Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) is an important cause of acute respiratory infection, lower respiratory tract disease, clinical complications, and death in older adults. There is currently no licensed vaccine against RSV infection. METHODS: In an ongoing, international, placebo-controlled, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive a single dose of an AS01E-adjuvanted RSV prefusion F protein-based candidate vaccine (RSVPreF3 OA) or placebo before the RSV season. The primary objective was to show vaccine efficacy of one dose of the RSVPreF3 OA vaccine against RSV-related lower respiratory tract disease, confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR), during one RSV season. The criterion for meeting the primary objective was a lower limit of the confidence interval around the efficacy estimate of more than 20%. Efficacy against severe RSV-related lower respiratory tract disease and RSV-related acute respiratory infection was assessed, and analyses according to RSV subtype (A and B) were performed. Safety was evaluated. RESULTS: A total of 24,966 participants received one dose of the RSVPreF3 OA vaccine (12,467 participants) or placebo (12,499). Over a median follow-up of 6.7 months, vaccine efficacy against RT-PCR-confirmed RSV-related lower respiratory tract disease was 82.6% (96.95% confidence interval [CI], 57.9 to 94.1), with 7 cases (1.0 per 1000 participant-years) in the vaccine group and 40 cases (5.8 per 1000 participant-years) in the placebo group. Vaccine efficacy was 94.1% (95% CI, 62.4 to 99.9) against severe RSV-related lower respiratory tract disease (assessed on the basis of clinical signs or by the investigator) and 71.7% (95% CI, 56.2 to 82.3) against RSV-related acute respiratory infection. Vaccine efficacy was similar against the RSV A and B subtypes (for RSV-related lower respiratory tract disease: 84.6% and 80.9%, respectively; for RSV-related acute respiratory infection: 71.9% and 70.6%, respectively). High vaccine efficacy was observed in various age groups and in participants with coexisting conditions. The RSVPreF3 OA vaccine was more reactogenic than placebo, but most adverse events for which reports were solicited were transient, with mild-to-moderate severity. The incidences of serious adverse events and potential immune-mediated diseases were similar in the two groups. CONCLUSIONS: A single dose of the RSVPreF3 OA vaccine had an acceptable safety profile and prevented RSV-related acute respiratory infection and lower respiratory tract disease and severe RSV-related lower respiratory tract disease in adults 60 years of age or older, regardless of RSV subtype and the presence of underlying coexisting conditions. (Funded by GlaxoSmithKline Biologicals; AReSVi-006 ClinicalTrials.gov number, NCT04886596.).

Efficacy and Safety of Respiratory Syncytial Virus (RSV) Prefusion F Protein Vaccine (RSVPreF3 OA) in Older Adults Over 2 RSV Seasons.

BACKGROUND: The adjuvanted RSV prefusion F protein-based vaccine (RSVPreF3 OA) was efficacious against RSV-related lower respiratory tract disease (RSV-LRTD) in ≥60-years-olds over 1 RSV season. We evaluated efficacy and safety of 1 RSVPreF3 OA dose and of 2 RSVPreF3 OA doses given 1 year apart against RSV-LRTD over 2 RSV seasons post-dose 1. METHODS: In this phase 3, blinded trial, ≥60-year-olds were randomized (1:1) to receive RSVPreF3 OA or placebo pre-season 1. RSVPreF3 OA recipients were re-randomized (1:1) to receive a second RSVPreF3 OA dose (RSV_revaccination group) or placebo (RSV_1dose group) pre-season 2; participants who received placebo pre-season 1 received placebo pre-season 2 (placebo group). Efficacy of both vaccine regimens against RSV-LRTD was evaluated over 2 seasons combined (confirmatory secondary objective, success criterion: lower limits of 2-sided CIs around efficacy estimates >20%). RESULTS: The efficacy analysis comprised 24 967 participants (RSV_1dose: 6227; RSV_revaccination: 6242; placebo: 12 498). Median efficacy follow-up was 17.8 months. Efficacy over 2 seasons of 1 RSVPreF3 OA dose was 67.2% (97.5% CI: 48.2-80.0%) against RSV-LRTD and 78.8% (95% CI: 52.6-92.0%) against severe RSV-LRTD. Efficacy over 2 seasons of a first dose followed by revaccination was 67.1% (97.5% CI: 48.1-80.0%) against RSV-LRTD and 78.8% (95% CI: 52.5-92.0%) against severe RSV-LRTD. Reactogenicity/safety of the revaccination dose were similar to dose 1. CONCLUSIONS: One RSVPreF3 OA dose was efficacious against RSV-LRTD over 2 RSV seasons in ≥60-year-olds. Revaccination 1 year post-dose 1 was well tolerated but did not seem to provide additional efficacy benefit in the overall study population. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT04886596.

