| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee
ASTHMA
Richard J. Martin
Division of Pulmonary Medicine
National Jewish Medical and Research Center
Denver, Colorado
There has been considerable controversy surrounding the effect of genetic polymorphisms on therapeutic responses to ß2-adrenergic agonists, based primarily on studies of short-acting ß-agonists (1–3). Three articles were highlighted in this session that address the effect of genetic polymorphisms on the response to long-acting ß2-adrenergic receptor agonists. Wechsler and colleagues (4) retrospectively analyzed ß2-adrenergic receptor polymorphisms in two prior Asthma Clinical Research Network studies. In the first study, patients with persistent asthma, which was controlled during a 6-week run-in period with triamcinolone, were randomized to regular salmeterol therapy while inhaled corticosteroids were discontinued (the Salmeterol or Corticosteroid [SOCS] study) or to continued triamcinolone. In the second study, patients were continued on inhaled corticosteroids while salmeterol was added (the Salmeterol ± Inhaled Corticosteroid [SLIC] study). In both studies, subjects who were homozygous for arginine (ARG) at the B16 position on the ß2-adrenergic receptor were compared with subjects who were homozygous for glycine (GLY) at the same locus. In the first study (SOCS), subjects who were ARG/ARG had a small but significant decline in morning peak expiratory flow between Weeks 6 and 16 after randomization to salmeterol. In the second study (SLIC), patients who were ARG/ARG had an initial increase in morning peak expiratory flow followed by a drop, with a significantly lower morning peak expiratory flow compared with patients who were GLY/GLY by Week 18. The findings suggest that subjects who are ARG/ARG have an impaired response to salmeterol both in the presence and the absence of inhaled corticosteroids. In both studies, the most pronounced differences between the genotypes were only evident at the latest time points.
The second article that was highlighted was also a retrospective analysis of two prior clinical trials. Bleecker and colleagues (5) studied the effect of ß2-adrenergic receptor genotype at B16 on response to salmetrol in two identical clinical trials (total n = 183) that compared fluticasone + salmeterol to monteleukast therapy in subjects with persistent asthma whose asthma was not controlled by short-acting ß-agonist alone. Only the fluticasone + salmeterol arm was analyzed for genotype in this study. In contrast to the findings of Wechsler and coworkers, there was no difference in morning peak expiratory flow or FEV1 in ARG/ARG, ARG/GLY, or GLY/GLY subjects during the 12 weeks of fluticasone + salmeterol therapy in the study nor were any differences seen during the short run-out trial. One potential explanation for the different findings in this study compared with Wechsler and colleagues' study is the shorter duration of these trials (12 wk vs. 16 to 18 wk).
The third article was a retrospective cross-sectional survey of the effect of the same ß2-receptor polymorphisms on the rate of asthma exacerbation in 546 Scottish patients with asthma (6). Among subjects who were ARG/ARG at the B16 position of the ß2-adrenergic receptor, the odds ratio of exacerbation was significantly higher (odds ratio, 2.05; 95% confidence interval, 1.19–3.53; P = 0.01) compared with patients who were GLY/GLY. This effect of the ARG/ARG genotype was only evident in patients who were being treated with long-acting ß-agonists. There was no significant difference in the rate of exacerbation between ARG/ARG and GLY/GLY subjects among patients who were not taking long-acting ß-agonists. Although these three retrospective studies do not settle the controversy, they do provide additional evidence that patients with the ARG/ARG genotype may have adverse responses to therapy with inhaled ß-agonists. Ongoing prospective, randomized, placebo-controlled studies will provide more definitive information in the next few years.
