New Insights in the Pathophysiology of Hospital- and Ventilator-Acquired Pneumonia: A Complex Interplay between Dysbiosis and Critical-Illness–Related Immunosuppression

Abstract

Both hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) have long been considered as diseases resulting from the invasion by pathogens of a previously sterile lung environment. Based on this historical understanding of their pathophysiology, our approaches for the prevention and treatment have significantly improved the outcomes of patients, but treatment failures remain frequent. Recent studies have suggested that the all-antimicrobial therapy-based treatment of pneumonia has reached a glass ceiling. The demonstration that the constant interactions between the respiratory microbiome and mucosal immunity are required to tune homeostasis in a state of symbiosis has changed our comprehension of pneumonia. We proposed that HAP and VAP should be considered as a state of dysbiosis, defined as the emergence of a dominant pathogen thriving at the same time from the catastrophic collapse of the fragile ecosystem of the lower respiratory tract and from the development of critical-illness–related immunosuppression. This multidimensional approach to the pathophysiology of HAP and VAP holds the potential to achieve future successes in research and critical care. Microbiome and mucosal immunity can indeed be manipulated and used as adjunctive therapies or targets to prevent or treat pneumonia.

Keywords

hospital-acquired pneumonia - dysbiosis - critical-illness–related immunosuppression

