Author: Elias J. Anaissie

Authors: Robert P. Baughman; Ganesh Raghu

Authors: Nicole Le Moual; Francine Kauffmann; Ellen A. Eisen; Susan M. Kennedy

Despite the increasing attention to the relationship between asthma and work exposures, occupational asthma remains underrecognized and its population burden underestimated. This may be due, in part, to the fact that traditional approaches to studying asthma in populations cannot adequately take into account the healthy worker effect (HWE). The HWE is the potential bias caused by the phenomenon that sicker individuals may choose work environments in which exposures are low; they may be excluded from being hired; or once hired, they may seek transfer to less exposed jobs or leave work. This article demonstrates that population- and workplace-based asthma studies are particularly subject to HWE bias, which leads to underestimates of relative risks. Our objective is to describe the HWE as it relates to asthma research, and to discuss the significance of taking HWE bias into account in designing and interpreting asthma studies. We also discuss the importance of understanding HWE bias for public health practitioners and for clinicians. Finally, we emphasize the timeliness of this review in light of the many longitudinal “child to young adult” asthma cohort studies currently underway. These prospective studies will soon provide an ideal opportunity to examine the impact of early workplace environments on asthma in young adults. We urge occupational and childhood asthma epidemiologists collaborate to ensure that this opportunity is not lost.

Authors: Jane A. Hoppin; David M. Umbach; Stephanie J. London; Paul K. Henneberger; Greg J. Kullman; Michael C. R. Alavanja; Dale P. Sandler

Rationale: Risk factors for asthma among farm women are understudied.

Objectives: We evaluated pesticide and other occupational exposures as risk factors for adult-onset asthma.

Methods: Studying 25,814 farm women in the Agricultural Health Study, we used self-reported history of doctor-diagnosed asthma with or without eczema and/or hay fever to create two case groups: patients with atopic asthma and those with nonatopic asthma. We assessed disease-exposure associations with polytomous logistic regression.

Measurements and Main Results: At enrollment (1993–1997), 702 women (2.7%) reported a doctor's diagnosis of asthma after age 19 years (282 atopic, 420 nonatopic). Growing up on a farm (61% of all farm women) was protective for atopic asthma (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.43–0.70) and, to a lesser extent, for nonatopic asthma (OR, 0.83; 95%CI, 0.68–1.02; P value for difference = 0.008). Pesticide use was almost exclusively associated with atopic asthma. Any use of pesticides on the farm was associated only with atopic asthma (OR, 1.46; 95% CI, 1.14–1.87). This association with pesticides was strongest among women who had grown up on a farm. Women who grew up on farms and did not apply pesticides had the lowest overall risk of atopic asthma (OR, 0.41; 95% CI, 0.27–0.62) compared with women who neither grew up on farms nor applied pesticides. A total of 7 of 16 insecticides, 2 of 11 herbicides, and 1 of 4 fungicides were significantly associated with atopic asthma; only permethrin use on crops was associated with nonatopic asthma.

Conclusions: These findings suggest that pesticides may contribute to atopic asthma, but not nonatopic asthma, among farm women.

Authors: Jadwiga A. Wedzicha; Peter M. A. Calverley; Terence A. Seemungal; Gerry Hagan; Zainab Ansari; Robert A. Stockley

Rationale: Exacerbations are key drivers of morbidity and mortality in chronic obstructive pulmonary disease (COPD).

Objectives: We compared the relative efficacy of the long-acting inhaled bronchodilator/antiinflammatory combination (salmeterol/fluticasone propionate) 50/500 μg twice daily and the long-acting bronchodilator (tiotropium) 18 μg once daily in preventing exacerbations and related outcomes in severe and very severe COPD.

Methods: A total of 1,323 patients (mean age, 64 yr, post-bronchodilator FEV1, 39% predicted) were randomized in this 2-year, double-blind, double-dummy parallel study.

