HIV Increases the Risk of Cigarette Smoke-Induced Emphysema Through MMP-9.

BACKGROUND: HIV is associated with an increased risk for emphysema. Matrix metalloproteinase 9 (MMP-9) is a lung tissue remodeling enzyme associated with emphysema. We previously found MMP-9 activity increases with increases in oxidative stress and that HIV increases alveolar oxidative stress. We hypothesized that HIV proteins would increase the risk of cigarette smoke-induced emphysema due to MMP-9. METHODS: HIV-1 transgenic rats and wild-type littermates were exposed to cigarette smoke or sham for 8 weeks. Lung compliance and histology were assessed. Bronchoalveolar lavage (BAL), primary alveolar macrophages (AM), and serum samples were obtained. A rat alveolar macrophage cell line was exposed to the HIV protein Tat, and MMP-9 levels were assessed by Western immunoblotting. MMP-9 protein expression and activity were assessed in AM from the HIV rat model by ELISA and cytoimmunofluoresence, respectively. Serum from human subjects with and without HIV and tobacco dependence was assessed for MMP-9 levels. RESULTS: MMP-9 expression was significantly increased in rat alveolar macrophages after Tat exposure. HIV-1 transgenic rats developed emphysema while wild-type littermates did not. MMP-9 expression was also increased in the serum, BAL, and AM of HIV-1 transgenic rats after exposure to cigarette smoke compared with wild-type rats. In parallel, serum samples from HIV+ smokers had higher levels of MMP-9 than subjects without HIV and those who did not smoke. CONCLUSION: The combination of HIV and cigarette smoke increases MMP-9 expression in experimental rat HIV models and human subjects. HIV and cigarette smoke both induce alveolar oxidative stress and thereby increase MMP-9 activity.

Alcohol impairs recognition and uptake of Mycobacterium tuberculosis by suppressing toll-like receptor 2 expression.

BACKGROUND: Alcohol impairs pulmonary innate immune function and is associated with an increased risk of tuberculosis (TB). Toll-like receptor 2 (TLR2) is a pattern recognition receptor on alveolar macrophages that recognizes Mycobacterium tuberculosis (Mtb). The expression of TLR2 depends, in part, on granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. Given our prior work demonstrating the suppression of GM-CSF signaling following chronic alcohol ingestion, we hypothesized that alcohol impairs TLR2 expression via the suppression of GM-CSF and thereby reduces the ability of the macrophage to recognize and phagocytose Mtb. METHODS: Primary alveolar macrophages were isolated from control-fed and alcohol-fed rats. Prior to cell isolation, some alcohol-fed rats were treated with intranasal GM-CSF and then endotracheally inoculated with an attenuated strain of Mtb. Primary macrophages were then isolated and immunofluorescence was used to determine phagocytic efficiency and TLR2 expression in the presence and absence of GM-CSF treatment and phagocytic efficiency in the presence and absence of TLR2 neutralization. RESULTS: TLR2 expression and phagocytosis of Mtb were significantly lower in the alveolar macrophages of alcohol-fed rats than control-fed rats. In parallel, blocking TLR2 signaling recapitulated this decreased phagocytosis of Mtb. In contrast, intranasal GM-CSF treatment restored TLR2 expression and Mtb phagocytosis in the alveolar macrophages of alcohol-fed rats to levels comparable to those of control-fed rats. CONCLUSIONS: Chronic alcohol ingestion reduces TLR2 protein expression and phagocytosis of Mtb, likely due to impaired GM-CSF signaling. GM-CSF restores membrane-bound TLR2 expression and phagocytic function.

The Impact of Alcohol Use Disorder on Tuberculosis: A Review of the Epidemiology and Potential Immunologic Mechanisms.

Globally, an estimated 107 million people have an alcohol use disorder (AUD) leading to 2.8 million premature deaths each year. Tuberculosis (TB) is one of the leading causes of death globally and over 8% of global TB cases are estimated to be attributable to AUD. Social determinants of health such as poverty and undernutrition are often shared among those with AUD and TB and could explain the epidemiologic association between them. However, recent studies suggest that these shared risk factors do not fully account for the increased risk of TB in people with AUD. In fact, AUD has been shown to be an independent risk factor for TB, with a linear increase in the risk for TB with increasing alcohol consumption. While few studies have focused on potential biological mechanisms underlying the link between AUD and TB, substantial overlap exists between the effects of alcohol on lung immunity and the mechanisms exploited by Mycobacterium tuberculosis (Mtb) to establish infection. Alcohol misuse impairs the immune functions of the alveolar macrophage, the resident innate immune effector in the lung and the first line of defense against Mtb in the lower respiratory tract. Chronic alcohol ingestion also increases oxidative stress in the alveolar space, which could in turn facilitate Mtb growth. In this manuscript, we review the epidemiologic data that links AUD to TB. We discuss the existing literature on the potential mechanisms by which alcohol increases the risk of TB and review the known effects of alcohol ingestion on lung immunity to elucidate other mechanisms that Mtb may exploit. A more in-depth understanding of the link between AUD and TB will facilitate the development of dual-disease interventions and host-directed therapies to improve lung health and long-term outcomes of TB.

