Venous Thromboembolism Among People With HIV: Design, Implementation, and Findings of a Centralized Adjudication System in Clinical Care Sites Across the United States.

BACKGROUND: People with HIV (PWH) are at increased risk for venous thromboembolism (VTE). We conducted this study to characterize VTE including provoking factors among PWH in the current treatment era. METHODS: We included PWH with VTE between 2010 and 2020 at 6 sites in the CFAR Network of Integrated Clinical Systems cohort. We ascertained for possible VTE using diagnosis, VTE-related imaging, and VTE-related procedure codes, followed by centralized adjudication of primary data by expert physician reviewers. We evaluated sensitivity and positive predictive value of VTE ascertainment approaches. VTEs were classified by type and anatomic location. Reviewers identified provoking factors such as hospitalizations, infections, and other potential predisposing factors such as smoking. RESULTS: We identified 557 PWH with adjudicated VTE: 239 (43%) had pulmonary embolism with or without deep venous thrombosis, and 318 (57%) had deep venous thrombosis alone. Ascertainment with clinical diagnoses alone missed 6% of VTEs identified with multiple ascertainment approaches. DVTs not associated with intravenous lines were most often in the proximal lower extremities. Among PWH with VTE, common provoking factors included recent hospitalization (n = 134, 42%), infection (n = 133, 42%), and immobilization/bed rest (n = 78, 25%). Only 57 (10%) PWH had no provoking factor identified. Smoking (46%), HIV viremia (27%), and injection drug use (22%) were also common. CONCLUSIONS: We conducted a robust adjudication process that demonstrated the benefits of multiple ascertainment approaches followed by adjudication. Provoked VTEs were more common than unprovoked events. Nontraditional and modifiable potential predisposing factors such as viremia and smoking were common.

Wellness and Coping of Physicians Who Worked in ICUs During the Pandemic: A Multicenter Cross-Sectional North American Survey.

OBJECTIVES: Few surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic. DESIGN: Cross-sectional survey using four validated instruments. SETTING: Sixty-two sites in Canada and the United States. SUBJECTS: Attending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 [55.6%]) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 [56.9%]) and burnout (259 [63.8%]). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures. CONCLUSIONS: Despite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness.

Global influenza surveillance systems to detect the spread of influenza-negative influenza-like illness during the COVID-19 pandemic: Time series outlier analyses from 2015-2020.

BACKGROUND: Surveillance systems are important in detecting changes in disease patterns and can act as early warning systems for emerging disease outbreaks. We hypothesized that analysis of data from existing global influenza surveillance networks early in the COVID-19 pandemic could identify outliers in influenza-negative influenza-like illness (ILI). We used data-driven methods to detect outliers in ILI that preceded the first reported peaks of COVID-19. METHODS AND FINDINGS: We used data from the World Health Organization's Global Influenza Surveillance and Response System to evaluate time series outliers in influenza-negative ILI. Using automated autoregressive integrated moving average (ARIMA) time series outlier detection models and baseline influenza-negative ILI training data from 2015-2019, we analyzed 8,792 country-weeks across 28 countries to identify the first week in 2020 with a positive outlier in influenza-negative ILI. We present the difference in weeks between identified outliers and the first reported COVID-19 peaks in these 28 countries with high levels of data completeness for influenza surveillance data and the highest number of reported COVID-19 cases globally in 2020. To account for missing data, we also performed a sensitivity analysis using linear interpolation for missing observations of influenza-negative ILI. In 16 of the 28 countries (57%) included in this study, we identified positive outliers in cases of influenza-negative ILI that predated the first reported COVID-19 peak in each country; the average lag between the first positive ILI outlier and the reported COVID-19 peak was 13.3 weeks (standard deviation 6.8). In our primary analysis, the earliest outliers occurred during the week of January 13, 2020, in Peru, the Philippines, Poland, and Spain. Using linear interpolation for missing data, the earliest outliers were detected during the weeks beginning December 30, 2019, and January 20, 2020, in Poland and Peru, respectively. This contrasts with the reported COVID-19 peaks, which occurred on April 6 in Poland and June 1 in Peru. In many low- and middle-income countries in particular, the lag between detected outliers and COVID-19 peaks exceeded 12 weeks. These outliers may represent undetected spread of SARS-CoV-2, although a limitation of this study is that we could not evaluate SARS-CoV-2 positivity. CONCLUSIONS: Using an automated system of influenza-negative ILI outlier monitoring may have informed countries of the spread of COVID-19 more than 13 weeks before the first reported COVID-19 peaks. This proof-of-concept paper suggests that a system of influenza-negative ILI outlier monitoring could have informed national and global responses to SARS-CoV-2 during the rapid spread of this novel pathogen in early 2020.

