ICU Management & Practice, Volume 16 - Issue 3, 2016

Controversies in Ventilator-Associated Pneumonia Diagnosis

Controversies in Ventilator-Associated Pneumonia Diagnosis
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Ventilator-associated pneumonia is a ‏major complication of mechanical ‏ventilation and represents the most ‏common reason for antibiotic prescription in ‏ventilated patients. Incidence ranges from 1.2 ‏to 8.5 cases per 1000 ventilator days or 9 to ‏27% cases per mechanically ventilated patient; ‏attributable mortality rates vary between 0% ‏and 70% (Chastre and Fagon 2002; Melsen et ‏al. 2013). The large variability of these figures ‏stems from the fact that both development and ‏outcome of VAP result from a complex interplay ‏between pathogens and host under the influence ‏of many factors: comorbidities, severity ‏and cause of the underlying critical illness, its ‏treatment and its evolution over time. Additionally, ‏uncertainty surrounds diagnosis of ‏VAP and many different diagnostic strategies ‏and criteria prevail. Clinical signs and symptoms, ‏biochemical markers of inflammation ‏and radiological signs of alveolar consolidation, ‏which are highly accurate for a diagnosis ‏of pneumonia in a walking patient in the ‏community are much less so in the critically ‏ill patient under mechanical ventilation. Clinical ‏and biochemical alterations may be absent, ‏or may have an alternative cause that can be ‏infectious or non-infectious. An infiltrate on ‏chest x-ray is required for diagnosis, as it has ‏high sensitivity, but is remarkably non-specific. ‏Inter-observer variability of chest x-ray interpretation ‏is large, especially when it comes to ‏deciding whether or not an infiltrate is ‘new’, ‏‘evolving’ and represents alveolar consolidation. ‏Increasing the number of diagnostic criteria ‏required for diagnosis gains specificity at the ‏cost of reduced sensitivity. The Clinical Pulmonary ‏Infection Score (CPIS) is a quantification ‏of these criteria in a summary score: a higher ‏CPIS score increases the likelihood that VAP is ‏present, but no single cut-off combining a high ‏sensitivity with a high or acceptable specificity ‏can be identified (Schurink et al. 2004). Despite ‏decades of study and an impressive amount ‏of published data, the question of how VAP ‏can be accurately diagnosed is not definitively ‏settled. In this contribution, four controversies ‏regarding VAP diagnosis are briefly discussed.


Invasively Obtained Microbiology Allows ‏Accurate Diagnosis of VAP


Adding microbiological data increases specificity ‏of VAP diagnosis (Chastre and Fagon ‏2002). However, the presence of a potential ‏pathogen in a respiratory sample of a mechanically ‏ventilated patient is in itself no proof for ‏VAP, as it may represent colonisation of lower ‏respiratory airways or contamination by flora ‏residing in the upper respiratory tract or in ‏the biofilm on the endotracheal tube. Invasive ‏diagnostics in VAP refer to the use of fiberoptic ‏or blind bronchoalveolar lavage or protected ‏specimen brush in order to sample more selectively ‏the distal airways and alveoli. Using these ‏samples for direct examination for the presence ‏of intracellular pathogens in alveolar macrophages ‏or polymorphonuclears and for quantitative ‏culturing further helps to distinguish ‏between colonisation and infection (Chastre ‏and Fagon 2002; Torres et al. 1996; Pugin et ‏al. 1991). As such, quantitative cultures of ‏invasively obtained samples may improve the ‏specificity of VAP diagnosis more than qualitative ‏culture of routinely obtained endotracheal ‏aspirates. However, the selection of a threshold ‏for quantitative cultures to discriminate ‏between infection and colonisation again ‏must strike a balance between specificity and ‏sensitivity. Thresholds for diagnosing VAP may ‏differ between populations. For example, some ‏authors have argued in favour of using a higher ‏threshold (>105 colony-forming units (CFU)/ ‏ml) in bronchoalveolar lavage (BAL) samples of ‏trauma patients than the one usually applied in ‏medical patients (>104 CFU/ml, to reduce the ‏number of false positives (Croce et al. 2004). ‏On the other hand, in patients who received ‏antibiotics prior to their BAL, the quantitative ‏threshold for VAP diagnosis should probably be ‏lowered to limit the number of false negatives. ‏However, in the absence of a true gold standard ‏for the diagnosis of VAP, test characteristics of ‏invasive microbiological techniques are not well ‏established. Quantitative cultures themselves are ‏often used as a form of gold standard to which ‏other diagnostic tests are compared, which may ‏lead to a form of circular reasoning (Pugin et ‏al. 1991). Regardless of the higher specificity ‏of invasive microbiology, clinical characteristics ‏must always be taken into account for a diagnosis ‏of VAP, as many patients with prolonged ‏mechanical ventilation have a high burden of ‏bacteria in the lower airways without signs of ‏infection (Baram et al. 2006). ‏