Household air pollution and risk of pulmonary tuberculosis in HIV-Infected adults.

BACKGROUND: In low- and middle-income countries countries, millions of deaths occur annually from household air pollution (HAP), pulmonary tuberculosis (PTB), and HIV-infection. However, it is unknown whether HAP influences PTB risk among people living with HIV-infection. METHODS: We conducted a case-control study among 1,277 HIV-infected adults in Bukavu, eastern Democratic Republic of Congo (February 2018 - March 2019). Cases had current or recent (<5y) PTB (positive sputum smear or Xpert MTB/RIF), controls had no PTB. Daily and lifetime HAP exposure were assessed by questionnaire and, in a random sub-sample (n=270), by 24-hour measurements of personal carbon monoxide (CO) at home. We used multivariable logistic regression to examine the associations between HAP and PTB. RESULTS: We recruited 435 cases and 842 controls (median age 41 years, [IQR] 33-50; 76% female). Cases were more likely to be female than male (63% vs 37%). Participants reporting cooking for >3h/day and ≥2 times/day and ≥5 days/week were more likely to have PTB (aOR 1·36; 95%CI 1·06-1·75) than those spending less time in the kitchen. Time-weighted average 24h personal CO exposure was related dose-dependently with the likelihood of having PTB, with aOR 4·64 (95%CI 1·1-20·7) for the highest quintile [12·3-76·2 ppm] compared to the lowest quintile [0·1-1·9 ppm]. CONCLUSION: Time spent cooking and personal CO exposure were independently associated with increased risk of PTB among people living with HIV. Considering the high burden of TB-HIV coinfection in the region, effective interventions are required to decrease HAP exposure caused by cooking with biomass among people living with HIV, especially women.

Tobacco Use and Health-Related Quality of Life Among Individuals with Depression Who Are Receiving Treatment for HIV in Cape Town, South Africa.

BACKGROUND: Tobacco use is the leading cause of preventable death worldwide, and prevalence rates are high among people living with HIV (PLWH), particularly in men. Depression is also common among PLWH, especially among smokers, who may use tobacco to manage mood. Although HIV and depression have been linked to functional impairment and poor health-related quality of life (HRQOL), little research has examined the degree to which smoking impacts these relationships in low- and middle-income countries with high HIV burden. METHOD: Participants (N = 289) were people living with HIV (PLWH) who were being assessed for inclusion in a study targeting depression as a barrier to HIV medication adherence. Linear regression models measured the effect of gender on tobacco use (assessed by the WHO-ASSIST) and on each of the five HRQOL functional impairment domains (assessed by the SF-21). Separate multivariable regression models examined the relationships between habitual tobacco use, defined as daily, almost daily, or weekly use, and the HRQOL domains. RESULTS: The prevalence of habitual tobacco use was 23.9% (48.1% among men, 15.5% among women). Habitual tobacco use was associated with decreased cognitive functioning for the whole sample (B = - 8.99, p < 0.05) and with lower levels of pain-related impairment for men (B = 18.1, p < 0.05). Although men reported more tobacco use (B = 8.50, p < 0.001), they reported less pain-related limitations than women (B = 8.70, p < 0.05). CONCLUSIONS: In our sample, men reported higher rates of habitual tobacco use than women. Smoking was associated with cognitive impairment and with less pain-related impairment among men. Future smoking cessation treatments tailored to PLWH who have symptoms of depression may benefit from strategies that consider pain management as a pathway to habitual smoking and recognize that motivations for use may differ by gender.

E-cigarette vapour enhances pneumococcal adherence to airway epithelial cells.