Characteristics and Outcomes of US Patients Hospitalized With COVID-19.

BACKGROUND: Understanding COVID-19 epidemiology is crucial to clinical care and to clinical trial design and interpretation. OBJECTIVE: To describe characteristics, treatment, and outcomes among patients hospitalized with COVID-19 early in the pandemic. METHODS: A retrospective cohort study of consecutive adult patients with laboratory-confirmed, symptomatic SARS-CoV-2 infection admitted to 57 US hospitals from March 1 to April 1, 2020. RESULTS: Of 1480 inpatients with COVID-19, median (IQR) age was 62.0 (49.4-72.9) years, 649 (43.9%) were female, and 822 of 1338 (61.4%) were non-White or Hispanic/Latino. Intensive care unit admission occurred in 575 patients (38.9%), mostly within 4 days of hospital presentation. Respiratory failure affected 583 patients (39.4%), including 284 (19.2%) within 24 hours of hospital presentation and 413 (27.9%) who received invasive mechanical ventilation. Median (IQR) hospital stay was 8 (5-15) days overall and 15 (9-24) days among intensive care unit patients. Hospital mortality was 17.7% (n = 262). Risk factors for hospital death identified by penalized multivariable regression included older age; male sex; comorbidity burden; symptoms-to-admission interval; hypotension; hypoxemia; and higher white blood cell count, creatinine level, respiratory rate, and heart rate. Of 1218 survivors, 221 (18.1%) required new respiratory support at discharge and 259 of 1153 (22.5%) admitted from home required new health care services. CONCLUSIONS: In a geographically diverse early-pandemic COVID-19 cohort with complete hospital folllow-up, hospital mortality was associated with older age, comorbidity burden, and male sex. Intensive care unit admissions occurred early and were associated with protracted hospital stays. Survivors often required new health care services or respiratory support at discharge.

Most Early-Treated Children With Perinatally Acquired HIV Have Preserved Lung Function at School Age.

BACKGROUND: Impaired lung function is common among older children with perinatally acquired HIV (PHIV) who initiated antiretroviral therapy (ART) late in childhood. We determined the prevalence of abnormal spirometry and cofactors for impaired lung function among school-age children with PHIV who initiated ART when aged 12 months or younger. SETTING: Children who received early ART in the Optimizing Pediatric HIV-1 Therapy study in Kenya and underwent spirometry at school age. METHODS: Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured. Abnormal spirometry was defined as follows: obstructive (FEV1/FVC <1.64 z score [zFEV1/FVC]) and restricted (zFVC <1.64 with zFEV1/FVC ≥1.64). Characteristics, including anthropometric and HIV-related data, were ascertained in infancy and at school age. Caregiver carbon monoxide exposure served as a proxy for school-age child exposure. Linear regression determined associations of cofactors with lung function. RESULTS: Among 40 children, the median age was 5 months at ART initiation and 8.5 years at spirometry. The mean zFEV1, zFVC, and zFEV1/FVC (SD) were 0.21 (1.35), 0.31 (1.22), and -0.24 (0.82), respectively. Five (13%) children had abnormal spirometry. Spirometry z scores were significantly lower among children with pre-ART pneumonia, WHO HIV stage 3/4, higher HIV RNA at 6 months after ART initiation, low anthropometric z scores, and higher carbon monoxide exposure. CONCLUSIONS: Most of the children with PHIV who initiated ART at age 12 months or younger had normal spirometry, suggesting that ART in infancy preserved lung function. However, 13% had abnormal spirometry despite early ART. Modifiable factors were associated with impaired lung function, providing potential targets for interventions to prevent chronic lung disease.

A cross-sectional analysis of diagnosis and management of chronic obstructive pulmonary disease in people living with HIV: Opportunities for improvement.