Invasively Obtained Microbiology ‏Improves Outcome in VAP


Proponents of invasive diagnostic strategies in ‏VAP have argued that these techniques improve patient outcome. The outcome benefit is attributed to the higher ‏diagnostic specificity, which helps the attending physician to avoid ‏unnecessary antibiotics and/or direct a search for alternative diagnosis ‏if VAP is refuted (Fagon et al. 2000). In a recent study, diagnostic ‏workup of clinically suspected VAP with invasively obtained quantitative ‏cultures below threshold led to an alternative diagnosis in ‏60% of cases (Schoemakers et al. 2014). Proponents of noninvasive ‏diagnostics state that the main treatment factor influencing outcome ‏is timely and appropriate empirical antibiotic therapy directed at all ‏likely involved pathogens; microbiological data serve only to guide ‏subsequent de-escalation of antibiotics. For this purpose, routine ‏endotracheal samples and semi-quantitative cultures may suffice ‏(Canadian Critical Care Trials Group 2006). In this view, invasive ‏sampling adds little benefit for the patient and has the disadvantage ‏of increased costs and potentially delayed effective therapy. A ‏meta-analysis comparing invasive and noninvasive strategies for ‏VAP diagnosis found no difference in outcome (Shorr et al. 2005), ‏but this has not settled the controversy. Recently, the need for antibiotic ‏stewardship measures in VAP management has revived the ‏discussion. Identification of the causal pathogen of VAP has been ‏identified as the main factor promoting de-escalation of empirical ‏antibiotics. As invasively obtained microbiological cultures are more ‏likely to represent the true causal pathogens of VAP compared to ‏cultures from noninvasive samples, the physician may be given ‏greater confidence to de-escalate. Giantsou et al. (2007) indeed ‏found higher de-escalation rates in patients subjected to BAL instead ‏of endotracheal aspirates. In addition, the higher specificity of ‏quantitative cultures in suspected VAP, translating into fewer false ‏positives, would also lead to fewer unnecessary antibiotic treatments ‏(Sharpe et al. 2015). However, in the Canadian Critical Care ‏Trials Group trial, which randomised between an invasive and a ‏noninvasive strategy for VAP diagnosis, no differences in the rate ‏of de-escalation or antibiotic stop were found between both arms, ‏nor was patient outcome different (Canadian Critical Care Trials ‏Group 2006). In addition, increased focus on antibiotic stopping ‏whenever possible, using repeated clinical evaluations (Micek et ‏al. 2004; Singh et al. 2000), or a protocol guided by sequential ‏procalcitonin measurements (De Jong et al. 2016) may achieve a ‏major effect without the use of invasive microbiology.

See Also: Nosocomial Pneumonia


Ventilator-Associated Tracheobronchitis (VAT) is a Separate ‏Condition of VAP


The observation that patients may have all clinical signs and symptoms ‏of VAP and respond to the microbiological criteria of VAP ‏in the absence of unambiguous infiltrates on chest x-ray has led to ‏the concept of ventilator-associated tracheobronchitis (VAT). VAT ‏represents a more limited infection of the lower respiratory tract ‏in ventilated patients. The association between VAT and mortality ‏is less obvious than in VAP, yet VAT appears to be associated with ‏a longer duration of mechanical ventilation (Nseir et al. 2005). It ‏is not clear whether VAT represents a precursor or early stage of ‏VAP, i.e. whether untreated it proceeds to VAP, or whether it is a ‏milder stage of infection, sitting in the continuum between lower ‏respiratory tract colonisation and clear-cut VAP (Rouby et al. 1992). ‏Moreover, as the absence of a new or worsening infiltrate on chest ‏x-ray makes the only distinction between VAT and VAP, inter-observer variability may lead to false classification of VAP ‏as VAT. VAT may progress to VAP in a third of ‏cases (Dallas et al. 2011); antibiotic treatment ‏of VAT thus may prevent evolution to VAP in ‏some patients but may not influence outcome in ‏others. Given the necessity to restrict antibiotics ‏as part of antibiotic stewardship, treatment of ‏VAT is not straightforward. Antibiotic therapy ‏in VAT, e.g. as delivered by inhalation (Palmer ‏et al. 2008) or systemically as a short course ‏(Nseir et al. 2008), may prevent full VAP and ‏thus have an overall antibiotic-sparing effect. ‏On the other hand, a strategy in which VAT ‏routinely is considered as an indication for ‏antibiotic therapy will increase the number of ‏antibiotic prescriptions in patients who will not ‏directly benefit from it, but still are exposed ‏to the harmful effects of antibiotics, especially ‏increased selection pressure.


