The source of this paradox lies in the ambiguity and inaccuracy inherent in VAP diagnosis. VAP is typically defined as the presence of fever, abnormal white blood cell count, purulent sputum, and new radiographic infiltrates. On intensive investigation, however, only a fraction of patients with these signs truly have histological pneumonia [12
]. Instead, up to two thirds of people who fulfill this definition have one or more alternative conditions that range from relatively benign, such as atelectasis and tracheobronchitis, to severe, such as acute respiratory distress syndrome or pulmonary infarction [13
The addition of microbiological criteria does little to improve accuracy. Many studies define VAP as the presence of greater than 1,000 colony-forming units per milliliter on culture of bronchoalveolar lavage fluid. This definition is attractive because it is objective, but unfortunately it is no more accurate than clinical criteria alone [15
]. The sensitivity and specificity of this definition relative to a histological gold standard are only 50%-70% and 40%-95%, respectively [16
]. False positives are due to contamination of the lavage specimen by bacteria colonizing the patient's endotracheal tube and upper airway. This effect is particularly marked in patients with prolonged ventilation. False negatives arise from the failure to sample the correct lung segment, insufficient bacterial growth to cross the quantitative threshold, and damping of bacterial growth by prior antibiotic exposure.
Much of VAP misdiagnosis stems from bacterial colonization superimposed upon non-infectious pulmonary processes such as fluid shifts, barotrauma, atelectasis, inflammatory reactions, and exacerbations of patients' underlying lung disease. These factors wax and wane in ways that are difficult to discern at the bedside, leading to the transient appearance of clinical syndromes suggestive of VAP. As often as not, these processes spontaneously resolve in short order without definitive therapy. Clinical trials for early empiric treatment of suspected VAP followed by reassessment 48 to 72 hours later hint at this process. In many patients, the VAP syndrome is no longer present on reassessment and antibiotics can safely be stopped without discernible impact on patient outcomes [20
Mislabelling benign events as VAP creates bias if prevention measures preferentially affect the more benign disorders over the more serious disorders present within the spectrum of conditions that look like VAP. This is particularly likely in studies that use a microbiological definition of VAP to assess interventions that work by decreasing bacterial colonization of the endotracheal tube. For example, the NASCENT (North American Silver-Coated Endotracheal Tube) study of silver-coated endotracheal tubes compared with conventional endotracheal tubes found a statistically significant 36% reduction in microbiologically confirmed VAP yet no difference in the rate of physician-suspected VAP (26% versus 31%, P
= 0.39) or patients with radiographic infiltrates and suggestive clinical signs (53% versus 56%, P
= 0.74) [8
]. This discrepancy between rates of microbiologically defined VAP versus clinically defined VAP suggests that silver-coated tubes preferentially decrease colonization rather than infection. This is further borne out by identical durations of mechanical ventilation, ICU stay, hospital stay, and mortality between patients with silver-coated versus conventional tubes. Other interventions that decrease microbial colonization, such as oral chlorhexidine and continuous aspiration of subglottic secretions, might also be subject to this bias.
Mislabelling benign events as VAP further contributes to the paradox by obscuring faint but true signals from bona fide pneumonias. Some interventions designed to prevent VAP may well reduce the frequency of bona fide pneumonias (and truly improve outcomes for this subset of patients), but the plethora of alternative conditions captured by the VAP definition dilute the signal coming from the subset of patients with true pneumonias. Generally low event rates in both the intervention and control groups of many studies compound the challenge of detecting significant impacts on outcomes. These effects may also explain some of the conflicting results in studies evaluating the attributable mortality of VAP: the failure of some studies to detect an impact on mortality [23
] despite a statistically significant impact in other studies [27
] and on meta-analysis [11
] may be due to damping of the 'true' VAP morbidity signal by misclassifying relatively benign conditions as VAP. Alternatively, VAP may be more of a marker for severity of illness in intubated patients rather than an independent source of morbidity in and of itself. Either way, the failure of multiple clinical trials to detect an impact of VAP prevention measures on patient outcomes suggests that the net benefit of these interventions on the population level is small.