ABSTRACT: Chronic obstructive pulmonary disease (COPD) is common in people living with HIV (PLWH). We sought to evaluate the appropriateness of COPD diagnosis and management in PLWH, comparing results to HIV-uninfected persons.We conducted a cross-sectional analysis of Veterans enrolled in the Examinations of HIV-Associated Lung Emphysema study, in which all participants underwent spirometry at enrollment and reported respiratory symptoms on self-completed surveys. Primary outcomes were misdiagnosis and under-diagnosis of COPD, and the frequency and appropriateness of inhaler prescriptions. Misdiagnosis was defined as having an International Classification of Diseases (ICD)-9 diagnosis of COPD without spirometric airflow limitation (post-bronchodilator forced expiratory volume in 1-second [FEV1]/Forced vital capacity [FVC] < 0.7). Under-diagnosis was defined as having spirometry-defined COPD without a prior ICD-9 diagnosis.The analytic cohort included 183 PLWH and 152 HIV-uninfected participants. Of 25 PLWH with an ICD-9 diagnosis of COPD, 56% were misdiagnosed. Of 38 PLWH with spirometry-defined COPD, 71% were under-diagnosed. In PLWH under-diagnosed with COPD, 85% reported respiratory symptoms. Among PLWH with an ICD-9 COPD diagnosis as well as in those with spirometry-defined COPD, long-acting inhalers, particularly long-acting bronchodilators (both beta-agonists and muscarinic antagonists) were prescribed infrequently even in symptomatic individuals. Inhaled corticosteroids were the most frequently prescribed long-acting inhaler in PLWH (28%). Results were overall similar amongst the HIV-uninfected.COPD was frequently misdiagnosed and under-diagnosed in PLWH, similar to uninfected-veterans. Among PLWH with COPD and a likely indication for therapy, long-acting inhalers were prescribed infrequently, particularly guideline-concordant, first-line long-acting bronchodilators. Although not a first-line controller therapy for COPD, inhaled corticosteroids were prescribed more often.

Community-Acquired Pneumonia and Risk of Cardiovascular Events in People Living With HIV.

Background Hospitalization with community-acquired pneumonia (CAP) is associated with an increased risk of cardiovascular disease (CVD) events in patients uninfected with HIV. We evaluated whether people living with HIV (PLWH) have a higher risk of CVD or mortality than individuals uninfected with HIV following hospitalization with CAP. Methods and Results We analyzed data from the Veterans Aging Cohort Study on US veterans admitted with their first episode of CAP from April 2003 through December 2014. We used Cox regression analyses to determine whether HIV status was associated with incident CVD events and mortality from date of admission through 30 days after discharge (30-day mortality), adjusting for known CVD risk factors. We included 4384 patients (67% [n=2951] PLWH). PLWH admitted with CAP were younger, had less severe CAP, and had fewer CVD risk factors than patients with CAP who were uninfected with HIV. In multivariable-adjusted analyses, CVD risk was similar in PLWH compared with HIV-uninfected (hazard ratio [HR], 0.89; 95% CI, 0.70-1.12), but HIV infection was associated with higher mortality risk (HR, 1.49; 95% CI, 1.16-1.90). In models stratified by HIV status, CAP severity was significantly associated with incident CVD and 30-day mortality in PLWH and patients uninfected with HIV. Conclusions In this study, the risk of CVD events during or after hospitalization for CAP was similar in PLWH and patients uninfected with HIV, after adjusting for known CVD risk factors and CAP severity. HIV infection, however, was associated with increased 30-day mortality after CAP hospitalization in multivariable-adjusted models. PLWH should be included in future studies evaluating mechanisms and prevention of CVD events after CAP.

Adverse health effects associated with household air pollution: a systematic review, meta-analysis, and burden estimation study.

