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Semin Respir Crit Care Med 2024; 45(06): 626-633
DOI: 10.1055/s-0044-1792111
Review Article

Bacteriology of Aspiration Pneumonia: The Lung Microbiome and the Changing Microbial Etiology

Francois Fadell
1   VA Western New York Healthcare System, Research and Development, Buffalo, New York
2   Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University at Buffalo, Buffalo, New York
,
Ranime Saliba
1   VA Western New York Healthcare System, Research and Development, Buffalo, New York
2   Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University at Buffalo, Buffalo, New York
,
Ali A. El-Solh
1   VA Western New York Healthcare System, Research and Development, Buffalo, New York
2   Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University at Buffalo, Buffalo, New York
3   Department of Anesthesiology, Jacobs School of Medicine, University at Buffalo, Buffalo, New York
4   Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York
› Author Affiliations Funding The study was supported in part by a grant from the U.S. Department of Veterans Affairs (AES IO1CX 001656).
› Further Information
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Abstract

Aspiration pneumonia refers to the process of alveolar inflammation induced by the inhalation of oropharyngeal secretions into the lower respiratory tract. Predisposing factors comprise swallowing dysfunction, impaired cough reflex, and degenerative neurological diseases. Accumulating evidence projects a fading contribution of anaerobic bacteria in aspiration pneumonia at the expense of Gram-negative bacilli, with Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, becoming the predominant organisms recovered from respiratory specimens. Aspiration of oropharyngeal secretions colonized with respiratory pathogens induces a profound disequilibrium of the lung microbiota resulting in a state of dysbiosis. Understanding this complex temporal variability between microbiome–host associations was only made possible with the introduction of metagenomic sequencing. In this narrative review, we summarize existing knowledge and elaborate on the evolving microbiology of aspiration pneumonia including the link between oral microbiome and pulmonary aspiration. We also highlight the progress and challenges in instituting microbiome-targeted strategies for preventing and treating the sequelae of aspiration pneumonia.

Keywords

aspiration pneumonia - microbiology - microbiome - diagnostic modalities

Note

The contents of this paper do not represent the views of the Department of Veterans Affairs or the U.S. Government.




Publication History

Article published online:
13 November 2024

© 2024. Thieme. All rights reserved.

