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1 Division of Occupational and Environmental Medicine, Division of Pulmonary and Critical Care Medicine, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California
Correspondence and requests for reprints should be addressed to Mark D. Eisner, M.D., M.P.H., 505 Parnassus Ave., M1097, San Francisco, CA 94143-0111. E-mail: mark.eisner{at}ucsf.edu
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Mark D. Eisner
University of California, San Francisco
San Francisco, California
Risk Factors for Chronic Obstructive Pulmonary Disease Development: Beyond Personal Smoking
Active smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). However, other exposures, such as passive smoking, could be important in the development of irreversible airflow obstruction. In this study by Yin and coworkers, baseline data was used from 15,379 never-smoking participants in the Guangzhou Biobank Cohort Study from southern China (1). All subjects were aged 50 years or greater, and the majority (88%) were women. Passive smoking was measured by a questionnaire that ascertained passive smoking during childhood and adulthood (at home and work). The study outcomes were chronic respiratory symptoms (cough, phlegm production, or dyspnea) and COPD defined as FEV1/FVC<0.70 (i.e., GOLD stage I or greater). For the COPD outcome, only 6,497 subjects with valid spirometry were included. Multivariable analysis was used to control for age, sex, educational level, exposure to occupational dust, and indoor pollutants such as biomass smoke. Cumulative passive smoke exposure during adulthood, which combined duration of exposure in years and average intensity of passive smoking in hours/week, was associated with COPD. For example, the highest category of passive smoking (>5 yr of at least 40 h/wk of total exposure) was associated with a greater risk of COPD (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.18–1.85). Passive smoking was also related to a greater risk of respiratory symptoms.
A notable study strength was the large population-based cohort with examination of both respiratory symptoms and lung function. The coherence of results for respiratory symptoms and COPD defined by spirometry increases the likelihood of a causal relationship between passive smoking and COPD. Evidence of an exposure–response relationship also supports a causal relationship. However, more than half of subjects had poor quality spirometry and were excluded from the analysis of COPD, so that selection bias cannot be ruled out. Passive smoking was defined by self-report, so exposure misclassification cannot be excluded. Self-reported exposure, although imperfect, is the only available exposure method for studies of COPD causation because COPD develops over many years and no existing biomarker can measure distant passive smoke exposure. In summary, this article adds to the literature that passive smoke exposure may cause COPD, but more research is needed before final conclusions can be formulated.
Occupational exposures, alone or in combination with smoking, could be important for the development of COPD. A case-referent analysis was performed within the FLOW (Function, Living, Outcomes, and Work) Study of COPD, a prospective cohort study of 1,202 patients with COPD and 302 matched control subjects without COPD recruited from an integrated health care delivery system (2). Occupational exposure was measured in two ways (1): reported exposure to vapors, gas, dusts, or fumes (VGDF) during the longest-held job; and (2) a job exposure matrix (JEM) that characterized the respondent's longest-held job as low, intermediate, or high probability of exposure to materials associated with chronic airway disease. Multivariable logistic regression controlled for age, sex, race, and smoking history. Reported VGDF exposure during the longest held job was associated with double the odds of COPD (OR, 2.13; 95% CI, 1.55–2.93); the population attributable fraction (PAF) was 31%. The high JEM category was also related to a greater risk of COPD (OR, 2.33; 95% CI, 1.45–3.72); the PAF was 14%. The combination of cigarette smoking and occupational exposure greatly increased the risk of COPD (OR, 14 for both smoking and VGDF; 6.7 for smoking only; and 2.0 for VGDF only). In conclusion, both smoking and occupational exposure are strong risk factors for developing COPD; elimination of one, but not the other, will not be fully effective in preventing the burden of COPD.