E-cigarette vapour contains free radicals with the potential to induce oxidative stress. Since oxidative stress in airway cells increases platelet-activating factor receptor (PAFR) expression, and PAFR is co-opted by pneumococci to adhere to host cells, we hypothesised that E-cigarette vapour increases pneumococcal adhesion to airway cells.Nasal epithelial PAFR was assessed in non-vaping controls, and in adults before and after 5 min of vaping. We determined the effect of vapour on oxidative stress-induced, PAFR-dependent pneumococcal adhesion to airway epithelial cells in vitro, and on pneumococcal colonisation in the mouse nasopharynx. Elemental analysis of vapour was done by mass spectrometry, and oxidative potential of vapour assessed by antioxidant depletion in vitroThere was no difference in baseline nasal epithelial PAFR expression between vapers (n=11) and controls (n=6). Vaping increased nasal PAFR expression. Nicotine-containing and nicotine-free E-cigarette vapour increased pneumococcal adhesion to airway cells in vitro Vapour-stimulated adhesion in vitro was attenuated by the PAFR blocker CV3988. Nicotine-containing E-cigarette vapour increased mouse nasal PAFR expression, and nasopharyngeal pneumococcal colonisation. Vapour contained redox-active metals, had considerable oxidative activity, and adhesion was attenuated by the antioxidant N-acetyl cysteine.This study suggests that E-cigarette vapour has the potential to increase susceptibility to pneumococcal infection.

Safety and Immunogenicity of Adenovirus 35 Tuberculosis Vaccine Candidate in Adults with Active or Previous Tuberculosis. A Randomized Trial.

RATIONALE: Administration of tuberculosis (TB) vaccines in participants with previous or current pulmonary TB may have the potential for causing harmful postvaccination immunologic (Koch-type) reactions. OBJECTIVES: To assess the safety and immunogenicity of three dose levels of the AERAS-402 live, replication-deficient adenovirus 35-vectored TB candidate vaccine, containing three mycobacterial antigens, in individuals with current or previous pulmonary TB. METHODS: We performed a phase II randomized, placebo-controlled, double-blinded dose-escalation study in an HIV-negative adult South African cohort (n = 72) with active pulmonary TB (on treatment for 1-4 mo) or pulmonary TB treated at least 12 months before study entry and considered cured. Safety endpoints included clinical assessment, flow volume curves, diffusing capacity of the lung for carbon monoxide, pulse oximetry, chest radiograph, and high-resolution thoracic computerized tomography scans. Cytokine expression by CD4 and CD8 T cells, after stimulation with Ag85A, Ag85B, and TB10.4 peptide pools, was examined by intracellular cytokine staining. MEASUREMENTS AND MAIN RESULTS: No apparent temporal or dose-related changes in clinical status (specifically acute, Koch phenomenon-like reactions), lung function, or radiology attributable to vaccine were observed. Injection site reactions were mild or moderate. Hematuria (by dipstick only) occurred in 25 (41%) of 61 AERAS-402 recipients and 3 (27%) of 11 placebo recipients, although no gross hematuria was reported. AERAS-402 induced robust CD8+ and moderate CD4+ T-cell responses, mainly to Ag85B in both vaccine groups. CONCLUSIONS: Administration of the AERAS-402 candidate TB vaccine to participants with current or previous pulmonary TB induced a robust immune response and is not associated with clinically significant pulmonary complications. Clinical trial registered with www.clinicaltrials.gov (NCT 02414828) and in the South African National Clinical Trials Register ( www.sanctr.gov.za DOH 27-0808-2060).

Incidence of occupational latent tuberculosis infection in South African healthcare workers.

The test-specific incidence of latent tuberculosis infection (LTBI) in healthcare workers from sub-Saharan Africa is unknown. 505 healthcare workers from South Africa were screened at baseline, and after 12 months, with a questionnaire, the tuberculin skin test (TST), and two T-cell assays (T-SPOT.TB and QuantiFERON-TB Gold-In-Tube). Test-specific conversion rates were calculated. The prevalence of presumed LTBI at baseline was 84, 69 and 62% using the TST, QuantiFERON-TB Gold-In-Tube and T-SPOT.TB, respectively. The annual test-specific conversion rate, depending on the cut-off point used, was as follows: TST 38%; QuantiFERON-TB Gold-In-Tube 13-22%; and T-SPOT.TB 18-22%. Annual reversion rates were 4, 7 and 16%, respectively. The annual TST conversion rate was significantly higher than that derived from published local community-based data (IRR 3.53, 95% CI 1.81-6.88). Factors associated with conversion (any test) included healthcare sector of employment, counselling of tuberculosis patients, and a baseline positive TST (for T-SPOT.TB). The annual rate of tuberculosis infection in South African healthcare workers was very high, irrespective of the testing method used, and may be explained by occupational exposure, as the rate was considerably higher than non-healthcare workers from the same community. Collectively, these data support the need for implementation of tuberculosis-specific infection control measures in Africa.

