Understanding the Host in the Management of Pneumonia. An Official American Thoracic Society Workshop Report

Cruz, Charles S. Dela; Evans, Scott E.; Restrepo, Marcos I.; Dean, Nathan C.; Torres, Antônio; Amara-Elori, Isabel; Awasthi, Shanjana; Caler, Elisabet; Cao, Bin; Chalmers, James D.; Chastre, Jean; Cohen, Taylor S.; Cohen, Alan H.; Crothers, Kristina; Di, Y. Peter; Egan, Marie E.; Feldman, Charles; Gautam, Samir; Halstead, E. Scott; Herold, Susanne; Jones, Barbara E.; Luna, Carlos M.; Niederman, Michael S.; Méndez, Raúl; Menéndez, Rosário; Mizgerd, Joseph P.; Nusrat, Roomi; Ramírez, Julio; Shindo, Yuichiro; Waterer, Grant; Yeligar, Samantha M.; Wunderink, Richard G.

doi:10.1513/annalsats.202102-209st

Cited by 23 publications

(15 citation statements)

References 88 publications

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“…In the lung, this process results in severe pneumonia, a leading cause of human death even before the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic ( 3 , 4 ). The outcome of pneumonia is determined by a balance between immune resistance and tissue resilience ( 1 , 5 ). Immune resistance is the host’s ability to eradicate pathogens, whereas tissue resilience is the ability of the lung to withstand the deleterious consequences of infection and inflammation ( 1 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

“…The outcome of pneumonia is determined by a balance between immune resistance and tissue resilience ( 1 , 5 ). Immune resistance is the host’s ability to eradicate pathogens, whereas tissue resilience is the ability of the lung to withstand the deleterious consequences of infection and inflammation ( 1 , 5 ). The complement system is a family of immune proteins that facilitate immune resistance by attacking microbes to decrease pathogen burden ( 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

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Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

et al. 2023

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The complement component C3 is a fundamental plasma protein for host defense, produced largely by the liver. However, recent work has demonstrated the critical importance of tissue-specific C3 expression in cell survival. Here, we analyzed the effects of local versus peripheral sources of C3 expression in a model of acute bacterial pneumonia induced by Pseudomonas aeruginosa . Whereas mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient only in liver-derived C3 remained protected, comparable to wild-type mice. Human lung transcriptome analysis showed that secretory epithelial cells, such as club cells, express high levels of C3 mRNA. Mice with tamoxifen-induced C3 gene ablation from club cells in the lung had worse pulmonary injury compared with similarly treated controls, despite maintaining normal circulating C3 levels. Last, in both the mouse pneumonia model and cultured primary human airway epithelial cells, we showed that stress-induced death associated with C3 deficiency parallels that seen in Factor B deficiency rather than C3a receptor deficiency. Moreover, C3-mediated reduction in epithelial cell death requires alternative pathway component Factor B. Thus, our findings suggest that a pathway reliant on locally derived C3 and Factor B protects the lung mucosal barrier.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

et al. 2023

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“…In severe pneumonia, endpoints such as death or extubation failure are easily ascertained, while other endpoints like clinical cure, microbiologic resolution, improvement in oxygenation and safety are not standardized and subject to bias in interpretation. 1 In studies with complex endpoints of interest, particularly events that require some analysis of clinical information, study protocols use adjudication committees to provide consistent, unbiased determination of the presence or absence of a diagnosis or an event. 2–4 Adjudication committees are established components of large cohort studies and randomized clinical trials in cardiovascular disease, oncology, interstitial lung disease and sepsis.…”