Since the publication of the American Thoracic Society Statement, "Occupational Contribution to the Burden of Airway Disease," this article adds important new information linking occupational exposures to the development of COPD (3). Other recent papers also confirm the link between workplace exposures and the risk of COPD (4–6). The issue was recently examined from a global perspective using data from the Burden of Obstructive Lung Disease (BOLD) study, the Latin American Project for the Investigation of Obstructive Lung Disease (PLATINO), and the European Community Respiratory Health Survey follow-up (6). An ecological analysis evaluated the sex-specific group-level prevalence of COPD (GOLD Stage II or greater) at each site against the prevalence of occupational exposure and ever-smoking. For each 10% increase in occupational exposure prevalence, the prevalence of COPD increased 0.8%. By comparison, for every 10% increase in the proportion of the ever-smoking population, the prevalence of COPD increased by 1.3%. Given the observed median population COPD prevalence of 3.4%, the model predicted that a 20% relative reduction in the disease burden (i.e., to a COPD prevalence of 2.7%) could be achieved by a 5.4% reduction in overall smoking prevalence or an 8.8% reduction in the prevalence of occupational exposures. On a global level, these findings indicate that both dusty trades and smoking are critical contributors to COPD.
Clinical Trials: COPD Progression and Long-term Outcomes
Previous short-term clinical trials lasting 6 weeks to 1 year have demonstrated the benefit of tiotropium for the treatment of COPD. The UPLIFT Study randomized 5,993 patients with moderate-to-severe COPD to tiotropium versus placebo and evaluated longer-term outcomes up to 4 years (7). In addition to the study intervention, all other respiratory medications were allowed except for inhaled anticholinergic drugs. The trial was designed to test the hypothesis that tiotropium reduces the progression of COPD defined as reduction of the rate of decline of mean FEV1 after Day 30. The study showed that tiotropium increased baseline FEV1 by 47 to 65 ml (post-bronchodilation), but did not slow the rate of decline after Day 30 (i.e., no impact on disease progression). Tiotropium also improved secondary study outcomes including health-related quality of life (St. George's Respiratory Questionnaire [SGRQ]), COPD exacerbations, hospitalizations, and respiratory failure. There was a suggestion of improved mortality in the tiotropium-treated group. Although tiotropium did not attenuate the progression of COPD, it conferred substantive clinical benefit that was maintained during the 4 years of the trial. In sum, tiotropium improved long-term health outcomes in COPD.
Smoking cessation has been the only intervention that slows the rate of decline of FEV1 among patients with COPD. An analysis of the TORCH study evaluated the impact of inhaled pharmacotherapy on the rate of decline of FEV1 (8). The TORCH study was a randomized controlled trial with four treatment arms in patients with moderate-to-severe COPD: SFC (salmeterol and fluticasone propionate), SAL (salmeterol), FP (fluticasone propionate), and placebo. The parent trial evaluated mortality as the primary endpoint. In this secondary analysis, the rate of lung function decline was slowest in patients treated with SFC (–39 ml/yr), intermediate in SAL (–42 ml/yr) and FP (–42 ml/yr), and fastest in placebo (–55 ml/yr). A substantive proportion of subjects withdrew from the study and could not contribute to this analysis (13%); only 64% of patients completed all six spirometry sessions. Based on these results, pharmacotherapy slowed the rate of lung function decline in COPD, and SFC had the greatest benefit. An important limitation was the substantive losses to follow-up, which could have biased the results (likely the observed results underestimate the true benefit).
Clinical Trials of Mucolytic Therapy: A Novel Approach for the Treatment of COPD?
This study is a randomized controlled trial of carbocisteine (500 mg orally three times per day) versus placebo conducted among 709 Chinese patients with moderate COPD (most had GOLD stage II-III) (9). The primary endpoint was exacerbation rate during 1 year of follow-up, defined as increased respiratory symptoms (after the Anthonisen definition). Secondary outcomes were health-related quality of life, which was measured by the SGRQ, and FEV1. Most participants were not treated with other COPD medications (< 20% were receiving inhaled β agonists, anticholinergic agents, or inhaled corticosteroids; < 30% were receiving methylxanthines). The rate of withdrawal from the trial was low (13%). In this trial, carbocisteine reduced the rate of exacerbations by 25% compared with placebo (from 1.35 to 1.01 exacerbations per year). Treatment with carbocisteine also improved health-related quality of life (SGRQ overall score and symptom subscale score). There was no impact of treatment on disease progression, as defined by FEV1 decline. Because most patients were not treated with other standard COPD medications, the value of adding carbocisteine to other inhaled medications is not known. The medication is also not approved by the U.S. FDA for the treatment of COPD.
