INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that increases susceptibility to chronic lung and liver diseases. There are limited data on testing rates in patients with cirrhosis. Guidelines recommend AATD testing in cryptogenic liver disease but not in patients with an established etiology. We aimed to quantify AATD testing patterns in a national cohort of patients with cirrhosis to inform guidelines. METHODS: In this retrospective cohort study of veterans with a new diagnosis of cirrhosis between January 1, 2008 and January 31, 2020, with follow-up until February 23, 2023, we identified predictors of testing, and of severe AATD (alpha-1 antitrypsin [AAT] < 57 mg/dL or PiSZ/PiZZ phenotype/genotype). RESULTS: Of the 126,210 patients with cirrhosis, 42,403 (33.6%) were tested, including 38,189 (30.3%) for AAT levels only, 1,103 (0.8%) for genotype/phenotype only, and 3,011 (2.4%) for both. Factors associated with higher AATD testing included specialist evaluation and White race, whereas patients with chronic obstructive pulmonary disease, hepatitis B/C, hepatocellular carcinoma, and hepatic decompensation were less likely to be tested. Only half of the patients with AAT levels of <57 mg/dL underwent genotype/phenotype testing. Most patients (94.7%) with severe AATD-associated liver disease also had an alternate etiology of liver disease, including metabolic dysfunction associated with steatotic liver disease (53.6%) or viral hepatitis (16.1%), and would be missed if testing only patients with cryptogenic liver disease. DISCUSSION: AATD testing rates in veterans with cirrhosis are low, and patients at high-risk are less likely to be tested. Guidelines are needed to emphasize universal AATD testing in patients with cirrhosis regardless of the presence of other risk factors.

BackgroundInflammation drives COPD development in people living with HIV (PLwHIV), and the HIV virus impairs T regulatory (Treg) cell responses that deter immune-mediated lung injury. This study sought to determine how cigarette smoke exposure alters lung Treg responses to increase COPD susceptibility in PLwHIV.MethodsLung lavage levels of the Treg chemoattractant CXCL11 were quantified in a cohort of 26 HIV-infected subjects and 34 age-matched controls. To ascertain how CXCL11 modifies lung Treg responses, analyses were then conducted using a chimeric HIV (EcoHIV) infection smoke exposure mouse model and elastase treatment of Treg depleted (DEREG) mice.ResultsCXCL11 lung lavage levels increased in HIV + subjects compared to controls. However, CXCL11 levels were significantly lower in those HIV + subjects with a reduced diffusing capacity for carbon monoxide compared to HIV + subjects with normal lung function. Cigarette smoke exposure reduced CXCL11 levels in HIV + current smokers and decreased lung Cxcl11 levels and Treg frequency in control and EcoHIV-infected mice. Cigarette smoke increased lung c-Src activity in mice and the c-Src inhibitor AZD0530 restored Cxcl11 expression in smoke exposed mice and alveolar macrophages. Direct administration of CXCL11 protein to the airways of EcoHIV infected or smoke exposed mice significantly enhanced lung Treg responses. Treg deficient DEREG mice exhibited increased airway resistance at baseline and had greater lung tissue destruction post elastase treatment.ConclusionsThese findings indicate that cigarette smoke activates c-Src to suppress CXCL11 levels thereby diminishing lung Treg responses that counter airways disease and lung tissue destruction in HIV-infected individuals.

