate |
Respiratory therapists or nurses |
Tracheal secretions |
1–10 ml |
1–10 ml |
1–1/10 |
≥105 ml |
Moderate-numerous or 3-4+ |
Easily obtained; primarily reported semiquantitatively with microscopy |
The quantitative approach.
It must be admitted that the basis for a quantitative approach is largely theoretical. Pneumonia is believed to occur when there is an overwhelmed host response to microbial intrusion into a sterile environment. Concentrations of bacteria in lung tissue reach levels of ≥104 CFU/g, while levels in secretions are ≥105 CFU/ml (5). Accounting for dilutional effects, corresponding thresholds can be set for tracheal aspirates (TA), protected specimen brushings (PSB), or bronchoalveolar lavage (BAL) fluid (2). In contrast, organism levels in samples from individuals without pneumonia are generally below the established thresholds (7). By convention, even semiquantitative cultures attach greater significance to abundant or predominant growth of potential pathogens in a sample containing indigenous microbial flora. What may not be appreciated is the fact that there is an easily demonstrated relationship between semiquantitative and quantitative results, a finding that has been verified for BAL fluid samples (9).
Regarding microbiologic results obtained from different sample types, the data have been deemed “reasonably similar” (10) and “rather equivalent” (7). However, advocates of bronchoscopy cite many studies showing that directed lower airway sampling is an excellent proxy for lung tissue (5) and better captures the incidence of VAP (11). Qualitatively, there is relatively good agreement among sample types, particularly when samples are collected prior to initiating therapy for a new-onset infection (5), which agrees “with the common sense notion that specimens obtained from locations only 5-15 cm apart along a widely patent airway in continuous motion are unlikely to have substantially different bacterial populations” (6). However, the finding that a greater proportion of patients have positive results when less invasive specimens are used also implies that organism diversity may decrease moving toward the lung parenchyma (11). In all studies, antibiotic therapy has been shown to confound interpretation of data (2, 5, 7).
Practical considerations.
If a noninvasive strategy is used, TA are easily obtained and microscopy may provide useful initial information (12). However, when an invasive strategy is used, BAL is often preferred due to the increased volume available for analysis (7). BAL also appears to offer improved microscopic data, as the probability of VAP with a positive Gram stain on BAL fluid is greatly increased (12). In addition, a positive Gram stain correlates reasonably well with quantitative cultures (7).
Methodologically, a quantitative culture can be performed similarly to a urine culture, with calibrated loops performing acceptably and easily incorporated into the workflow (13). However, as has been previously shown for other fluid samples, accuracy may exceed ±10% and intra-assay variability for colony counts is high. Therefore, it is recommended that BAL fluid quantitative culture results near an established threshold should not be strictly or solely used to characterize a patient as VAP positive or negative (14). The question then becomes whether this method offers any advantages over a semiquantitative approach. One recent study suggests that a semiquantitative method may overestimate potential pathogens (9), but the choice to use a calibrated loop method is actually rooted in historical observations that quantitative methods may improve recognition of more slowly growing organisms (15) and the observation that the “superiority over other methods can only be judged by experience and depends to some extent on ease in recognition and comfort in counting which cannot be readily communicated in a paper” (16).
Another factor that must be considered but is only rarely specifically addressed in studies is specimen quality. It stands to reason that any sample with excessive contamination may yield noninterpretable quantitative or semiquantitative culture results, but a standard approach to assessing quality has not been established. A related issue is that few studies specifically differentiate organisms considered potential pathogens from those considered primarily nonpathogens. It is of note that the proposed NHSN criteria attempt to address both specimen quality, using microscopic criteria similar to those accepted for sputa, and organism significance, through exclusion of organisms considered to be of low pathogenic potential (8).
The value of quantitative cultures.
A determination of the value of quantitative cultures is difficult to make given the lack of a universally accepted definition. However, several recent summary analyses have provided some insights. In terms of clinical outcome, a comprehensive Cochrane review of the impact of qualitative culture of noninvasive samples and quantitative culture of invasive samples revealed no significant differences with respect to number of days on mechanical ventilation, length of intensive care unit (ICU) stay, or antibiotic change (17). In contrast, a meta-analysis of invasive approaches to the diagnosis of VAP concluded that invasive sampling led to significantly more antibiotic modifications (11), and in a separate study, de-escalation therapy rates were significantly higher when guided by results of quantitative BAL fluid cultures than when guided by quantitative TA cultures (18). Since de-escalation therapy by definition requires that a pathogen has been identified, the greater impact using invasive approaches supports the general concept of equivalent sensitivity but greater specificity of diagnosis using invasive strategies (2, 7). The lack of impact on other outcome monitors likely reflects the empirical use of effective broad-spectrum agents (11).
Should quantitative cultures of BAL fluid be performed?
The opinion of this author is that quantitative culture of BAL fluid should be performed for optimal management in patients with VAP. Practically speaking, the method is comparable to that typically used for urine cultures, and there are potential benefits in recognizing more slowly growing organisms, including multiply resistant pathogens. In addition, there are substantial data that specificity of diagnosis and therefore appropriate antimicrobial therapy are improved using this approach. At the same time, one should recognize that quantitative culture results are “inherently unstable” (3). As for urine cultures, procrustean adherence to a quantitative threshold in interpreting results for an individual patient is overly simplistic (19). This is particularly true when using results to define VAP rates for public reporting, as rates may be manipulated simply by adjusting thresholds (4). In fact, the revised draft NHSN guidelines for public reporting of ventilator-associated complications (VAC) and infection-related VAC (IVAC) do not rely upon use of quantitative culture results. Rather, results based on “positive” cultures are used primarily for internal monitoring and quality improvement (8). One should also remain aware of the overall complexity of diagnosis of VAP. Rarely is a single result the basis for diagnosis, and algorithms that integrate clinical and microbiologic findings are recommended (12). The evidence suggests that clinical findings can alert the physician to the possibility of VAP, and examination of noninvasive secretions can refine the clinical suspicions. When suspicion leads to a decision to initiate treatment, then bronchoscopy with BAL fluid collection prior to initiating or changing therapy can reliably rule out VAP and perhaps direct efforts toward other sources of infection or confirm an etiology so that the therapeutic approach can be reassessed. Finally, cumulative antibiogram data on significant isolates can be developed to determine appropriate empirical therapy in subsequent cases (7, 11, 12). However, it is clear that the diagnosis of VAP will remain a controversial, even contentious topic (2, 3). Recent molecular findings that traditional methods may have underestimated the microbial complexity of infected lungs (20) will only add to the controversy.
… a man misses a good part of his education who does not get knocked about a bit by his colleagues in discussions and criticisms.
—Sir William Osler (1)
Vickie Baselski