Although anti-IgE therapy has been modestly successful in patients with moderate to severe asthma, new treatments for severe asthma are needed. Tumor necrosis factor (TNF)-
is a pleiotropic inflammatory cytokine that is increased in the bronchoalveolar lavage fluid of patients with severe asthma. Ten subjects with severe refractory asthma were compared with 10 subjects with mild to moderate asthma (7). TNF- levels were significantly higher in the peripheral blood monocytes of the patients with severe asthma compared with patients with mild/moderate asthma or normal healthy control subjects. The 10 subjects with severe asthma were then treated with etanercept, a soluble TNF- receptor or placebo in a 10-week, double-blind, placebo-controlled crossover study. Treatment with etanercept led to a significant increase in FEV1 of approximately 300 ml compared with treatment with placebo, accompanied by significant improvements in methacholine-induced bronchial hyperresponsiveness and asthma-related quality of life, and reduced sputum histamine levels. Although this study was small, the findings are encouraging and suggest that therapy targeted at TNF- may prove to be useful in the treatment of severe asthma.
LUNG TRANSPLANTATION
Paul A. Corris
Institute of Cellular Medicine
University of Newcastle and Freeman Hospital
Newcastle, United Kingdom
Recipient Selection
Success in lung transplantation begins with appropriate selection of candidates. An update to the 1998 International Guidelines for the Selection of Lung Transplant Candidates was published in 2006 (8). Several new recommendations were made. For patients with chronic obstructive pulmonary disease (COPD), the BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity) index (9), which includes body mass index, the degree of airflow obstruction, the degree of dyspnea, and the exercise capacity as measured by the 6-minute-walk distance, is now recommended as a selection tool. Patients with a BODE index of 7 to 10 (on a scale of 1 to 10) have a median survival of about 3 years and would benefit from lung transplantation. With this in mind, all patients with COPD with a BODE index of more than 5 are candidates for referral for evaluation. Patients with cystic fibrosis should be referred for evaluation when their FEV1 falls below 30% of predicted or if there is a rapid decline in FEV1, particularly in young, female patients. Of note, patients with cystic fibrosis who are colonized with genomovar III Burkholderia cepacia have high mortality rates after transplantation and many centers now will not offer transplantation to such patients. With the advent of improved medical therapy for pulmonary arterial hypertension, the guidelines now recommend that patients with pulmonary arterial hypertension undergo transplantation when there are persistent New York Heart Association functional class III or IV symptoms despite maximal medical therapy. Finally, because of the rapidly progressive course of idiopathic pulmonary fibrosis (IPF), these patients should be referred for transplant evaluation at the time of a radiographic or histologic diagnosis of usual interstitial pneumonitis or a histologic diagnosis of nonspecific interstitial pneumonia, regardless of vital capacity. For all patients with end-stage lung disease, referral for lung transplantation should not be based on a single factor but on an overall assessment of the patient's functional status, physiologic parameters, and rate of decline.
Several other notable articles on the topic of recipient selection were discussed. Choong and coworkers retrospectively assessed the affect of mild or moderate coronary artery disease (single- or multivessel coronary artery stenoses, <50%) on short- and long-term outcomes from lung transplantation and found no adverse effects (10). In another retrospective study, McAnally and colleagues examined the association between preoperative corticosteroid therapy on survival after lung transplantation (11). Patients who were receiving no or low-dose corticosteroids (<0.42 mg/kg/m2 per day) had significantly better survival than patients receiving high-dose corticosteroids (
0.42 mg/kg/m2 per day) despite generally similar pretransplantation characteristics other than that there were slightly more patients with IPF in the high-dose group. These findings support the avoidance of high-dose corticosteroids in patients who are awaiting lung transplantation. Finally, two studies investigated risk factors for mortality in patients awaiting lung transplantation. Lederer and colleagues demonstrated that a six-minute-walk distance of less than 207 m was associated with an almost fivefold increase in mortality in patients with IPF, even when adjusted for other physiologic variables (12). Six-minute-walk distance was superior to FEV1 for predicting outcome in this group of patients. In a multicenter cohort study, Belkin and associates found that, in 343 patients with cystic fibrosis, mortality was associated with an FEV1 of less than 30% predicted and a PaCO2 of greater than 50 mm Hg (13).
