Publications

BACKGROUND

Matrix metalloproteinase-9 (MMP-9) may be important in the progression of emphysema, but there have been few longitudinal clinical studies of MMP-9 including pulmonary status and COPD exacerbation outcomes.

METHODS

We utilized data from the placebo arm (n=126) of a clinical trial of patients with alpha1-antitrypsin deficiency (AATD) and emphysema to examine the links between plasma MMP-9 levels, pulmonary status, and COPD exacerbations over a one year observation period. Pulmonary function, computed tomography lung density, incremental shuttle walk test (ISWT), and COPD exacerbations were assessed at regular intervals over 12 months. Prospective analyses used generalized estimating equations to incorporate repeated longitudinal measurements of MMP-9 and all endpoints, controlling for age, gender, race-ethnicity, leukocyte count, and tobacco history. A secondary analysis also incorporated highly-sensitive C-reactive protein levels in predictive models.

RESULTS

At baseline, higher plasma MMP-9 levels were cross-sectionally associated with lower FEV1 (p=0.03), FVC (p<0.001), carbon monoxide transfer factor (p=0.03), resting oxygen saturation (p=0.02), and ISWT distance walked (p=0.02) but were not associated with radiographic lung density or total lung capacity (TLC). In longitudinal analyses, MMP-9 predicted a further decline in transfer factor (p=0.04) and oxygen saturation (p<0.001). MMP-9 also predicted worsening lung density (p=0.003), increasing TLC (p=0.02), and more frequent COPD exacerbations over follow-up (p=0.003). Controlling additionally for hs-CRP levels did not substantively change the longitudinal associations between MMP-9 and these outcomes.

CONCLUSIONS

Increased plasma MMP-9 levels generally predicted pulmonary status declines, including worsening transfer factor and lung density as well as greater COPD exacerbations in AATD-associated emphysema.

INTRODUCTION

People with α1-antitrypsin deficiency are at increased risk for the development of chronic obstructive pulmonary disease. Previous retrospective epidemiologic studies have found that exposure to occupational dust among those with α1-antitrypsin deficiency is a risk factor at the group level for poorer lung function, but on an individual clinical basis, a causal attribution can be difficult to establish.

CASE PRESENTATION

We describe the case of a 68-year-old Caucasian man with a 25 pack-year smoking history who presented with new-onset dyspnea on exertion in the setting of workplace dust exposure. During his evaluation, he was found to have α1-antitrypsin deficiency with evidence of development of pulmonary emphysema. Workplace spirometric monitoring over 10 years of surveillance for an on-the-job respirator fit program demonstrated a sharp downward slope in forced expiratory volume in one second, or FEV1, during his periods of most significant dust exposure, which was attenuated after discontinuation of his workplace exposure.

CONCLUSION

Patients with α1-antitrypsin disease should be assessed for occupational exposures and closely monitored for work-accelerated progression of lung function decline. More generally, this case report supports the biological plausibility of occupationally associated chronic obstructive pulmonary disease, underscoring that work-associated pulmonary disease can be multi-factorial.

PURPOSE

: The independent contribution of physical inactivity to disability in obstructive lung disease (OLD) is difficult to study, partly because inactivity may reflect disease severity. We examined the relationship of physical inactivity to disability progression over a 1-year period among a group of older adults with OLD.

METHODS

: A population-based cohort with self-reported physician-diagnosed emphysema, chronic obstructive pulmonary disease, or chronic bronchitis (n = 206) completed baseline interviews and in-person spirometry, with 1-year followup interviews. The Community Health Activities Model Program for Seniors physical activity questionnaire provided estimates of energy expenditure; we defined inactivity as no expenditure in moderate- or vigorous-intensity activities. Disability was measured with the Valued Life Activity (VLA) disability scale; increased disability was defined as a 10% or greater increase in VLA disability score over 1-year followup. Logistic regression tested the relationship between baseline inactivity and disability increase, controlling for age, sex, baseline VLA disability, comorbidities, smoking, and pulmonary function (forced expiratory volume in 1 second, % predicted).

RESULTS

: Of 206 subjects, 48 (27%) were physically inactive at baseline; 42.9% of individuals whose disability increased were inactive at baseline compared with 23.4% of those who did not experience a disability increase. With adjustment for covariates, increased disability after 1 year was significantly (P = .04) more likely among individuals who were inactive at baseline (Odds Ratio =2.4; 95% confidence interval, 1.02-5.9).