Summary: Reducing the Burden of COPD
There are two complementary approaches to reduce the overall burden of COPD. The first approach is to elucidate the risk factors for disease onset and prevent exposure to these factors. Based on the available data, preventing cigarette smoking and occupational exposures will reduce the prevalence of COPD. Passive smoking is a potential risk factor for COPD onset, but more data are needed. The second approach is to effectively treat COPD with medications that improve long-term outcomes. Smoking cessation is critical. Beyond it, the use of tiotropium and salmeterol-fluticasone improve long-term COPD health outcomes. "Triple therapy," with the combination of tiotropium, salmeterol, and fluticasone, is promising for patients with severe disease or frequent exacerbations, but more data are required before this can be widely recommended (10).
TREATMENT OF TOBACCO DEPENDENCE
David P. L. Sachs
Stanford University Medical Center
Stanford, California
Improving Tobacco-dependence Treatment
The treatment of nicotine withdrawal symptoms is a cornerstone of successful smoking cessation. The timing of when to begin nicotine patch therapy, which is the most commonly used nicotine replacement strategy, has been a subject for debate. This meta-analysis of four randomized controlled clinical trials (total n = 755) showed that initiation of the nicotine patch 2 to 4 weeks before the patient stops smoking improved outcomes compared with the traditional approach of starting the patch on the target stop date (11). The pooled odds ratio for continuous abstinence was 2.2 at 6 months, indicating an approximate doubling of the success of treatment. Although the treatment duration was short, ranging from 4 to 12 weeks, pretreatment with the nicotine patch increased the quit rate at both 6 weeks (OR, 2.0) and 6 months (OR, 2.2). Importantly, pretreatment with the nicotine patch 2 to 4 weeks before the target quit date was safe, with no difference in adverse events. The meta-analysis clearly supports the clinical value and safety of beginning nicotine patch therapy 2 weeks before the patient stops smoking.
While clinical experience suggests that treatment with adequate doses of medications for tobacco dependence, such as nicotine replacement therapy or other pharmacotherapy, are necessary to avoid symptoms of withdrawal and prevent relapse, research studies have not clearly shown that nicotine withdrawal symptoms precede and cause relapse. A small cohort study of 137 subjects who stopped smoking without the aid of pharmacotherapy evaluated the impact of nicotine withdrawal symptoms on the risk of relapse (12). Subjects rated nicotine withdrawal symptoms on a simple scale (ranging from none [0] to severe [4]) that assessed symptoms of cigarette craving, nicotine withdrawal symptoms, and smoking urges. Among these subjects who relapsed (n = 111), withdrawal symptoms increased sharply in the 2 to 3 days preceding smoking relapse. Conversely, withdrawal symptoms remained persistently low in the minority of subjects who did not relapse (n = 26). The study clearly documented that an increase in nicotine withdrawal symptoms preceded relapse.
This study confirms that failure to suppress nicotine withdrawal symptoms will markedly increase the risk of relapse and return to smoking. Because nicotine withdrawal symptoms sharply increase only 2 to 3 days before relapse, it is important to quantitatively monitor the severity of nicotine withdrawal symptoms at each office visit and instruct patients to call their physician's office promptly if they experience increased symptoms. Prompt recognition of nicotine withdrawal symptoms, especially craving for cigarettes, will allow for a change in treatment plan to prevent relapse.
