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University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
INTRODUCTION
This is the third in a series of four executive summaries from the Clinical Year in Review Symposium presented at the 2005 International Meeting of the American Thoracic Society. The salient points of each talk have been abstracted by the session chair based on the annotated bibliography submitted by the presenters.
SLEEP-DISORDERED BREATHING
David P. White
Division of Sleep Medicine
Harvard University School of Medicine
Boston, Massachusetts
One proposed alternative to in-lab polysomnography (PSG) for the diagnosis of obstructive sleep apnea (OSA) is home oximetry. Whitelaw and coworkers (1) randomized 288 symptomatic patients referred to a sleep center to diagnosis via home oximetry or PSG. Quality-of-life, assessed by the Sleep Apnea Quality of Life Index (SAQLI), was the primary outcome. After a clinical encounter with each patient and review of the diagnostic study, a sleep physician predicted whether they would experience improved quality-of-life with an autotitrating continuous positive airway pressure (CPAP) device for 4 wk. There was no difference in quality-of-life (60% correct for PSG and 63% correct for home oximetry) or CPAP compliance between the two groups. This study suggests that home oximetry is equivalent to PSG for the diagnosis of OSA if quality-of-life after therapy with CPAP is the primary outcome.
Loop gain, a measure of ventilatory control instability, may play a role in the pathogenesis of OSA. Wellman and colleagues (2) hypothesized that individual variability in loop gain is important in a subset of patients with collapsibility of the pharyngeal airway during sleep. They measured Respiratory Disturbance Index (RDI), loop gain, and pharyngeal airway collapsibility (by Pcrit) in 25 patients with OSA during supine non–rapid eye movement (NREM) sleep. Loop gain correlated modestly with RDI (r = 0.36) in the cohort. The relationship between RDI and loop gain, however, was much more robust (r = 0.88) in patients with mild to moderate airway collapsibility (Pcrit around 0 cm H2O). The authors concluded that ventilatory control instability may be a determinant of OSA severity in individuals with pharyngeal collapse.
Levels of inflammatory cytokines, including tumor necrosis factor–
(TNF-), are elevated in patients with OSA and in healthy, sleep-deprived individuals. Vgontzas and colleagues (3) postulated that these cytokines contribute to daytime somnolence in OSA. They treated eight patients with placebo or etanercept, a TNF- antagonist, and evaluated a number of sleep-related parameters. The impact on the Multiple Sleep Latency Test (MSLT) was the primary outcome; in patients treated with etanercept, the MSLT increased by 3.1 ± 1.0 min when compared to placebo. In addition, the RDI decreased from 52.9 ± 9.1 to 44.3 ± 10.3 (p < 0.05) in those receiving etanercept. The authors conclude from this small study that TNF- may be involved in the pathogenesis and clinical manifestations of OSA.
Veasey and coworkers (4) studied the impact of intermittent hypoxia (IH) without sleep fragmentation on sleepiness and brain regions controlling sleep–wake function in mice. Mice exposed to IH over a 9-wk period were compared to sham mice. The treated mice slept 225 more minutes in both NREM and rapid eye movement (REM) sleep than sham mice in the 24 h immediately after IH, and 156 min longer two weeks into recovery. IH-treated mice were also found to be generally sleepier at baseline and when sleep-deprived. Finally, the investigators found evidence of redox injury in the thalamus and rostral basal forebrain in treated animals. They concluded that oxidative injury to the brain from IH may negatively impact the arousal state.
The role of multilevel (tongue and palate) radio frequency tissue (RF) ablation as a treatment for OSA was studied by Steward and compared to nasal CPAP (5). Twenty-two individuals with a mean RDI of 31.0 ± 17.7 were treated with multilevel RF therapy; a number of outcomes were evaluated before and 2 to 3 mo after therapy. There was a reported drop in RDI (12.2 ± 3.5 events/h), and a statistically significant improvement in the Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire (FOSQ) compared to baseline in treated patients. Importantly, there was no difference in any outcome parameter when compared to CPAP. Adverse effects of RF tissue ablation were minimal. The long-term impact and safety of this procedure should be studied.