Publication History

Article published online:
31 January 2022

• References

• 1 Eber MR, Laxminarayan R, Perencevich EN, Malani A. Clinical and economic outcomes attributable to health care-associated sepsis and pneumonia. Arch Intern Med 2010; 170 (04) 347-353
• 2 Melsen WG, Rovers MM, Groenwold RHH. et al. Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies. Lancet Infect Dis 2013; 13 (08) 665-671
• 3 Titov I, Wunderink RG, Roquilly A. et al. A randomized, double-blind, multicenter trial comparing efficacy and safety of imipenem/cilastatin/relebactam versus piperacillin/tazobactam in adults with hospital-acquired or ventilator-associated bacterial pneumonia (RESTORE-IMI 2 Study). Clin Infect Dis 2020; ciaa803
• 4 Roquilly A, Chanques G, Lasocki S, Foucrier A, Fermier B, De Courson H. et al. Implementation of French recommendations for the prevention and the treatment of hospital-acquired pneumonia: a cluster-randomized trial. Clin Infect Dis Off Publ Infect Dis Soc Am 2020; ciaa1441
• 5 Gill SR, Pop M, Deboy RT. et al. Metagenomic analysis of the human distal gut microbiome. Science 2006; 312 (5778): 1355-1359
• 6 Hasleton PS. The internal surface area of the adult human lung. J Anat 1972; 112 (Pt 3): 391-400
• 7 Mathieu E, Escribano-Vazquez U, Descamps D. et al. Paradigms of lung microbiota functions in health and disease, particularly, in asthma. Front Physiol 2018; 9: 1168
• 8 Fromentin M, Ricard J-D, Roux D. Respiratory microbiome in mechanically ventilated patients: a narrative review. Intensive Care Med 2021; 47 (03) 292-306
• 9 Venkataraman A, Bassis CM, Beck JM. et al. Application of a neutral community model to assess structuring of the human lung microbiome. MBio 2015; 6 (01) e02284-e14
• 10 Dickson RP, Erb-Downward JR, Freeman CM. et al. Bacterial topography of the healthy human lower respiratory tract. MBio 2017; 8 (01) e02287-e16
• 11 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
• 12 Sze MA, Dimitriu PA, Hayashi S. et al. The lung tissue microbiome in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 185 (10) 1073-1080
• 13 Brestoff JR, Artis D. Commensal bacteria at the interface of host metabolism and the immune system. Nat Immunol 2013; 14 (07) 676-684
• 14 Segal LN, Alekseyenko AV, Clemente JC. et al. Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation. Microbiome 2013; 1 (01) 19
• 15 Dickson RP, Erb-Downward JR, Prescott HC. et al. Intraalveolar catecholamines and the human lung microbiome. Am J Respir Crit Care Med 2015; 192 (02) 257-259
• 16 Lloyd CM, Marsland BJ. Lung homeostasis: influence of age, microbes, and the immune system. Immunity 2017; 46 (04) 549-561
• 17 Barcik W, Boutin RCT, Sokolowska M, Finlay BB. The role of lung and gut microbiota in the pathology of asthma. Immunity 2020; 52 (02) 241-255
• 18 Mammen MJ, Sethi S. COPD and the microbiome. Respirology 2016; 21 (04) 590-599
• 19 Caverly LJ, LiPuma JJ. Cystic fibrosis respiratory microbiota: unraveling complexity to inform clinical practice. Expert Rev Respir Med 2018; 12 (10) 857-865
• 20 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
• 21 Bahrani-Mougeot FK, Paster BJ, Coleman S. et al. Molecular analysis of oral and respiratory bacterial species associated with ventilator-associated pneumonia. J Clin Microbiol 2007; 45 (05) 1588-1593
• 22 Kelly BJ, Imai I, Bittinger K. et al. Composition and dynamics of the respiratory tract microbiome in intubated patients. Microbiome 2016; 4: 7
• 23 Kyo M, Nishioka K, Nakaya T. et al. Unique patterns of lower respiratory tract microbiota are associated with inflammation and hospital mortality in acute respiratory distress syndrome. Respir Res 2019; 20 (01) 246
• 24 Dickson RP, Schultz MJ, van der Poll T. et al; Biomarker Analysis in Septic ICU Patients (BASIC) Consortium. Lung microbiota predict clinical outcomes in critically ill patients. Am J Respir Crit Care Med 2020; 201 (05) 555-563
• 25 Erb-Downward JR, Thompson DL, Han MK. et al. Analysis of the lung microbiome in the “healthy” smoker and in COPD. PLoS One 2011; 6 (02) e16384
• 26 Huang YJ, Erb-Downward JR, Dickson RP, Curtis JL, Huffnagle GB, Han MK. Understanding the role of the microbiome in chronic obstructive pulmonary disease: principles, challenges, and future directions. Transl Res 2017; 179: 71-83
• 27 Huang W-C, Wu M-F, Huang C-C. et al. Dynamics of the lung microbiome in intensive care patients with chronic obstructive pulmonary disease and community-acquired pneumonia. Sci Rep 2020; 10 (01) 11046
• 28 Ruff WE, Greiling TM, Kriegel MA. Host-microbiota interactions in immune-mediated diseases. Nat Rev Microbiol 2020; 18 (09) 521-538
• 29 Morris A, Beck JM, Schloss PD. et al; Lung HIV Microbiome Project. Comparison of the respiratory microbiome in healthy nonsmokers and smokers. Am J Respir Crit Care Med 2013; 187 (10) 1067-1075
• 30 Zakharkina T, Martin-Loeches I, Matamoros S. et al. The dynamics of the pulmonary microbiome during mechanical ventilation in the intensive care unit and the association with occurrence of pneumonia. Thorax 2017; 72 (09) 803-810
• 31 Lankelma JM, van Vught LA, Belzer C. et al. Critically ill patients demonstrate large interpersonal variation in intestinal microbiota dysregulation: a pilot study. Intensive Care Med 2017; 43 (01) 59-68