Donor Evaluation and Management
Donor lung availability continues to limit the rate of lung transplantation for end-stage lung disease. Investigators in San Antonio tested the value of a donor management protocol on rates of lung donation and recipient outcomes (14). The San Antonio Lung Transplant (SALT) donor management protocol included educational and management interventions with the aim of increasing the number of donor organs. Donor management interventions included performing ventilator recruitment maneuvers, restricting fluid administration, administering diuretics, and implementing techniques for preventing aspiration. Investigators were able to increase the percentage of lung retrieved from organ donors from 11.5 to 25.5% with no adverse effect on outcomes. Survival of lung recipients was not adversely affected by this protocol, and outcomes did not differ between standard donors and donors who were considered marginal before the implementation of the management interventions. This study supports the need for a coordinated and active management program for multiorgan donors to maximize the number of suitable donor lungs.
Two novel experimental studies reported that low-dose carbon monoxide attenuated endothelial cell injury, inflammatory cytokine gene expression, and inflammation in animal models of lung transplantation (15, 16), adding to the growing body of literature suggesting that carbon monoxide may have protective effects in ischemia–reperfusion injury. These studies are particularly interesting in light of reports of successful thoracic organ transplantation from carbon monoxide–poisoned organ donors (17, 18).
Obliterative Bronchiolitis
Increasingly, obliterative bronchiolitis after lung transplantation is considered to be more than just a manifestation of alloimmune response (19). Chronic epithelial injury as a result of infection, oxidant stress, and gastroesophageal reflux is believed to contribute to the pathophysiology of obliterative bronchiolitis. Several experimental studies addressed issues of alloantigen-independent mechanisms of obliterative bronchiolitis. Foremost were two articles addressing the role of viral infections in obliterative bronchiolitis. Mikols and colleagues (20) demonstrated that, in a murine lung allograft model, epithelial injury was more marked with concurrent viral infection, and pathologic features of obliterative bronchiolitis were associated with increases in the innate epithelial cell macrophage chemoattacactant IL-12 p80. Kuo and colleagues (21) demonstrated enhanced graft fibrosis in a murine orthotopic tracheal transplant model with Sendai virus infection. The fibrotic response was reduced with pretransplant immunization against Sendai virus.
In a clinical study, Verleden and colleagues attempted to define the population of patients with obliterative bronchiolitis who might benefit from azithromycin therapy (22). Azithromycin reduced both bronchoalveolar lavage neutrophilia and IL-8 mRNA levels in patients with obliterative bronchiolitis, although only 6 of 14 patients responded to treatment. Patients who had higher bronchoalveolar lavage levels of neutrophils before treatment were more likely to have a functional response to azithromycin, with improved FEV1.
Medical Problems Post-Transplantation
Morbidity after lung transplantation remains high. Common problems identified in the 2006 report of the International Society of Heart and Lung Transplantation (23) within the first 5 years after transplantation include hypertension (86%), renal dysfunction (39%), hyperlipidemia (49%), diabetes (32%), and bronchiolitis obliterans (34%). Infections are also very common and contribute substantially to morbidity and mortality. Yip and colleagues (24) hypothesized that hypogammaglobulinemia contributes to the high incidence of infections in lung transplant recipients. In a retrospective cohort study, IgG levels were measured before and after lung transplantation in 40 patients. Before transplantation, 15% of patients had mild hypogammaglobulinemia and none had severe hypogammaglobulinemia. All of the patients with pretransplant hypogammaglobulinemia had COPD and there was no association with steroid use. After transplantation, 58% of patients had mild hypogammaglobulinemia and 15% of patients had severe hypogammaglobulinemia. Lower pretransplant IgG levels were associated with the risk of severe post-transplant hypogammaglobulinemia. These findings suggest that hypogammaglobulinemia is common both before and after lung transplantation. The efficacy of IgG supplementation in this setting has not been studied.
