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1 Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana
IDIOPATHIC PULMONARY FIBROSIS
Marvin I. Schwartz
Department of Medicine
University of Colorado
Denver, Colorado
In his review, Dr. Schwartz summarized the idiopathic and familial forms of pulmonary fibrosis, as well as chronic hypersensitivity pneumonitis (CHP) and nonspecific interstitial pneumonitis.
Pulmonary fibrosis remains a significant health problem whose true incidence and prevalence has been believed to be increasing in recent years. Using a database from the National Center for Health Statistics, Olson and colleagues (1) clearly show for the first time that the mortality rates have increased from 1992 to 2003. Although these data do not confirm that the prevalence is increasing, they do suggest that there have been improvements in reporting and identification of fibrotic lung diseases. Of note, two-thirds of deaths in all patients reported were due to fibrotic lung disease. The trends increased for both men and women. The age-adjusted mortality increased for both sexes, and the authors of this report suggest that this trend will continue.
One of the variants of idiopathic pulmonary fibrosis (IPF) is the accelerated form of this disease. The genetics that characterize the differences between slow progression of IPF and the rapidly progressive form of this disease were previously unknown. To address this question, Dr. Selman and associates examined gene expression profiles in 88 patients with histologically proven, slowly progressing IPF and 26 patients with the rapid variant (2). To be included in the "slow" group, symptoms had to present for more than 2 years, whereas the "rapid" group was symptomatic for less than 6 months. Surgical lung biopsy was performed in 31% of the patients studied. There were more men than women in the rapid group, but there were no differences between the groups in terms of age, physiologic profiles, or bronchoalveolar lavage (BAL) differential cell counts. The data showed multiple differences in gene expression profiles in the two groups. Two genes, adenosine 2B receptor and prominin-1/CD133, were expressed more strongly in the rapid group. In addition, expression of matrix metalloproteinases and markers of fibroblast activation was more pronounced in the rapid group. This report raises the question that certain gene profiles may be associated with differential responses to treatments, and reveals potential targets for therapeutic intervention in each form of this disease.
Historical studies have shown that smoking is associated with the onset of IPF. However, the relationship to smoking status relative to outcome in IPF remains unclear. A retrospective review of 249 patients with IPF, 39 of whom had biopsy-proven disease (3), reported that, when current smokers were compared with former smokers (n = 166), a better outcome was noted in the current smoking group. However, when the authors compared nonsmokers with either former smokers or the combined group of current and former smokers, there was increased survival in the nonsmoking group (n = 63). Collectively, these data show that smoking negatively impacts survival in patients with IPF.
Although the familial form of pulmonary fibrosis is rare (occurs in 5% in all patients with IPF), the clinical characteristics of this illness are not well defined. In a report from Rosas and colleagues (4), clinical summaries of 164 subjects from 18 families with familial pulmonary fibrosis were reported. Notably, occult interstitial lung disease was detected by high-resolution chest computed tomography (HRCT) in 31 of 143 persons studied. These individuals were younger than their cohorts and were less likely to be smokers. However, open lung biopsies that were conducted in asymptomatic persons revealed several histologic subtypes, which include IPF and nonspecific interstitial pneumonia (NSIP). Finally, this reports highlights that smoking increases the risk of developing lung disease in familial pulmonary fibrosis.
Radiologic imaging is used increasingly to distinguish various forms of lung disease. However, there are limited reports using HRCT to discern the differences between CHP from other forms of fibrotic disease, such as IPF and NSIP. Silva and colleagues (5) conducted a retrospective analysis of 66 patients, 18 of whom had CHP, 23 of whom had IPF, and 25 of whom had a diagnosis of NSIP. In this report, it was not clear if NSIP was idiopathic or associated with a connective tissue disease (see below). The radiologic features that distinguished CHP were decreased attenuation and vascularity, the presence of centrilobular nodules, and the absence of lower zone–predominant infiltrates. In contrast, IPF and NSIP are lower zone predominant. On the basis of these findings, the authors were able to correctly diagnose 70 of 132 readings (53%), and they were able to differentiate NSIP from IPF. Although these results are intriguing, it is interesting to speculate what the data would have revealed if surgical lung biopsy were reported from each group relative to the radiologic pattern observed. Another finding from this study confirmed that CHP has a better prognosis than IPF.
