Edward Eden

Determinants of Airflow Obstruction in Severe Alpha 1- Antitrypsin Deficiency

Background: Severe α1-antitrypsin (AAT) deficiency is an autosomal recessive genetic condition associated with an increased but variable risk for chronic obstructive pulmonary disease (COPD). A study was undertaken to assess the impact of chronic bronchitis, pneumonia, asthma and sex on the development of COPD in individuals with severe AAT deficiency. Methods: The AAT Genetic Modifier Study is a multicentre family-based cohort study designed to study the genetic and epidemiological determinants of COPD in AAT deficiency. 378 individuals (age range 33–80 years), confirmed to be homozygous for the SERPINA1 Z mutation, were included in the analyses. The primary outcomes of interest were a quantitative outcome, forced expiratory volume in 1 s (FEV1) percentage predicted, and a qualitative outcome, severe airflow obstruction (FEV1 <50% predicted). Results: In multivariate analysis of the overall cohort, cigarette smoking, sex, asthma, chronic bronchitis and pneumonia were risk factors for reduced FEV1 percentage predicted and severe airflow obstruction (p<0.01). Index cases had lower FEV1 values, higher smoking histories and more reports of adult asthma, pneumonia and asthma before age 16 than non-index cases (p<0.01). Men had lower pre- and post-bronchodilator FEV1 percentage predicted than women (p<0.0001); the lowest FEV1 values were observed in men reporting a history of childhood asthma (26.9%). This trend for more severe obstruction in men remained when index and non-index groups were examined separately, with men representing the majority of non-index individuals with airflow obstruction (71%). Chronic bronchitis (OR 3.8, CI 1.8 to 12.0) and a physician’s report of asthma (OR 4.2, CI 1.4 to 13.1) were predictors of severe airflow obstruction in multivariate analysis of non-index men but not women. Conclusion: In individuals with severe AAT deficiency, sex, asthma, chronic bronchitis and pneumonia are risk factors for severe COPD, in addition to cigarette smoking. These results suggest that, in subjects severely deficient in AAT, men, individuals with symptoms of chronic bronchitis and/or a past diagnosis of asthma or pneumonia may benefit from closer monitoring and potentially earlier treatment.

Adult Patients With Bronchiectasis: A First Look at the US Bronchiectasis Research Registry

Objectives We sought to describe the characteristics of adult patients with bronchiectasis enrolled in the US Bronchiectasis Research Registry (BRR). Methods The BRR is a database of patients with non‐cystic‐fibrosis bronchiectasis (NCFB) enrolled at 13 sites in the United States. Baseline demographic, spirometric, imaging, microbiological, and therapeutic data were entered into a central Internet‐based database. Patients were subsequently analyzed by the presence of NTM. Results We enrolled 1,826 patients between 2008 and 2014. Patients were predominantly women (79%), white (89%), and never smokers (60%), with a mean age of 64 ± 14 years. Sixty‐three percent of the patients had a history of NTM disease or NTM isolated at baseline evaluation for entry into the BRR. Patients with NTM were older, predominantly women, and had bronchiectasis diagnosed at a later age than those without NTM. Gastroesophageal reflux disease (GERD) was more common in those with NTM, whereas asthma, primary immunodeficiency, and primary ciliary dyskinesia were more common in those without NTM. Fifty‐one percent of patients had spirometric evidence of airflow obstruction. Patients with NTM were more likely to have diffusely dilated airways and tree‐in‐bud abnormalities. Pseudomonas and Staphylococcus aureus isolates were cultured less commonly in patients with NTM. Bronchial hygiene measures were used more often in those with NTM, whereas antibiotics used for exacerbations, rotating oral antibiotics, steroid use, and inhaled bronchodilators were more commonly used in those without NTM. Conclusions Adult patients with bronchiectasis enrolled in the US BRR are described, with differences noted in demographic, radiographic, microbiological, and treatment variables based on stratification of the presence of NTM.