CONCLUSIONS

: Physically inactive individuals with OLD had more than double the odds of an increase in disability, even after controlling for baseline disability, lung function, and other covariates. These results provide strong support for the importance of maintaining physical activity among individuals with OLD.

Development of asthma and allergic inflammation involves innate immunity, but the environmental contributions remain incompletely defined. Analysis of dust collected from the homes of asthmatic individuals revealed that the polysaccharide chitin is environmentally widespread and associated with β-glucans, possibly from ubiquitous fungi. Cell wall preparations of Aspergillus isolated from house dust induced robust recruitment of eosinophils into mouse lung, an effect that was attenuated by enzymatic degradation of cell wall chitin and β-glucans. Mice expressing constitutively active acidic mammalian chitinase in the lungs demonstrated a significant reduction in eosinophil infiltration after fungal challenge. Conversely, chitinase inhibition prolonged the duration of tissue eosinophilia. Thus, fungal chitin derived from home environments associated with asthma induces eosinophilic allergic inflammation in the lung, and mammalian chitinases, including acidic mammalian chitinase, limit this process.

Lung transplantation in mechanically ventilated (MV) patients has been associated with decreased posttransplant survival. Under the Lung Allocation Score (LAS) system, patients at greatest risk of death on the waiting list, particularly those requiring MV, are prioritized for lung allocation. We evaluated whether pretransplant MV is associated with poorer posttransplant survival in the LAS era. Using a national registry, we analyzed all adults undergoing lung transplantation in the United States from 2005 to 2010. Propensity scoring identified nonventilated matched referents for 419 subjects requiring MV at the time of transplantation. Survival was evaluated using Kaplan-Meier methods. Risk of death was estimated by hazard ratios employing time-dependent covariates. We found that pretransplant MV was associated with decreased overall survival after lung transplantation. In the first 6 months posttransplant, ventilated subjects had a twofold higher risk of death compared to nonventilated subjects. However, after 6 months posttransplant, survival did not differ by MV status. We also found that pretransplant MV was not associated with decreased survival in noncystic fibrosis obstructive lung diseases. These results suggest that under the LAS, pretransplant MV is associated with poorer short-term survival posttransplant. Notably, the increased risk of death appears to be strongest the early posttransplant period and limited to certain pretransplant diagnoses.

BACKGROUND AND AIMS

This review summarizes the scientific literature relevant to occupational risk factors for chronic obstructive pulmonary disease (COPD).

MATERIAL AND METHODS

This review emphasizes recent work in the field, while placing this in the context of two previous systematic reviews of the subject.

RESULTS

Both the earlier summaries of the literature estimated that the population attributable risk percent (PAR%) of COPD linked to occupational exposures is approximately 15%. More recent studies also strongly support the association between workplace exposures and COPD. Among never smokers, the PAR% for work-related factors may approach 40%. Emerging data also indicate that occupational exposures, at a minimum, are additive to smoking-associated risk of COPD.

CONCLUSIONS

The PAR% for work-related COPD is at least 15%. Scientific significance. The consistency, strength, and plausibility of these data support a causal relationship between occupational exposures and COPD.

BACKGROUND

Anion gap metabolic acidosis is typically encountered in the emergency department (ED) setting as the result of shock, other endogenous metabolic derangements, or from exogenous toxicants. The differential diagnosis for toxicant-related acidosis (exemplified by common mnemonics) emphasizes acute overdose.

CASE REPORT

The case we present manifested an anion gap (AG) metabolic acidosis due to a chronic intoxication: acetaminophen (APAP) overuse over a period of weeks. Lactic acidemia did not account for the AG. In this case, chronic APAP overuse, combined with decreased caloric intake and weight loss, was associated with excess 5-oxoproline (pyroglutamic acid), an organic acid accounting for the AG metabolic acidosis. Overproduction of 5-oxoproline is attributed to depleted glutathione stores, leading to perturbation in the γ-glutamyl cycle. The patient was treated with supportive care and with N-acetylcysteine (NAC). By repleting glutathione, NAC may facilitate the resolution of excess 5-oxoproline.

CONCLUSIONS

The ED differential diagnosis of AG metabolic acidosis in chronic APAP overuse, especially with concomitant nutritional compromise, should include 5-oxoprolinemia.