Reducing Asthma Severity from Tobacco Use
Secondhand smoke (SHS) exposure is a well-established cause of childhood asthma. Among children who have pre-existing asthma, SHS exposure increases asthma severity and poor asthma health outcomes. Consequently, successful treatment of the parents' tobacco dependence is critical for effective clinical management of childhood asthma. This study evaluated smoking parents of children with asthma to elucidate parental beliefs about SHS exposure and their readiness to change smoking behavior among the primary caregivers of 519 smoke-exposed children aged 3 to 12 years with asthma (13). Based on the survey data, the child's home was the most common site of exposure (85%), followed by a daycare or child-care setting (19%), and a grandparent's house (9%). The urine cotinine to creatinine ratio (CCR) was used as a biomarker of SHS exposure during the previous 1 to 2 days. The CCR was lowest if neither the primary caregiver nor day-care provider smoked (mean CCR, 14.0), intermediate if either smoked (mean CCR, 22.2 and mean CCR, 26.3, respectively), and highest if both smoked (mean CCR, 39.6). Interestingly, parental rating of the level of their child's exposure was highly inaccurate, correlating only 0.11 with the CCR. Most parents also reported that SHS exposure had no significant effect on their child's asthma. Despite this perception, the majority of parents had recently made efforts to reduce their child's exposure including smoking cessation, keeping the child out of places in which smoking occurs, and creating smoke-free homes (or areas within the home).
There are several key messages from this study. The home is a key source of SHS exposure, but daycare centers and other people's homes are also important exposure sources. Despite the scientific evidence, parents are largely unaware of the deleterious effect of SHS on childhood asthma. It is promising that parents usually are receptive to reducing their children's SHS exposure. Consequently, treatment of parental tobacco dependence should be offered to all smoking parents of asthmatic children, both for their own health and achievement of better asthma control for their children.
Surprisingly, adults with asthma have the same smoking prevalence as persons without asthma (14). An important question is whether cigarette smoking attenuates the effectiveness of asthma medications. A randomized controlled trial of 44 nonsmokers and 39 light smokers with asthma evaluated the impact of an 8-week treatment with inhaled beclomethasone HFA or oral montelukast on FEV1. Montelukast had no effect on FEV1 in either group of subjects. Beclomethasone therapy improved FEV1 by an average of 170 ml in nonsmoking individuals with asthma, but failed to benefit smoking individuals with asthma. Based on these data, the authors concluded that smoking attenuates the clinical response to inhaled corticosteroids. A corollary is that treatment of tobacco dependence should be offered to all smoking adults with asthma. The time course for return of steroid responsiveness is unknown.
Depression and Suicidality in Cigarette Users
Cigarette smokers have a much higher prevalence of major depressive disorders and suicidality. A population-based study estimated the relationship between nicotine dependence, by both cigarette smoking and smokeless tobacco use, and mental disorders in the United States (15). Face-to-face surveys (n = 43 093) were conducted in the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions. DSM-IV criteria were used to define nicotine use, nicotine dependence, and mental disorders. Cigarette smoking with nicotine dependence was associated with all mental disorders examined compared with nonsmokers: any mood disorder, major depression, bipolar disorder, mania/hypomania, any anxiety disorder, phobia, and panic attack. Nicotine-dependent smokeless tobacco users had a higher prevalence of any anxiety disorder and phobia. In the absence of nicotine dependence, cigarette smoking was associated with panic disorder, whereas smokeless tobacco use was not associated with any mental disorder. Consequently, health care providers who treat tobacco dependence must be alert to the high prevalence of mental disorders among cigarette smokers. They should also be aware of the different patterns of mental disorders among cigarette smokers and smokeless tobacco users among nicotine-dependent patients.