BACKGROUND:Alpha-1 antitrypsin deficiency (AATD) may cause chronic lung and liver disease, yet data on major adverse liver outcomes (MALO) across heterozygous and homozygous Z-allele genotypes remains limited. We assessed the risk of MALO across AATD Pi*MZ, Pi*SZ, and Pi*ZZ genotypes compared to the wildtype Pi*MM. METHODS:This retrospective cohort study utilized the Veterans Analysis of Liver Disease cohort (January 2000-April 2025). Genotypes were identified using validated natural language processing (κ=0.89). Multivariable Fine-Gray models estimated the hazard of MALO. RESULTS:Among 22,537 participants with genotype testing (19,665 Pi*MM, 1,656 Pi*MZ, 281 Pi*SZ, and 935 Pi*ZZ) and 352,612 person-years of follow up, MALO risk increased sequentially with allele burden: Pi*MZ (aHR 1.25, 1.11-1.40), Pi*SZ (aHR 1.51, 1.17-1.94), and Pi*ZZ (aHR 1.80, 1.57-2.07), versus Pi*MM. MALO incidence rates for Pi*MM, Pi*MZ, Pi*SZ, and Pi*ZZ, were 11.3, 13.0, 14.6, and 19.2 for 1,000 person-years respectively, while five-year MALO probability was 3.5%, 5.5%, 5.3%, and 8.1% respectively. Pi*ZZ was associated with significantly increased risk of all individual MALO components: decompensation, HCC, liver transplantation (LT), and liver-related death (LRD). Pi*SZ and Pi*MZ were associated with higher risk of decompensation, LT, and LRD, but not HCC. A sensitivity analysis restricted to participants with MASLD showed consistent findings. CONCLUSION:In this national longitudinal cohort of veterans with documented AATD genotype testing and median follow-up of 15.9 years, we observed an increased risk of MALO in both homozygous and heterozygous Z-allele carriers, underscoring the need for timely diagnosis and enhanced clinical surveillance among veterans with known AATD genotypes.

RATIONALE:AAT (alpha-1 antitrypsin) deficiency (AATD) is a known but underrecognized genetic cause of chronic obstructive pulmonary disease (COPD) and liver disease. Little is known about the epidemiology and burden of AATD among U.S. veterans. OBJECTIVES:To examine the veteran characteristics and epidemiology of AATD and severe AATD throughout the Veterans Health Administration. METHODS:Data were obtained from the electronic health record to describe demographic, clinical, testing outcomes, and geographic data for veterans between January 1, 2010, and December 31, 2019. Multivariable logistic regression analysis was performed to evaluate veteran characteristics associated with AATD. We defined intermediate AATD as a serum AAT concentration >57 and <100 mg/dl or any allelic combination other than PI*MM, PI*MS, PI*SZ, and PI*ZZ. Severe AATD was defined by PI*ZZ and PI*SZ genotypes as well as any combination with a serum AAT concentration ≤57 mg/dl (≤11 μmol/L). RESULTS:Among 12 million veterans enrolled during the study period, 175,508 were tested for AATD; 8,832 received diagnoses of intermediate AATD and 3,088 of severe AATD. The positivity rate of AATD varied year to year, ranging from 62 to 76 cases per 1,000 persons tested. AATD occurred in 57 cases per 1,000 persons tested with COPD, and there were 66 cases of AATD per 1,000 persons tested with liver disease; however, testing rates of COPD (4.04%) or liver disease (17.91%) were low. There was a heterogeneous distribution of AATD throughout the United States. Factors associated with detection and diagnosis of AATD included younger age, White race, and no history of tobacco use. CONCLUSIONS:This study represents a national analysis of AATD in the Veterans Health Administration. Although the annual positivity rates of AATD among those tested varied over the decade, it confirmed AATD is prevalent in veterans. However, the number of eligible veterans tested is low, which highlights the need for increased awareness of this condition.

Objective: This study compared delayed- versus immediate-reward financial incentives using a weekly reward frequency. Methods: Smokers were randomized in a single blinded study of 2 groups: Reward Group used an immediate-reward strategy and Banked-Money Group used a delayed-reward strategy. Subjects received personalized smoking cessation plans, presented weekly for smoking tests measuring exhaled CO (COex) and received $40 for passing. The Reward Group immediately received $40 whereas the Banked-Money Group's $40 was placed in an account they could access only upon successful study completion. During the first 3 months, subjects could fail 2 tests before a 3rd disqualified them. During the last month, any positive smoking test disqualified them. If disqualified, the Reward Group members kept all previously received rewards however the Banked-Money Group members lost all accrued money. Follow up visits occurred at 3 and 6 months after trial completion. Results: Twelve (33%) participants quit smoking in intention to treat analysis with 9 (75%) remaining abstinent 6 months after trial completion. The Reward Group had 5 of 15 (33%) quit versus 7 of 16 (43.8%) in the Banked-Money Group. Conclusions: This pilot trial shows the financial incentive protocol is feasible with favorable quit rates compared to previously published data.