BACKGROUND: 3 billion people worldwide rely on polluting fuels and technologies for domestic cooking and heating. We estimate the global, regional, and national health burden associated with exposure to household air pollution. METHODS: For the systematic review and meta-analysis, we systematically searched four databases for studies published from database inception to April 2, 2020, that evaluated the risk of adverse cardiorespiratory, paediatric, and maternal outcomes from exposure to household air pollution, compared with no exposure. We used a random-effects model to calculate disease-specific relative risk (RR) meta-estimates. Household air pollution exposure was defined as use of polluting fuels (coal, wood, charcoal, agricultural wastes, animal dung, or kerosene) for household cooking or heating. Temporal trends in mortality and disease burden associated with household air pollution, as measured by disability-adjusted life-years (DALYs), were estimated from 2000 to 2017 using exposure prevalence data from 183 of 193 UN member states. 95% CIs were estimated by propagating uncertainty from the RR meta-estimates, prevalence of household air pollution exposure, and disease-specific mortality and burden estimates using a simulation-based approach. This study is registered with PROSPERO, CRD42019125060. FINDINGS: 476 studies (15·5 million participants) from 123 nations (99 [80%] of which were classified as low-income and middle-income) met the inclusion criteria. Household air pollution was positively associated with asthma (RR 1·23, 95% CI 1·11-1·36), acute respiratory infection in both adults (1·53, 1·22-1·93) and children (1·39, 1·29-1·49), chronic obstructive pulmonary disease (1·70, 1·47-1·97), lung cancer (1·69, 1·44-1·98), and tuberculosis (1·26, 1·08-1·48); cerebrovascular disease (1·09, 1·04-1·14) and ischaemic heart disease (1·10, 1·09-1·11); and low birthweight (1·36, 1·19-1·55) and stillbirth (1·22, 1·06-1·41); as well as with under-5 (1·25, 1·18-1·33), respiratory (1·19, 1·18-1·20), and cardiovascular (1·07, 1·04-1·11) mortality. Household air pollution was associated with 1·8 million (95% CI 1·1-2·7) deaths and 60·9 million (34·6-93·3) DALYs in 2017, with the burden overwhelmingly experienced in low-income and middle-income countries (LMICs; 60·8 million [34·6-92·9] DALYs) compared with high-income countries (0·09 million [0·01-0·40] DALYs). From 2000, mortality associated with household air pollution had reduced by 36% (95% CI 29-43) and disease burden by 30% (25-36), with the greatest reductions observed in higher-income nations. INTERPRETATION: The burden of cardiorespiratory, paediatric, and maternal diseases associated with household air pollution has declined worldwide but remains high in the world's poorest regions. Urgent integrated health and energy strategies are needed to reduce the adverse health impact of household air pollution, especially in LMICs. FUNDING: British Heart Foundation, Wellcome Trust.

Validation of the global lung initiative 2012 multi-ethnic spirometric reference equations in healthy urban Zimbabwean 7-13 year-old school children: a cross-sectional observational study.

BACKGROUND: The 2012 Global Lung Function Initiative (GLI2012) provide multi-ethnic spirometric reference equations (SRE) for the 3-95 year-old age range, but Sub-Saharan African populations are not represented. This study aimed to evaluate the fit of the African-American GLI2012 SRE to a population of healthy urban and peri-urban Zimbabwean school-going children (7-13 years). METHODS: Spirometry and anthropometry were performed on black-Zimbabwean children recruited from three primary schools in urban and peri-urban Harare, with informed consent and assent. Individuals with a history or current symptoms of respiratory disease or with a body mass index-z score (BMI) < - 2 were excluded. Spirometry z-scores were generated from African-American GLI2012 SRE, which adjust for age, sex, ethnicity and height, after considering all GLI2012 modules. Anthropometry z-scores were generated using the British (1990) reference equations which adjust for age and sex. The African-American GLI2012 z-score distribution for the four spirometry measurements (FVC, FEV1, FEV1/FVC and MMEF) were evaluated across age, height, BMI and school (as a proxy for socioeconomic status) to assess for bias. Comparisons between the African-American GLI2012 SRE and Polgar equations (currently adopted in Zimbabwe) on the percent-predicted derived values were also performed. RESULTS: The validation dataset contained acceptable spirometry data from 712 children (344 girls, mean age: 10.5 years (SD 1.81)). The spirometry z-scores were reasonably normally distributed, with all means lower than zero but within the range of ±0.5, indicating a good fit to the African-American GLI2012 SRE. The African-American GLI2012 SRE produced z-scores closest to a normal distribution. Z-scores of girls deviated more than boys. Weak correlations (Pearson's correlation coefficient < 0.2) were observed between spirometry and anthropometry z-scores, and scatterplots demonstrated no systematic bias associated with age, height, BMI or socioeconomic status. The African-American GLI2012 SRE provided a better fit for Zimbabwean paediatric spirometry data than Polgar equations. CONCLUSION: The use of African-American GLI2012 SRE in this population could help in the interpretation of pulmonary function tests.

Endothelial Activation, Innate Immune Activation, and Inflammation Are Associated With Postbronchodilator Airflow Limitation and Obstruction Among Adolescents Living With HIV.