INTERSTITIAL LUNG DISEASE
Ganesh Raghu
Division of Pulmonary and Critical Care Medicine
University of Washington Medical Center
Seattle, Washington
Idiopathic interstitial pneumonias (IIP), including idiopathic pulmonary fibrosis (IPF), usually develop sporadically, but familial cases have clearly been identified, suggesting a genetic basis in some patients. In particular, mutations in surfactant protein C (SFTPC) have been linked to familial pulmonary fibrosis (FPF). Lawson and colleagues (6) investigated the presence of SFTPC in sporadic cases of IIP. The SFTPC gene was sequenced in 89 patients with IPF, 46 patients with nonspecific interstitial pneumonia (NSIP), and 104 normal control subjects. A total of 13 sequence variations in the SFTPC gene were found in patients with pulmonary fibrosis, and none in control subjects. In only one patient was the sequence change predictive of a change in the amino acid sequence of the precursor SFTPC protein, indicating a plausible role in clinical disease. The authors conclude that mutations in the SFTPC gene are very uncommon.
There has been debate in the literature about what the gold standard for the diagnosis of IIP is, and whether a confident medical diagnosis can be made. Flaherty and coworkers (7) brought together three expert pulmonologists, two radiologists, and two pulmonary pathologists who reviewed 58 consecutive cases of IIP. Each physician was given information in sequential fashion, and asked to note their diagnostic impression and level of confidence in their diagnosis at each step. IPF (30 patients) and NSIP (15 patients) were the most common consensus pathologic diagnoses. Pulmonologists identified 75% of the IPF cases before the pathology findings were revealed, while the radiologists identified 48%. The confidence level increased as more data became available, and a high level of confidence was more likely to be correlated with a final diagnosis of IPF. Histopathologic information had the most significant impact on the final diagnosis, especially in patients with a diagnosis other than IPF. This study suggests that interactions between clinicians, radiologists, and pathologists are crucial to the diagnostic approach to IIP.
Six-minute walk tests (6MWT) are commonly used in clinical practice to evaluate the functional status, as well as the presence and severity, of oxyhemoglobin desaturation with ambulation in patients with pulmonary disease. Hallstrand and colleagues (8) prospectively studied parameters of the timed walk test (TWT), a modified 6MWT, in 28 patients with IPF followed for more than four years, to assess its utility as a measure of disease progression and survival. The mortality rate was 78.6% over the entire follow-up period. Strong correlation was found between end exercise pulse oxygen saturation (SpO2), walk-velocity, diffusion capacity for carbon monoxide (DLCO) and resting partial pressure of arterial oxygen (PaO2). In univariate Cox proportional-hazards models, end-exercise SpO2, change in SpO2 with walk, walk velocity, and walk distance were associated with survival. This study suggests that changes in timed walk test performance over time correlate with disease progression and prognosis.
There is no proven treatment for IPF, a progressive and devastating parenchymal lung disease. The efficacy of pirfenidone, an antifibrotic compound, was studied in a randomized, placebo-controlled prospective clinical trial by Azuma and coworkers (9) One hundred seven patients with IPF were randomized to receive pirfenidone (72 patients) vs. placebo (35 patients). There was no difference in the primary endpoint, change in the lowest SpO2 during 6-minute exercise test (6MET), between the two groups at 6 mo. However, in a prospectively defined subset whose SpO2 was maintained at 
80% during baseline 6MET, there was a statistically significant improvement in SpO2 nadir at 6 and 9 mo when compared with placebo. In addition, rate of decline in the forced vital capacity (FVC) was less steep, and the incidence of acute exacerbations lower in the pirfenidone group. Photosensitivity, gastrointestinal symptoms, fatigue, and liver function test (LFT) abnormalities were significant adverse events with the drug. Interestingly, the study was discontinued early in favor of pirfenidone. A larger clinical trial of pirfenidone in IPF is warranted.
