REVIEW ARTICLE Jorge Ibrain Figueira Salluh1,2, Vicente Cés de Souza-Dantas3 , Ignacio Martin-Loeches4,5, Ventilator-associated tracheobronchitis: an update Thiago Costa Lisboa6,7, Ligia Sarmet Cunha Farah Rabello1,2, Nseir Saad8,9, Pedro Póvoa10,11 Traqueobronquite associada à ventilação mecânica: uma atualização 1. Instituto D’Or de Pesquisa e Ensino - Rio de Janeiro (RJ), Brazil. 2. Postgraduate Program in Internal Medicine, Universidade Federal do Rio de Janeiro - Rio de ABSTRACT Janeiro (RJ), Brazil. with increased patient costs, length 3. Faculdade de Medicina, Universidade Federal Ventilator-associated lower of stay, antibiotic use, and duration do Rio de Janeiro - Rio de Janeiro, (RJ), Brazil. respiratory tract infection is one of 4. Multidisciplinary Intensive Care Research of mechanical ventilation. Although Organization, Department of Clinical Medicine, the most frequent complications in we still need clear evidence, especially Trinity Centre for Health Sciences, St. James’s mechanically ventilated patients. concerning treatment modalities, the University Hospital -Dublin, Ireland. Ventilator-associated tracheobronchitis present study on ventilator-associated 5. CIBER Enfermedades Respiratorias, Critical has been considered a disease that does tracheobronchitis highlights that there Care Center, Sabadell Hospital, Corporación not warrant antibiotic treatment by the Sanitaria Universitaria Parc Taulí, Universitat are important impacts of including Autonoma de Barcelona - Sabadell, Spain. medical community for many years. this condition in clinical management 6. Rede Institucional de Pesquisa e Inovação em In the last decade, several studies have and epidemiological and infection Medicina Intensiva, Complexo Hospitalar Santa shown that tracheobronchitis could surveillance. Casa de Misericórdia de Porto Alegre - Porto be considered an intermediate process Alegre (RS), Brazil. that leads to ventilator-associated Keywords: Critical care; Mortality; 7. Critical Care Department and Infection Control Committee, Hospital de Clínicas de Porto Alegre, pneumonia. Furthermore, ventilator- Nosocomial infection; Pneumonia; Universidade Federal do Rio Grande do Sul - associated tracheobronchitis has a Healthcare-associated pneumonia; Porto Alegre (RS), Brazil. limited impact on overall mortality Pneumonia, ventilator-associated; 8. Critical Care Center, Centre Hospitalier but shows a significant association Ventilator-associated tracheobronchitis Universitaire de Lille - Lille, France. 9. School of Medicine, University of Lille - Lille, France. 10. Polyvalent Intensive Care Unit, Centro Hospitalar de Lisboa Ocidental, São Francisco Xavier Hospital - Lisboa, Portugal. INTRODUCTION 11. NOVA Medical School, CEDOC, New University of Lisbon, Campo Mártires da Pátria - Ventilator-associated lower respiratory tract infection (VA-LRTI) is one of Lisboa, Portugal. the most frequent complications in mechanically ventilated patients.(1,2) There has been a reduction in the ventilator-associated pneumonia (VAP) prevalence Conflicts of interest: None. over the last two decades.(3) This decrease has been associated with improvements in the knowledge of physiopathology and the implementation of adequate Submitted on February 27, 2019 Accepted on April 22, 2019 programs for prevention.(3) In contrast, ventilator-associated tracheobronchitis (VAT), which is characterized by signs of respiratory infection without new Corresponding author: radiographic infiltrates in patients who have been ventilated for at least 48 hours, Vicente Cés de Souza-Dantas Faculdade de Medicina has been neglected and considered a disease that does not warrant antibiotic Universidade Federal do Rio de Janeiro treatment by the vast majority of the medical community for many years.(4) R. Prof. Rodolpho Paulo Rocco, 255, 13º andar - In the last decade, several epidemiological studies have shown that VAT Ilha do Fundão Zip code: 21941-590 - Rio de Janeiro (RJ), Brazil could be considered a precursor of VAP. Furthermore, although VAT has a E-mail: vicentecsdantas@gmail.com limited impact on mortality, it shows a significant association with increased patient costs, length of stay (LOS), antibiotic use, and duration of mechanical Responsible editor: Felipe Dal-Pizzol ventilation (MV).