BACKGROUND: Chronic inflammation, innate immune activation, T-cell imbalance and endothelial activation have been linked with lung diseases. We sought to determine whether markers of these pathophysiologic pathways were associated with spirometry and chest computed tomography (CT) abnormalities among adolescents living with HIV (ALWH). SETTING: Coptic Hope Center for Infectious Diseases in Nairobi, Kenya. METHODS: We performed a cross-sectional study of ALWH (10-19 years old). Participants underwent chest CT, spirometry, and venipuncture for serum biomarkers. We also collected demographic, anthropometric, T-cell subset, antiretroviral therapy, and exposure data. We compared characteristics and biomarkers by airflow obstruction [postbronchodilator FEV1/FVC z-score (zFEV1/FVC) < -1.64]. We used multivariable linear regression to determine associations of log10-transformed biomarkers and chest CT abnormalities with lower postbronchodilator zFEV1/FVC (airflow limitation). We performed exploratory principal components analysis on biomarkers, and determined associations of factors with postbronchodilator zFEV1/FVC and chest CT abnormalities. RESULTS: Of 47 participants with acceptable quality spirometry, 21 (45%) were female, median age was 13 years and 96% had perinatally-acquired HIV. Median CD4 was 672 cells/µL. Overall, 28% had airflow obstruction and 78% had a chest CT abnormality; airflow obstruction was associated with mosaic attenuation (P = 0.001). Higher endothelial activation (sVCAM-1, sICAM-1), inflammation and innate immune activation (serum amyloid-A, sTREM-1, sCD163), and T-cell imbalance (lower CD4/CD8) markers were associated with airflow limitation. Factors comprising endothelial and innate immune activation were associated with airflow limitation. CONCLUSIONS: Endothelial activation, innate immune activation, T-cell imbalance, and chronic inflammation are associated with airflow limitation and obstruction, providing insights into chronic lung disease pathophysiology among ALWH.

Global Health-related Training Opportunities. A National Survey of Pulmonary and Critical Care Medicine Fellowship Programs.

Rationale: Clinical and research training opportunities in global health are of increasing interest to medical trainees, but little is known about such opportunities in U.S.-based pulmonary and pulmonary/critical care medicine (PCCM) fellowship programs.Objectives: Summarize currently available global health-related training opportunities and identify potential barriers to implementing global health curricula among U.S.-based PCCM fellowship programs.Methods: We sent a confidential, online, targeted needs assessment to PCCM fellowship program directors and associate program directors. Data collected included program demographics, currently available global health-related clinical and research training opportunities, potential barriers to the implementation of global health-related programmatic content, and perceived interest in global health-related training opportunities by current and/or prospective trainees. To evaluate for nonresponse bias, we performed an online search to identify global health-related training opportunities offered by nonresponding programs.Results: Out of 171 surveyed programs, 63 PCCM fellowship programs (37%) provided survey responses. Most responses (n = 56, 89%) were from combined PCCM training programs; 66% (n = 40) of programs offered at least one component of global health-related clinical or research training. Overall, 27% (n = 17) had a Ruth L. Kirschstein National Research Service Award Institutional Research Training Grant (National Institutes of Health T32), 73% (n = 46) had fewer than 35 faculty members, and 51% (n = 32) had at least one faculty member conducting global health-focused research. Most responding programs (66%, n = 40) offered at least one global health-related educational component. Among programs that would like to offer global health-related training components, the most common barriers included competing priorities for lecture content and a lack of in-division mentors with global health experience, a champion for global health-related activities, and established partnerships outside the United States.Conclusions: PCCM program leaders are interested in offering global health-related training opportunities, but important barriers include lack of mentorship, dedicated fellowship time, and established global partnerships. Future research is needed to better understand global health-related interests and training needs of incoming fellows and to design creative solutions for providing global health-related training across academic institutions with variable global health-related training capacities.

Tuberculosis and other bacterial co-infection in Cambodia: a single center retrospective cross-sectional study.