LUNG TRANSPLANTATION
Selim M. Arcasoy
Division of Pulmonary, Allergy, and Critical Care Medicine
Columbia University College of Physicians and Surgeons
New York, New York
Lung transplantation remains a treatment option for patients with advanced lung disease. Trulock and colleagues (10) presented data from an international registry on parameters salient to transplantation. The number of lung transplants increased by 17% overall from 1999 to 2002. Transplant activity for chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and IPF increased, but declined by 15% for primary pulmonary hypertension (PPH). Of note, the number of transplants for IPF increased by 113%. Bilateral lung transplantation increased by 83%, while the number of single lung transplants remained constant since 1994. Survival rates since 1993 also increased, owing to improved survival in the first post-transplant year. Survival rates were 74% at 1 yr, 58% at 3 yr, 47% at 5 yr, and 24% at 10 yr.
Three recent publications about long-term outcomes were also presented. de Perrot and coworkers (11) documented the experience from the University of Toronto in 501 lung transplant recipients from 1983–2003. Cystic Fibrosis, COPD, and pulmonary fibrosis were the top three single major indications for the procedure. The overall 5-, 10-, and 15-yr survival was 55.1%, 35.3%, and 26.5%, respectively. The authors pointed out that recipient diagnosis influenced survival. Patients with CF without Burkholderia cepacia infection, and with PPH, had greater than 50% survival at 10 yr, whereas patients with COPD had a 10-yr survival rate of 43%.
In two separate papers (12, 13), investigators from the University of Southern California reported their data on recipient outcomes and donor perioperative complications following living lobar lung transplantation. A total of 128 procedures were performed in 123 patients from 1993 to 2003, 84% of whom had CF. Actuarial survival was 70% and 45% at 1 and 5 yr, respectively, comparable to data for cadaveric transplantation. The major causes of death were infection (52%) and obliterative bronchioloitis (13%). The authors commented that this was despite the fact that their patients were sicker than usual; 67.5% were hospitalized and 17.9% were intubated at the time of the procedure. Donor lobectomy appeared to be a safe procedure. There were no donor deaths, and 80.2% had no complications following surgery. Thoracostomy tube duration for longer than 14 d was the most common complication.
Christie and colleagues (14) performed a retrospective cohort study assessing the clinical outcomes of patients who develop primary graft failure (PGF), a severe form of acute lung injury after lung transplantation. In a group of 255 transplant patients, the incidence of PGF was 11.8%. All-cause mortality at 30 d was 63% in patients with PGF and only 8.8% in those without PGF. Patients with PGF experienced longer mean hospital length of stay and duration of mechanical ventilation, and had worse exercise tolerance assessed by 6MWT distance achieved within the first 12 post-transplant months. The authors conclude that PGF has significant short- and long-term negative impact on transplantation outcomes.
Bronchiolitis obliterans syndrome (BOS), chronic allograft dysfunction characterized by progressive airflow obstruction, is a major cause of death in lung transplant recipients. Hopkins and coworkers (15) asked the question of whether minimal rejection (grade A1) in the first year after transplantation is associated with BOS. They studied 184 patients who underwent 1,159 biopsies; 128 biopsies in 128 individuals showed minimal rejection. Seventy-eight patients developed greater than two episodes of A1 rejection; BOS developed in 63% of these patients compared to 43% in subjects with one or fewer A1 lesions. Minimal rejection is therefore not a trivial histologic finding, but there is presently no evidence that treatment prevents BOS.
Immunosuppression is a critically important aspect of lung transplantation. Iacono and colleagues (16) reported results of a trial of inhaled cyclosporine (CyA) in transplant patients. This single-center, double-blind, and placebo-controlled trial randomized 56 patients to receive aerosolized cyclosporine 33 mg thrice weekly versus placebo within 6 wk of the procedure. The drug was continued for 2 yr. There was no difference in the primary endpoint, which was the incidence of acute rejection. Secondary endpoints including survival, the development of BOS, and BOS free-survival were significantly better in the treatment arm. In particular, there was a fourfold risk reduction overall mortality in the aerosolized cyclosporine group when compared to placebo. Verification of the results of this small, single-center trial is needed.
PEDIATRIC PULMONARY DISEASE
Julian Allen
Division of Pulmonary Medicine
University of Pennsylvania School of Medicine
Philadelphia, Pennsylvania
The review of pediatric pulmonary disease focused on four general topics.