• 32 Sulaiman I, Wu BG, Li Y. et al. Evaluation of the airway microbiome in nontuberculous mycobacteria disease. Eur Respir J 2018; 52 (04) 1800810
• 33 Stewart CJ, Mansbach JM, Wong MC. et al. Associations of nasopharyngeal metabolome and microbiome with severity among infants with bronchiolitis. a multiomic analysis. Am J Respir Crit Care Med 2017; 196 (07) 882-891
• 34 Cadwell K. The virome in host health and disease. Immunity 2015; 42 (05) 805-813
• 35 Molyneaux PL, Mallia P, Cox MJ. et al. Outgrowth of the bacterial airway microbiome after rhinovirus exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013; 188 (10) 1224-1231
• 36 de Steenhuijsen Piters WAA, Heinonen S, Hasrat R. et al. Nasopharyngeal microbiota, host transcriptome, and disease severity in children with respiratory syncytial virus infection. Am J Respir Crit Care Med 2016; 194 (09) 1104-1115
• 37 Bousbia S, Papazian L, Saux P. et al. Repertoire of intensive care unit pneumonia microbiota. PLoS One 2012; 7 (02) e32486
• 38 Libert N, Bigaillon C, Chargari C. et al. Epstein-Barr virus reactivation in critically ill immunocompetent patients. Biomed J 2015; 38 (01) 70-76
• 39 Limaye AP, Kirby KA, Rubenfeld GD. et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 2008; 300 (04) 413-422
• 40 Krause R, Moissl-Eichinger C, Halwachs B. et al. Mycobiome in the lower respiratory tract - a clinical perspective. Front Microbiol 2017; 7: 2169
• 41 Krause R, Halwachs B, Thallinger GG. et al. Characterisation of Candida within the mycobiome/microbiome of the lower respiratory tract of ICU patients. PLoS One 2016; 11 (05) e0155033
• 42 Azoulay E, Timsit J-F, Tafflet M. et al; Outcomerea Study Group. Candida colonization of the respiratory tract and subsequent pseudomonas ventilator-associated pneumonia. Chest 2006; 129 (01) 110-117
• 43 Roux D, Gaudry S, Dreyfuss D. et al. Candida albicans impairs macrophage function and facilitates Pseudomonas aeruginosa pneumonia in rat. Crit Care Med 2009; 37 (03) 1062-1067
• 44 Roux D, Gaudry S, Khoy-Ear L. et al. Airway fungal colonization compromises the immune system allowing bacterial pneumonia to prevail. Crit Care Med 2013; 41 (09) e191-e199
• 45 Chikina AS, Nadalin F, Maurin M. et al. Macrophages maintain epithelium integrity by limiting fungal product absorption. Cell 2020; 183 (02) 411-428.e16
• 46 Souza DG, Vieira AT, Soares AC. et al. The essential role of the intestinal microbiota in facilitating acute inflammatory responses. J Immunol 2004; 173 (06) 4137-4146
• 47 Weiner HL. The mucosal milieu creates tolerogenic dendritic cells and T(R)1 and T(H)3 regulatory cells. Nat Immunol 2001; 2 (08) 671-672
• 48 Worbs T, Bode U, Yan S. et al. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J Exp Med 2006; 203 (03) 519-527
• 49 van Vught LA, Scicluna BP, Wiewel MA. et al. Comparative analysis of the host response to community-acquired and hospital-acquired pneumonia in critically ill patients. Am J Respir Crit Care Med 2016; 194 (11) 1366-1374
• 50 Netea MG, Joosten LAB, Latz E. et al. Trained immunity: a program of innate immune memory in health and disease. Science 2016; 352 (6284): aaf1098
• 51 Weis S, Carlos AR, Moita MR. et al. Metabolic adaptation establishes disease tolerance to sepsis. Cell 2017; 169 (07) 1263-1275.e14
• 52 Divangahi M, Aaby P, Khader SA. et al. Trained immunity, tolerance, priming and differentiation: distinct immunological processes. Nat Immunol 2021; 22 (01) 2-6
• 53 van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol 2017; 17 (07) 407-420
• 54 Roquilly A, McWilliam HEG, Jacqueline C. et al. Local modulation of antigen-presenting cell development after resolution of pneumonia induces long-term susceptibility to secondary infections. Immunity 2017; 47 (01) 135-147.e5
• 55 Domínguez-Andrés J, Novakovic B, Li Y. et al. The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. Cell Metab 2019; 29 (01) 211-220.e5
• 56 Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 2013; 13 (03) 260-268
• 57 Ong DSY, Bonten MJM, Spitoni C. et al; Molecular Diagnosis and Risk Stratification of Sepsis Consortium. Epidemiology of multiple herpes viremia in previously immunocompetent patients with septic shock. Clin Infect Dis 2017; 64 (09) 1204-1210
• 58 Peronnet E, Venet F, Maucort-Boulch D. et al; MIP Rea Study Group. Association between mRNA expression of CD74 and IL10 and risk of ICU-acquired infections: a multicenter cohort study. Intensive Care Med 2017; 43 (07) 1013-1020
• 59 Venet F, Filipe-Santos O, Lepape A. et al. Decreased T-cell repertoire diversity in sepsis: a preliminary study. Crit Care Med 2013; 41 (01) 111-119
• 60 Venet F, Lukaszewicz A-C, Payen D, Hotchkiss R, Monneret G. Monitoring the immune response in sepsis: a rational approach to administration of immunoadjuvant therapies. Curr Opin Immunol 2013; 25 (04) 477-483
• 61 Vourc'h M, Roquilly A, Broquet A. et al. Exoenzyme T plays a pivotal role in the IFN-γ production after Pseudomonas challenge in IL-12 primed natural killer cells. Front Immunol 2017; 8: 1283
• 62 Bogunovic D, Byun M, Durfee LA. et al. Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency. Science 2012; 337 (6102): 1684-1688