BACKGROUND: Cambodia, a lower middle-income country of about 16 million individuals in southeast Asia, endures a high burden of both tuberculosis and other lower respiratory infections. Differentiating tuberculosis from other causes of respiratory infection has important clinical implications yet may be challenging to accomplish in the absence of diagnostic microbiology facilities. Furthermore, co-infection of tuberculosis with other bacterial lower respiratory infections may occur. The objective of this study was to determine the prevalence and etiologies of tuberculosis and other bacterial co-infection and to analyze the clinical and radiographic characteristics of patients presenting with respiratory infection to a provincial referral hospital in Cambodia. METHODS: We performed a retrospective, cross-sectional analysis of laboratory and clinical data, on patients presenting with respiratory symptoms to a chest clinic of a 260-bed provincial referral hospital in Cambodia. We analyzed mycobacterial and bacterial sputum test results, and demographics, medical history and chest radiography. RESULTS: Among 137 patients whose treating clinicians ordered sputum testing for tuberculosis and other bacteria, the median age was 52 years, 54% were male, 3% had HIV infection, and 26% were current smokers. Nearly all had chronic respiratory symptoms (> 96%) and abnormal chest radiographs (87%). Sputum testing was positive for tuberculosis in 40 patients (30%) and for bacteria in 60 patients (44%); 13 had tuberculosis and bacterial co-infection (9% overall; 33% of tuberculosis patients). Clinical characteristics were generally similar across pulmonary infection types, although co-infection was identified in 43% of patients with one or more cavitary lesions on chest radiography. Among those with bacterial growth on sputum culture, Gram negative bacilli (Klebsiella and Pseudomonas spp.) were the most commonly isolated. CONCLUSIONS: Among patients with symptoms of respiratory infections whose treating clinicians ordered sputum testing for tuberculosis and other bacteria, 9% of all patients and 33% of tuberculosis patients had tuberculosis and bacterial co-infection. Greater availability of microbiologic diagnostics for pulmonary tuberculosis and bacterial infection is critical to ensure appropriate diagnosis and management.

Adolescent age is an independent risk factor for abnormal spirometry among people living with HIV in Kenya.

OBJECTIVES: As life expectancy of people living with HIV (PLWH) improves in low-income and middle-income countries (LMICs), the spectrum of HIV-related pulmonary complications may reflect a greater burden of chronic lung diseases as in high-income countries. We determined whether the risk of abnormal spirometry was greater among adolescent compared with adult PLWH at the Coptic Hope Center for Infectious Diseases in Nairobi, Kenya, and evaluated the role of other cofactors for abnormal spirometry. DESIGN: We prospectively enrolled adolescent and adult PLWH for this cross-sectional study. METHODS: Data collection included standardized questionnaires, clinical assessment, and prebronchodilator and postbronchodilator spirometry. Adolescents additionally underwent noncontrast chest computed tomography. Multivariable logistic regression determined associations of adolescent age with abnormal spirometry, adjusting for cofactors. RESULTS: Of 427 PLWH, 21 (40%) adolescents and 64 (17%) adults had abnormal spirometry. Among adolescents, 80% had abnormal chest CTs, and 79% had at least one respiratory symptom. Adolescent age (adjusted odds ratio 3.22; 95% confidence interval 1.48-6.98) was independently associated with abnormal spirometry, adjusting for recent CD4, HIV clinical stage, low BMI, indoor kerosene use, smoking pack-years, and prior pulmonary tuberculosis. Additional important cofactors for abnormal spirometry included prior pulmonary tuberculosis (3.15; 1.70-5.58), kerosene use (1.77; 1.04-3.04) and smoking pack-years (1.05; 1.00-1.10). Adolescent age, prior pulmonary tuberculosis, and smoking pack-years were significantly associated with airflow limitation. CONCLUSION: Adolescent age was independently associated with increased risk of abnormal spirometry, particularly airflow limitation. Studies to improve prevention, detection, and management of chronic lung disease across the lifespan among PLWH are needed in LMICs.

Impact of HIV infection on α1-antitrypsin in the lung.

Emphysema is one of the most common lung diseases in HIV+ individuals. The pathogenesis of HIV-associated emphysema remains unclear; however, radiographic distribution and earlier age of presentation of emphysema in the lungs of HIV+ patients are similar to deficiency of α1-antitrypsin (A1AT), a key elastase inhibitor in the lung. Reduced levels of circulating A1AT in HIV+ patients suggest a potential mechanism for emphysema development. In the present study we asked if A1AT levels and activity in the bronchoalveolar lavage fluid (BALF) differ in HIV+ and HIV- patients with and without emphysema. A1AT levels were measured by ELISA in plasma and BALF from a cohort of 21 HIV+ and 29 HIV- patients with or without emphysematous changes on chest CT scan. To analyze A1AT function, we measured elastase activity in the BALF and assessed oxidation and polymerization of A1AT by Western blotting. Total A1AT was increased in the BALF, but not in the plasma, of HIV+ compared with HIV- patients, regardless of the presence or absence of emphysema. However, antielastase activity was decreased in BALF from HIV+ patients, suggesting impaired A1AT function. Higher levels of the oxidized form of A1AT were detected in BALF from HIV+ than HIV- patients, which may account for the decreased antielastase activity. These findings suggest that, in the lungs of HIV+ patients, posttranslational modifications of A1AT produce a "functional deficiency" of this critical elastase inhibitor, which may contribute to emphysema development.