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  • References

  • 1 Mendelson CL. The aspiration of stomach contents into the lungs during obstetric anesthesia. Am J Obstet Gynecol 1946; 52: 191-205
    CrossrefPubMedSearch in Google Scholar
  • 2 Doyle RL, Szaflarski N, Modin GW, Wiener-Kronish JP, Matthay MA. Identification of patients with acute lung injury. Predictors of mortality. Am J Respir Crit Care Med 1995; 152 (6 Pt 1): 1818-1824
    CrossrefPubMedSearch in Google Scholar
  • 3 Bynum LJ, Pierce AK. Pulmonary aspiration of gastric contents. Am Rev Respir Dis 1976; 114 (06) 1129-1136
    PubMedSearch in Google Scholar
  • 4 Mandell LA, Niederman MS. Aspiration pneumonia. N Engl J Med 2019; 380 (07) 651-663
    CrossrefPubMedSearch in Google Scholar
  • 5 Goodwin RS. Prevention of aspiration pneumonia: a research-based protocol. Dimens Crit Care Nurs 1996; 15 (02) 58-71 , quiz 72
    CrossrefPubMedSearch in Google Scholar
  • 6 Reza Shariatzadeh M, Huang JQ, Marrie TJ. Differences in the features of aspiration pneumonia according to site of acquisition: community or continuing care facility. J Am Geriatr Soc 2006; 54 (02) 296-302
    CrossrefPubMedSearch in Google Scholar
  • 7 Marrie TJ, Durant H, Yates L. Community-acquired pneumonia requiring hospitalization: 5-year prospective study. Rev Infect Dis 1989; 11 (04) 586-599
    CrossrefPubMedSearch in Google Scholar
  • 8 Lanspa MJ, Jones BE, Brown SM, Dean NC. Mortality, morbidity, and disease severity of patients with aspiration pneumonia. J Hosp Med 2013; 8 (02) 83-90
    CrossrefPubMedSearch in Google Scholar
  • 9 Teramoto S, Yoshida K, Hizawa N. Update on the pathogenesis and management of pneumonia in the elderly-roles of aspiration pneumonia. Respir Investig 2015; 53 (05) 178-184
    CrossrefPubMedSearch in Google Scholar
  • 10 Kalil AC, Metersky ML, Klompas M. et al. Executive summary: 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. Clin Infect Dis 2016; 63 (05) 575-582
    CrossrefPubMedSearch in Google Scholar
  • 11 Almirall J, Rofes L, Serra-Prat M. et al. Oropharyngeal dysphagia is a risk factor for community-acquired pneumonia in the elderly. Eur Respir J 2013; 41 (04) 923-928
    CrossrefPubMedSearch in Google Scholar
  • 12 Kikuchi R, Watabe N, Konno T, Mishina N, Sekizawa K, Sasaki H. High incidence of silent aspiration in elderly patients with community-acquired pneumonia. Am J Respir Crit Care Med 1994; 150 (01) 251-253
    CrossrefPubMedSearch in Google Scholar
  • 13 Loeb M, McGeer A, McArthur M, Walter S, Simor AE. Risk factors for pneumonia and other lower respiratory tract infections in elderly residents of long-term care facilities. Arch Intern Med 1999; 159 (17) 2058-2064
    CrossrefPubMedSearch in Google Scholar
  • 14 Langmore SE, Terpenning MS, Schork A. et al. Predictors of aspiration pneumonia: how important is dysphagia?. Dysphagia 1998; 13 (02) 69-81
    CrossrefPubMedSearch in Google Scholar
  • 15 Terré-Boliart R, Orient-López F, Guevara-Espinosa D, Ramón-Rona S, Bernabeu-Guitart M, Clavé-Civit P. [Oropharyngeal dysphagia in patients with multiple sclerosis]. Rev Neurol 2004; 39 (08) 707-710
    PubMedSearch in Google Scholar
  • 16 DeToledo JC, Lowe MR, Gonzalez J, Haddad H. Risk of aspiration pneumonia after an epileptic seizure: a retrospective analysis of 1634 adult patients. Epilepsy Behav 2004; 5 (04) 593-595
    CrossrefPubMedSearch in Google Scholar
  • 17 Foocharoen C, Siriphannon Y, Mahakkanukrauh A, Suwannaroj S, Nanagara R. Incidence rate and causes of infection in Thai systemic sclerosis patients. Int J Rheum Dis 2012; 15 (03) 277-283
    CrossrefPubMedSearch in Google Scholar