Electronic cigarettes. A position statement of the forum of international respiratory societies.

BACKGROUND: Awareness and usage of electronic cigarettes has exponentially increased during the last few years, especially among young people and women in some countries. The rapid acceptance of electronic cigarettes may be attributed in part to the perception created by marketing and the popular press that they are safer than combustible cigarettes. GOALS: To alert and advise policy makers about electronic cigarettes and their potential hazards. METHODS: Using The Union's position paper on electronic cigarettes as the starting template, the document was written using an iterative process. Portions of the manuscript have been taken directly from the position papers of participating societies. RESULTS: Because electronic cigarettes generate less tar and carcinogens than combustible cigarettes, use of electronic cigarettes may reduce disease caused by those components. However, the health risks of electronic cigarettes have not been adequately studied. Studies looking at whether electronic cigarettes can aid smoking cessation have had inconsistent results. Moreover, the availability of electronic cigarettes may have an overall adverse health impact by increasing initiation and reducing cessation of combustible nicotine delivery products. CONCLUSIONS: The health and safety claims regarding electronic nicotine delivery devices should be subject to evidentiary review. The potential benefits of electronic cigarettes to an individual smoker should be weighed against potential harm to the population of increased social acceptability of smoking and use of nicotine, the latter of which has addictive power and untoward effects. As a precaution, electronic nicotine delivery devices should be restricted or banned until more information about their safety is available. If they are allowed, they should be closely regulated as medicines or tobacco products.

HIV associated Lymphocytic Interstitial Pneumonia: a clinical, histological and radiographic study from an HIV endemic resource-poor setting.

BACKGROUND: There is a paucity of clinical and histopathological data about HIV-associated lymphocytic interstitial pneumonitis (LIP) in adults from HIV endemic settings. The role of Ebstein-Barr virus (EBV) in the pathogenesis remains unclear. METHODS: We reviewed the clinical, radiographic and histopathological features of suspected adult LIP cases at the Groote Schuur Hospital, Cape Town South Africa, over a 6 year period. Archived tissue sections were stained for CD3, CD4, CD8, CD20 and LMP-1 antigen (an EBV marker). RESULTS: 42 cases of suspected LIP(100% HIV-infected) were identified. 75% of patients were empirically treated for TB prior to being referred to the chest service for further investigation. Tissue samples were obtained using trans-bronchial biopsy. 13/42 were classified as definite LIP (lymphocytic infiltrate with no alternative diagnosis), 19/42 probable LIP (lymphocytic infiltrate but evidence of anthracosis or fibrosis) and 10 as non-LIP (alternative histological diagnosis). Those with definite LIP were predominantly young females (85%) with a median CD4 count of 194 (IQR 119-359). Clinical or radiological features had poor predictive value for LIP. Histologically, the lymphocytic infiltrate comprised mainly B cells and CD8 T cells. The frequency of positive EBV LMP-1 antigen staining was similar in definite and non- LIP patients [(2/13 (15%) vs. 3/10 (30%); p = 0.52]. CONCLUSIONS: In a HIV endemic setting adult HIV-associated LIP occurs predominantly in young women. The diagnosis can often be made on transbronchial biopsy and is characterized by a predominant CD8 T cell infiltrate. No association with EBV antigen was found.

Cigarette smoke impairs cytokine responses and BCG containment in alveolar macrophages.