Background Elevations in body mass index (BMI) impacts morbidity in subjects with chronic obstructive pulmonary disease (COPD) in general, but little is known about is impact in subjects with COPD related to alpha-1 antitrypsin deficiency (AATD-COPD). Research Question What is the prevalence and clinical impact of high BMI in AATD-COPD?. Study Design and Methods: 646 subjects completed clinical and health related quality of life (HRQoL) questionnaires for 2 years. Subjects were grouped by baseline BMI categories (underweight, normal, overweight, obese, and morbidly obese) to compare symptoms, exacerbations, HRQoL and 5-year and 10-year survival. Relation between changes in BMI over time on HRQoL was assessed. Results The cohort’s mean age (55 ± 9.2 years), gender distribution (50.1% males) and mean %FEV1 (36.6 ± 17.0%) was similar across all BMI categories. A third (31.6%) had normal BMI, 5.6% were underweight and 62% had a high BMI (37.3% overweight, 16.1% obese and 9.4% morbidly obese). Subjects with a high BMI had significantly worse St George’s Respiratory Questionnaire (SGRQ) and SF-36 physical composite scores compared to normal weight subjects. Patients with morbid obesity had the highest odds of being in the worst SGRQ (OR 3.8, 95% CI 1.9-7.8) and SF-36 physical composite (OR 4.2, 95% CI 2.1-8.1) quartiles and experienced more emergency room visits and hospitalizations compared to normal weight patients (p<0.05). Subjects who transitioned to a higher BMI category overtime reported worsening of SGRQ and SF-36 physical composite scores (p<0.05) and vice versa. Despite their higher morbidity, no difference in survival was observed between subjects with high BMI and normal BMI after a mean follow up of 9 years. Interpretation BMI above normal is prevalent in subjects with AATD-COPD and is associated with greater comorbidity and poor HRQoL but does not impact survival. HRQoL is inversely affected by BMI changes over time.

Background: Alpha - 1 antitrypsin deficiency (AATD) is characterized by low alpha - 1 antitrypsin (AAT) levels, predisposing individuals to lung disease. The standard of care, plasma - derived AAT (pdAAT), is delivered as weekly infusions to maintain serum AAT concentrations >= 11 mu M (approximate to 50% of those in healthy individuals). INBRX - 101, a recombinant human AAT - Fc fusion protein, was designed to have a longer half - life and achieve higher AAT levels than pdAAT. Methods: In this phase 1 dose - escalation study (N=31), adults with AATD received 1 dose (part 1) or 3 doses (part 2) of 10 (part 1), 40, 80, or 120mg/kg INBRX - 101 every 3 weeks (Q3W) via intravenous infusion. The primary endpoint was safety and tolerability. Secondary endpoints were pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of INBRX - 101. Results: INBRX - 101 was well tolerated. Most treatment - emergent adverse events were grade <= 2. In part 2 (n=18; each dose, n=6), dose - related increases in serum functional AAT (fAAT) were observed; mean fAAT levels remained above the 21 mu M target for up to 4 weeks after the final dose in the 120 - mg/kg cohort. Antidrug antibodies had no meaningful impact on PK or PD. INBRX - 101 was detected in pulmonary epithelial lining fluid (PELF) from all patients assessed (n=11), and PELF fAAT increased after dosing. PK/PD modeling projected steady - state serum fAAT >= 21 mu M at 120mg/kg Q3W (average concentration approximate to 43 mu M; trough concentration approximate to 28 mu M) and Q4W (approximate to 34 mu M; approximate to 21 mu M). Conclusion: The favorable safety profile and ability to maintain serum fAAT levels >21 mu M with extended - interval dosing, support a phase 2 trial evaluating Q3W and Q4W dosing of INBRX - 101.