  • 18 Levin K, Colon A, DiPalma J, Fitzpatrick S. Using the radionuclide salivagram to detect pulmonary aspiration and esophageal dysmotility. Clin Nucl Med 1993; 18 (02) 110-114
    CrossrefPubMedSearch in Google Scholar
  • 19 Adnet F, Baud F. Relation between Glasgow Coma Scale and aspiration pneumonia. Lancet 1996; 348 (9020): 123-124
    CrossrefPubMedSearch in Google Scholar
  • 20 Mizock BA. Risk of aspiration in patients on enteral nutrition: frequency, relevance, relation to pneumonia, risk factors, and strategies for risk reduction. Curr Gastroenterol Rep 2007; 9 (04) 338-344
    CrossrefPubMedSearch in Google Scholar
  • 21 Gomes GF, Pisani JC, Macedo ED, Campos AC. The nasogastric feeding tube as a risk factor for aspiration and aspiration pneumonia. Curr Opin Clin Nutr Metab Care 2003; 6 (03) 327-333
    CrossrefPubMedSearch in Google Scholar
  • 22 Fox KA, Mularski RA, Sarfati MR. et al. Aspiration pneumonia following surgically placed feeding tubes. Am J Surg 1995; 170 (06) 564-566 , discussion 566–567
    CrossrefPubMedSearch in Google Scholar
  • 23 El Solh AA, Brewer T, Okada M, Bashir O, Gough M. Indicators of recurrent hospitalization for pneumonia in the elderly. J Am Geriatr Soc 2004; 52 (12) 2010-2015
    CrossrefPubMedSearch in Google Scholar
  • 24 Quagliarello V, Ginter S, Han L, Van Ness P, Allore H, Tinetti M. Modifiable risk factors for nursing home-acquired pneumonia. Clin Infect Dis 2005; 40 (01) 1-6
    CrossrefPubMedSearch in Google Scholar
  • 25 Hata R, Noguchi S, Kawanami T. et al. Poor oral hygiene is associated with the detection of obligate anaerobes in pneumonia. J Periodontol 2020; 91 (01) 65-73
    CrossrefPubMedSearch in Google Scholar
  • 26 Mira A, Simon-Soro A, Curtis MA. Role of microbial communities in the pathogenesis of periodontal diseases and caries. J Clin Periodontol 2017; 44 (Suppl. 18) S23-S38
    CrossrefPubMedSearch in Google Scholar
  • 27 Winning L, Lundy FT, Blackwood B, McAuley DF, El Karim I. Oral health care for the critically ill: a narrative review. Crit Care 2021; 25 (01) 353
    CrossrefPubMedSearch in Google Scholar
  • 28 Kikutani T, Tamura F, Tashiro H, Yoshida M, Konishi K, Hamada R. Relationship between oral bacteria count and pneumonia onset in elderly nursing home residents. Geriatr Gerontol Int 2015; 15 (04) 417-421
    CrossrefPubMedSearch in Google Scholar
  • 29 Bächli P, Baars S, Simmler A, Zbinden R, Schulthess B. Impact of MALDI-TOF MS identification on anaerobic species and genus diversity in routine diagnostics. Anaerobe 2022; 75: 102554
    CrossrefPubMedSearch in Google Scholar
  • 30 Zarco MF, Vess TJ, Ginsburg GS. The oral microbiome in health and disease and the potential impact on personalized dental medicine. Oral Dis 2012; 18 (02) 109-120
    CrossrefPubMedSearch in Google Scholar
  • 31 Overmann J, Abt B, Sikorski J. Present and future of culturing bacteria. Annu Rev Microbiol 2017; 71: 711-730
    CrossrefPubMedSearch in Google Scholar
  • 32 Tortuyaux R, Voisin B, Cordonnier C, Nseir S. Could polymerase chain reaction-based methods differentiate pneumonitis from bacterial aspiration pneumonia?. Crit Care Med 2018; 46 (01) e96-e97
    CrossrefPubMedSearch in Google Scholar
  • 33 Darie AM, Khanna N, Jahn K. et al. Fast multiplex bacterial PCR of bronchoalveolar lavage for antibiotic stewardship in hospitalised patients with pneumonia at risk of Gram-negative bacterial infection (Flagship II): a multicentre, randomised controlled trial. Lancet Respir Med 2022; 10 (09) 877-887
    CrossrefPubMedSearch in Google Scholar
  • 34 Tavares DA, Handem S, Carvalho RJ. et al. Identification of Streptococcus pneumoniae by a real-time PCR assay targeting SP2020. Sci Rep 2019; 9 (01) 3285
    CrossrefPubMedSearch in Google Scholar