Ventilator-Associated Events (VAE) Are a ‏Better Concept for Monitoring of Quality ‏of Intensive Care


The lack of accuracy of diagnostic criteria of ‏VAP, and especially the inter-observer variability ‏of chest x-ray interpretation hampers the ‏use of VAP as a quality indicator for benchmarking ‏intensive care unit (ICUs). Ego et al. ‏(2015) found that VAP incidence in their ICU ‏population varied tremendously according to ‏the different sets of diagnostic criteria used. ‏Reports about achieving zero VAP rates may thus ‏reflect the use of overly specific (and too little ‏sensitive) diagnostic criteria rather than true ‏absence of VAP. This has led to a radical change ‏in the Centers for Disease Control and Prevention ‏(CDC) approach to surveillance of complications ‏of mechanical ventilation, dismissing ‏subjective criteria (such as chest x-ray interpretation) ‏and broadening the concept of VAP ‏to that of ventilator-associated events (VAE). ‏VAE refers to a respiratory deterioration of ‏a mechanically ventilated patient after initial ‏improvement and stabilisation, and is diagnosed ‏on the basis of more objective criteria such ‏as ventilator settings and oxygenation indices: ‏this deterioration may or may not be due to ‏infection. A new definition of VAP is tied within ‏this framework and is defined as VAE together ‏with signs of inflammation or newly started ‏antibiotics, purulent secretions and presence ‏of pathogens in respiratory cultures: the label ‏‘possible VAP’ and ‘probable VAP’ is applied if ‏only one, and two respectively, of the last two ‏criteria are met. Studies have shown that VAE ‏poorly correlate with ‘traditionally diagnosed’ ‏VAP (Klein Kouwenberg et al. 2013): less severe ‏VAP is missed by VAE and a large number of ‏VAE are not due to VAP. On the other hand, ‏Bouadma et al. (2015) found a good correlation ‏between VAE and antibiotic consumption ‏in their multicentre OUTCOMEREA database, ‏suggesting that VAE could represent a proxy for ‏true VAP. Whether or not VAE is preventable is ‏a matter of discussion (Klompas et al. 2015); ‏this is however a cardinal prerequisite for its ‏use as a quality indicator.


Conflict of Interest


Pieter Depuydt declares that he has no conflict ‏of interest. Liesbet De Bus declares that ‏she has no conflict of interest.




BAL bronchoalveolar lavage

CFU colony-forming unit

CPIS Clinical Pulmonary Infection Score

ICU intensive care unit

VAE ventilator-associated event

VAP ventilator-associated pneumonia

VAT ventilator-associated tracheobronchitis

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Giantsou E, Liratzopoulos N, Efraimidou E et al. (2007) De-escalation therapy rates are significantly higher by bronchoalveolar lavage than by tracheal aspirate. Intensive Care Med, 33(9): 1533-40.


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Schoemakers RJ, Schnabel R, Oudhuis G et al. (2014) Alternative diagnosis in the putative ventilator-associated pneumonia patients not meeting lavage-based diagnostic criteria. Scand J Infect Dis, 46(12): 868-74.


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Sharpe JP, Magnotti LJ, Weinberg JA et al. (2015) Adherence to an established diagnostic threshold for ventilator-associated pneumonia contributes to low false-negative rates in trauma patients. J Trauma Acute Care Surg, 78(3): 468-73.


Shorr AF, Sherner JH, Jackson Wl et al. (2005) Invasive approaches to the diagnosis of ventilator-associated pneumonia: a meta-analysis. Crit Care Med, 33(1): 46-53.


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