In another notable study, Chernenko and colleagues (25) described the clinical characteristics of 17 patients with Mycobacterium abscessus infection after lung transplantation. Most of the infections were de novo and respiratory infection was the most common site, although a number of soft tissue infections were also noted. Outcomes were generally good, with only two deaths due to progressive disease and 10 microbiological cures.
CYSTIC FIBROSIS
Michael R. Knowles
Pulmonary Research and Treatment Center
University of North Carolina
Chapel Hill, North Carolina
Newborn Screening
The Centers for Disease Control and Prevention recently recommended the addition of cystic fibrosis (CF) to state newborn screening programs based on more than 20 publications over the past several years and several in the past year (26, 27). Infants diagnosed with CF through newborn screening have improved nutritional status, better growth, and lower risk for life-threatening complications or death in infancy and early childhood, although benefits in pulmonary function have not yet been detected. Delayed diagnosis can lead to significant cognitive dysfunction and nutritional failure. Guidelines for implementation of CF newborn screening were published in 2007 (28). A well-designed system for newborn screening is essential to achieve the greatest benefit with limited adverse consequences for patients and their families. This report highlights the benefits of newborn screening as well as the risks, including the need for follow-up of large numbers of CF carriers identified by genetic screening, the risk of false positives, and the risk for newly diagnosed infants to acquire health care–associated infections such as Pseudomonas aeruginosa as a result of diagnostic evaluation and/or early treatment.
Genetic Modifiers
CF is a recessive genetic disorder with great variability in clinical phenotype that cannot be explained by mutations in CFTR, the disease-causing gene. Gene modifier studies are based on the concept that non-CFTR genetic factors play a large role in phenotypic heterogeneity. The demonstration of a strong contribution of non-CFTR genetic factors has previously been reported in only one study (29). Two articles were discussed that report data from a United States study of genetic and nongenetic factors in disease phenotype in monozygotic and dizygotic twins and close siblings with CF. In the first study (30) of 47 monozygotic twin pairs, 10 dizygous twin pairs, and 231 sibling pairs, all with CF, there was a much stronger correlation of spirometry for monozygotic twins compared with dizygotic twins or other siblings. Heritability estimates were high for siblings living in the same environment (range, 0.54–1.0). Taken together, these findings indicate substantial genetic control of variation in lung disease severity, independent of CFTR genotype. In the second study (31), there was greater concordance for meconium ileus for monozygotic twins (n = 65 pairs) versus dizygotic twins (n = 23 pairs) or sibling pairs (n = 349). By contrast, the risk for distal intestinal obstruction was primarily determined by nongenetic factors. These studies indicate substantial genetic contributions to the severity of clinical disease in CF and provide strong support for the ongoing study of gene modifiers to develop a better understanding of the pathophysiology of CF and to identify novel treatments. A whole genome scan for genetic modifiers is currently underway through a collaboration among investigators at the University of North Carolina, Case Western Reserve University, and Johns Hopkins University, and Canadian investigators.
Treatment
Macrolides in patients with CF without P. aeruginosa.
Chronic macrolide therapy is well established in patients with CF who are chronically infected with P. aeruginosa, and reduces the frequency of pulmonary exacerbations regardless of the presence or absence of an improvement in FEV1 (32). The initial study of macrolides in CF was based on the reported beneficial effects of macrolide therapy in Japanese patients with diffuse panbronchiolitis associated with P. aeruginosa. Although the benefit of macrolides in both diffuse panbronchiolitis and CF is believed to be from immunomodulatory effects rather than solely from antimicrobial effects, it is not known whether macrolides are beneficial in patients with CF who do not have P. aeruginosa infection. In addition, the safety of chronic macrolide therapy in younger patients with CF has not been established. A French study (33) compared chronic azithromycin to placebo in 82 young patients (mean age, 11 yr) with CF; 62 patients were not infected with P. aeruginosa. After 1 year of treatment, there was no difference in FEV1 between groups, but the number of pulmonary exacerbations was reduced and the time to exacerbation was longer in patients who received azithromycin. These findings are encouraging with regard to the safety and efficacy of azithromycin in this clinical setting. A larger study is underway in North America with plans to enroll 300 patients with CF who are not infected with P. aeruginosa.