  • 35 Carney SM, Clemente JC, Cox MJ. et al. Methods in lung microbiome research. Am J Respir Cell Mol Biol 2020; 62 (03) 283-299
    CrossrefPubMedSearch in Google Scholar
  • 36 Lane DJ, Pace B, Olsen GJ, Stahl DA, Sogin ML, Pace NR. Rapid determination of 16S ribosomal RNA sequences for phylogenetic analyses. Proc Natl Acad Sci U S A 1985; 82 (20) 6955-6959
    CrossrefPubMedSearch in Google Scholar
  • 37 Zhang Y, Ji P, Wang J, Zhao F. RiboFR-Seq: a novel approach to linking 16S rRNA amplicon profiles to metagenomes. Nucleic Acids Res 2016; 44 (10) e99
    CrossrefPubMedSearch in Google Scholar
  • 38 Whiteside SA, McGinniss JE, Collman RG. The lung microbiome: progress and promise. J Clin Invest 2021; 131 (15) 131
    CrossrefPubMedSearch in Google Scholar
  • 39 Johnson JS, Spakowicz DJ, Hong BY. et al. Evaluation of 16S rRNA gene sequencing for species and strain-level microbiome analysis. Nat Commun 2019; 10 (01) 5029
    CrossrefPubMedSearch in Google Scholar
  • 40 Wilson MR, Naccache SN, Samayoa E. et al. Actionable diagnosis of neuroleptospirosis by next-generation sequencing. N Engl J Med 2014; 370 (25) 2408-2417
    CrossrefPubMedSearch in Google Scholar
  • 41 Mac Aogáin M, Lau KJX, Cai Z. et al. Metagenomics reveals a core macrolide resistome related to microbiota in chronic respiratory disease. Am J Respir Crit Care Med 2020; 202 (03) 433-447
    CrossrefPubMedSearch in Google Scholar
  • 42 Millares L, Pérez-Brocal V, Ferrari R. et al. Functional metagenomics of the bronchial microbiome in COPD. PLoS One 2015; 10 (12) e0144448
    CrossrefPubMedSearch in Google Scholar
  • 43 Simner PJ, Miller S, Carroll KC. Understanding the promises and hurdles of metagenomic next-generation sequencing as a diagnostic tool for infectious diseases. Clin Infect Dis 2018; 66 (05) 778-788
    CrossrefPubMedSearch in Google Scholar
  • 44 Schmieder R, Edwards R. Quality control and preprocessing of metagenomic datasets. Bioinformatics 2011; 27 (06) 863-864
    CrossrefPubMedSearch in Google Scholar
  • 45 Hasan MR, Rawat A, Tang P. et al. Depletion of human DNA in spiked clinical specimens for improvement of sensitivity of pathogen detection by next-generation sequencing. J Clin Microbiol 2016; 54 (04) 919-927
    CrossrefPubMedSearch in Google Scholar
  • 46 Pendleton KM, Erb-Downward JR, Bao Y. et al. Rapid pathogen identification in bacterial pneumonia using real-time metagenomics. Am J Respir Crit Care Med 2017; 196 (12) 1610-1612
    CrossrefPubMedSearch in Google Scholar
  • 47 Zhou H, Larkin PMK, Zhao D. et al. Clinical impact of metagenomic next-generation sequencing of bronchoalveolar lavage in the diagnosis and management of pneumonia: a multicenter prospective observational study. J Mol Diagn 2021; 23 (10) 1259-1268
    CrossrefPubMedSearch in Google Scholar
  • 48 Xu H, Zhang R, Zhang X, Cheng Y, Lv L, Lin L. Microbiological profile of patients with aspiration pneumonia identified by combined detection methods. Infect Drug Resist 2024; 17: 2077-2088
    CrossrefPubMedSearch in Google Scholar
  • 49 Marchesi JR, Ravel J. The vocabulary of microbiome research: a proposal. Microbiome 2015; 3: 31
    CrossrefPubMedSearch in Google Scholar
  • 50 Charlson ES, Bittinger K, Haas AR. et al. Topographical continuity of bacterial populations in the healthy human respiratory tract. Am J Respir Crit Care Med 2011; 184 (08) 957-963
    CrossrefPubMedSearch in Google Scholar
  • 51 Dickson RP, Erb-Downward JR, Freeman CM. et al. Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography. Ann Am Thorac Soc 2015; 12 (06) 821-830
    CrossrefPubMedSearch in Google Scholar
  • 52 Sommariva M, Le Noci V, Bianchi F. et al. The lung microbiota: role in maintaining pulmonary immune homeostasis and its implications in cancer development and therapy. Cell Mol Life Sci 2020; 77 (14) 2739-2749