The lesion of NSIP may occur in a variety of settings, but its relationship to connective tissue diseases has not been established. To address this question, Kinder and coworkers (6) examined 28 consecutive patients with idiopathic interstitial pneumonia (IIP) who met the following criteria for undifferentiated connective tissue disease (UCTD): one clinical manifestation of connective tissue disease, serologic evidence of systemic inflammation in the absence of clinical infection, and absence of sufficient American College of Rheumatology criteria for another connective tissue disease. Compared with the control group (i.e., patients with IIP without UCTD [n = 47]), the patients with UCTD were more likely to be women, younger, and nonsmokers than the IIP control subjects. Compared with the control group, patients with UCTD–interstitial lung disease were significantly more likely to have ground-glass opacities on HRCT and an NSIP pattern on biopsy, and less likely to have honeycombing on HRCT or usual interstitial pneumonia on biopsy. Interestingly, 88% of patients classified as idiopathic NSIP met the criteria for UCTD, suggesting that NSIP may be an autoimmune disease.
OCCUPATIONAL MEDICINE
Rebecca Bascom
Department of Medicine
Milton Hershey Medical Center
Pennsylvania State College of Medicine
Hershey, Pennsylvania
Dr. Bascom provided a comprehensive overview of key topics related to occupational medicine and pulmonary disease.
Flock Workers
Flock worker's lung was reported initially in association with exposure to nylon flock in 1996, and later reports revealed similar exposures in association with other synthetic fabrics. The lesion is characterized by lymphocytic bronchiolitis and peribronchiolitis with lymphoid hyperplasia. As described in a report from Antao and colleagues (7), rayon flock exposure can now be associated with card manufacturing. In a cross-sectional study of 239 participants from a plant that employed 850 workers, flock workers were identified as those working in the processing area at least 1 hour weekly. Only 175 workers reported wearing air-purifying respirators, and none had been fit tested. Although flock exposure occurred during many points of the production process, the highest exposures were documented when the worker blew dust from his/her clothing using compressed air, and not during actual manufacturing. Symptoms reported included dyspnea, wheezing, and irritation of the upper respiratory tract. This report confirms the value of a thorough occupational history, the importance of identifying both routine and episodic tasks that lead to exposure, and mucosal irritation as an indicator of workplace exposures.
Occupation and Lung Function Decline
Occupational exposures are well known to be associated with periodic or prolonged declines in lung function. The purpose of a study conducted by the Lung Health Study Group (8) was to determine the influence of continued occupational dust and fume exposures on the rate of decline in lung function in participants with preexisting chronic obstructive pulmonary disease (COPD). The group consisted of 5,724 adult current smokers diagnosed with early COPD (post-bronchodilator FEV1/FVC < 0.7 and FEV1 of 55–90% predicted). Key findings from this study revealed that an average rate of 0.25% decline annually in FEV1 due to continued fume exposure would account for a 7.5% drop over 30 working years above that which would be expected to occur secondary to COPD alone. Although the effects appear small, fume exposure on a background of COPD was associated with accelerated loss of lung function. These data are also consistent with a report from Blanc and Toren (9), who reported that smoking plus dust exposure in the workplace was associated with increased rates of emergency and hospital care. Moreover, this report demonstrated that occupational exposures to gases, dusts, and fumes in nonsmokers may account for up to one-third of COPD incidence, and nearly 50% of mortality due to COPD.
Effects of September 11 World Trade Center Disaster Exposures
Dr. Bascom's group reported a follow-up evaluation of New York City police officers 19 months after an initial health screening conducted September 28 to October 12, 2001 (10). Of the 575 officers contacted, cough had a 5% prevalence pre–September 11 and rose to 43% during the follow-up evaluation. Although cough had resolved in 19% of police officers, shortness of breath and wheeze were present in 41 and 12%, respectively. A key feature of this article was the delayed onset of symptoms in many of those exposed. Although cough was the predominant early symptom, the exposures included many irritant respirable materials, each of which may have variable effects on the upper and lower respiratory tract, with variable temporal patterns. Accordingly, Bascom and colleagues recommended the need for our clinical practices to recognize heterogenous respiratory symptoms after high-level and complex inhalation exposures, and to continue to monitor these patients even in the absence of initial symptoms.