LUNG CANCER
Douglas Arenberg
University of Michigan
Ann Arbor, Michigan
Assessment of Lung Cancer Risk
Three publications were reviewed that used genome-wide association studies (GWAS) of more than 300,000 single-nucleotide polymorphisms (SNPs) in a total of 9,400 patients with lung cancer and more than 30,000 control subjects (16–18). Together, these studies identified a locus on chromosome 15q24-25 that was associated with susceptibility for lung cancer. This locus of approximately 88 kb contains several genes that comprise subunits of the nicotinic acetylcholine receptor CHRNA3, CHRNA5, and CHRNB4. The risk of lung cancer increased with the number of copies of these alleles (OR 1.3 for one copy and OR 1.8 for two copies). These associations persisted after statistical control for smoking duration, age, sex, and country of origin. Moreover, these alleles were also related to nicotine dependence and smoking quantity, which was defined as average number of cigarettes currently smoked currently or during the prior period of smoking (for ex-smokers). Interestingly, candidate genes in this locus are involved in both nicotine's effects on the central nervous system and its effects on alveolar epithelium, pulmonary neuroendocrine cells, and lung cancer cell lines.
Prediction of lung cancer risk would have important ramifications for screening and early detection of lung cancer. Cassidy and coworkers used data from 579 individuals with lung cancer and from 1,157 age- and sex-matched control subjects from the Liverpool Lung Project (LLP) to calculate risk estimates of developing lung cancer during a 5-year follow-up period (19). Multivariable conditional logistic regression analysis was used to develop a predictive model for lung cancer. The final predictive model included smoking duration, history of pneumonia, occupational exposure to asbestos (1 yr of working life or greater), prior diagnosis of cancer, and family history of lung cancer (first-degree relatives). The area under the receiver operating characteristic (ROC) curve was 0.70, which indicated modest predictive value. Based on the model, the authors estimated risk estimates for different combinations of factors. For example, a 77-year-old male nonsmoker, with a family history of lung cancer and occupational exposure to asbestos, has an absolute risk of 3.17% (95% CI, 1.67–5.95). Defining a 2.5% risk of lung cancer as the trigger to increase surveillance yielded a sensitivity of 0.62 and specificity of 0.70, whereas a 6.0% cutoff yielded a sensitivity of 0.34 and specificity of 0.90. In sum, the predictive model has potential to increase the risk stratification for lung cancer, but the overall accuracy of the model was only modest and limits its practical utility. Further research should build on these findings and include more detailed information about occupational exposures, environmental exposures, and clinical history.
Individualized Therapy
Cancer staging has been the most common way to individualize therapy. Adjuvant chemotherapy for non–small cell lung cancer (NSCLC) improves survival for patients with stage II and IIIA NSCLC who undergo surgical resection. The efficacy of adjuvant chemotherapy, however, for treatment of IB disease has been unclear. In this article by Strauss and colleagues, the results of Cancer and Leukemia Group B (CALGB) 9633, which was a randomized controlled trial of paclixatel and carboplatin (4 cycles) administered within 4 to 8 weeks of surgical resection of confirmed T2N0 NSCLC (lobectomy or pneumonectomy) conducted among 344 patients followed for a median of 74 months, were reported (20). There was no clear impact of adjuvant chemotherapy on survival (hazard ratio, 0.83; 95% CI, 0.64–1.08; P = 0.12). There was a suggestion of survival benefit among patients with large tumors (
4 cm diameter) in post hoc analysis. The study was underpowered and did not rule out a small or modest treatment benefit. Importantly, changes in the "T" definitions for the staging system will be implemented soon, which will "upstage" some T2 tumors to T3 (and will increase them from stage I to stage II or greater).
The current trend is to individualize cancer therapy based on molecular phenotypes, moving the field beyond clinical cancer staging based on manifest features of the disease. Brock and coworkers evaluated the association between gene methylation and recurrence of the lung cancer (21). Cases included were 51 patients who had stage I NSCLC and who underwent curative resection but developed a recurrence within 40 months after resection, and control subjects with stage I NSCLC who underwent curative resection but did not develop a recurrence. The investigators evaluated the impact of methylation of seven genes in the tumor and lymph nodes on the risk of tumor recurrence. The frequency of promoter methylation was greater in cases compared with control subjects for four genes: the cyclin-dependent kinase inhibitor 2A gene p16, the H-cadherin gene CDH13, the Ras association domain family 1 gene RASSF1A, and the adenomatous polyposis coli gene APC. Of these genes, methylation of the promoter regions of p16 and CDH13 was most strongly associated with an increased risk of recurrent cancer. Based on these results, methylation of the promoter region of four genes identifies cells with potential for metastatic spread and can be used as predictors of early recurrence in resected NSCLC. In the future, this technique may be used as a biomarker to identify patients who may benefit most from adjuvant chemotherapy.