Withdrawal of inhaled corticosteroids.
Although inhaled corticosteroids are used in as many as 50% of patients with CF in the United States and Europe, systematic review of controlled trials has previously concluded that there is "no evidence from existing trials to support the practice of prescribing inhaled steroids in cystic fibrosis" (34). In a report by Balfour-Lynn and colleagues (35), the safety of withdrawing inhaled corticosteroids from patients who were already using them was tested in a double-blind placebo-controlled study. Notably, 15% of eligible patients were not enrolled because their physicians were unwilling to withdraw inhaled corticosteroids. In the remaining 171 patients who were studied, withdrawal of corticosteroids had no effect on time to exacerbation regardless of age, atopy, FEV1, or presence or absence of infection with P. aeruginosa. There was a nonsignificant trend for an increase in lung-related adverse events in the placebo (withdrawal) group. The authors conclude that it appears safe to consider withdrawal of inhaled corticosteroids in many patients with CF. Potential advantages would include a reduction in the drug burden on patients and in adverse effects, as well as financial savings.
ACUTE RESPIRATORY DISTRESS SYNDROME
Antonio Pesenti
Department of Anesthesia and Intensive Care
Ospedale San Gerardo dei Tintori
University of Milano-Bicocca
Monza, Italy
Fluid and Catheter Treatment of Acute Respiratory Distress Syndrome
In a long-awaited study, the ARDS Network investigators reported the results of a large randomized trial of two fluid management strategies in patients with acute respiratory distress syndrome (ARDS) (36). One thousand patients were randomized to either liberal or conservative fluid management. Fluid therapy was managed by detailed algorithms. The goal of the liberal management strategy was to maximize oxygen delivery and organ perfusion with a central venous pressure (CVP) goal of 10 to 14 mm Hg and a pulmonary arterial occlusion pressure (PAOP) goal of 14 to 18 mm Hg. The goal of the conservative management strategy was to minimize lung edema with a CVP goal of less than 4 mmHg and a PAOP goal of less than 8 mm Hg. Patients in the liberal strategy group had a positive fluid balance of approximately 7 L over the first 7 days, similar to fluid balance in prior ARDS Network studies in which fluid management was not protocolized (37, 38). Patients in the conservative fluid strategy group had no net fluid gain over the first 7 days. There was no difference in 60-day mortality between the two groups. Patients in the conservative fluid group had significantly more days alive and free of mechanical ventilation and more intensive care unit–free days, suggesting that a restrictive fluid management strategy improves lung function and is beneficial in ARDS. Of note, only 10% of patients who were screened were enrolled because of extensive exclusion criteria. Although the mean PAOP was 15.6 mm Hg, 30% of patients had a PAOP greater than 18 mm Hg at baseline. This finding suggests that mild volume overload is not uncommon in patients who have had ARDS for 24 to 48 hours.
Patients in the ARDS Network fluid management trial were also randomized to insertion of either a central venous line or a pulmonary artery catheter for invasive monitoring and fluid management (39). There was no difference in clinical outcomes, including mortality and duration of mechanical ventilation, between treatment groups. More complications were reported in the pulmonary artery catheter group. Most of these complications were arrhythmias that occurred at the time of catheter insertion. Also of note, 21% of screened patients were excluded because of the preexisting presence of a pulmonary artery catheter, perhaps excluding some patients who might have derived benefit from pulmonary artery catheterization. The authors conclude that pulmonary artery catheterization is not indicated for the routine management of acute lung injury and ARDS.