BACKGROUND: There is a strong epidemiological link between smoking and tuberculosis (TB), but the association is confounded by socioeconomic and other factors. A direct relationship between cigarette smoke and poor treatment-related outcomes in patients with TB is therefore questionable. We investigated whether constituents of tobacco smoke impair mycobacterial host immune responses in vitro. METHODOLOGY: Preparation of a cigarette smoke extract (CSE) from Marlboro Red cigarettes was standardised and reproducibility verified by mass spectroscopy. Macrophages were derived from peripheral blood monocytes (MDM) and alveolar macrophages from bronchoalveolar lavage fluid from healthy non-smoking volunteers. Mycobacterial uptake (flow cytometric detection of fluorescence using green fluorescent protein-labelled BCG), cytokine responses (ELISA) and mycobacterial containment (colony forming units) was evaluated in both macrophage populations with and without co-culture with CSE, nicotine and a nicotine receptor blocker. RESULTS: Cigarette smoke failed to impair the uptake of mycobacteria by monocyte-derived or alveolar macrophages. CSE (vs no CSE) reduced the mean (SD) BCG-driven macrophage (MDM) interferon γ (IFN-γ), tumour necrosis factor α (TNF-α) and interleukin 10 (IL-10) responses by 56.4 (18.6)%, 67.0 (33.4)% and 77.7 (27.7)%, respectively (p<0.001). Nicotine alone impaired IL-10 and TNF-α production by 48.8 (37)% and 49 (50)%, respectively (p<0.05) through an α-7 nicotine receptor-independent mechanism. In 5-day cultures, CSE impaired mycobacterial (BCG) containment in both monocyte-derived and alveolar macrophages. CONCLUSIONS: Cigarette smoke attenuates effector cytokine responses and impairs mycobacterial containment within infected human macrophages derived from the peripheral blood and alveolar compartments, thus supporting the hypothesis that cigarette smoke subverts mycobacteria-related immunity.

Regulatory T cells attenuate mycobacterial stasis in alveolar and blood-derived macrophages from patients with tuberculosis.

RATIONALE: There are hardly any data about the frequency of CD4(+)CD25(+)Foxp3(+) regulatory T cells (T-Regs) in the lungs of patients with active tuberculosis (TB). OBJECTIVES: To obtain data about the frequency of CD4(+)CD25(+)Foxp3(+) T-Regs, and their impact on mycobacterial containment, in the lungs of patients with active TB. METHODS: Patients with pulmonary TB (n = 49) and healthy volunteers with presumed latent TB infection (LTBI; n = 38) donated blood and/or bronchoalveolar lavage (BAL) cells obtained by bronchoscopy. T-cell phenotype (Th1/Th2/Th17/T-Reg) and functional status was evaluated using flow-cytometry and (3)H-thymidine proliferation assays, respectively. H37Rv-infected alveolar and monocyte-derived macrophages were cocultured with autologous T-Regs and purified protein derivative (PPD) preprimed T-Reg-depleted effector cells. Mycobacterial containment was evaluated by counting CFUs. MEASUREMENTS AND MAIN RESULTS: In blood and BAL T-Reg levels were higher in TB versus LTBI (P < 0.04), and in TB the frequency of T-Regs was significantly higher in BAL versus blood (P < 0.001). T-Reg-mediated suppression of T-cell proliferation in blood and BAL was concentration-dependent. Restriction of mycobacterial growth in infected alveolar and monocyte-derived macrophages was significantly diminished, and by up to 50%, when T-Regs were cocultured with PPD-primed CD4(+) effector T cells. The levels of CD8(+) T-Regs (CD8(+)CD25(+)Foxp3(+)), IL-17-producing T-Regs (IL-17(+)CD4(+)CD25(+)Foxp3(+)), and IL-17-producing T cells were similar in BAL-TB versus BAL-LTBI. Within the TB group compartmentalization of responses was prominent (T-Reg, IFN-γ, tumor necrosis factor-α, IL-17, and IL-22 significantly higher in BAL vs. blood). CONCLUSIONS: In patients with TB the alveolar compartment is enriched for CD4(+) T-Regs. Peripheral blood-derived T-Regs decrease the ability of alveolar and monocyte-derived macrophages to restrict the growth of Mycobacterium tuberculosis in the presence of effector cells. Collectively, these data suggest that CD4(+)CD25(+)FoxP3(+) T-Regs subvert antimycobacterial immunity in human TB.

Comparison of same day diagnostic tools including Gene Xpert and unstimulated IFN-γ for the evaluation of pleural tuberculosis: a prospective cohort study.

