Keywords
Ventilator-associated pneumonia (VAP) diagnosis is a challenge because gold standard is lacking and confirmation is based on respiratory cultures and techniques with important limitations. Presentation with clinical signs of community-acquired pneumonia is unusual, bacteremia is uncommon, onset undetermined, and it usually presents as progressive hypoxemia (or increase in vasoactive drugs) in a ventilated patient with purulent respiratory secretions, being a post-hoc diagnosis after ruling out other infectious sites
1
. Half episodes are caused by unidentified organisms and heterogeneity in diagnosis is huge, with important geographical differences in strategies and pathogens 2
, 3
. Moreover, microbiologic tests may require hours to days of incubation and, classically, additional time is needed to identify organisms and further determination of susceptibility. For that reason, in general, antimicrobial therapy is empirical and often requires broad spectrum with subsequent emergence of antimicrobial resistance. Also, and more importantly, it is essential to develop fast diagnostic techniques and investigate airways microbe population that can immediately predict causative microorganisms without specimen processing. In this context, still remain many important research questions which need to be answered (Table 1).Table 1Top 25 Questions in the Research Agenda for VAP
| 1) What is the role of clinical microbiologists in VAP diagnosis? |
| 2) What is the best diagnostic paradigm for VAP? |
| 3) What time is acceptable for rapid diagnostic tests? |
| 4) What is the duration of prior antibiotic exposure influencing identification and outcome? |
| 5) How to differentiate between infection vs. colonization of lower respiratory tract?, 6) Is it relevant to differentiate VAP from ventilator-associated tracheobronchitis (VAT)? |
| 7) What is the role of respiratory viruses in VAP? |
| 8) Are chest-X rays needed or can be replaced by lung ultrasounds? |
| 9) What is the role of biomarkers and ‘omics’, if any, in diagnosis? |
| 10) Patients with tracheostomy and endotracheal tubes are comparable? |
| 11) Adults data can be transferred to mechanically ventilated children? |
| 12) What is the role of hypoxemia in the decision-process making? |
| 13) How to stratify (for severity and benchmarking) different VARI and its influence in diagnosis? |
| 14) How to optimize diagnosis to increase patient enrollment in randomized clinical trials? |
| 15) What is the cost-efficacy of new diagnostic tests? |
| 16) When is the VAP onset? |
| 17) Does techniques used in reference centers can be applied in non-university hospitals. |
| 18) What diagnosis strategy should be implemented in low-income and middle-income countries? |
| 19) What is the contribution of identifying virulence factors in diagnosis of VAP? |
| 20) Are new diagnostic tools improving outcomes and justifying increasing costs? |
| 21) How predetermined colonization pressure influences diagnosis? |
| 22) Is feasible to identify pneumonia onset with anticipation for pre-emptive therapy? |
| 23) What is the contribution of surveillance to diagnosis? |
| 24) Is diagnosis using a signature in breath expired metabolites a non-invasive technique contributing to better identification? |
| 25) What are the responsible agents for episodes with unidentified organisms and how to reduce its prevalence? |
In this issue of the International Journal of Infectious Diseases, Prat and Lacoma (ref) describe the clinical role of bacteria in the respiratory tract and review novel therapeutic approaches. Its excellent review is welcome because contains interesting considerations that can help to answer some of the formulated questions.
We agree with the authors that the role of clinical microbiologists is not limited to report a laboratory result; their expertise in laboratory diagnostic methods, susceptibility testing and interpretation of microbiological results go beyond that and should be taken for the optimal management of patients. In our opinion, a team working with fluent communication is highly recommended for optimal management; indeed, all microbiological results should be interpreted based on patient comorbidities, period of hospitalization, previous antibiotics and clinical presentation (hypoxemia) and images
4
. To detect bacteria in a respiratory sample does not mean an infection. Even if presumed, we have to translate it to the context patient before taking therapeutic decisions. We disregard decisions based only on microbiologic findings.In this scenario, what is the optimal diagnostic approach for VAP? The recent Guidelines published by the Infectious Diseases Society of America/The American Thoracic Society (IDSA/ATS) provide recommendations for diagnosis and treatment of adults with Hospital-acquired (HAP) and VAP
5
. These guidelines suggest performing, with low quality evidence, noninvasive samples (endotracheal aspiration) with semiquantitive cultures for VAP diagnosis. Once again, a personalized approach is required; we agree with the recommendation in the use of noninvasive samples because there is low evidence of superiority on outcomes of invasive samples in non-immunocompromised patients; however, based in our experience, quantitative methods (that report number of bacterial colonies) should be preferred for VAP management because they are associated with high specificity and informs on bacteria burden which correlates with probability of infection - Kalil A.C.
- Metersky M.L.
- Klompas M.
- Muscedere J.
- Sweeney D.A.
- Palmer L.B.
- et al.
Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society.
Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2016; 63: e61-e111
4
. However, immunocompromissed patients require brochoalveolar lavage and lung transplants 6
might benefit of a transbronchial biopsy. We also endorse the use of E-test antibiotic strips applied directly to respiratory tract samples. Bouza et al., 7
reported that use of rapid E-test was associated with increased administration of appropriate antimicrobial therapy and reduced the report of antimicrobial susceptibility in 1.4 days (compared with 4.2 days for those using standard diagnostic methods). Then, the difficulty in the differentiation between infection vs. colonization remains a challenge nowadays. This represents, in our opinion, a key point in the research agenda in VAP. The introduction of polymerase chain reaction (PCR) tests has increased the ability to detect microorganisms in clinical samples, including those difficult to grow. Adding mecA identification to specimens with Gram-positive cocci (or GenExpert® to Gram-negative specimens) is already an advance - Bouza E.
- Torres M.V.
- Radice C.
- Cercenado E.
- de Diego R.
- Sanchez-Carrillo C.
- et al.
Direct E-test (AB Biodisk) of respiratory samples improves antimicrobial use in ventilator-associated pneumonia.
Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2007; 44: 382-387
8
in this way. However, differentiation between colonization, active infection or excretion of non-viable microorganisms remains an open issue with newer molecular techniques. Novel technologies such as gene expression diagnostics 9
and also the study of respiratory microbiome are very promising tools that could allow us to enter into the era of “personalized medicine”. Quantitative techniques might split colonization from infection. We strongly believe that only point-of-care tests, available within two hours, justify increasing costs, being able to modify outcomes. Introducing molecular tests require a new paradigm focusing on phenotypes rather than the organism, and trials are needed to measure the impact on appropriate antibiotic use, stewardship, time to resolution and period of MV as primary end-points. Microarrays are the most frequently used gene expression platform, being a promising tool for improving diagnosis in Lower Respiratory Tract Infection (LRTI), demonstrating its usefulness in the differentiation of bacterial and viral infections 10
, 11
. This technique is based on the immune response of the patient against the pathogen rather than detection of the microorganisms. The human microbiome is also a new non-culture-based technique that has been developed to characterize the entire population of microbes resident on the body surfaces. Recent studies have shown that investigation of the respiratory microbiome is an emerging field, and these findings may provide a different vision about respiratory diseases 12
, 13
, suggesting that airways have a microbiome that varies from health to disease 14
. Understanding the factors that affect the composition of the lower airway microbiota in VAP will help us to look for new therapeutics and diagnosis challenges to improve outcome in this patients.Another factor that should be considered in the research agenda in VAP is the differentiation between bacteria and respiratory viruses. What is the role of respiratory viruses in the development of VAP? This question has not yet been answered. After the 2009 influenza A (H1N1) pandemic it was established the importance of this virus causing pneumonia
15
. However, the role of respiratory virus in the development of VAP is still underestimated and only few studies analyze severe pneumonia and viral etiology. In the study performed in Finland by Karhu et al., 16
, it was found a viral etiology of severe pneumonia in 24 patients (49%). Although, a viral etiology is currently recognized as a cause of severe pneumonia, no recommendation was done in the 2016 IDSA/ATS Guidelines 5
. In our opinion, we also need more studies to understand the role of cytomegalovirus and herpes virus - Kalil A.C.
- Metersky M.L.
- Klompas M.
- Muscedere J.
- Sweeney D.A.
- Palmer L.B.
- et al.
Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society.
Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2016; 63: e61-e111
17
, 18
in ventilated patients.Biomarkers are another piece of the VAP diagnosis that need more research effort. The 2016 IDSA/ATS guidelines recommended avoid performing biomarkers for diagnosis. Sequential use of old and newer biomarkers is more promising
19
, particularly to anticipate poor resolution, and more studies are needed, enclosing metabolomics in breath condensate of the espiratory tube.Current interest emerges in identifying ventilator-associated tracheobronchitis (VAT) and differentiating from VAP, because it is increasing MV period
6
. Indeed, it is treated with aerosolized antibiotics in many ICUs 20
. Chest radiographs are expensive, time-consuming and difficult to assess, and bedside ultrasounds - Sole-Lleonart C.
- Roberts J.A.
- Chastre J.
- Poulakou G.
- Palmer L.B.
- Blot S.
- et al.
Global survey on nebulization of antimicrobial agents in mechanically ventilated patients: a call for international guidelines.
Clinical microbiology and infection: the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2016; 22: 359-364
21
can replace it in trained sites, because they have additional benefits when performed bedside. We believe that the concept of ventilator-associated respiratory infections (VARI) has advantages and in the decision process it might be more important the degree of hypoxemia rather than chest images 1
. Finally, as documented by Peña-Lopez et al in children 22
, where limited literature is available, differences between artificial airways (tracheostomy or endotracheal tube) should not be missed in VARI.Peña-López Y, Pujol M, Campins M, González-Antelo A, Rodrigo JA, Balcells J, et al. Implementing a Care bundle approach reduces Ventilator-associated pneumonia and delays Ventilator-associated tracheobronchitis in children: Differences according to endotracheal or tracheostomy devices. International Journal of Infectious Diseases: In Press.