Corticosteroid Therapy for Persistent ARDS
Fibroproliferation, ongoing inflammation, prolonged mechanical ventilation, and high mortality characterize persistent ARDS. Based on prior reports suggesting that corticosteroids might improve clinical outcomes in persistent ARDS, the ARDS Network performed a multicenter, randomized, double-blind, placebo-controlled trial of corticosteroids in 180 patients with persistent ARDS of at least 7 days' duration (40). A single dose of 2 mg/kg of methylprednisolone was followed by a dose of 0.5 mg/kg every 6 hours for 14 days, a dose of 0.5 mg/kg every 12 hours for 7 days, and then tapering of the dose. The study drug was tapered over a period of 4 days if 21 days of treatment had been completed and the patient was unable to breathe without assistance for a period of 48 hours. Tapering occurred over a 2-day period if the patient was able to breathe for a period of 48 hours without assistance. There were no differences in mortality between the groups. In post hoc analysis, methylprednisolone was associated with significantly increased 60- and 180-day mortality rates among patients enrolled at least 14 days after the onset of ARDS. In the entire group, methylprednisolone increased the number of ventilator-free and shock-free days during the first 28 days in association with an improvement in oxygenation, respiratory-system compliance, and blood pressure, with fewer days of vasopressor therapy. As compared with placebo, methylprednisolone did not increase the rate of infectious complications but was associated with a higher rate of neuromuscular weakness. The authors conclude that the routine use of methylprednisolone for persistent ARDS is not indicated despite the improvement in cardiopulmonary physiology. In addition, initiating methylprednisolone therapy more than 2 weeks after the onset of ARDS may increase the risk of death.
Lung Recruitment and Positive End-Expiratory Pressure in ARDS
In ARDS, the effects of positive end-expiratory pressure (PEEP) may depend on the degree of recruitability of lung tissue. Gattinoni and colleagues examined the relationship between the percentage of potentially recruitable lung, as indicated by computed tomography, and the clinical and physiologic effects of PEEP (41). Sixty-eight patients with acute lung injury/ARDS underwent whole-lung computed tomography during breath-holding sessions at 5, 15, and 45 cm H2O airway pressures. The percentage of potentially recruitable lung was defined as the proportion of lung tissue in which aeration was restored at airway pressures between 5 and 45 cm H2O. The percentage of potentially recruitable lung varied widely, accounting for a mean of 13 ± 11% of the lung weight, and was highly correlated with the percentage of lung tissue in which aeration was maintained after the application of PEEP (r2 = 0.72, P < 0.001). In some patients, lung recruitability was almost negligible, whereas in others it was equal to 25 to 35% or more of the lung parenchyma. Patients with a higher percentage of potentially recruitable lung (> median value of 9%) had greater total lung weights, poorer oxygenation, poorer respiratory-system compliance, higher levels of dead space, and higher rates of death than patients with a lower percentage of potentially recruitable lung. The authors speculate that knowledge of the percentage of potentially recruitable lung may be important for establishing the therapeutic efficacy of PEEP. Setting levels of PEEP independently of the percentage of potentially recruitable lung could offset the possible benefits of PEEP by causing overdistension of normal lung in patients with a low percentage of recruitable lung.
Villar and colleagues studied the effect of a ventilatory strategy aimed at applying PEEP levels above the lower inflection point of the pressure–volume curve (Pflex) of the respiratory system in established ARDS (42). Patients meeting the American-European Consensus Conference definition for ARDS were ventilated for 24 hours, and only those patients with a PaO2/FIO2 of 200 or less on a standard ventilator setting were enrolled. One hundred three patients were randomized into two ventilatory strategies: conventional mechanical ventilation (VT, 9–11 ml/kg predicted body weight; PEEP 5 cm H2O) or Pflex group (VT, 5–8 ml/kg predicted body weight; PEEP set at 2 cm H2O above the lower inflection point of the pressure–volume curve of the respiratory system). Mortality and ventilator-free days were significantly better in the Pflex group, and the number of additional organ failures was higher in the control group. Potential mechanisms for the improved outcomes include the prevention of lung recruitment/derecruitment by PEEP or the avoidance of overdistension injury due to lower VT and plateau pressure in the Pflex group.
FOOTNOTES
Conflict of Interest Statement: L.B.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
REFERENCES
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
