Inflammatory mediators and lung abnormalities in HIV: A systematic review

Abstract

HIV and pneumonia infections have both been shown to negatively impact lung function. However, evidence of the role of inflammation on lung dysfunction in HIV and pneumonia co-infected individuals remains limited. We aimed to systematically review the association of inflammatory markers and lung abnormalities in HIV and pneumonia co-infected individuals. This systematic review was registered with the International Prospective Register of Systematic Reviews on August 15, 2017 (registration number CRD42017069254) and used 4 databases (Cochrane Central Register of Controlled Trials, PubMed Central, Clinical Trials.gov and Google Scholar). All clinical trial, observational, and comparative studies targeting adult (> 18 years old) populations with HIV, pneumonia, or both, that report on immune response (cytokine, chemokine, or biomarker), and lung abnormality as an outcome were eligible. Data selection, risk of bias and extraction were performed independently by 2 blinded reviewers. Due to heterogeneity among the articles, a qualitative synthesis was performed. Our search strategy identified 4454 articles of which, 7 met our inclusion criteria. All of the studies investigated the ability of circulating biomarkers to predict lung damage in HIV. None of the articles included patients with both HIV and pneumonia, nor pneumonia alone. Markers of inflammation (IL-6, TNF-α, CRP), innate defense (cathelicidin), monocyte and macrophage activation (sCD14, sCD163 and, IL-2sRα), endothelial dysfunction (ET-1) and general immune health (CD4/CD8 ratio) were associated with lung abnormalities in HIV. This review highlights the lack of available information regarding the impact of inflammatory mediators on lung function in HIV and pneumonia populations, therefore opportunities to prevent lung damage with available anti-inflammatory treatment or to investigate new ones still remain.

Fig 1. PRISMA flow diagram of the search and review process.

Fig 2. A proposed framework for the hypothesized pathogenesis of lung abnormality among individuals with HIV and pneumonia co-infection.

In a normal and healthy alveolus, the immune system works together to maintain an immune quiescent state (top left panel) [45]. However, in individuals with HIV and in those with pneumonia, innate response markers are affected [36,63] and elevated levels of markers of inflammation (IL-6, TNF-α and CRP) [5,21,35,40,41,48,49,68,69], macrophage activation (sCD14, sCD163, and IL-2sRα) [35,37,40,41,55,66,69] and endothelial dysfunction (ET-1) [69] have been reported. HIV alters the immune environment and affects the host response [67], therefore it is hypothesized that HIV-infected individuals who contract pneumonia will have a decreased ability to clear the invading pathogen, leading to increased fibroblast activation, extracellular matrix deposition and tissue remodeling resulting in impaired gas exchange and greater lung abnormality (top right panel).