Section: Introductionmentioning

confidence: 99%

An Adjudication Protocol for Severe Bacterial and Viral Pneumonia

Pickens¹,

Gao²,

Walter³

et al. 2022

Preprint

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Rationale: Clinical endpoints that constitute successful treatment in severe pneumonia are difficult to ascertain and vulnerable to bias. Utility of a protocolized adjudication procedure to determine meaningful endpoints in severe pneumonia is not well described. Objectives: To develop and validate a protocol for classification and adjudication of clinical endpoints in severe bacterial and viral pneumonia in a prospective cohort of critically ill, mechanically ventilated patients. Methods: Each episode of pneumonia was independently reviewed by two of six pulmonary and critical care physician adjudicators. If a discrepancy in at least one critical answer occurred between the two adjudicators, a third adjudicator reviewed the case and answered the specific question(s) for which there was a lack of agreement. If discrepancy remained after all three adjudications, consensus was achieved through committee review. Results: Evaluation of 784 pneumonia episodes during 593 hospitalizations achieved a 79% crude rate of interobserver agreement defined as agreement between 2 of 3 reviewers. Culture-negative pneumonia was associated with increased interobserver agreement. Multiple episodes of pneumonia and bacterial and viral co-infection in the initial episode of pneumonia were associated with decreased interobserver agreement. For bacterial pneumonia, patients with an adjudicated day 7-8 clinical impression of cure for the initial episode of pneumonia were more likely to be discharged alive compared to patients with a day 7-8 clinical impression of indeterminate (p < 0.01), superinfection (p = 0.03), or a combined impression of persistence and superinfection (p = 0.04). In viral pneumonia, patients with an adjudicated clinical impression of cure for an initial episode of viral pneumonia were more likely to be discharged alive compared to patients with an adjudicated clinical impression of persistence (p < 0.01), indeterminate (p < 0.01), or bacterial superinfection (p < 0.01). Conclusions: We developed and validated a protocol for classification and adjudication of clinical endpoints in severe pneumonia. This protocol can be applied to cohorts of patients with severe pneumonia to provide uniform assessment of patient-centered endpoints.

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“…In the lung, this process results in severe pneumonia, a leading cause of death, even before the SARS-CoV-2 pandemic ( 3, 4 ). The outcome in pneumonia is determined by a balance between immune resistance and tissue resilience of the host ( 1, 5 ). Immune resistance is the host’s ability to eradicate pathogens, whereas tissue resilience is the ability of the lung to withstand the deleterious consequences of infection and inflammation ( 1, 5 ).…”

Section: Introductionmentioning

confidence: 99%

“…The outcome in pneumonia is determined by a balance between immune resistance and tissue resilience of the host ( 1, 5 ). Immune resistance is the host’s ability to eradicate pathogens, whereas tissue resilience is the ability of the lung to withstand the deleterious consequences of infection and inflammation ( 1, 5 ). The complement system is a family of immune proteins that facilitate immune resistance by attacking microbes to decrease pathogen burden ( 6, 7 ).…”

Section: Introductionmentioning

confidence: 99%

Lung epithelial cell-derived C3 protects against pneumonia-induced lung injury

Ozantürk¹,

Sahu²,

Kulkarni³

et al. 2022

Preprint

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The complement component C3 is a fundamental plasma protein for host defense. However, recent work has demonstrated the critical importance of local C3 expression in cell survival. Here we analyzed the effects of local versus peripheral sources of C3 expression in a model of bacterial pneumonia. While mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient in liver-deficient C3 remain protected, comparable to wildtype mice. Human lung transcriptome analysis showed secretory epithelial cells are a major source of C3. Mice with a C3 gene ablation from lung epithelial cells had worse pulmonary injury compared to wild type, despite maintaining normal circulating C3 levels. Finally, in human cellular and mouse pneumonia models, we show that C3 reduces epithelial cell death mediated through the alternative pathway component Factor B. Thus, our findings suggest that a locally-derived C3-Factor B pathway protects the lung mucosal barrier.

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Understanding the Host in the Management of Pneumonia. An Official American Thoracic Society Workshop Report

Cited by 23 publications

References 88 publications

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

An Adjudication Protocol for Severe Bacterial and Viral Pneumonia

Lung epithelial cell-derived C3 protects against pneumonia-induced lung injury

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