A network meta-analysis of different positive airway pressure interventions in obesity hypoventilation syndrome.

Continuous positive airway pressure (CPAP) and different types of non-invasive ventilation (NIV) have been studied in obesity hypoventilation syndrome such as bi-level PAP with back-up rate (BPAP-BUR), BPAP without BUR, and the new hybrid devices that target a pre-set volume by adjustment of pressure support (VT-PS). Although several studies have compared one PAP intervention with the other, none has compared all four in a head-to-head design, which formed the basis of this network meta-analysis. PubMed and Web of Science were searched for potentially includable randomised active comparator trials. Changes in partial pressure of carbon dioxide (PaCO2 ) and Epworth Sleepiness Score (ESS) were the primary outcomes of interest. Network meta-analysis was done in R program using the 'frequentist' framework. A total of seven trials were included. Only VT-PS and BPAP-BUR showed statistically significant reductions in PaCO2 compared to control, with no significant inter-PAP differences except for the comparison between VT-PS and CPAP. Only VT-PS showed a statistically significant improvement in ESS as compared to control, with no other significant inter-PAP differences. P-score ranking (based on effect size and standard errors) and Hasse diagram ranked VT-PS and BPAP as superior to other PAPs for both primary outcomes. There were no significant differences between the different PAP interventions for hospital or emergency department admissions. The results of this network meta-analysis suggest superiority of VT-PS and BPAP over other PAP interventions at least for daytime hypercapnia and subjective daytime somnolence.

Improving adherence to pulmonary hypertension screening in patients with systemic sclerosis: Overcoming the provider-level barriers.

Background: Pulmonary arterial hypertension is a life-limiting complication in patients with systemic sclerosis. Current recommendations suggest a minimum screening of an annual transthoracic echocardiogram and pulmonary function test. We hypothesize that modifiable provider-level hurdles contribute to inadequate screening and can be alleviated. Methods and Results: We performed a longitudinal study over 23 months of all systemic sclerosis patients seen in pulmonary and/or rheumatology clinics. Pulmonary arterial hypertension screening was measured monthly as percentage of patients with up-to-date transthoracic echocardiogram and pulmonary function test out of the total systemic sclerosis patients with an outpatient encounter that month. Tests were considered "up-to-date" if they were performed 12 months prior or within the next 6 months post-encounter. Baseline adherence to PAH screening was assessed using a 9-month preproject period. Physicians in rheumatology and pulmonary clinics were surveyed for knowledge and perceived as barriers to screening. Interventions focused on provider-level hurdles to improve the screening rate to >90%. Adherence to systemic sclerosis-associated pulmonary arterial hypertension was compared between baseline and post-intervention phases as a continuous variable using nonparametric Mann-Whitney-Wilcoxon test and as categorical variable using chi-square test for overall adherence rate. A total of 18 providers were surveyed, of which 67% knew minimal screening recommendations and 44% identified "difficulty ordering tests" as a barrier. Our interventions were as follows: (1) didactic education and literature dissemination and (2) best practice alert in the electronic medical record to facilitate just-in-time ordering of screening. Adherence was measured for 23 months, comprising 166 systemic sclerosis patients. Monthly adherence to pulmonary arterial hypertension screening increased by 10.4% (69.2%-79.6%, p = 0.01 with chi-square and p = 0.09 with Mann-Whitney-Wilcoxon test), with an increase in transthoracic echocardiogram by 7.5% and pulmonary function test by 4.9%. Conclusion: Provider-level hurdles contribute to sub-optimal systemic sclerosis-associated pulmonary arterial hypertension screening. Lack of knowledge and difficulty in ordering tests were major barriers. Structured education and decision-support aids improve screening. These interventions, however, were insufficient to improve screening to a goal target of >90%.

Paracentesis Simulation: A Comprehensive Approach to Procedural Education.

Introduction: Structured procedural education and assessment of competency are growing needs for residency and fellowship programs. Simulation is a useful way to learn, experience, and practice procedural skills with competence. Paracentesis is a common procedure encountered in internal medicine. This educational resource for paracentesis education includes didactics, cases, and assessments to address cognitive skills, a simulation experience to address psychomotor procedural skills, and an entrustment-based assessment tool. Methods: Prior to the simulation, learners completed preprocedural didactics and self-assessments. Utilizing a paracentesis trainer, ultrasound, and paracentesis kit, the case of a 46-year-old male with ascites in need of a paracentesis was presented. During the simulation, learners initially performed a paracentesis step by step, with assistance and feedback from the case instructor. This was immediately followed by paracentesis without assistance, where the instructor evaluated the learners with an assessment tool encompassing a procedural checklist, global skill assessment scale, and entrustment scale. Afterwards, learners completed case-based reviews and returned to the simulation lab several months later to repeat an unassisted paracentesis. Results: The curriculum was used with internal medicine and medicine-pediatric residents of all training levels. To date, over 120 residents have completed the curriculum. Residents reported an increase in self-confidence and competence using ultrasound to identify ascites and performing a paracentesis. Learners provided positive feedback. Discussion: This curriculum offers the opportunity for both cognitive and psychomotor paracentesis education in a low-risk simulation environment. The comprehensive strategy with didactics, cases, and multiple simulations is designed to promote knowledge and skill retention.