Measurements and Main Results: Primary endpoint was health care utilization exacerbation rate. Other endpoints included health status measured by St. George's Respiratory Questionnaire (SGRQ), mortality, adverse events, and study withdrawal. Probability of withdrawing from the study was 29% greater with tiotropium than salmeterol/fluticasone propionate (P = 0.005). The modeled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group (rate ratio, 0.967; 95% confidence interval [CI], 0.836–1.119]; P = 0.656). The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate versus tiotropium (difference 2.1 units; 95% CI, 0.1–4.0; P = 0.038). Mortality was significantly lower in the salmeterol/fluticasone propionate group; 21 (3%) of patients in this group died compared with 38 (6%) in the tiotropium group (P = 0.032). More pneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium (P = 0.008).

Conclusions: We found no difference in exacerbation rate between salmeterol/fluticasone propionate and tiotropium. More patients failed to complete the study while receiving tiotropium. A small statistically significant beneficial effect was found on health status, with an unexpected finding of lower deaths in salmeterol/fluticasone propionate–treated patients.

Clinical trial registered with www.clinicaltrials.gov (NCT 00361959).

Authors: Wouter Meersseman; Katrien Lagrou; Johan Maertens; Alexander Wilmer; Greet Hermans; Steven Vanderschueren; Isabel Spriet; Eric Verbeken; Eric Van Wijngaerden

Rationale: Invasive aspergillosis (IA) is an important cause of mortality in patients with hematologic malignancies. However, IA appears to be gaining a foothold in the intensive care unit (ICU) in patients without classical risk factors. A recent study described 89 cases of IA in patients in a medical ICU without leukemia or cancer. The diagnosis of IA remains difficult and is often established too late. Galactomannan (GM) is an exo-antigen released from Aspergillus hyphae while they invade host tissue.

Objectives: This prospective single-center study was conducted to investigate the role of GM in bronchoalveolar lavage (BAL) fluid as a tool for early diagnosis of IA in the ICU.

Methods: All patients with risk factors identified in our earlier study were evaluated. BAL for culture and GM detection, serum GM levels, and computed tomography scan were obtained for all included patients with signs of pneumonia. Patients were classified as having proven, probable, or possible IA.

Measurements and Main Results: A total of 110 patients out of 1,109 admissions were eligible. There were 26 proven IA cases. Using a cutoff index of 0.5, the sensitivity and specificity of GM detection in BAL fluid was 88 and 87%, respectively. The sensitivity of serum GM was only 42%. In 11 of 26 proven cases, BAL culture and serum GM remained negative, whereas GM in BAL was positive.

Conclusions: IA is common in immunocompromised, critically ill patients. GM detection in BAL fluid seems to be useful in establishing or excluding the diagnosis of IA in the ICU.

Authors: Stephen M. Bianchi; Lynne R. Prince; Kathleen McPhillips; Lucy Allen; Helen M. Marriott; Graham W. Taylor; Paul G. Hellewell; Ian Sabroe; David H. Dockrell; Peter W. Henson; Moira K. B. Whyte

Rationale: Cystic fibrosis lung disease is characterized by accumulation of apoptotic neutrophils, indicating impaired clearance of dying cells. Pseudomonas aeruginosa, the principal microbial pathogen in cystic fibrosis, manipulates apoptosis induction via production of toxic metabolites. Whether these metabolites, particularly pyocyanin, can also modulate apoptotic cell engulfment is unknown.

Objectives: To assess the effects of pyocyanin on apoptotic cell engulfment by macrophages in vitro and in vivo and to investigate potential mechanisms of the observed effects.

Methods: Human monocyte–derived macrophages were treated with pyocyanin before challenge with apoptotic neutrophils, apoptotic Jurkat cells, or latex beads, and phagocytosis was assessed by light microscopy and flow cytometry. Effects of pyocyanin production on apoptotic cell clearance in vivo were assessed in a murine model, comparing infection by wild-type or pyocyanin-deficient P. aeruginosa. Oxidant production was investigated using fluorescent probes and pharmacologic inhibition and Rho GTPase signaling by immunoblotting and inhibitor studies.

Measurements and Main Results: Pyocyanin treatment impaired macrophage engulfment of apoptotic cells in vitro, without inducing significant macrophage apoptosis, whereas latex bead uptake was preserved. Macrophage ingestion of apoptotic cells was reduced and late apoptotic/necrotic cells were increased in mice infected with pyocyanin-producing P. aeruginosa compared with the pyocyanin-deficient strain. Inhibition of apoptotic cell uptake involved intracellular generation of reactive oxygen species (ROS) and effects on Rho GTPase signaling. Antioxidants or blockade of Rho signaling substantially restored apoptotic cell engulfment.