Isocyanate Asthma
Isocyanates are used in the production of polyurethanes for use in foams, paints, varnishes, and insulating materials, among others. Worldwide, isocyanates remain the most common cause of immunologic occupational asthma in industrialized countries despite established acceptable levels of the most common monomers of these compounds. In an attempt to reduce health risks, isocyanates have been reformulated into compounds with a lower vapor pressure. However, Pronk and colleagues (11) report sobering statistics revealing that, despite reformulations, isocyanates remain an important cause of sensitization and respiratory disease in various spray painting industries. This cross-sectional study of 581 workers in Dutch spray painting industries revealed that COPD-like symptoms of cough, phlegm production, and dyspnea were three times more common among spray painters compared with office workers, whereas asthmalike symptoms of wheezing and chest tightness were twice as common. A particular strength of this study was that it excluded workers who left the industry, which makes the exposure–response relationships all the more impressive.
Durable Fibers
Although the health risks associated with asbestos have been well described and recent new exposures are believed to rare, a recent study examining vermiculite exposure reveals some disturbing information (12). Vermiculite contains asbestos fibers, and was shipped worldwide from its main source, which was Libby, Montana, from 1921 to 1990. Although asbestos exposure due to vermiculite ended in 1980, a cohort of miners from Libby revealed interstitial and pleural disease consistent with asbestos exposure 25 years later. Perhaps most concerning is the exposure of these individuals was less than 2.21 fibers/cc-years, which is much lower than the allowable level of 4.5 fibers/cc-years established by the Occupational Safety and Health Administration. Because home repair and remodeling activities may disrupt attic insulation containing vermiculite, new exposures to amphibole asbestos are still possible, which could create new health care concerns in the future.
LUNG TRANSPLANTATION
Alan Glanville
Department of Thoracic Medicine
St. Vincent's Hospital
Darlinghurst, Australia
Dr. Glanville presented five topics as follows: lung transplant (LTx) activity and practices, candidate selection, early complications, biomarkers, and immunosuppression trials.
Lung Transplant Activity and Practices
Since 1980, the International Society of Heart and Lung Transplantation (ISHLT) had accrued data on 3,262 heart–lung and 23,716 LTx recipients worldwide. The most recent compilation of LTx activity data reveals that, of the 146 centers participating in data collection, 54% of these performed fewer than 10 transplants annually, and that more than 50% of the transplants reported were conducted by 23 centers (13). This latter group performed over 30 transplants annually. Due to lower complication rates and improved outcomes, the trend toward bilateral lung transplants continues and now comprises 63% of all transplants, with cystic fibrosis (CF) the most common indication, and the indication of IPF increasing from 15 to 32% of all transplants. Transplants conducted for COPD decreased to 32% from 41%. Of note, the 1-year survival for IPF post-transplant has decreased by 40% for the 2003–2005 reporting period, compared with 1999–2000. The changes in survival may reflect the new allocation system enacted in the United States in 2005, which was designed to balance the risk of death on the waiting list with the likelihood of survival post-transplant. Overall survival at 1 and 5 years is now 81 and 52%, respectively. However, the conditional half-life post-transplant is currently unchanged compared with 1988–1994. Although the overall survival of transplants conducted in patients with IPF and COPD have lower long-term outcome rates in adult recipients, transplantation for CF in adults continues to have the best long-term survival.
Candidate Selection
In contrast to adults, pediatric patients with CF who received LTx were reported recently to have very poor 5-year survival—approximately 32% (14). The U.S. CF Foundation Registry and Organ Procurement and Transplantation Network were used to identify 514 children (age, 6–18 yr) with CF who were on the wait list for LTx for the period of 1992–2002. Four variables were associated with risk of poor outcome: Burkholderia cepacia infection decreased wait-list and post-LTx survival, diagnosis of diabetes mellitus decreased wait-list survival only, older age decreased post-transplant survival only, and Staphylococcus aureus infection increased wait-list survival but decreased post LTx survival. The data, although controversial, suggested that most children with CF listed for LTx using the old allocation model (pre-2005) had a reduced survival benefit. The lack of survival benefit could in part be due to the possibility that patients who underwent transplant were not very ill. However, questions remain, such as the true effects of LTx on survival and quality of life in these patients. Dr. Glanville stated that the challenge to the transplant and CF community is to demonstrate improved post-LTx survival in this group. To do so may require a different study format and the inclusion of centers with a demonstrated high volume of LTx for CF.