(4) DOI: 10.5935/0103-507X.20190079 Rev Bras Ter Intensiva. 2019;31(4):541-547 This is an open access article under the CC BY license https://creativecommons.org/licenses/by/4.0/). 542 Salluh JI, Souza-Dantas VC, Martin-Loeches I, Lisboa TC, Rabello LS, Saad N, et al. Although there are no consensual gold standard a CT unit, it is important to keep in mind the potential definitions to diagnose these infectious complications, deleterious effects of transport in critically ill patients. diagnoses usually include clinical, radiologic and For instance, Bercault et al conducted a study in 118 microbiologic criteria.(1,5) Because no diagnostic criteria for patients transported out of the intensive care unit (ICU) VAT are widely accepted, its existence is still questioned by and found that the intrahospital transport of mechanically some authors, and its prevalence can vary from almost 0% ventilated patients was associated with an increased rate to 15% in patients who are mechanically ventilated.(6,7) of VAP (odds ratio [OR] 3.1; 95% confidence interval An improved understanding of VAT could have [95%CI] 1.4 - 6.7).(8) important implications for early diagnosis, initiation of With respect to etiology, VAT does not seem to differ antimicrobials, and prevention. However, the concept of from VAP. There are several observational studies that VAT is controversial, unlike VAP, and several important show that nonfermenting gram-negative bacteria are factors remain unclear, such as its definition, degree of the most frequent cause of VAT, and they account for overlap with VAP, diagnostic criteria, and appropriate approximately two-thirds of VAP episodes.(9,10) Some treatment regimens.(4) authors have also reported that multidrug resistant (MDR) pathogens are present in as many as one-third of Diagnosis and outcomes VAT episodes.(11,12) As previously stated, one important aspect of VAT Currently, the treatment of VAT has not been fully is the definition for such entities (Table 1). After a supported by any guidelines, including the recently careful review of published papers that defined VAT, launched Infectious Diseases Society of America and we concluded that definition might be, at times, a pure American Thoracic Society guidelines for the treatment jigsaw. Some definitions considered etiologies, thresholds, of hospital-acquired pneumonia.(5) While there are no or systemic symptoms; however, a common feature is the randomized control trials showing a benefit of VAT lack of lung infiltrates in portable chest X-ray (CRX). treatment, a good number of observational studies have This is obviously a good common denominator, but shown the association of inadequate treatment or no- identifying this feature in daily clinical practice is not treatment for VAT and the subsequent development of as easy as it seems. For instance, in a study published by VAP.(4,13-17) Self et al including patients admitted to an emergency A meta-analysis evaluating various strategies for department in the United States (US), they found a high the treatment of VAT found that the administration of discordance between CRX and computed tomography systemic antimicrobials (with or without aerosolized (CT) for the detection of pulmonary opacities.(7) The antimicrobials) in patients with VAT was not associated authors concluded that CRX had poor sensitivity with decreased mortality (OR 0.56; 95%CI 0.27 - and a poor positive predictive value for detecting 1.14). However, when other endpoints were assessed, a new infiltrates, leading to significant rates of the most of the studies that provided relevant data noted misdiagnosis of pneumonia. Considering these findings that administration of antimicrobial agents in patients and extrapolating the results to mechanically ventilated with VAT was associated with a decreased frequency of patients, diagnosis becomes even more difficult. subsequent pneumonia and an increase in ventilator-free Unfortunately, recent developments in lung imaging days. However, it remains unclear whether the length of in critical care patients have not been promising. We ICU stay and the duration of MV could be shortened.