Conclusions: These studies demonstrate that P. aeruginosa can manipulate the inflammatory microenvironment through inhibition of apoptotic cell engulfment, and suggest potential strategies to limit pulmonary inflammation in cystic fibrosis.

Authors: Lourdes Barrera; Felipe Mendoza; Joaquín Zuñiga; Andrea Estrada; Ana C. Zamora; Emma I. Melendro; Remedios Ramírez; Annie Pardo; Moisés Selman

Rationale: Hypersensitivity pneumonitis (HP) exhibits a diverse outcome. Patients with acute/subacute HP usually improve, whereas patients with chronic disease often progress to fibrosis. However, the mechanisms underlying this difference are unknown.

Objectives: To examine the T-cell profile from patients with subacute HP and chronic HP.

Methods: T cells were obtained by bronchoalveolar lavage from 25 patients with subacute HP, 30 patients with chronic HP, and 8 control subjects. T-cell phenotype and functional profile were evaluated by flow cytometry, cytometric bead array, and immunohistochemistry.

Measurements and Main Results: Patients with chronic HP showed higher CD4⁺:CD8⁺ ratio (median, 3.05; range, 0.3–15; subacute HP: median, 1.3; range, 0.1–10; control: median, 1.3; range, 0.7–2.0; P < 0.01), and a decrease of γδT cells (median, 2.0; range, 0.5–3.4; subacute HP: median, 10; range, 4.8–17; control: median, 15; range, 5–19; P < 0.01). Patients with chronic HP exhibited an increase in the terminally differentiated memory CD4⁺ and CD8⁺ T-cell subsets compared with patients with subacute HP (P < 0.05). However, memory cells from chronic HP showed lower IFN-γ production and decreased cytotoxic activity by CD8⁺ T lymphocytes. Chronic HP displayed a Th2-like phenotype with increased CXCR4 expression (median, 6%; range, 1.7–36, vs. control subjects: median, 0.7%; range, 0.2–1.4; and subacute HP: median, 2.2%; range, 0.1–5.3; P < 0.01), and decreased CXCR3 expression (median, 4.3%; range, 1.4–25%, vs. subacute HP: median, 37%; range, 4.9–78%; P < 0.01). Likewise, supernatants from antigen-specific–stimulated cells from chronic HP produced higher levels of IL-4 (80 ± 63 pg/ml vs. 25 ± 7 pg/ml; P < 0.01), and lower levels of IFN-γ (3,818 ± 1671 pg/ml vs. 100 ± 61 pg/ml; P < 0.01) compared with subacute HP.

Conclusions: Our findings indicate that patients with chronic HP lose effector T-cell function and exhibit skewing toward Th2 activity, which may be implicated in the fibrotic response that characterizes this clinical form.

Authors: Gerald S. Horan; Susan Wood; Victor Ona; Dan Jun Li; Matvey E. Lukashev; Paul H. Weinreb; Kenneth J. Simon; Kyungmin Hahm; Normand E. Allaire; Nicola J. Rinaldi; Jaya Goyal; Carol A. Feghali-Bostwick; Eric L. Matteson; Carl O'Hara; Robert Lafyatis; Gerald S. Davis; Xiaozhu Huang; Dean Sheppard; Shelia M. Violette

Rationale: Transforming growth factor (TGF)-β has a central role in driving many of the pathological processes that characterize pulmonary fibrosis. Inhibition of the integrin αvβ6, a key activator of TGF-β in lung, is an attractive therapeutic strategy, as it may be possible to inhibit TGF-β at sites of αvβ6 up-regulation without affecting other homeostatic roles of TGF-β.

Objectives: To analyze the expression of αvβ6 in human pulmonary fibrosis, and to functionally test the efficacy of therapeutic inhibition of αvβ6-mediated TGF-β activation in murine bleomycin–induced pulmonary fibrosis.

Methods: Lung biopsies from patients with a diagnosis of systemic sclerosis or idiopathic pulmonary fibrosis were stained for αvβ6 expression. A range of concentrations of a monoclonal antibody that blocks αvβ6-mediated TGF-β activation was evaluated in murine bleomycin–induced lung fibrosis.