Early Complications
Of the early complications after LTx, primary graft dysfunction (PGD) remains a significant cause of early morbidity and mortality. To address the late effects of PGD, Daud and colleagues (15) conducted a retrospective analysis of 334 adult LTx recipients and graded the severity of PGD according to ISHLT criteria. The impacts of PGD on bronchiolitis obliterans syndrome (BOS) stage 1 and survival were assessed in a statistical model that incorporated acute rejection, lymphocytic bronchitis, and community-acquired respiratory virus infections. The data showed that absence of PGD (PGD grade 0) was associated with a significantly higher freedom of BOS stage 1, whereas PGD grades 1,2,3 were associated with the onset of BOS (P < 0.004). Notably, the relationship of PGD to BOS was independent of acute rejection or viral infection. Moreover, there was no association between PGD and acute rejection or lymphocytic bronchitis. The level of increased risk of BOS associated with PGD was directly related to the severity of immediate PGD. This important study provides an explanation as to why some pulmonary allografts fail in the absence of demonstrable acute rejection or lymphocytic bronchitis.
Ischemia and reperfusion injury (IRI) is an invariable consequence of the LTx procedure, and has been linked to the onset of PGD. Surfactant proteins have been shown to be altered during IRI, which could contribute to altered lung physiology post-IRI. Kermeen and colleagues (16) reported a retrospective review of 106 consecutive LTx patients using synthetic lung surfactant for intrabronchial delivery. Five patients who underwent bilateral LTx and one who underwent a repeat heart–lung transplant were diagnosed with IRI. Surfactant was administered, on average, 37 hours post-transplant. Significant resolution of pulmonary infiltrates occurred within 24 hours, with successful extubation at a mean of 13.5 days. Notably, survival was 100% at 19 months. Although these results are intriguing, future studies will require a control group and larger numbers of patients to determine if exogenous surfactant replacement will be a promising, cost-effective, and noninvasive therapeutic alternative for treating these patients.
Biomarkers of Pulmonary Allograft Rejection
Aspiration of gastric contents has been shown to be associated with increased rejection episodes. The purpose of a study from Stovold and colleagues (17) was to determine if BAL pepsin could serve as a marker of gastric aspiration. Pepsin was measured in 36 LTxpatients, 4 normal volunteers, and 17 patients with unexplained cough. Compared with control subjects, BAL pepsin was elevated in stable LTx recipients, including those with acute rejection and BOS. The highest levels were in patients with grade A2 or higher acute vascular rejection (P < 0.004). Although this study provides additional solid evidence that gastric aspiration contributes to allograft injury, future studies will need to determine if fundoplication will be a preventative strategy for these patients. In addition, this reports suggests that BAL pepsin may become a biomarker of allograft injury post-transplant.
Immunosuppression Trials
The optimal regimens for immunosuppression post-LTx continues to evolve. In a single-center trial, and the only immunosuppression trial reported in 2007, Hachem and coworkers (18) compared the efficacy of tacrolimus (n = 44) versus cyclosporine (n = 46) as de novo calcineurin inhibition in combination with azathioprine and prednisone post-LTx. Compared with tacrolimus, patients randomized to cyclosporine were significantly more likely to develop the primary endpoint, which included the following: grade A3 or greater acute rejection score, lymphocytic bronchitis score greater than B4, or BOS stage 0-p. However, there was a trend toward higher incidence of diabetes in the tacrolimus group, but there was no overall difference in graft survival or total number of infections. The conclusions of the study indicate that tacrolimus was associated with a lower burden of acute rejection and lymphocytic bronchitis, and possibly freedom from BOS stage 0-p. However, larger trials are warranted, and the roles of mycophenolate and everolimus have yet to be reported in similar trials.
FOOTNOTES
Conflict of Interest Statement: D.S.W. is a cofounder of ImmuneWorks, which was founded in 2006. The company will develop novel therapeutics for immune mediated diseases. D.S.W. does not receive any salary. As of this date, he has received $9,000 in royalties from ImmuneWorks but no other forms of payment.
(Received in original form June 18, 2008; accepted in final form June 23, 2008)
REFERENCES
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