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Yale University School of Medicine, New Haven, Connecticut
OCCUPATIONAL LUNG DISEASE
William S. Beckett
Department of Pulmonary and Critical Care Medicine
University of Rochester School of Medicine
Rochester, New York
Occupational asthma (OA) remains a significant problem for patients and employers alike. In a comprehensive review of the existing literature, Beach and colleagues (1) tackle the best diagnostic approach to this problem. They conclude that, in patients with high pretest probability of OA by history, either nonspecific (e.g., methacholine) challenge or skin-prick testing improves sensitivity and specificity in the diagnosis, although neither can be relied on to fully confirm or exclude OA. When compared to the research "gold standard" of specific inhalational challenge, methacholine challenge improved sensitivity to 84% and, therefore, should be used in the diagnostic approach to the patient with suspected OA. Nicholson and colleagues (2) also addressed the issue of OA identification and prevention in their 2005 evidence-based guidelines. They point out that 1 in 10 cases of new or recurrent asthma is occupational, and that, interestingly, allergic rhinitis occurring with exposure to a known cause of asthma predicts subsequent asthma development. Early diagnosis and exposure avoidance does improve prognosis and should be advised to these individuals and their employers.
Another important area of interest in the field of occupational medicine is that of home environmental factors that my effect adult asthma severity. Blanc and colleagues (3) examined 226 California adults with asthma and rhinitis and made home measures of total dust, dust mite, cat dander, dog dander, endotoxin, and glucan levels. They also measured nitrogen dioxide, volatile organic compounds, carbon monoxide, carbon dioxide, temperature, and humidity levels in each of these homes. Levels were compared to FEV1% predicted, as well as to severity of asthma scores and responses to questionnaires of health status and quality-of-life. The authors conclude that total milligrams of dust in the bed and dog ownership correlated with lower FEV1, whereas visible damp patches, mold, and elevated glucan levels all were associated with lower general health status in these adults. Thorne and colleagues (4) likewise attempted to sort out which of many factors may be causal in asthma propagation in a nationwide survey of dust samples from 831 housing units. They found a clear association between endotoxin levels and the prevalence of diagnosed asthma, asthma symptoms within the preceding year, current use of asthma medications, and self-reported wheezing. This study included both children and adults, but it is worth noting that the association with endotoxin was demonstrable only in the adult population.
Another controversial area in occupational lung disease is the purported association of diesel exhaust with the development of lung cancer. Garshik and colleagues (5) attempted to examine this issue by following up on the mortality experience of U.S. railway workers over the age of 38 yr between the years of 1959 and 1996. They noted that jobs associated with operating railroad trains had a relative risk of lung cancer of 1.40 (confidence interval, 1.30–1.51). Of note, however, is the fact that lung cancer mortality did not increase with increasing years of work. A major limitation acknowledged by the authors is the lack of concomitant tobacco smoke exposure data.
Finally, Tarlo (6) offered us the American College of Chest Physicians evidence-based guidelines on occupational and environmental considerations in chronic coughers. She cites multiple environmental factors, including irritants, cigarette smoke, cooking fumes, animal dander, dust mite antigen, fungi, and cockroach antigens as potential contributors to cough. These contributors are often associated with other pulmonary conditions, including hypersensitivity pneumonitis, asthma, and interstitial lung diseases. She emphasizes that recognition of these contributing factors by the practicing clinician may lead to better prognosis and less need for medications.
PULMONARY VASCULAR DISEASE
Vallerie V. McLaughlin
Pulmonary Hypertension Program
University of Michigan Health System
Ann Arbor, Michigan
When Rich and colleagues (7) published their findings that a subgroup of patients with idiopathic pulmonary arterial hypertension (IPAH) benefited from high-dose calcium channel blocking agents, it represented the first oral therapeutic option for these unfortunate individuals. Subsequent enthusiasm for the use of these agents has been limited by the realization that sustained benefit may be more difficult to predict. Sitbon and colleagues (8) helped to clarify the role of these agents in their retrospective analysis of 557 IPAH patients in their center in France. Acute vasoresponders were defined as those with mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) drops of 20% or more from baseline. Acute responders were treated with calcium channel blockers and followed clinically. Patients were considered long-term responders if they remained in New York Heart Association functional class I or II with sustained hemodynamic improvement without the need for other specific pulmonary arterial hypertension (PAH) therapy. They found that 12.6% met the definition as acute responders, and only 6.8% of the 557 cohort fulfilled criteria for long-term responders. These patients all had more dramatic vasodilator responses, with mPAP generally less than 40 mm Hg and PVR less than 6 Wood units. This special subgroup had excellent long-term (> 5 yr) survival, whereas less stringent criteria for "response" resulted in a 48% 5-yr survival. As such, the authors conclude that the use of calcium channel blockers should be limited to those fulfilling long-term responder criteria for acute vasodilator responses at the time of their initial right-heart catheterization.