(18) do have new tools, such as lung ultrasonography; Biomarkers however, the methodology to diagnose VAP has not been adequately validated. In addition, these techniques, while Despite the limitations, some biomarkers, namely, potentially easy to perform, are still associated with a steep C-reactive protein (CRP) and procalcitonin (PCT), can learning curve. Ideally, portable CT scans will help in provide additional useful information for the clinical, the future, but this technology is not available in most laboratory and radiologic evaluation of a patient with hospitals worldwide. When choosing to bring a patient to suspected VA-LRTI.(19,20) Rev Bras Ter Intensiva. 2019;31(4):541-547 Ventilator-associated tracheobronchitis 543 Table 1 - Ventilator-associated events Ventilator-associated condition Increase in daily minimum PEEP of ≥ 3cm∕water or by FIO2 > 0.2 sustained for ≥ 2 days VAC PLUS (At least 2) Temperature of < 36°C or > 38°C OR Leukocyte count of ≤4000 or ≥12,000∕mm3 OR Cough OR New or increased production of sputum OR Rhonchi and wheezing OR Ventilator-associated tracheobronchitis Gram staining of endotracheal aspirate or bronchoalveolar lavage showing ≥ 25 neutrophils and ≤ 10 epithelial cells∕field PLUS Absence of new or progressive pulmonary infiltrates PLUS ETA with ≥10 CFU∕mm 5 3 OR PSB ≥103 CFU∕mm3 OR BAL culture with ≥104 CFU∕mm3 within 2 days before or after the onset of a VAC, excluding the first 2 days of MV IF NEGATIVE Use of new antibiotics continued for at least 4 days within 2 days before or after the onset of a VAC, excluding the first 2 days of MV VAT Ventilator-associated pneumonia PLUS Presence of new or progressive pulmonary infiltrates PEEP - positive end-expiratory pressure; FIO2 - fraction of inspired oxygen; VAC - ventilator-associated condition; ETA - endotracheal aspirate; PSB - protected specimen brush; BAL - bronchoalveolar-lavage; CFU - colony-forming units; MV - mechanical ventilation; VAT - ventilator-associated tracheobronchitis. Studies by our group showed that on the day of As a result, in the assessment of an individual patient confirmed VAP, both CRP and PCT levels could be under MV, CRP seems to be more useful in VA-LRTI useful.(21,22) Recently, we showed that among patients patients, since its concentration increases in both VAP with documented VA-LRTI, the levels of CRP and PCT and VAT. In contrast, PCT seems to particularly increase were significantly higher in VAP patients than in VAT in severe forms of VA-LRTI, that is, VAP, making it not patients.(23) Moreover, we found that CRP and PCT overly useful in the situation of VAT suspicion. concentrations in confirmed VAT patients were 14mg/ dL and 0,64ng/mL (median), respectively. According to Tracheobronchitis in special populations a recently proposed biomarker algorithm established to Some patient subgroups should be considered promote antibiotic stewardship,(24) CRP was below the separately, as some epidemiological, microbiological and infectious threshold level of 3mg/dL in 12% of VAT therapeutic aspects are specific to these subgroups. patients. However, according to the same algorithm, PCT Ventilated chronic obstructive pulmonary disease was below the threshold (1ng/mL) in 58% of the VAT (COPD) patients are at increased risk of nosocomial patients and was < 0.25ng/mL in 16% of these patients. respiratory infections. Nosocomial tracheobronchitis in Rev Bras Ter Intensiva. 2019;31(4):541-547 544 Salluh JI, Souza-Dantas VC, Martin-Loeches I, Lisboa TC, Rabello LS, Saad N, et al. COPD patients is associated with a prolonged duration of factors predispose these patients to infection, including of MV and ICU LOS.(25,26) The presence of bacteria in the host defense impairment and prolonged exposure to high lower airways of patients with COPD implies a breach bacterial loads. This exposure can occur through the of host defense mechanisms, initiating a vicious cycle of airway, and proper care of respiratory therapy devices is epithelial cell damage, impaired mucociliary clearance, essential to minimize the risk for infection.(32) Ventilator- mucus hypersecretion, increased submucosal vascular associated respiratory infections generally involve highly leakage, and inflammatory cell infiltration, thereby resistant pathogens, and individualized therapeutic promoting further dysfunction in host defenses and decisions are necessary to enhance the odds of appropriate bacterial adherence and growth.