    CrossrefPubMedSearch in Google Scholar
  • 53 Alsayed AR, Abed A, Khader HA. et al. Molecular accounting and profiling of human respiratory microbial communities: toward precision medicine by targeting the respiratory microbiome for disease diagnosis and treatment. Int J Mol Sci 2023; 24 (04) 24
    CrossrefPubMedSearch in Google Scholar
  • 54 Dickson RP, Erb-Downward JR, Freeman CM. et al. Bacterial topography of the healthy human lower respiratory tract. MBio 2017; 8 (01) 8
    CrossrefPubMedSearch in Google Scholar
  • 55 Goeteyn E, Grassi L, Van den Bossche S. et al. Commensal bacteria of the lung microbiota synergistically inhibit inflammation in a three-dimensional epithelial cell model. Front Immunol 2023; 14: 1176044
    CrossrefPubMedSearch in Google Scholar
  • 56 Wang L, He Y, Li H, Ai Q, Yu J. The microbiota protects against Pseudomonas aeruginosa pneumonia via γδ T cell-neutrophil axis in mice. Microbes Infect 2020; 22 (08) 294-302
    CrossrefPubMedSearch in Google Scholar
  • 57 Whiteson KL, Bailey B, Bergkessel M. et al. The upper respiratory tract as a microbial source for pulmonary infections in cystic fibrosis. Parallels from island biogeography. Am J Respir Crit Care Med 2014; 189 (11) 1309-1315
    CrossrefPubMedSearch in Google Scholar
  • 58 Pettigrew MM, Tanner W, Harris AD. The lung microbiome and pneumonia. J Infect Dis 2021; 223 (12, Suppl 2): S241-S245
    CrossrefPubMedSearch in Google Scholar
  • 59 Dickson RP, Erb-Downward JR, Huffnagle GB. Towards an ecology of the lung: new conceptual models of pulmonary microbiology and pneumonia pathogenesis. Lancet Respir Med 2014; 2 (03) 238-246
    CrossrefPubMedSearch in Google Scholar
  • 60 Belizário J, Garay-Malpartida M, Faintuch J. Lung microbiome and origins of the respiratory diseases. Curr Res Immunol 2023; 4: 100065
    CrossrefPubMedSearch in Google Scholar
  • 61 Lloyd CM, Marsland BJ. Lung homeostasis: influence of age, microbes, and the immune system. Immunity 2017; 46 (04) 549-561
    CrossrefPubMedSearch in Google Scholar
  • 62 Wu BG, Sulaiman I, Tsay JJ. et al. Episodic aspiration with oral commensals induces a MyD88-dependent, pulmonary T-helper cell type 17 response that mitigates susceptibility to Streptococcus pneumoniae . Am J Respir Crit Care Med 2021; 203 (09) 1099-1111
    CrossrefPubMedSearch in Google Scholar
  • 63 Horn KJ, Schopper MA, Drigot ZG, Clark SE. Airway Prevotella promote TLR2-dependent neutrophil activation and rapid clearance of Streptococcus pneumoniae from the lung. Nat Commun 2022; 13 (01) 3321
    CrossrefPubMedSearch in Google Scholar
  • 64 Natalini JG, Singh S, Segal LN. The dynamic lung microbiome in health and disease. Nat Rev Microbiol 2023; 21 (04) 222-235
    CrossrefPubMedSearch in Google Scholar
  • 65 Dickson RP, Singer BH, Newstead MW. et al. Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome. Nat Microbiol 2016; 1 (10) 16113
    CrossrefPubMedSearch in Google Scholar
  • 66 Barfod KK, Vrankx K, Mirsepasi-Lauridsen HC. et al. The murine lung microbiome changes during lung inflammation and intranasal vancomycin treatment. Open Microbiol J 2015; 9: 167-179
    CrossrefPubMedSearch in Google Scholar
  • 67 Bartlett JG, Gorbach SL, Finegold SM. The bacteriology of aspiration pneumonia. Am J Med 1974; 56 (02) 202-207
    CrossrefPubMedSearch in Google Scholar
  • 68 Cesar L, Gonzalez C, Calia FM. Bacteriologic flora of aspiration-induced pulmonary infections. Arch Intern Med 1975; 135 (05) 711-714
    CrossrefPubMedSearch in Google Scholar
  • 69 Lorber B, Swenson RM. Bacteriology of aspiration pneumonia. A prospective study of community- and hospital-acquired cases. Ann Intern Med 1974; 81 (03) 329-331