Changes in health-related quality of life and factors predicting long-term outcomes in older adults admitted to intensive care units

Objectives:The aims of this study were to determine predictors of survival after hospital discharge and to describe the impact of intensive care unit admission on health-related quality of life at 6 months after hospital discharge in older adults admitted to intensive care units. Design:Prospective longitudinal observational study with administered questionnaire. Settings and Patients:Patients 65 yrs of age and older who were admitted to the medical, surgical, and coronary intensive care units for >24 hrs in a large urban teaching hospital system from August 2007 to May 2008 with a follow-up period ending April 2009. Interventions:Administered questionnaire to patients or proxies. Measurements and Main Results:Four hundred eighty-four patients 65 yrs old and older were enrolled. Data were collected on demographics, comorbidities, intensive care unit admission diagnoses, Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment score, Glasgow Coma Scale score at intensive care unit admission, intensive care unit interventions, and disposition after hospital discharge. A health-related quality of life survey was administered to patients, their proxies, or caregivers at intensive care unit admission, and to hospital survivors at 6 months after hospital discharge. Three hundred sixty-seven (75.8%) and 318 (65.7%) of enrolled patients were alive at hospital discharge and at 6 months, respectively. Mean age of survivors was 77.8 ± 8.5. Independent predictors of death at 6 months were: number of days during the 30 days before hospitalization that the patient felt their “physical health was not good” on the health-related quality of life survey [odds ratio = 1.08; confidence interval 1.04–1.12], a higher Acute Physiology and Chronic Health Evaluation II score [odds ratio = 1.09; 95% confidence interval 1.06–1.12], and chronic pulmonary disease as a comorbidity [odds ratio = 2.22; 95% confidence interval 1.04–4.78]. Of the 318 survivors at 6 months after hospital discharge, 297 (93.4%) completed the health-related quality of life questionnaire. When assessing whether changes in health-related quality of life over time were affected by age in our study cohort of 65 yrs old and older, we found that the oldest survivors, age 86.3 yrs old and older, had worse health-related quality of life over time, including more days spent with poor physical health (p < .004) and mental health (p < .001), while the youngest survivors, age 65–69.3 yrs old, showed improvement in health-related quality of life with fewer days spent with poor physical health (p < .004) and mental health (p < .001) at follow-up compared to baseline. These differences remained after adjusting for severity of illness and other potential confounders. Conclusions:One-third of adults 65 yrs old and older admitted to the intensive care unit die within 6 months of hospital discharge. Among survivors at 6 months, health-related quality of life has significantly worsened over time in the oldest patients but improved in the youngest. Our study in a large cohort of mixed intensive care unit patients identifies additional prognostic factors and significant quality of life information in intensive care unit survivors well after hospital discharge. This additional information may guide clinicians in their discussions with patients, families, and other providers as they decide on what treatments and interventions to pursue.

Adult Bronchiectasis Patients: A First Look at the United States Bronchiectasis Research Registry.

Objectives We sought to describe the characteristics of adult patients with bronchiectasis enrolled in the US Bronchiectasis Research Registry (BRR). Methods The BRR is a database of patients with non‐cystic‐fibrosis bronchiectasis (NCFB) enrolled at 13 sites in the United States. Baseline demographic, spirometric, imaging, microbiological, and therapeutic data were entered into a central Internet‐based database. Patients were subsequently analyzed by the presence of NTM. Results We enrolled 1,826 patients between 2008 and 2014. Patients were predominantly women (79%), white (89%), and never smokers (60%), with a mean age of 64 ± 14 years. Sixty‐three percent of the patients had a history of NTM disease or NTM isolated at baseline evaluation for entry into the BRR. Patients with NTM were older, predominantly women, and had bronchiectasis diagnosed at a later age than those without NTM. Gastroesophageal reflux disease (GERD) was more common in those with NTM, whereas asthma, primary immunodeficiency, and primary ciliary dyskinesia were more common in those without NTM. Fifty‐one percent of patients had spirometric evidence of airflow obstruction. Patients with NTM were more likely to have diffusely dilated airways and tree‐in‐bud abnormalities. Pseudomonas and Staphylococcus aureus isolates were cultured less commonly in patients with NTM. Bronchial hygiene measures were used more often in those with NTM, whereas antibiotics used for exacerbations, rotating oral antibiotics, steroid use, and inhaled bronchodilators were more commonly used in those without NTM. Conclusions Adult patients with bronchiectasis enrolled in the US BRR are described, with differences noted in demographic, radiographic, microbiological, and treatment variables based on stratification of the presence of NTM.