BACKGROUND

Information is scant assessing outcomes in lung transplantation (LT) in advanced occupational lung diseases (OLD).

AIMS

To analyse survival after LT for OLD.

METHODS

Using data from the US Organ Procurement and Transplantation Network Registry (OPTN-R), we identified subjects aged ≥ 18 years transplanted for OLD from 2005 to 2010. OPTN-R selected referents of corresponding age, sex and body mass index (BMI) who underwent LT for other diagnoses were also identified. Post-LT survival time was estimated with Cox proportional hazard models. Baseline age, BMI, forced expiratory volume in 1 s, creatinine, lung allocation score, donor age, donor lung ischaemic time and transplant type (single versus bilateral) were included as covariates. Time-dependent covariates were used to model differences in relative risk over time.

RESULTS

Thirty-seven males underwent LT for silicosis (n = 19) or other OLD (n = 18) during the analytic period (0.5% of all LTs). For non-silicotic OLD, 6-month and 1- and 3-year survival estimates were 66, 55 and 55%, compared with the silicotic group (86, 86 and 76%) and referent group (89, 84 and 67%). During the first year post-transplant, those with OLD (silicosis and others combined) manifested an overall 2-fold increased mortality risk [hazard ratio (HR) 2.3, 95% CI 1.3-4.4; P < 0.05] compared to referents. In stratified analysis, this increased risk of death was restricted to those with non-silicotic OLD (HR 3.1, 95% CI 1.5-6.6; P < 0.01). Poorer survival was limited to the first year post-LT.

CONCLUSIONS

Subjects undergoing LT for OLD other than silicosis may be at increased risk of death in the first year post-transplantation.

INTRODUCTION

The clinical scenario of a new or worsening pleural effusion following the initiation of antituberculous therapy has been classically referred to as a 'paradoxical' pleural response, presumably explained by an immunological rebound phenomenon. Emerging evidence suggests that there also may be a role for a lupus-related reaction in the pathophysiology of this disorder.

CASE PRESENTATION

An 84-year-old Asian man treated with isoniazid, along with rifampin, pyrazinamide and ethambutol for suspected extrapulmonary tuberculosis, presented with a recurrent pleural effusion, his third episode since the initiation of this therapy. The first effusion occurred one month after the start of treatment, without any prior evidence of pulmonary tuberculosis involvement. Follow-up testing, including thoracoscopic pleural biopsies, never confirmed tuberculosis infection. Further evaluation yielded serological evidence suggesting drug-induced lupus. No effusions recurred following the discontinuation of isoniazid, although other antituberculosis medications were continued.

CONCLUSION

The immunological rebound construct is inconsistent with the evolution of this case, which indicates rather that drug-induced lupus may explain at least some cases of new pleural effusions following the initiation of isoniazid.

OBJECTIVE

To investigate the cross-sectional association between COPD severity and disturbed sleep and the longitudinal association between disturbed sleep and poor health outcomes.

METHODS

Ninety eight adults with spirometrically-confirmed COPD were recruited through population-based, random-digit telephone dialing. Sleep disturbance was evaluated using a 4-item scale assessing insomnia symptoms as: difficulty falling asleep, nocturnal awakening, morning tiredness, and sleep duration adequacy. COPD severity was quantified by: FEV(1) and COPD Severity Score, which incorporates COPD symptoms, requirement for COPD medications and oxygen, and hospital-based utilization. Subjects were assessed one year after baseline to determine longitudinal COPD exacerbations and emergency utilization and were followed for a median 2.4 years to assess all-cause mortality.

RESULTS

Sleep disturbance was cross-sectionally associated with cough, dyspnea, and COPD Severity Score, but not FEV(1). In multivariable logistic regression, controlling for sociodemographics and body-mass index, sleep disturbance longitudinally predicted both incident COPD exacerbations (OR=4.7; p=0.018) and respiratory-related emergency utilization (OR=11.5; p=0.004). In Cox proportional hazards analysis, controlling for the same covariates, sleep disturbance predicted poorer survival (HR=5.0; p=0.013). For all outcomes, these relationships persisted after also controlling for baseline FEV(1) and COPD Severity Score.

CONCLUSIONS

Disturbed sleep is cross-sectionally associated with worse COPD and is longitudinally predictive of COPD exacerbations, emergency health care utilization, and mortality.