BACKGROUND: The accuracy of currently available same-day diagnostic tools (smear microscopy and conventional nucleic acid amplification tests) for pleural tuberculosis (TB) is sub-optimal. Newer technologies may offer improved detection. METHODS: Smear-microscopy, adenosine deaminase (ADA), interferon gamma (IFN-γ), and Xpert MTB/RIF [using an unprocessed (1 ml) and centrifuged (~20 ml) sample] test accuracy was evaluated in pleural fluid from 103 consecutive patients with suspected pleural TB. Culture for M.tuberculosis and/or histopathology (pleural biopsy) served as the reference standard. Patients were followed prospectively to determine their diagnostic categorisation. RESULTS: Of 93 evaluable participants, 40 had definite-TB (reference positive), 5 probable-TB (not definite but treated for TB) and 48 non-TB (culture and histology negative, and not treated for TB). Xpert MTB/RIF sensitivity and specificity (95% CI) was 22.5% (12.4 - 37.6) and 98% (89.2 - 99.7), respectively, and centrifugation did not improve sensitivity (23.7%). The Xpert MTB/RIF internal positive control showed no evidence of inhibition. Biomarker specific sensitivity, specificity, PPV, and NPVs were: ADA (48.85 IU/L; rule-in cut-point) 55.3% (39.8 - 69.9), 95.2% (83.9 - 98.7), 91.4 (73.4 - 95.4), 69.7% (56.7 - 80.1); ADA (30 IU/L; clinically used cut-point) 79% (63.7 - 89), 92.7% (80.6 - 97.5), 91.0 (73.4 - 95.4), 82.7% (69.3 - 90.1); and IFN-γ (107.7 pg/ml; rule-in cut-point) 92.5% (80.2 - 97.5), 95.9% (86.1 - 98.9), 94.9% (83.2 - 98.6), 93.9% (83.5 - 97.9), respectively (IFN-γ sensitivity and NPV better than Xpert [p < 0.05] and rule-in ADA [p < 0.05]). CONCLUSION: The usefulness of Xpert MTB/RIF to diagnose pleural TB is limited by its poor sensitivity. IFN-γ is an excellent rule-in test and, compared to ADA, has significantly better sensitivity and rule-out value in a TB-endemic setting.

Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial.

IMPORTANCE: Behavioral approaches and pharmacotherapy are of proven benefit in assisting smokers to quit, but it is unclear whether combining nicotine replacement therapy (NRT) with varenicline to improve abstinence is effective and safe. OBJECTIVE: To evaluate the efficacy and safety of combining varenicline and a nicotine patch vs varenicline alone in smoking cessation. DESIGN, SETTING, AND PARTICIPANTS: Randomized, blinded, placebo-controlled clinical trial with a 12-week treatment period and a further 12-week follow-up conducted in 7 centers in South Africa from April 2011 to October 2012. Four hundred forty-six generally healthy smokers were randomized (1:1); 435 were included in the efficacy and safety analyses. INTERVENTIONS: Nicotine or placebo patch treatment began 2 weeks before a target quit date (TQD) and continued for a further 12 weeks. Varenicline was begun 1 week prior to TQD, continued for a further 12 weeks, and tapered off during week 13. MAIN OUTCOMES AND MEASURES: Tobacco abstinence was established and confirmed by exhaled carbon monoxide measurements at TQD and at intervals thereafter up to 24 weeks. The primary end point was the 4-week exhaled carbon monoxide-confirmed continuous abstinence rate for weeks 9 through 12 of treatment, ie, the proportion of participants able to maintain complete abstinence from smoking for the last 4 weeks of treatment, as assessed using multiple imputation analysis. Secondary end points included point prevalence abstinence at 6 months, continuous abstinence rate from weeks 9 through 24, and adverse events. Multiple imputation also was used to address loss to follow-up. RESULTS: The combination treatment was associated with a higher continuous abstinence rate at 12 weeks (55.4% vs 40.9%; odds ratio [OR], 1.85; 95% CI, 1.19-2.89; P = .007) and 24 weeks (49.0% vs 32.6%; OR, 1.98; 95% CI, 1.25-3.14; P = .004) and point prevalence abstinence rate at 6 months (65.1% vs 46.7%; OR, 2.13; 95% CI, 1.32-3.43; P = .002). In the combination treatment group, there was a numerically greater incidence of nausea, sleep disturbance, skin reactions, constipation, and depression, with only skin reactions reaching statistical significance (14.4% vs 7.8%; P = .03); the varenicline-alone group experienced more abnormal dreams and headaches. CONCLUSIONS AND RELEVANCE: Varenicline in combination with NRT was more effective than varenicline alone at achieving tobacco abstinence at 12 weeks (end of treatment) and at 6 months. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01444131.