(26) Additionally, COPD empirical therapy. In these patients, adjunctive nebulized patients are at increased risk of infection with MDR antimicrobials have potential as a rescue therapy strategy. gram-negative bacilli, such as Pseudomonas aeruginosa.(27,28) The presence of these MDR pathogens could be associated Ventilator-associated tracheobronchitis as a quality with a poor prognosis.(28) Interestingly, in recent years, metric patients with COPD, especially those who are critically Intensive care units have always been at the center ill and admitted to an ICU, are being increasingly of national quality improvement programs, first by the recognized as belonging to a population at particular Institute for Healthcare Improvement(33) in the US and risk for Aspergillus. A recent report identified Aspergillus followed by many international initiatives. However, it tracheobronchitis in 5% of critically ill COPD patients.(29) seems that despite the initial increase in reporting, recent Therefore, although Aspergillus tracheobronchitis is not data suggests a new phenomenon: the “eradication of common in critically ill COPD patients, in this subgroup VAP”.(34) This has been ascribed to several factors, from of patients, early suspicion, diagnosis, and treatment the penalization of ICUs to discrepancies in diagnostic could be lifesaving. measures, lack of a gold standard for diagnosis, and In immunocompromised critically ill patients, such as poor agreement between clinical and surveillance those with hematological malignancies, cancer therapy or methodologies, among others.(1,35-37) transplantation recipients, considering fungal (including In recent years, VAT has been progressively studied, Aspergillus) or viral etiologies of tracheobronchitis is and evidence has demonstrated its impact on the outcomes crucial, as early suspicion, diagnosis and treatment are the of ICU patients.(4) The increase in VAT diagnoses in cornerstones of proper management.(30) ICUs has had some unintended consequences. The first The respiratory tract of patients with cystic fibrosis is of which was that some patients who would have been frequently colonized with multiple potential pathogens. previously diagnosed with VAP were now diagnosed with The development of tracheobronchitis in these patients VAT. However, as VAP, like other potentially avoidable is not rare, and the need for wide-spectrum antibiotics hospital-acquired infections, started to be monitored is common. The presence of VAT in these patients and in some cases associated with financial penalties, the requires the consideration of potential resistant gram- incentive to misclassify VAP as VAT increased, as VAT was negative bacilli, such as P. aeruginosa and carbapenem- associated with minor or no financial consequences and resistant strains of Klebsiella pneumoniae, and other did not potentially decrease the ICU’s quality indicators. Enterobacteriaceae, such as Alcaligenes xylosoxidans, For the above-described reasons, perhaps the best way Acinetobacter spp., Stenotrophomonas maltophilia, and to proceed would also be to include the VAT rate as a Burkholderia spp. as potential pathogens. This makes the quality indicator. This proposition has evident pros and empirical antimicrobial choice complex, and previous cons. Those in favor of it state that if the mechanisms of microbiological data availability might be useful to improve acquisition of VAT are similar to those of VAP and perhaps the appropriateness of and individualize treatment. VAP is a continuum of VAT, then it is also a preventable Chronic critically ill patients are a specific population condition.(38) Additionally, as most ICUs diagnose and with an increasing prevalence in the ICU.(31) Critical treat VAT, its impact on patient management, resource illness is associated with prolonged MV, increasing the risk use and antibiotic use is not negligible.(39) Finally, the for ventilator-associated respiratory infections. A number application of this concept would adequately cover the Rev Bras Ter Intensiva. 