For some time now, clinicians treating PAH have been aware that the high density of phosphodiesterase 5 in the lung vasculature makes phosphodiesterase 5 inhibitors an attractive potential strategy in the treatment of PAH. Anecdotal case reports (9) and small uncontrolled series (10, 11) lent credence to the biological plausibility of this approach. Galie and his colleagues (12) offer the PAH community the first randomized, double-blind, placebo-controlled study assessing the use of sildenafil citrate for PAH therapy. A total of 278 patients with PAH (idiopathic, connective tissue–associated PAH, or PAH persistent after repair of congenital systemic-to-pulmonary shunts) received placebo or 20, 40, or 80 mg of sildenafil 3 times a day for 12 wk. The primary outcome was 6-min walk distance (6MWD), and secondary measures were mPAP, PVR, and functional class. At the end of 12 wk, there was a significant increase in 6MWD (45, 46, and 50 m, respectively, for the 20, 40, and 80-mg dose groups). Reduction in mPAP and PVR of statistical significance were also noted in the sildenafil groups, and functional class improved in all the dose groups as well. The incidence of the composite endpoint of time to clinical worsening (defined as death, need for hospitalization for worsening PAH, lung transplantation, or the need to add a second therapy) did not differ over the 12-wk trial between placebo- and sildenafil-treated patients. When extension data was examined in 222 patients completing 1 yr of therapy, the improvement in 6MWD was sustained at 51 m compared to baseline 6MWD.
The advisability of relying on oral endothelial receptor antagonism in IPAH patients with New York Heart Association class III and IV functional status was assessed by Provencher and colleagues (13). In their retrospective study, 103 patients with IPAH were treated with bosentan as first-line therapy between November 1999 and May 2004. 6MWD and hemodynamics were recorded at baseline and after 4 and 12 mo. Mean follow-up was 24 ± 15 mo. Significant improvements in 6MWD (from 322 ± SE 105 to 364 ± 109 m; p = < 0.001) and hemodynamics (2.32 ± 0.54 to 2.71 ± 0.63 L min–1 m2; p = < 0.001; total pulmonary resistance, 15.0 ± SE 5.4 to 12.2 ± 4.5 mm Hg L–1 m2; p = < 0.001) were seen at 4 mo, although drops in mPAP were not statistically significant (58 ± 13 to 55 ± 13 mm Hg; p = 0.012). These changes persisted to 12 mo. Event-free status, defined as survival without transplantation, prostanoid therapy initiation, or hospitalization for right-heart failure, were 61 and 44% at Year 1 and Year 2, respectively. A total of 44% required addition of prostanoid therapy during the follow-up. Overall survival estimates were 90% at 4 mo and 87% at 1 yr.
The best way to diagnose pulmonary embolism (PE) has been the subject of debate for many decades. In a study by the Christopher Study investigators (14), 3,306 patients at 12 centers were assessed by a simplified algorithm for PE events. Patients categorized as "PE unlikely" had D-Dimer testing and, if negative, PE was considered excluded. All others underwent computerized tomography pulmonary angiography (CTPA); most (88%) using a multidetector scanner. All those with negative D-Dimers or negative CTPA had anticoagulation withheld, and the patients were followed for 3 months. A total of 5 of 1,057 (0.5%) with a negative D-Dimer proved to develop a nonfatal thromboembolic event during this follow-up. Among the 1,505 patients with negative CTPA, 1.3% declared themselves as having a venous thromboembolic event during the 3 mo follow-up. Death due to PE was believed possible in 7 of these 20 patients. CTPA found PE in 674 (10.4%) of the original cohort. The authors conclude from these data that use of a simple clinical decision rule in conjunction with D-Dimer testing and CTPA is an effective way to evaluate the patient with possible PE.