LUNG TRANSPLANTATION
Jonathan B. Orens
Johns Hopkins University
Baltimore, Maryland
Lung Transplantation Activity and Outcomes
The International Society for Heart and Lung Transplantation (ISHLT) registry includes data on all heart and lung transplants performed since 1984. The twenty-fifth ISHLT report by Christie and colleagues was an important contribution to the lung transplant literature this year (22). The registry includes 25,950 lung transplants performed through June 2007. One hundred forty-seven centers reported transplants in 2007, and a total of 2,168 transplants were performed in 2006. The volume of lung transplantation varies markedly among centers, with slightly more than half of centers (53%) performing less than 10 transplants per year and 16% of centers performing 30 or more transplants per year. During the past decade, most transplantation is performed for COPD (36%), followed by idiopathic pulmonary fibrosis (20%), cystic fibrosis (16%), and 
1-antitrypsin deficiency (8%). The overall survival rate was 88% at 3 months, 78% at 1 year, 51% at 5 years, and 28% at 10 years. Survival remains poorer for older patients, diagnosis of idiopathic pulmonary fibrosis or idiopathic pulmonary arterial hypertension, and for those in receipt of a single lung transplant (versus double lung transplant). Early death (during the first 30 d) is due primarily to graft failure, non-CMV infections, cardiovascular complications, and technical problems. Later deaths (after the first year) are mostly caused by bronchiolitis obliterans syndrome and non-CMV infections.
Candidate Selection
The survival benefit of lung transplantation for COPD has been a topic of extended debate because published data have been inconsistent. This study used data obtained from the United Network for Organ Sharing database on 8,182 patients to estimate the survival benefit of lung transplantation for COPD (23). Two multivariable models were developed to describe survival on the waiting list and survival after lung transplantation. The models were used to simulate the survival time of patient cohorts with different sets of prognostic factors and to compare the expected survival with and without transplantation. The main outcome measure was defined as difference between median survival with transplantation and that without transplantation. Based on the simulation, half of patients undergoing single lung transplantation and nearly two-thirds of patients having double lung transplantation had improved survival. The survival benefit was greater for double lung transplantation than for single lung transplantation (mean difference, 307 d). After double lung transplantation, 45% of patients would gain 1 year or more, 26% would lose at least 1 year, and 29% would have less than 1 year change in expected survival. Major determinants of the survival effect of transplantation were systolic pulmonary artery pressure, FEV1, body mass index, exercise capacity, functional status, and the need for continuous mechanical ventilation or oxygen. As an illustrative example, 79% of patients with an FEV1 less than 16% predicted would gain at least 1 year of life after double lung transplantation, compared with only 11% of those with an FEV1 more than 25%. The authors noted that external validation of their models is required before translating these results into clinical practice.
Risk Factors for Chronic Rejection
Brochiolitis obliterans syndrome is a major cause of late mortality after lung transplantation. Recurrent episodes of acute rejection of the pulmonary allograft are a risk factor for bronchiolitis obliterans syndrome. Consequently, elucidating the factors responsible for bronchiolitis obliterans has important clinical implications. Glanville and coworkers evaluated a retrospective cohort of 341 patients who underwent lung transplantation and survived at least 90 days (24). Transbronchial lung biospsy was used for surveillance and clinical indication. They were graded on the basis of the ISHLT Lung Rejection Study Group recommendations for grade A (acute vascular rejection) and grade B (lymphocytic bronchiolitis). Of the 1,770 biopsies, the B grades were B0 (normal) in 501 patients, B1 (minimal) in 762 patients, B2 (mild) in 176 patients, and B3 (moderate) in 70 patients, and B4 (severe) in 75 patients. In multivariable Cox proportional hazards analysis, the highest B grade was associated with a greater risk of subsequent development of bronchiolitis obliterans syndrome (relative risk [RR], 1.62; 95% CI, 1.31–2.00). Both highest B grade and bronchiolitis obliterans syndrome were risk factors for death, whereas acute vascular rejection was not. The article concluded that severe lymphocytic bronchiolities is associated with an increased risk of bronchiolitis obliterans syndrome and death after lung transplantation, independent of acute vascular rejection. Limitations of the study included its retrospective design, single-center experience, and subjective nature of classifying transbronchial lung biopsies.