Survey of New York City Resident Physicians on Cause-of-Death Reporting, 2010

Introduction Death certificates contain critical information for epidemiology, public health research, disease surveillance, and community health programs. In most teaching hospitals, resident physicians complete death certificates. The objective of this study was to examine the experiences and opinions of physician residents in New York City on the accuracy of the cause-of-death reporting system. Methods In May and June 2010, we conducted an anonymous, Internet-based, 32-question survey of all internal medicine, emergency medicine, and general surgery residency programs (n = 70) in New York City. We analyzed data by type of residency and by resident experience in reporting deaths. We defined high-volume respondents as those who completed 11 or more death certificates in the last 3 years. Results A total of 521 residents from 38 residency programs participated (program response rate, 54%). We identified 178 (34%) high-volume respondents. Only 33.3% of all respondents and 22.7% of high-volume residents believed that cause-of-death reporting is accurate. Of all respondents, 48.6% had knowingly reported an inaccurate cause of death; 58.4% of high-volume residents had done so. Of respondents who indicated they reported an inaccurate cause, 76.8% said the system would not accept the correct cause, 40.5% said admitting office personnel instructed them to “put something else,” and 30.7% said the medical examiner instructed them to do so; 64.6% cited cardiovascular disease as the most frequent diagnosis inaccurately reported. Conclusion Most resident physicians believed the current cause-of-death reporting system is inaccurate, often knowingly documenting incorrect causes. The system should be improved to allow reporting of more causes, and residents should receive better training on completing death certificates.

Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner

Background The use of electronic (e)-cigarettes is increasing rapidly, but their lung health effects are not established. Clinical studies examining the potential long-term impact of e-cigarette use on lung health will take decades. To address this gap in knowledge, this study investigated the effects of exposure to aerosolised nicotine-free and nicotine-containing e-cigarette fluid on mouse lungs and normal human airway epithelial cells. Methods Mice were exposed to aerosolised phosphate-buffered saline, nicotine-free or nicotine-containing e-cigarette solution, 1-hour daily for 4 months. Normal human bronchial epithelial (NHBE) cells cultured at an air-liquid interface were exposed to e-cigarette vapours or nicotine solutions using a Vitrocell smoke exposure robot. Results Inhalation of nicotine-containing e-cigarettes increased airway hyper-reactivity, distal airspace enlargement, mucin production, cytokine and protease expression. Exposure to nicotine-free e-cigarettes did not affect these lung parameters. NHBE cells exposed to nicotine-containing e-cigarette vapour showed impaired ciliary beat frequency, airway surface liquid volume, cystic fibrosis transmembrane regulator and ATP-stimulated K+ ion conductance and decreased expression of FOXJ1 and KCNMA1. Exposure of NHBE cells to nicotine for 5 days increased interleukin (IL)-6 and IL-8 secretion. Conclusions Exposure to inhaled nicotine-containing e-cigarette fluids triggered effects normally associated with the development of COPD including cytokine expression, airway hyper-reactivity and lung tissue destruction. These effects were nicotine-dependent both in the mouse lung and in human airway cells, suggesting that inhaled nicotine contributes to airway and lung disease in addition to its addictive properties. Thus, these findings highlight the potential dangers of nicotine inhalation during e-cigarette use.

Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency

BackgroundThe development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency.MethodsThe current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD.ResultsThree SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed.ConclusionsIREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.

The prevalence of alpha-1 antitrypsin deficiency among patients found to have airflow obstruction.