BRONCHIECTASIS
Gregory Tino
Pulmonary, Allergy, and Critical Care Division
University of Pennsylvania School of Medicine
Philadelphia, Pennsylvania
The prevalence and economic burden of non–cystic fibrosis (CF) bronchiectasis (NCFB) in the United States was assessed in 2005 in a retrospective cohort study by Weycker and colleagues (15). Data were extracted from a health care claims database incorporating more than 30 U.S. health plans encompassing 5.6 million covered lives. A total of 1,424 persons with NCFB were identified, for an overall prevalence of 52.3 per 100,000 adults. Mean age of bronchiectasis diagnosis was 61 yr, and 68% were women. Prevalence increased with age, and was higher among women than among men at all ages. Extrapolating from the current U.S. population, the authors estimated that there are about 110,000 patients over the age of 18 yr with NCFB. When matched for age, sex, geographic region, and several selected comorbidities, patients with NCFB generally used more medical resources, with treatment costs of NCFB estimated at $630 million annually in the United States.
The use of nebulized tobramycin in CF has become an important and validated standard of care in this disease (16). Scheinberg and colleagues (17) assessed this strategy in NCFB in an open-label, uncontrolled trial. A total of 300 mg nebulized tobramycin was given twice daily to 41 adults with severe diffuse bronchiectasis and a history of Pseudomonas aeruginosa in 9 centers throughout the United States. Patients were given 14 d of treatment, followed by 14 d "drug holiday" periods over 12 wk. Follow-up for an additional 40 wk was performed; 31 of 41 (75.6%) completed 3 full cycles of nebulized tobramycin, with 10 withdrawals due to adverse events. During the 12-wk treatment period, pulmonary severity symptom scores improved significantly (p = 0.006), as did St. George's Respiratory Questionnaire (SGRQ) scores. Surveillance sputum cultures revealed a 22.2% eradication rate of P. aeruginosa. Treatment-emergent adverse events were common, such as cough (43.9%), dyspnea (34.1%), and sputum volume increases (29.3%), as well as hoarseness (26.8%), which appeared to occur more commonly in women. Roughly 85% of all subjects experienced at least one adverse event believed to be secondary to the nebulized tobramycin solution. The authors conclude that, whereas nebulized tobramycin resulted in significant improvements in respiratory symptoms and health-related quality of life, some subjects cannot tolerate this therapy, and additional trials are needed to stratify who will benefit the most.
Bronchial wall inflammation is an integral part of NCFB pathobiology, and, as such, inhaled corticosteroids may have a role in therapy. Tsang and colleagues (18) assessed 86 patients with NCFB who received either 500 µg fluticasone twice daily (n = 43) or matched placebo (n = 43) in a double-blind fashion over a 52-wk period. Patients proved to be well matched with regard to age, other comorbidities, and distribution of bacterial pathogens, including P. aeruginosa. A total of 35 patients in the fluticasone group and 38 subjects in the placebo group completed the study. No difference in the frequency of exacerbations, FEV1, or sputum purulence score were found between the two groups. Volume of sputum in 24 hr was notably less in the fluticasone-treated group (odds ratio, 2.5; 95% confidence interval, 1.1–6.0; p = 0.03), especially in those with P. aeruginosa. In a similar study of fluticasone in bronchiectasis, Martinez-Garcia and colleagues (19) studied 93 patients in a randomized, double-blind study of 2 different doses of inhaled fluticasone. Patients were randomized to 250 µg twice daily versus 500 µg twice daily for 6 mo. No placebo group was included. Baseline data were collected and subsequently recollected at 1, 3, and 6 mo. Significant improvement in dyspnea, sputum production, cough-free days, and need for short-acting bronchodilator were seen in the 1,000-µg-daily group only. No changes in pulmonary function measures, frequency of exacerbations, severity of exacerbations, or sputum microbiology were noted. There was a significant improvement in health-related quality of life, as assessed by the St. George's Respiratory Questionnaire, by 3 mo in patients at the higher dose of fluticasone, and this persisted to the 6-mo time point.
Another class of agents with antiinflammatory properties of interest in this disease is that of the macrolide antibiotics. Cymbala and colleagues (20) performed a single center, open-label crossover study of 12 patients to assess the impact of azithromycin use. Patients were randomized to receive 500 mg azithromycin twice weekly after a 1-mo washout period or no macrolide for 6 mo; 11 of the 12 patients were included in the analysis. A total of 73% received the azithromycin phase first. While on azithromycin, patients experienced fewer exacerbations compared to those not on azithromycin (5 vs. 16; p = 0.019). Mean 24-hr sputum volumes also were reduced (15%; p = 0.005). No change in any measure of pulmonary function could be demonstrated. Clearly, larger multicenter trials are needed to corroborate these findings before macrolides are adopted as a routine part of NCFB care, but this small study does lend credence to their possible role.