Background: Inflammation drives COPD in people living with HIV, and the HIV virus impairs T regulatory (Treg) cell responses that deter immune-mediated lung injury. Aims: We determined how cigarette smoke exposure alters lung Treg responses to increase the susceptibility to COPD in people living with HIV. Methods: Lung lavage levels of the Treg chemoattractant CXCL11 were quantified in a cohort of 26 HIV-infected subjects and 42 age-matched controls. To ascertain how CXCL11 modifies lung Treg responses, analyses were conducted using a chimeric HIV (EcoHIV) infection smoke exposure mouse model and elastase treatment of Treg depleted (DEREG) mice. Results: CXCL11 lung lavage levels increased in HIV+ subjects compared to controls. However, CXCL11 levels were significantly lower in those HIV+ subjects with a reduced diffusing capacity for carbon monoxide compared to HIV+ subjects with normal lung function. Cigarette smoke exposure reduced CXCL11 levels in human subjects and decreased lung Cxcl11 levels and Treg frequency in control and EcoHIV-infected mice. Cigarette smoke increased lung c-Src activity in mice and the c-Src inhibitor AZD0530 restored Cxcl11 expression in smoke exposed mice and alveolar macrophages. Direct administration of CXCL11 protein to the airways of EcoHIV infected or smoke exposed mice significantly enhanced lung Treg responses. Treg deficient DEREG mice exhibited increased airway resistance at baseline and had greater lung tissue destruction post elastase treatment. Conclusions: Cigarette smoke activates c-Src to suppress CXCL11 levels thereby diminishing lung Treg responses that counter airways disease and lung tissue destruction in HIV+ individuals.

SESSION TITLE: Chest Infections Case Report Posters 36 SESSION TYPE: Case Report Posters PRESENTED ON: 10/11/2023 12:00 pm - 12:45 pm INTRODUCTION: Granulomatous hepatitis is a rare finding in patients with tuberculosis (TB), and it can mimic malignancy in the right clinical scenario. In patients with cirrhosis, elevated tumor markers may raise concern for hepatocellular carcinoma (HCC). However, it is important to consider other causes of granulomatous hepatitis, such as tuberculosis, especially in patients with a history of tuberculosis exposure or immunosuppression. CASE PRESENTATION: A 49-year-old male originally from South America previously incarcerated, with a history of polysubstance abuse and homelessness, presented to the emergency department complaining of worsening abdominal distention, chills, fevers, and productive cough. CT chest revealed diffuse ground glass opacity in the lungs with fine nodular infiltrations, sputum smear was found to be AFB positive, despite a negative QuantiFERON. CT abdomen without contrast revealed diffuse nodularity of the liver with large ascites and thickening of the omental fat, likely related to hepatocellular disease or liver cirrhosis. Serum tumor biomarkers, carcinoembryonic antigen (CEA) and cancer antigen 125 tumour marker (CA 125), were found to be elevated to 8.1 ng/mL and 79 U/mL, respectively, raising concern for malignancy. A liver biopsy showed granulomatous hepatitis with acid-fast bacilli. The patient was started on anti-tuberculosis treatment with rifampin, isoniazid, pyrazinamide, and ethambutol. Following five weeks of treatment, tumor markers decreased to normal levels, and repeat US abdomen demonstrated a normal sonographic appearance of the liver. DISCUSSION: Tuberculosis is a globally common infection with significant morbidity and mortality, predominantly in developing nations. Extrapulmonary TB accounts for 15% of total TB cases. Moreover, Gastrointestinal (GI) TB, as an extrapulmonary form, accounts for 1% to 3% of all TB cases worldwide. The elevated levels of CEA and CA 125 tumor markers in our patient raised concerns for the presence of malignancy, particularly given his history of cirrhosis. While CEA and CA 125 are not specific to liver cancer, their elevation can be associated with various gastrointestinal cancers, including HCC. The fact that our patient had an echogenic heterogeneous liver with diffuse nodularity of the contour representing cirrhotic changes also increased suspicion for HCC. However, the liver biopsy ultimately revealed granulomatous hepatitis with acid fast bacilli, indicating tuberculosis as the underlying cause for the elevated tumor markers.It is important to note that elevated CEA and CA 125 tumor markers are not exclusive to malignancy, and can be found in various other conditions such as inflammatory bowel disease, autoimmune disorders, and infections. Therefore, these markers should be interpreted in conjunction with other clinical and radiographic findings to guide appropriate diagnostic and treatment decisions. CONCLUSIONS: Granulomatous hepatitis is a rare manifestation of tuberculosis and can be challenging to diagnose, particularly in cirrhotic patients where the clinical picture can mimic malignancy. This case highlights the importance of considering granulomatous hepatitis in the differential diagnosis of cirrhotic patients presenting with abnormal liver function and elevated tumor biomarkers. Also, in the presence of hepatic tuberculosis, the trend of tumor biomarkers such as CEA and CA 125 might pose a potential signal for treatment response in the appropriate clinical setting. REFERENCE #1: Eraksoy H. Gastrointestinal and abdominal tuberculosis. Gastroenterology Clinics of North America. 2021;50(2):341–60. REFERENCE #2: Park M, Dhawan R, Whittaker E, Kon OM. CA 125 and TB. BMJ Case Reports. 2021;14(1). REFERENCE #3: Duffy MJ, Sturgeon C, Lamerz R, Haglund C, Holubec VL, Klapdor R, Nicolini A, Topolcan O, Heinemann V. Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update. Int J Cancer. 2014 Oct 1;134(7):2513-22 DISCLOSURES: No disclosure on file for Michael Campos No relevant relationships by Kareem Eid No relevant relationships by michael schweitzer No relevant relationships by Abel Triana