Treatment for Chronic Rejection
Gottlieb and colleagues evaluated the impact of treatment with azithromycin on patients with bronchiolitis obliterans syndrome. In an uncontrolled, unblended, single-center study, 81 adult heart and lung transplant recipients with bronchiolitis obliterans syndrome were treated with azithromycin 250 mg orally three times per week (25). The investigators found that nearly one-third of treated patients (30%) manifested improvement of FEV1 at 6-month follow-up. The remainder of the cohort remained stable (46%) or deteriorated (46%). Most patients who responded did so within 3 months of instituting therapy. Bronchoalveolar lavage fluid revealing neutrophilia appeared to predict a positive response to therapy. Because this study was uncontrolled, definitive conclusions about the efficacy of azithromycin cannot be established. A multicenter, randomized, placebo-controlled clinical trial is required to further evaluate this promising therapy.
Transplantation for Cystic Fibrosis
Infection with Burkholderia cepacia complex has been associated with increased mortality in cystic fibrosis (CF) treated with lung transplantation. Alexander and coworkers performed a retrospective cohort study evaluating the impact of B. cepacia complex infection on mortality and re-infection after lung transplantation (26). In the cohort of 75 patients with CF, 16 were infected with B. cepacia complex during the year before transplantation. Of the subcohort with infection, 88% had B. cepacia complex recovered after transplantation; in all cases, they retained the same pretransplant strain. Survival (1 mo, 1 yr, 3 yr, and 5 yr) was 97%, 92%, 76%, and 63% for noninfected patients; 89%, 89%, 67%, and 56% for patients infected with B. cepacia complex species other than B. cenocepacia; and 71%, 29%, 29%, and 29% for patients with B. cenocepacia.
Pretransplantation infection with B. cenocepacia was associated with a sixfold increased risk of death after transplantation compared with other B. cepacia complex organisms and an eightfold risk compared with those without infection. In summary, infection with B. cepacia complex species does not substantively effect 5-year survival, whereas infection with B. cenocepacia portends a poor prognosis and diminished survival.
Innovations in Lung Transplantation
The first case of a successful lung transplantation performed intentionally with an ABO-incompatible donor was recently reported by Struber and colleagues (27) This procedure is not typically performed because of the risk of hyper-acute rejection. The patient was a 21-year-old female with cystic fibrosis who developed refractory ventilatory failure requiring arterio-venous interventional lung assist for extracorporeal carbon dioxide removal. Because of the urgency of the clinical situation, ABO-incompatible transplantation was attempted. She was blood type O and the donor was type AB. Transplantation was successfully performed using a preoperative, perioperative, and postoperative antibody depletion protocol that included plasmapharesis, intravenous immunoglobulin (IVIG), rituximab, and immunoadsorption. At the time of this report, the patient was alive (9 mo after transplantation). Future studies will be necessary to test the safety and efficacy of this procedure.
FOOTNOTES
This is the third in a series of four executive summaries of the Clinical Year in Review sessions presented at the American Thoracic Society International Conference in May, 2009. The main topics of each talk have been abstracted by the session chair based on the annotated bibliography provided by each presenter.
Conflict of Interest Statement: M.D.E. served as a consultant for Genentech and served as an expert witness for DLA Piper $5,001–$10,000. He received grant support from Roche $50,001–$100,000 and from the NIH $100,001 or more.
(Received in original form June 9, 2009; accepted in final form June 16, 2009)
REFERENCES
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