Abstract Introduction: Alpha-1 antitrypsin deficiency (AATD) is a genetic disease that may be manifested by chronic obstructive pulmonary disease. Despite professional society guidelines that recommend broad testing of at-risk individuals, fewer than 10% of affected individuals have been identified. The goals of this study were to estimate the frequency of abnormal AAT genotypes among patients found to have fixed airflow obstruction and to assess the feasibility of having Pulmonary Function Laboratory personnel administer the study. Methods: Nineteen medical centers in the United States participated in the study. Eligible patients (> GOLD II, FEV1/FVC ratio < 0.7, with post-bronchodilator FEV1<80% predicted) were offered testing for AATD by the Pulmonary Function Laboratory personnel at the time of pulmonary function testing. Results: A total of 3,457 patients were tested, of whom 3152 were eligible. Deficient patients (ZZ, SZ) constituted 0.63% of subjects, while 10.88% were carriers (MS, MZ). Neither demographic (except African-American race) nor post-bronchodilator pulmonary function variables (FEV1, FVC, FEV1/FVC ratio, TLC, and FEV1/FVC) allowed us to predict AAT heterozygote or deficiency status. Conclusions: The prevalence of AATD among patients undergoing pulmonary function tests with fixed airflow obstruction was 0.63%. Pulmonary Function Laboratory personnel effectively conducted the study.

Circulating polymers in α1-antitrypsin deficiency

To the Editor: Most individuals carry two wild-type M alleles of the SERPINA1 gene which encodes α1-antitrypsin. 95% of severe deficiency of α1-antitrypsin is associated with the Z allele (Glu342Lys; denoted PiZZ in the homozygote), and with the retention and polymerisation of α1-antitrypsin within hepatocytes [1]. These polymers are contained within periodic acid–Schiff-positive, diastase-resistant inclusions that are associated with neonatal hepatitis, cirrhosis and hepatocellular carcinoma. The concomitant lack of circulating α1-antitrypsin predisposes the Z α1-antitrypsin homozygote to early-onset emphysema. Polymers of α1-antitrypsin form within the lung as a result of local inflammation and exposure to cigarette smoke [2]. They have also been identified in the skin of an individual with α1-antitrypsin deficiency and panniculitis [3] and in a renal biopsy from an individual with α1-antitrypsin deficiency and vasculitis [4]. It is unknown whether these polymers form locally or are deposited in these tissues from a circulating source, and whether extrahepatic polymers are associated with any disease phenotypes. We have assessed whether polymers of α1-antitrypsin are present within serum, from where they originate, and whether they are associated with clinical features in individuals with PiZZ α1-antitrypsin deficiency. In this investigation we used ELISA with the anti-α1-antitrypsin polymer monoclonal antibody (2C1) [5] to assess the presence of polymers in the plasma of 1) 518 individuals with PiZZ α1-antitrypsin deficiency; 2) an individual with α1-antitrypsin deficiency who underwent liver transplantation; and 3) 293 individuals with a mixture of α1-antitrypsin phenotypes. The specificity of the 2C1 antibody was confirmed by using it to immunoprecipitate polymers from the plasma of individuals with and without a positive signal …

Virus-cell membrane fusion does not predict efficient infection of alveolar macrophages by human immunodeficiency virus type 1 (HIV-1)

Alveolar macrophages (AM) are the principal target cells for HIV-1 in lung tissue. To investigate the mechanisms of HIV-1 infection and efficient replication in these cells we isolated AM from 14 HIV-1 negative donors and exposed them to two virus isolates, either N1T, which replicates well in T lymphocytic and monocytic cell lines, or ADA, a monocytotropic virus. Membrane fluorescence dequenching assays demonstrated that HIV-1/N1T fuses efficiently with AM plasma membranes at neutral pH and that this interaction requires cellular CD4. Despite efficient fusion, AM from eight of 14 donors were not susceptible to productive infection with N1T. In contrast, ADA replicated in all AM populations tested. Soluble CD4 blocked infection of AM by either N1T or ADA, indicating that, like membrane fusion, entry of infectious virus requires an interaction with cellular CD4. Analysis of HIV-1 DNA accumulation in infected cells by enzymatic amplification revealed that productive infection by ADA correlated with a high HIV-1 DNA copy number and abortive infection by N1T was characterized by little or no stable cDNA. These studies suggest that the differences between the two HIV-1 strains studied in their ability to replicate in AM reside in phases of the virus life cycle that follow virus-cell fusion.