Markers of chronic obstructive pulmonary disease are associated with mortality in people living with HIV.

OBJECTIVE: Aging people living with HIV (PLWH) face an increased burden of comorbidities, including chronic obstructive pulmonary disease (COPD). The impact of COPD on mortality in HIV remains unclear. We examined associations between markers of COPD and mortality among PLWH and uninfected study participants. DESIGN: Longitudinal analysis of the Examinations of HIV-Associated Lung Emphysema (EXHALE) cohort study. METHODS: EXHALE includes 196 PLWH and 165 uninfected smoking-matched study participants who underwent pulmonary function testing and computed tomography (CT) to define COPD and were followed. We determined associations between markers of COPD with mortality using multivariable Cox regression models, adjusted for smoking and the Veterans Aging Cohort Study (VACS) Index, a validated predictor of mortality in HIV. RESULTS: Median follow-up time was 6.9 years; the mortality rate was 2.7/100 person-years among PLWH and 1.7/100 person-years among uninfected study participants (P = 0.11). The VACS Index was associated with mortality in both PLWH and uninfected study participants. In multivariable models, pulmonary function and CT characteristics defining COPD were associated with mortality in PLWH: those with airflow obstruction (forced expiratory volume in 1 s/ forced vital capacity <0.7) had 3.1 times the risk of death [hazard ratio 3.1 (95% confidence interval 1.4-7.1)], compared with those without; those with emphysema (>10% burden) had 2.4 times the risk of death [hazard ratio 2.4 (95% confidence interval 1.1-5.5)] compared with those with ≤ 10% emphysema. In uninfected subjects, pulmonary variables were not significantly associated with mortality, which may reflect fewer deaths limiting power. CONCLUSION: Markers of COPD were associated with greater mortality in PWLH, independent of the VACS Index. COPD is likely an important contributor to mortality in contemporary PLWH.

A Low Peripheral Blood CD4/CD8 Ratio Is Associated with Pulmonary Emphysema in HIV.

OBJECTIVES: The prevalence of emphysema is higher among HIV-infected (HIV+) individuals compared to HIV-uninfected persons. While greater tobacco use contributes, HIV-related effects on immunity likely confer additional risk. Low peripheral blood CD4+ to CD8+ T-lymphocyte (CD4/CD8) ratio may reflect chronic inflammation in HIV and may be a marker of chronic lung disease in this population. Therefore, we sought to determine whether the CD4/CD8 ratio was associated with chronic obstructive pulmonary disease (COPD), particularly the emphysema subtype, in a cohort of HIV+ subjects. METHODS: We performed a cross-sectional analysis of 190 HIV+ subjects enrolled in the Examinations of HIV Associated Lung Emphysema (EXHALE) study. Subjects underwent baseline laboratory assessments, pulmonary function testing and chest computed tomography (CT) analyzed for emphysema severity and distribution. We determined the association between CD4/CD8 ratio and emphysema, and the association between CD4/CD8 ratio and pulmonary function markers of COPD. RESULTS: Mild or greater emphysema (>10% lung involvement) was present in 31% of subjects. Low CD4/CD8 ratio was associated with >10% emphysema in multivariable models, adjusting for risk factors including smoking, current and nadir CD4 count and HIV RNA level. Those with CD4/CD8 ratio <0.4 had 6.3 (1.1-39) times the odds of >10% emphysema compared to those with a ratio >1.0 in fully adjusted models. A low CD4/CD8 ratio was also associated with reduced diffusion capacity (DLCO). CONCLUSIONS: A low CD4/CD8 ratio was associated with emphysema and low DLCO in HIV+ subjects, independent of other risk factors and clinical markers of HIV. The CD4/CD8 ratio may be a useful, clinically available, marker for risk of emphysema in HIV+ subjects in the antiretroviral therapy (ART) era.