2019;31(4):541-547 Ventilator-associated tracheobronchitis 545 full spectrum of “VA-LRTI”, yielding realistic rates. Of pneumonia. Although associated with a significantly course, there are limitations (Table 2) to this concept; the lower mortality than ventilator-associated pneumonia, main one is the lack of robust evidence suggesting that tracheobronchitis survivors had a similar duration of the VAP bundle or specific VAP preventive measures are mechanical ventilation and length of stay in the intensive effective for VAT prevention. care unit. Additionally, the progression of ventilator- associated tracheobronchitis to ventilator-associated Table 2 - Limitations to ventilator-associated tracheobronchitis as a quality pneumonia was significantly increased when patients indicator with ventilator-associated tracheobronchitis were VAT surveillance definitions are subjective given inappropriate or no antibiotics. Although these VAT surveillance is very complex to automate disorders could occur independently, some evidence Discordance regarding the diagnosis of VAT is frequent suggests that they are somewhat related and that, if left Mortality attributable to VAT is low untreated or inappropriately treated, ventilator-associated Little evidence of VAT preventive measures and its impact on outcomes exists tracheobronchitis is highly likely to progress to pneumonia. It is difficult to compare VAT rates between ICUs Finally, we acknowledge the urgent need for a consensus VAT - ventilator-associated tracheobronchitis; ICU - intensive care unit. in the diagnosis and management of ventilator-associated tracheobronchitis. Further large randomized studies Thus, future studies on VAP prevention should be are needed to clarify the effect of appropriate antibiotic extended to VAT to produce the necessary evidence. treatment on the length of stay in the intensive care unit Moreover, ideally, indicators should be safe, effective, and duration of mechanical ventilation in these patients. efficient, equitable, and timely. Therefore, it would be Funding useful, perhaps, to create future initiatives to develop quality indicators that are less prone to interobserver The present manuscript had no source of funding. Dr. variability (e.g., antibiotic dose after 48 hours in the ICU Salluh is supported in part by individual research grants as a surrogate of ICU-acquired infections).(40,41) from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação Carlos Chagas Filho de CONCLUSIONS Amparo à Pesquisa do Rio de Janeiro (FAPERJ). Ventilator-associated tracheobronchitis is a frequent Authors’ contributions and clinically relevant infectious complication in patients under mechanical ventilation for more than 48 All authors contributed equally. hours, with a similar incidence to ventilator-associated RESUMO desses pacientes, assim como do tempo de internação na unida- As infecções do trato respiratório inferior associadas à ven- de de terapia intensiva e hospitalar, do uso de antibióticos, e da tilação mecânica são uma das complicações mais frequentes em duração da ventilação mecânica. Embora ainda necessitemos de pacientes em ventilação mecânica. Há muitos anos, a traqueo- evidências científicas mais robustas, especialmente no que tange bronquite associada à ventilação mecânica tem sido considerada às modalidades terapêuticas, os dados atuais a respeito da tra- uma doença que não demanda antibioticoterapia. Na última queobronquite associada à ventilação mecânica salientam que década, diversos estudos demonstraram que a traqueobronquite há desfechos suficientemente importantes que exigem vigilância associada à ventilação mecânica deve ser considerada um pro- epidemiológica e controle clínico adequados. cesso intermediário que leva à pneumonia associada à ventilação mecânica, uma vez que apesar de ter impacto limitado sobre Descritores: Terapia intensiva; Mortalidade; Infecção a mortalidade dos pacientes gravemente enfermos internados nosocomial; Pneumonia; Pneumonia associada a assistência nas unidades de terapia intensiva, em contrapartida, demonstra à saúde; Pneumonia associada à ventilação mecânica; associação significativa com o aumento dos custos hospitalares Traqueobronquite associada a ventilação mecânica Rev Bras Ter Intensiva. 2019;31(4):541-547 546 Salluh JI, Souza-Dantas VC, Martin-Loeches I, Lisboa TC, Rabello LS, Saad N, et al. REFERENCES 1. 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