In conclusion, the research agenda should focus on a new paradigm focusing on antibiotic susceptibility rather than organisms. Speed is life, so in addition to Gram stain, what molecular tests (and biomarkers) can contribute to improve diagnosis with management implications within the first two hours after diagnosis need to be identified. This is not only of academic interest, due the current scenario of limited antimicrobial options and the urgent need to improve enrolment
23
in HAP/VAP clinical trials.- Knirsch Ch.
- Alemayehu D.
- Botgros R.
- Comic-Savic S.
- Friedland D.
- Holland T.L.
- et al.
Improving conduct and feasibility of clinical trials to evaluate antibacterial drugs to treat Hospital-Acquired bacterial pneumonmia and ventilator-associated bacterial penumonia: Recommendations of the Clinical Trials Transformation Initiative Antibacterial Drug Development Project Team.
Clinical Infectious Diseases. 2016; 63: S29-S36
Acknowledgement
Supported in part by an ESCMID Grant (EUVAE project). This publication was also partially supported by FISS PI14/1296 and AGAUR 2014 SGR 278 and CIBERES-Fondos FEDER (PCI Pneumonia). Eleonora Bunsow is supported by a grant from the INCOMED programme.
References
- Respiratory infections in patients undergoing mechanical ventilation.The Lancet. Respiratory medicine. 2014; 2: 764-774
- Nosocomial pneumonia in 27 ICUs in Europe: perspectives from the EU-VAP/CAP study.European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical Microbiology. 2016;
- Spectrum of practice in the diagnosis of nosocomial pneumonia in patients requiring mechanical ventilation in European intensive care units.Critical care medicine. 2009; 37: 2360-2368
- Diagnostic testing for ventilator-associated pneumonia.Clinics in chest medicine. 1999; 20 (x): 671-679
- Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society.Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2016; 63: e61-e111
- Ventilator-associated respiratory infection following lung transplantation.The European respiratory journal. 2015; 45: 726-737
- Direct E-test (AB Biodisk) of respiratory samples improves antimicrobial use in ventilator-associated pneumonia.Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2007; 44: 382-387
- Pneumonia in immunocompetent patients: combination antibiotic therapy.Minerva anestesiologica. 2014; 80: 495-503
- Promising new assays and technologies for the diagnosis and management of infectious diseases.Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2013; 56: 996-1002
- Superiority of transcriptional profiling over procalcitonin for distinguishing bacterial from viral lower respiratory tract infections in hospitalized adults.The Journal of infectious diseases. 2015; 212: 213-222
- Robust classification of bacterial and viral infections via integrated host gene expression diagnostics.Science translational medicine. 2016; 8: 346ra391
- The microbiome and the lung.Annals of the American Thoracic Society. 2014; 11: S227-S232
- Towards an ecology of the lung: new conceptual models of pulmonary microbiology and pneumonia pathogenesis.The Lancet. Respiratory medicine. 2014; 2: 238-246
- The role of the lung microbiome in health and disease. A National Heart, Lung, and Blood Institute workshop report.American journal of respiratory and critical care medicine. 2013; 187: 1382-1387
- Influenza and endemic viral pneumonia.Critical care clinics. 2013; 29: 1069-1086
- Lower respiratory tract virus findings in mechanically ventilated patients with severe community-acquired pneumonia.Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2014; 59: 62-70
- Cytomegalovirus and herpes simplex virus effect on the prognosis of mechanically ventilated patients suspected to have ventilator-associated pneumonia.PloS one. 2012; 7: e51340
- Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation.American journal of respiratory and critical care medicine. 2007; 175: 935-942
- Mid-regional proadrenomedullin: An early marker of response in critically ill patients with severe community-acquired pneumonia?.Revista portuguesa de pneumologia. 2016;
- Global survey on nebulization of antimicrobial agents in mechanically ventilated patients: a call for international guidelines.Clinical microbiology and infection: the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2016; 22: 359-364
- Ultrasound assessment of antibiotic-induced pulmonary reaeration in ventilator-associated pneumonia.Critical care medicine. 2010; 38: 84-92
Peña-López Y, Pujol M, Campins M, González-Antelo A, Rodrigo JA, Balcells J, et al. Implementing a Care bundle approach reduces Ventilator-associated pneumonia and delays Ventilator-associated tracheobronchitis in children: Differences according to endotracheal or tracheostomy devices. International Journal of Infectious Diseases: In Press.
- Improving conduct and feasibility of clinical trials to evaluate antibacterial drugs to treat Hospital-Acquired bacterial pneumonmia and ventilator-associated bacterial penumonia: Recommendations of the Clinical Trials Transformation Initiative Antibacterial Drug Development Project Team.Clinical Infectious Diseases. 2016; 63: S29-S36
Article info
Publication history
Published online: September 21, 2016
Corresponding Editor: Eskild Petersen, Aarhus, DenmarkIdentification
Copyright
© 2016 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
User license
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0) | How you can reuse 
Elsevier's open access license policy
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0)
Permitted
For non-commercial purposes:
- Read, print & download
- Redistribute or republish the final article
- Text & data mine
- Translate the article (private use only, not for distribution)
- Reuse portions or extracts from the article in other works
Not Permitted
- Sell or re-use for commercial purposes
- Distribute translations or adaptations of the article
Elsevier's open access license policy