    CrossrefPubMedSearch in Google Scholar
  • 70 Bartlett JG, Gorbach SL. The triple threat of aspiration pneumonia. Chest 1975; 68 (04) 560-566
    CrossrefPubMedSearch in Google Scholar
  • 71 Brook I, Finegold SM. Bacteriology of aspiration pneumonia in children. Pediatrics 1980; 65 (06) 1115-1120
    CrossrefPubMedSearch in Google Scholar
  • 72 Hayashi M, Iwasaki T, Yamazaki Y. et al. Clinical features and outcomes of aspiration pneumonia compared with non-aspiration pneumonia: a retrospective cohort study. J Infect Chemother 2014; 20 (07) 436-442
    CrossrefPubMedSearch in Google Scholar
  • 73 Suzuki J, Ikeda R, Kato K. et al. Characteristics of aspiration pneumonia patients in acute care hospitals: a multicenter, retrospective survey in Northern Japan. PLoS One 2021; 16 (07) e0254261
    CrossrefPubMedSearch in Google Scholar
  • 74 El-Solh AA, Pietrantoni C, Bhat A. et al. Microbiology of severe aspiration pneumonia in institutionalized elderly. Am J Respir Crit Care Med 2003; 167 (12) 1650-1654
    CrossrefPubMedSearch in Google Scholar
  • 75 Tokuyasu H, Harada T, Watanabe E. et al. Effectiveness of meropenem for the treatment of aspiration pneumonia in elderly patients. Intern Med 2009; 48 (03) 129-135
    CrossrefPubMedSearch in Google Scholar
  • 76 El-Solh AA, Pietrantoni C, Bhat A. et al. Colonization of dental plaques: a reservoir of respiratory pathogens for hospital-acquired pneumonia in institutionalized elders. Chest 2004; 126 (05) 1575-1582
    CrossrefPubMedSearch in Google Scholar
  • 77 Fourrier F, Duvivier B, Boutigny H, Roussel-Delvallez M, Chopin C. Colonization of dental plaque: a source of nosocomial infections in intensive care unit patients. Crit Care Med 1998; 26 (02) 301-308
    CrossrefPubMedSearch in Google Scholar
  • 78 Ewan VC, Sails AD, Walls AW, Rushton S, Newton JL. Dental and microbiological risk factors for hospital-acquired pneumonia in non-ventilated older patients. PLoS One 2015; 10 (04) e0123622
    CrossrefPubMedSearch in Google Scholar
  • 79 Cilloniz C, Martin-Loeches I, Garcia-Vidal C, San Jose A, Torres A. Microbial etiology of pneumonia: epidemiology, diagnosis and resistance patterns. Int J Mol Sci 2016; 17 (12) 17
    CrossrefPubMedSearch in Google Scholar
  • 80 Mori H, Hirasawa H, Oda S, Shiga H, Matsuda K, Nakamura M. Oral care reduces incidence of ventilator-associated pneumonia in ICU populations. Intensive Care Med 2006; 32 (02) 230-236
    CrossrefPubMedSearch in Google Scholar
  • 81 Otsuji K, Fukuda K, Ogawa M, Fujino Y, Kamochi M, Saito M. Dynamics of microbiota during mechanical ventilation in aspiration pneumonia. BMC Pulm Med 2019; 19 (01) 260
    CrossrefPubMedSearch in Google Scholar
  • 82 Roquilly A, Marret E, Abraham E, Asehnoune K. Pneumonia prevention to decrease mortality in intensive care unit: a systematic review and meta-analysis. Clin Infect Dis 2015; 60 (01) 64-75
    CrossrefPubMedSearch in Google Scholar
  • 83 Roquilly A, Torres A, Villadangos JA. et al. Pathophysiological role of respiratory dysbiosis in hospital-acquired pneumonia. Lancet Respir Med 2019; 7 (08) 710-720
    CrossrefPubMedSearch in Google Scholar
  • 84 Cheema HA, Shahid A, Ayyan M. et al. Probiotics for the prevention of ventilator-associated pneumonia: an updated systematic review and meta-analysis of randomised controlled trials. Nutrients 2022; 14 (08) 14
    CrossrefPubMedSearch in Google Scholar
  • 85 Zhao J, Li LQ, Chen CY, Zhang GS, Cui W, Tian BP. Do probiotics help prevent ventilator-associated pneumonia in critically ill patients? A systematic review with meta-analysis. ERJ Open Res 2021; 7 (01) 7
    CrossrefPubMedSearch in Google Scholar