Sputum Color as a Marker for Bacteria in Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis.

Rationale: Diagnosing bacterial infection as the etiology in acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) remains challenging. Sputum discoloration is easily measured and often used as a marker of bacterial infection in AECOPD, although high-quality evidence for this practice is lacking. Objectives: To determine the diagnostic accuracy of sputum color as a marker for bacteria in AECOPD. Methods: Articles were searched for in electronic databases, and the gray literature were reviewed. Quality assessment of included articles was performed using the revised Quality Assessment of Diagnostic Accuracy Studies tool. A meta-analysis was conducted using a bivariate logistic regression model with random effects. Analysis was conducted on individual sputum samples rather than on individual participants so that each sample represented a unique index test. Results: Of the 1,600 candidate studies, 13 eligible studies satisfied the inclusion criteria. These included prospective cohort studies (n = 3), cross-sectional studies (n = 3), and secondary analyses of randomized controlled trials (n = 7). The included studies were all from Europe and North America. Most studies scored high risk of bias in at least one domain. In total, this systematic review and meta-analysis included 5,770 sputum samples. The estimated pooled sensitivity and specificity were 81% (95% confidence interval [CI], 70-88%) and 50% (95% CI, 35-65%), respectively, and these results were not significantly altered in a series of sensitivity analyses. Conclusions: Sputum color has limited value as a stand-alone test in diagnosing bacterial infection as the etiology in AECOPD because of its moderate sensitivity and poor specificity.

Triple Therapy with Mometasone/Indacaterol/Glycopyrronium or Doubling the ICS/LABA Dose in GINA Step 4: IRIDIUM Analyses.

INTRODUCTION: GINA guidelines recommend increasing the dose of inhaled corticosteroids (ICS) as a step-up option for patients with inadequately controlled asthma at GINA step 4 [inadequately controlled asthma on medium-dose ICS/long-acting beta-2 agonist (LABA)]. The aim of this study was to compare the efficacy and safety of long-acting muscarinic antagonists (LAMA) add-on to medium-dose ICS/LABA in patients at GINA 2022 step 4. METHODS: This post hoc analysis of the IRIDIUM study evaluated the change from baseline in trough forced expiratory volume (FEV1 ) in patients receiving medium-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL at Week 26. Other outcomes included improvement in lung functions [peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow between 25% and 75% of the FVC (FEF)25-75%)], asthma control [Asthma Control Questionnaire (ACQ-7)], responder analysis (≥ 0.5 unit improvement in ACQ-7), and reduction in asthma exacerbations at Weeks 26 and 52. RESULTS: A total of 1930 patients were included in this analysis. Medium-dose MF/IND/GLY improved trough FEV1 versus high-dose MF/IND (Δ 41 mL; 95% CI - 7-90) and high-dose FLU/SAL (Δ 88 mL; 95% CI 39-137) at Week 26 which were sustained until Week 52. Exacerbation rates were 16% lower with medium-dose MF/IND/GLY versus high-dose MF/IND for all (mild, moderate, and severe) exacerbations and 21-30% lower versus high-dose FLU/SAL for all (mild, moderate, and severe), moderate or severe, and severe exacerbations over 52 weeks. Further improvements in other lung functions were observed with medium-dose MF/IND/GLY. No new safety signals were identified. CONCLUSION: Medium-dose MF/IND/GLY improved lung function and reduced asthma exacerbations compared to high-dose ICS/LABA and may be an undervalued option in patients at GINA 2022 step 4. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02571777.

Efficacy of mometasone/indacaterol/glycopyrronium in patients with inadequately controlled asthma with respect to baseline eosinophil count: Post hoc analysis of IRIDIUM study.