• 63 Wilson NS, Behrens GMN, Lundie RJ. et al. Systemic activation of dendritic cells by toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity. Nat Immunol 2006; 7 (02) 165-172
• 64 Neupane AS, Willson M, Chojnacki AK. et al. Patrolling alveolar macrophages conceal bacteria from the immune system to maintain homeostasis. Cell 2020; 183 (01) 110-125.e11
• 65 Roquilly A, Jacqueline C, Davieau M. et al. Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis. Nat Immunol 2020; 21 (06) 636-648
• 66 Yao Y, Jeyanathan M, Haddadi S. et al. Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell 2018; 175 (06) 1634-1650.e17
• 67 van Nood E, Vrieze A, Nieuwdorp M. et al. Duodenal infusion of donor feces for recurrent Clostridium difficile . N Engl J Med 2013; 368 (05) 407-415
• 68 Moayyedi P, Surette MG, Kim PT. et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 2015; 149 (01) 102-109.e6
• 69 Pamer EG. Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens. Science 2016; 352 (6285): 535-538
• 70 Yadava K, Pattaroni C, Sichelstiel AK. et al. Microbiota promotes chronic pulmonary inflammation by enhancing IL-17A and autoantibodies. Am J Respir Crit Care Med 2016; 193 (09) 975-987
• 71 Klarin B, Adolfsson A, Torstensson A, Larsson A. Can probiotics be an alternative to chlorhexidine for oral care in the mechanically ventilated patient? A multicentre, prospective, randomised controlled open trial. Crit Care 2018; 22 (01) 272
• 72 Manzanares W, Lemieux M, Langlois PL, Wischmeyer PE. Probiotic and synbiotic therapy in critical illness: a systematic review and meta-analysis. Crit Care 2016; 19: 262
• 73 Besselink MG, van Santvoort HC, Buskens E. et al; Dutch Acute Pancreatitis Study Group. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371 (9613): 651-659
• 74 Davison JM, Wischmeyer PE. Probiotic and synbiotic therapy in the critically ill: state of the art. Nutrition 2019; 59: 29-36
• 75 Routy B, Le Chatelier E, Derosa L. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359 (6371): 91-97
• 76 Zhu W, Winter MG, Byndloss MX. et al. Precision editing of the gut microbiota ameliorates colitis. Nature 2018; 553 (7687): 208-211
• 77 Roquilly A, Mahe PJ, Seguin P. et al. Hydrocortisone therapy for patients with multiple trauma: the randomized controlled HYPOLYTE study. JAMA 2011; 305 (12) 1201-1209
• 78 Asehnoune K, Seguin P, Allary J. et al; Corti-TC Study Group. Hydrocortisone and fludrocortisone for prevention of hospital-acquired pneumonia in patients with severe traumatic brain injury (Corti-TC): a double-blind, multicentre phase 3, randomised placebo-controlled trial. Lancet Respir Med 2014; 2 (09) 706-716
• 79 Venkatesh B, Finfer S, Cohen J. et al; ADRENAL Trial Investigators and the Australian–New Zealand Intensive Care Society Clinical Trials Group. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 2018; 378 (09) 797-808
• 80 Annane D, Renault A, Brun-Buisson C. et al; CRICS-TRIGGERSEP Network. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med 2018; 378 (09) 809-818
• 81 Cohen J, Blumenthal A, Cuellar-Partida G. et al. The relationship between adrenocortical candidate gene expression and clinical response to hydrocortisone in patients with septic shock. Intensive Care Med 2021; 47 (09) 974-983
• 82 Nantes University Hospital. Human recombinant interferon gamma-1b for the prevention of hospital-acquired pneumonia in critically ill patients: a double-blind, international, phase 2, randomized, placebo-controlled trial - the PREV-HAP study. clinicaltrials.gov; 2021 Mar [cited 2021 Aug 12]. Report No.: NCT04793568. Available at: https://clinicaltrials.gov/ct2/show/NCT04793568
• 83 Gokhale MS, Vainstein V, Tom J. et al. Single low-dose rHuIL-12 safely triggers multilineage hematopoietic and immune-mediated effects. Exp Hematol Oncol 2014; 3 (01) 11
• 84 Döcke WD, Randow F, Syrbe U. et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 1997; 3 (06) 678-681
• 85 Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155 (03) 1151-1164
• 86 Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 2013; 13 (12) 862-874
• 87 Gaborit BJ, Roquilly A, Louvet C. et al. Regulatory T cells expressing tumor necrosis factor receptor type 2 play a major role in CD4+ T-cell impairment during sepsis. J Infect Dis 2020; 222 (07) 1222-1234
• 88 Gaborit BJ, Chaumette T, Chauveau M. et al. Circulating Treg cells expressing TNF receptor type 2 contributes to sepsis-induced immunosuppression in patients during sepsis shock. J Infect Dis 2021; jiab276
• 89 den Hartog I, Zwep LB, Vestjens SMT. et al. Metabolomic profiling of microbial disease etiology in community-acquired pneumonia. PLoS One 2021; 16 (06) e0252378
• 90 Banoei MM, Vogel HJ, Weljie AM. et al; Canadian Critical Care Translational Biology Group (CCCTBG). Plasma metabolomics for the diagnosis and prognosis of H1N1 influenza pneumonia. Crit Care 2017; 21 (01) 97
• 91 Adamko DJ, Saude E, Bear M, Regush S, Robinson JL. Urine metabolomic profiling of children with respiratory tract infections in the emergency department: a pilot study. BMC Infect Dis 2016; 16 (01) 439
• 92 Wunderink RG, Roquilly A, Croce M. et al. A phase 3, randomized, double-blind study comparing tedizolid phosphate and linezolid for treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia. Clin Infect Dis 2021; 73 (03) e710-e718