INTRODUCTION: Pulmonary embolism (PE) is a serious and potentially life-threatening condition that can be challenging to diagnose, especially in patients with underlying comorbidities.Early detection and treatment of PE are essential to prevent morbidity and mortality.Endobronchial ultrasound (EBUS) has emerged as a useful tool for staging lung cancer and diagnosing other thoracic conditions.However, incidental findings during EBUS procedures are rare and often underreported.In this case report, we present a patient with lung cancer who underwent EBUS and was incidentally found to have a PE.The diagnosis was confirmed using chest CT angiography (CTA).We discuss the diagnosis, treatment, and outcome of this patient and emphasize the importance of reporting such findings to raise awareness among clinicians and researchers.CASE PRESENTATION: An 86-year-old female with a history of cough and shortness of breath presented to the clinic for a check-up.A chest X-ray revealed a right upper lobe mass, and subsequent computed tomography (CT) confirmed a 2.5 cm adenocarcinoma of the lung with hilar and mediastinal lymphadenopathy.The patient underwent an EBUS procedure for staging purposes.During the procedure, an incidental finding of pulmonary embolism was discovered in the right upper lobe.(Figure 1) A CT pulmonary angiogram was obtained, confirming the presence of an acute nonocclusive pulmonary embolism in the distal right main pulmonary artery, extending into the right lower lobar artery.Ultrasound doppler of lower extremities confirmed an acute deep vein thrombosis (DVT) of the left common femoral, profunda, and femoral veins.The patient was started on anticoagulation therapy with direct oral anticoagulant (DOAC) and the lymph nodes were negative for malignancy.The decision was made to start radiotherapy, rather than surgery, given her history of PE and a close follow-up with his medical oncologist showed no progression of the disease at 6 and 9 months. DISCUSSION:The gold standard test for PE is CTA, however, in situations where CTA cannot be conducted due to certain reasons like renal failure, allergy to the contrast material, or contraindication for radiation exposure, alternative diagnostic tests such as a ventilation-perfusion scan can be considered to rule out the diagnosis.However, the usefulness of other modalities such as EBUS has not been fully explored.In this case, our patient underwent EBUS-TBNA for the diagnosis and staging of lung cancer.During the procedure, a pulmonary embolism was incidentally detected using endoscopic ultrasound.The embolism was subsequently confirmed on CTA.The patient was started on anticoagulation therapy and was closely monitored for any signs of complications. CONCLUSIONS:In conclusion, the detection of a PE during EBUS-TBNA is a rare occurrence, with only a few case reports published in the literature.However, it highlights the importance of careful examination of the images obtained during the procedure, as well as the need for a high level of suspicion for PE in patients with lung cancer.Early detection and prompt treatment of PEs can reduce the risk of complications such as pulmonary infarction, right ventricular dysfunction, and death.