Lung transplantation for NCFB was examined by Beirne and colleagues (21) in 22 patients from the United Kingdom who had lung transplants for NCFB. Single-lung and heart-lung transplantation was undergone by seven and six patients, respectively, whereas nine patients received bilateral lung transplants. Kaplan-Meier survival curves revealed 68% 1-yr and 62% 5-yr survivals. For single-lung transplant recipients, 1-yr survival was 57% versus 73% for those with bilateral procedures. Significant improvements in FEV1 and FVC persisted for over 5 yr. The authors conclude that lung transplantation can be performed in NCFB with success comparable to that of CF and other conditions.
Finally, King and colleagues (22) studied 101 bronchiectasis patients in Australia, all nonsmokers. Mean age was 54 (± 14) yr, with 84 patients having idiopathic bronchiectasis. Two thirds of this cohort were women. Patients were followed for a minimum of 2 yr (mean 8.0 ± 4.9 yr). FEV1 declined on average 49 ml/yr, higher than previously reported rates of decline. Medical Research Council dyspnea scores were worse on follow-up (p < 0.005), and daily sputum production was higher (32 ± 29 ml vs. 47 ± 34 ml). A total of 11 of 101 subjects had died at a mean age of 73 yr during the follow-up period—6 from progressive respiratory failure believed to be due directly to bronchiectasis.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
James C. Hogg
McDonald Research Laboratory
St. Paul's Hospital
Vancouver, British Columbia, Canada
The mucosal immune responses in chronic obstructive pulmonary disease (COPD) have not been extensively studied. Moraxella catarrhalis is an important pathogen in the lower respiratory tract in these patients and, as such, Murphy and colleagues (23) studied sputum supernatant samples of 10 adults with COPD before and after clearance of M. catarrhalis. Flow cytometric analysis revealed that IgA is the predominant isotype responding to M. catarrhalis, and that the presence of a secretory component indicated that local mucosal response is likely. Response to M. catarrhalis surface adhesion antigens (Ag) Usp1, Hag, and UspA2 were specifically noted, along with a subset of patients who responded to the iron-regulated proteins TbpB, CopB, and lipooligosaccharide. This study offers a more specific understanding of the directed immune response to outer membrane antigens that allow bacterial adherence to the respiratory epithelium in patients with COPD.
Also in the arena of mucosal immune response in COPD, Sullivan and colleagues (24) asked the question "are the T lymphocytes recruited to the lung in severe COPD oligoclonal in nature?" To do so, they isolated and cultured mononuclear cells from the lung tissue of eight patients with advanced COPD along with six control subjects without the disease. They found that T cells recognized the Ag presented to T-cell receptor by the major histocompatibility complex class I and II, and that the diversity of the response is possible by rearrangement of genes expressing the variable junctional-to-constant regions of the T-cell receptor. The authors also showed that there was indeed oligoclonal T-cell response in patients with COPD, suggesting response to a relatively small number of antigens.
The notion that compounds of cigarette smoke may serve as an Ag in COPD has been proposed by our Dutch colleagues in a recent study (25). Van der Strate and colleagues studied the lungs of eight patients with COPD in conjunction with a smoking mouse model. Lymphoid follicles consisting of B cells and follicular dendritic cells with adjacent T cells were seen in both the parenchyma and bronchial walls of all eight patients. A clonal process was observed in all follicles, with oligoclonal antigen-specific proliferation noted. Similar lymphoid follicles were observed in mice that had developed pulmonary inflammation and progressive air space enlargement after smoking, with proportionate increases in the number of B cell follicles as time and smoke exposure increased. Specific viral or bacterial nucleic acid could not be detected, and the authors suggest that antibodies are generated against either tobacco smoke residue or extracellular matrix components as probable Ags. Although similar findings have been noted in work by D'hulst and colleagues (26) in a Balb/c mouse model, it is interesting to note that cigarette smoke exposure does not require T- or B-cell presence to result in the emphysema phenotype, because immunodeficient scid mice likewise develop emphysema with chronic tobacco smoke exposure in their model.
FOOTNOTES
Conflict of Interest Statement: T.K.T. has served on Advisory Boards for Actelion Pharmaceuticals and Encycive Pharmaceutical, receiving $1,500 in 2004 from Actelion and $4,000 from Encycive in 2006. In addition, he has participated as a speaker at conferences sponsored by Actelion, receiving $14,500 in 2006, $3,500 in 2005, and $4,500 in 2004.
REFERENCES
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