Airway Hyperresponsiveness, Asthma, and Interventions
Morgan and coworkers (17) reported the results of a randomized, controlled trial assessing the impact of environmental intervention on 937 inner-city children with atopic asthma. They found that comprehensive remediation for dust mites, passive smoking, cockroaches, molds, and other environmental allergens resulted in a 20% reduction in asthma symptom days and less asthma-related healthcare utilization. There was, however, no impact on spirometry or peak flow testing.
The effects of inhaled corticosteroids (ICS) on airway function were studied in a randomized, placebo-controlled trial by Merkus and coworkers (18). Children between the ages of 9 and 16 yr were randomized to treatment with ß-agonists alone or ß-agonists and ICS for up to 3 yr. ICS use was associated with improved symptoms and airflow in the central and intermediate airways. The possibility of airway remodeling was suggested by persistently reduced small airway flows.
Two studies addressed the impact of neonatal lung function on lung function at 10 to 11 yr of age, but came to disparate conclusions. Turner and colleagues (19) found in a study of 243 patients that reduced neonatal lung function resulted in impaired lung function at age 11 yr, whereas Wilson and colleagues (20) found no such relationship. In both studies, wheezing at age 4 was associated with increased atopy and bronchial hyperresponsiveness later in life. In Wilson and coworkers' study, certain ß2 adrenergic receptor polymorphisms, including Gln27 and Arg16, were linked to reduced neonatal lung function.
Early Intervention in Cystic Fibrosis Pulmonary Disease
It has been postulated that early diagnosis of CF, accompanied by early initiation of antiinflammatory therapy, may positively impact the natural history of the disease. Ratjen and colleagues (21) conducted a study in 105 patients with CF, in which they performed bronchoalveolar lavage (BAL) before and after 3 yr of therapy with recombinant DNAse (rhDNase), focusing on neutrophil percentage in BAL fluid. Patients with normal and elevated BAL fluid neutrophils not treated with rhDNase were found to have a further increase in neutrophils. Elastase and interleukin 8 (IL-8) levels were also elevated. Patients with high neutrophil counts treated with rhDNase did not exhibit this elevation. This study supports the notion of an antiinflammatory effect of rhDNase, but no clinical conclusions could be drawn.
Sleep Apnea, Hypertension, and Metabolic Syndrome
The role of OSA in metabolic syndrome, which includes obesity, hypercholesterolemia, insulin resistant diabetes, hypertension (HTN), and inflammation, was addressed in a study by Amin and coworkers (22). They found that OSA in children is associated with 24-h blood pressure (BP) dysregulation, the degree of which is correlated with severity of OSA. Twenty-four-hour ambulatory BP was measured in 60 children (mean age 10.8 ± 3.5 yr), 39 of whom had OSA and 21 with primary snoring. Children with OSA had significantly greater mean BP variability during wakefulness and sleep, higher night-to-day systolic BP, and smaller nocturnal dipping of mean BP. This may lead to sustained HTN if OSA is left untreated or if other risk factors develop.
Lung Growth and Epidemiology of Respiratory Disease
New techniques can now measure lung function in normal infants, thus allowing research on factors impacting lung growth. Lucas and colleagues (23) measured pulmonary function, including forced expiratory volume (FEV) at 0.4 s and FVC, in 131 normal-term infants from 5 to 14 wk of age. They observed that lower rates of fetal growth and higher rates of early infancy weight gain are associated with impaired lung development. The FEV0.4 was not related to birth weight. They hypothesize that smaller infants may "catch up" with regard to weight gain, but not airway growth. An alternate explanation is that obesity impairs airway growth.
FOOTNOTES
Conflict of Interest Statement: G.T. is the Principal Investigator for the InterMune sponsored INSPIRE trial studying the efficacy of interferon-
in IPF. He has received honoraria for dinner programs and Grand Rounds sponsored by InterMune, and has participated in Advisory Board meetings. He perceives no conflict of interest in this manuscript, as he was excerpting other colleagues' presentations.
* Co-Chair, Clinical Year in Review 
REFERENCES
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