Several studies have documented increased exercise capacity with supplemental oxygen therapy in patients with COPD and exertional hypoxemia, but a large trial failed to demonstrate a survival benefit in this population. Due to the heterogeneity observed in therapeutic responses, we sought to retrospectively evaluate survival in male COPD patients with exertional hypoxemia who had a clinically meaningful improvement in exercise capacity while using supplemental oxygen compared to their 6-minute walk test distance (6MWD) while walking on room air. We defined them as responders or non-responders based on a change in 6MWD of greater or less than 54m. We compared their clinical and physiologic characteristics, and their survival over time. From 817 COPD subjects who underwent an assessment for home oxygen during the study period, 140 met inclusion criteria, with 70 (50%) qualifying as responders. There were no significant differences in demographics, lung function, or baseline oxygenation between the groups. The only difference noted was in the baseline 6MWD on room air, with responders to oxygen therapy having significantly lower values (137 ± 74m, 27 ± 15% predicted) compared to non-responders (244 ± 108, 49 ± 23% predicted). Despite their poorer functional capacity, mortality was significantly lower in responders after adjusting for age, comorbidities, and FEV 1 (HR 0.51; CI 0.31–0.83; p = 0.007) compared to non-responders after a median follow-up time of 3 years. We conclude that assessing the immediate effects of oxygen on exercise capacity may be an important way to identify individuals with exertional hypoxemia who may benefit in the long-term from ambulatory oxygen. Prospective long-term studies in this subset of patients with exercise induced hypoxemia are warranted.

Rationale: Landmark studies of long-term oxygen therapy (LTOT) in patients with chronic obstructive pulmonary disease (COPD) used arterial oxygen pressure (PaO2) to define severe hypoxemia; however, oxygen saturation as measured by pulse oximetry (SpO(2)) is commonly used instead. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend evaluation with arterial blood gas (ABG) analysis if SpO(2) is <= 92%. This recommendation has not been evaluated in stable outpatients with COPD undergoing testing for LTOT. Objectives: To evaluate the performance of SpO(2) compared with ABG analysis of PaO2 and arterial oxygen saturation (SaO(2)) to detect severe resting hypoxemia in patients with COPD. Methods: Retrospective analysis of paired SpO(2) and ABG values from stable outpatients with COPD who underwent LTOT assessment in a single center. We calculated false negatives (FNs) as an SpO(2)>88% or>89% in the presence of pulmonary hypertension with a PaO2 <= 55mmHg or <59mmHg in the presence of pulmonary hypertension. Test performance was assessed using receiver operating characteristic (ROC) analysis, intraclass correlation coefficient (ICC), test bias, precision, and accuracy root-mean-square (Arms). An adjusted multivariate analysis was used to evaluate factors affecting SpO(2) bias. Results: Of 518 patients, the prevalence of severe resting hypoxemia was 74 (14.3%), with 52 missed by SpO(2) (FN, 10%), including 13 (2.5%) with an SpO(2).92% (occult hypoxemia). FNs and occult hypoxemia in Black patients were 9% and 1.5%, respectively, and were 13% and 5%, respectively, among active smokers. The correlation between SpO(2) and SaO(2) was acceptable (ICC= 0.78; 95% confidence interval, 0.74-0.81); and the bias of SpO(2) was 0.45%, with a precision of 2.6 (24.65 to 15.55%) and Arms of 2.59. These measurements were similar in Black patients, but in active smokers, correlation was lower and bias showed greater overestimation of SpO(2). ROC analysis suggests that the optimal SpO(2) cutoff to warrant LTOT evaluation by ABG analysis is <94%. Conclusions: SpO(2) as the only measure of oxygenation carries a high FN rate in detecting severe resting hypoxemia in patients with COPD undergoing evaluation for LTOT. Reflex measurement of PaO2 by ABG analysis should be used as recommended by GOLD, ideally at a cutoff higher than an SpO2 <92%, especially in active smokers.