BACKGROUND: Baseline characteristics could potentially guide asthma treatments. We evaluated whether baseline eosinophil levels affect the efficacy of mometasone/indacaterol/glycopyrronium (MF/IND/GLY) in patients with inadequately controlled asthma. METHOD: In this post hoc analysis of IRIDIUM study, efficacy of high-dose MF/IND/GLY (160/150/50 µg, once-daily [o.d.]) versus high-dose MF/IND (320/150 µg o.d.) and high-dose fluticasone/salmeterol (FLU/SAL [500/50 µg, twice-daily [b.i.d.]); and efficacy of pooled MF/IND/GLY (160/150/50 µg and 80/150/50 µg) versus pooled MF/IND (320/150 µg and 160/150 µg) was evaluated in patient subgroups with baseline blood eosinophil count of <300 cells/µL or ≥300 cells/µL. RESULTS: Overall, 3065 patients were included. At Week 26, high-dose MF/IND/GLY showed improved trough FEV1 versus high-dose MF/IND (Δ78mL [<300 cells/µL]; Δ54mL [≥300 cells/µL]) and FLU/SAL (Δ112mL [<300 cells/µL]; Δ98mL [≥300 cells/µL]). Similarly, pooled MF/IND/GLY also showed improved trough FEV1 versus pooled MF/IND (Δ75mL [<300 cells/µL]; Δ68mL [≥300 cells/µL]). Over 52 weeks, high-dose MF/IND/GLY reduced the annualized rate of moderate or severe asthma exacerbations by 23% and 10%, severe exacerbations by 31% and 15%, and all exacerbation by 33% and 10% versus high-dose MF/IND for subgroups with <300 cells/µL and ≥300 cells/µL, respectively; and by 33% and 41%, 45% and 42%, 42% and 39% versus FLU/SAL, respectively. Similarly, pooled MF/IND/GLY reduced exacerbations by 22% and 8%, 21% and 7%, 27% and 8%, versus pooled MF/IND, for the respective subgroups. CONCLUSION: MF/IND/GLY showed improvement in lung function and reduction in asthma exacerbations over MF/IND and FLU/SAL independent of baseline eosinophil levels, indicating that eosinophil levels did not affect the efficacy of MF/IND/GLY in patients with inadequately controlled asthma. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02571777 (IRIDIUM).

Comparison of the effects of electronic cigarette vapours and tobacco smoke extracts on human neutrophils in vitro.

Background: Electronic cigarettes (ECs) are electronic aerosol delivery systems composed of nicotine and various chemicals, which are widely used to facilitate smoking cessation. Although ECs are considered safer than cigarettes, they do, however, contain chemical toxicants, some of which may interact with cells of the host's innate immune system of which neutrophils constitute a key component. Methods: The current study was designed to compare the effects of aqueous EC aerosol extracts (ECEs; with or without nicotine) with those of cigarette smoke extract (CSE) on neutrophil and platelet reactivity in vitro. Neutrophil reactivity is characterised by the generation of reactive oxygen species (ROS), degranulation (elastase release) and the release of extracellular DNA (neutrophil extracellular trap (NET) formation: NETosis), which were measured using chemiluminescence, spectrophotometric and microscopic procedures, respectively. Platelet reactivity was measured according to the magnitude of upregulated expression of the adhesion molecule CD62P on activated cells using a flow cytometric procedure. Results: Exposure of neutrophils to either ECEs or CSE caused a significant inhibition of ROS generation and elastase release by N-formyl-l-methionyl-l-leucyl-l-phenylalanine (1 µM)-activated neutrophils. Pre-treatment of neutrophils with CSE also resulted in a marked attenuation of phorbol 12-myristate 13-acetate (6.25 nM)-mediated release of extracellular DNA, which was unaffected by the ECEs. Similarly, CSE, but not the ECEs, inhibited the expression of CD62P by platelets activated with ADP (100 µM). Conclusions: These observations suggest that ECE aerosols may inhibit some of the immuno-protective activities of neutrophils such as ROS production and elastase release by activated cells, the effect of which was not enhanced by inclusion of nicotine. The inhibitory effects of CSE were significantly more pronounced than those of ECEs, especially so for suppression of NET formation and platelet activation. If operative in vivo, these harmful immunosuppressive effects of ECEs may compromise intrinsic pulmonary antimicrobial defence mechanisms, albeit less so than cigarette smoke.