The lung microbiome impacts on lung function, making any smoking-induced changes in the lung microbiome potentially significant. The complex co-occurrence and co-avoidance patterns between the bacterial taxa in the lower respiratory tract (LRT) microbiome were explored for a cohort of active (AS), former (FS) and never (NS) smokers. Bronchoalveolar lavages (BALs) were collected from 55 volunteer subjects (9 NS, 24 FS and 22 AS). The LRT microbiome composition was assessed using 16S rRNA amplicon sequencing. Identification of differentially abundant taxa and co-occurrence patterns, discriminant analysis and biomarker inferences were performed. The data show that smoking results in a loss in the diversity of the LRT microbiome, change in the co-occurrence patterns and a weakening of the tight community structure present in healthy microbiomes. The increased abundance of the genus Ralstonia in the lung microbiomes of both former and active smokers is significant. Partial least square discriminant and DESeq2 analyses suggested a compositional difference between the cohorts in the LRT microbiome. The groups were sufficiently distinct from each other to suggest that cessation of smoking may not be sufficient for the lung microbiota to return to a similar composition to that of NS. The linear discriminant analysis effect size (LEfSe) analyses identified several bacterial taxa as potential biomarkers of smoking status. Network-based clustering analysis highlighted different co-occurring and co-avoiding microbial taxa in the three groups. The analysis found a cluster of bacterial taxa that co-occur in smokers and non-smokers alike. The clusters exhibited tighter and more significant associations in NS compared to FS and AS. Higher degree of rivalry between clusters was observed in the AS. The groups were sufficiently distinct from each other to suggest that cessation of smoking may not be sufficient for the lung microbiota to return to a similar composition to that of NS.

Rationale: Chronic obstructive pulmonary disease (COPD) and alpha-1 antitrypsin deficiency (AATD) are underrecognized diseases. This is in part due to the underdiagnosis and lack of confirmation of COPD but also from poor adherence to AATD screening recommendations. Objectives: A clinical decision support system (CDSS) to guide primary care providers improves spirometry testing and confirmation of COPD diagnosis in subjects at risk and improves AATD screening in patients with confirmed COPD. Methods: A CDSS was created to be applied to all Veterans attending single-center Veterans Affairs primary care clinics. The CDSS had an algorithmic dialogue with components executed in phases during different clinic visits: screening for COPD risk using the COPD population screening (COPD-PS) questionnaire, spirometry recommendation, and ordering tool for subjects with a prior diagnosis of COPD or subjects considered high risk by the COPD-PS, dialogue to confirm or discard the diagnosis of COPD, and recommendations for AATD screening in subjects with confirmed COPD. The latter was performed by ordering alpha-1 antitrypsin (AAT) serum levels. Each step of the CDSS algorithm approach was recorded and available to be retrieved at a later date for analysis. Results: Over 6 years, a total of 6,235 Veterans >40 years of age completed the CDSS. According to the COPD-PS questionnaire, 962 (18.5%) subjects were identified as high risk for COPD. An additional 579 subjects with a prior diagnosis of COPD also entered the subsequent steps of the CDSS algorithm. Of the high-risk cohort, the CDSS led to an increase in spirometry testing from 24% to 83% and led to a new diagnosis of COPD in 342 (43%). In the prior COPD diagnosis group, spirometry testing increased from 58% to 84%, leading to COPD reconfirmation in only 326 (67%). A total of 489 (68%) subjects with confirmed COPD completed AAT testing prompted by the CDSS, with 23 subjects identified with AATD and one with severe AATD. Conclusions: In the Veterans Affairs system, the use of a clinical decision support system algorithm that incorporates screening for COPD and AATD improves COPD over- and underdiagnosis and screening rates of AATD in a primary care setting.