Measurements and Main Results: αvβ6 is overexpressed in human lung fibrosis within pneumocytes lining the alveolar ducts and alveoli. In the bleomycin model, αvβ6 antibody was effective in blocking pulmonary fibrosis. At high doses, there was increased expression of markers of inflammation and macrophage activation, consistent with the effects of TGF-β inhibition in the lung. Low doses of antibody attenuated collagen expression without increasing alveolar inflammatory cell populations or macrophage activation markers.

Conclusions: Partial inhibition of TGF-β using αvβ6 integrin antibodies is effective in blocking murine pulmonary fibrosis without exacerbating inflammation. In addition, the elevated expression of αvβ6, an activator of the fibrogenic cytokine, TGF-β, in human pulmonary fibrosis suggests that αvβ6 monoclonal antibodies could represent a promising new therapeutic strategy for treating pulmonary fibrosis.

Authors: Steven K. Huang; Scott H. Wettlaufer; Cory M. Hogaboam; Kevin R. Flaherty; Fernando J. Martinez; Jeffrey L. Myers; Thomas V. Colby; William D. Travis; Galen B. Toews; Marc Peters-Golden

Rationale: Prostaglandin (PG) E2, a cyclooxygenase-derived lipid mediator, is a potent down-regulator of fibroblast activation in normal lung fibroblasts. Although fibroblasts from patients with idiopathic pulmonary fibrosis are known to exhibit a defect in PGE2 synthesis, there is little information about their responsiveness to this lipid mediator.

Objectives: To compare responses to PGE2 in normal, usual interstitial pneumonia (UIP), and other diffuse parenchymal lung disease (DPLD) fibroblasts.

Methods: Fibroblasts were grown in vitro from well characterized control (n = 7), UIP (n = 17), or other DPLD (n = 13) lung tissue. The effects of PGE2 on fibroblast proliferation and collagen expression were determined.

Measurements and Main Results: Only 3 of 12 UIP fibroblast lines exhibited PGE2-mediated inhibition of both collagen synthesis and cell proliferation, as opposed to 6 of 6 nonfibrotic control cell lines. The degree of PGE2 resistance in DPLD fibroblasts was quite variable, with UIP cells exhibiting the greatest degree of resistance to PGE2, whereas other DPLD fibroblasts manifested a degree of resistance intermediate to control and UIP. The resistance to suppression of collagen expression correlated with worse lung function. Molecular mechanisms for resistance included altered E prostanoid receptor profiles and diminished expression of the downstream kinase, protein kinase A.

Conclusions: The recognition that UIP fibroblasts manifest variable refractoriness to PGE2 suppression sheds new light on the activation phenotype of these cells and on the pathogenesis of fibrotic lung disease.

Authors: Talmadge E. King; Jürgen Behr; Kevin K. Brown; Roland M. duBois; Lisa Lancaster; Joao A. de Andrade; Gerd Stähler; Isabelle Leconte; Sébastien Roux; Ganesh Raghu

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease lacking effective treatment.

Objectives: To determine the effects of bosentan on exercise capacity and time to disease progression in patients with IPF.

Methods: In a double-blind, multicenter trial, patients with IPF were randomized to receive oral bosentan 62.5 mg twice daily for 4 weeks, increased to 125 mg twice daily thereafter, or placebo, for 12 months or longer. The primary efficacy endpoint was change from baseline up to Month 12 in exercise capacity, as measured by a modified six-minute-walk test. Secondary endpoints were time to death or disease progression (worsening pulmonary function tests [PFTs] or acute decompensation), change in PFT scores, and quality of life (QOL) assessed using Short-Form 36 and St. George's Respiratory Questionnaire.

Measurements and Main Results: A total of 158 patients randomly received bosentan (n = 74) or placebo (n = 84). Bosentan showed no superiority over placebo in six-minute-walk distance (6MWD) up to Month 12, the primary efficacy endpoint. A trend in favor of bosentan was observed in the secondary endpoint of time to death or disease progression (hazard ratio [HR], 0.613; 95% confidence interval [CI], 0.328−1.144; P = 0.119), which was more pronounced in a patient subgroup diagnosed using surgical lung biopsy (post hoc analysis; HR, 0.315; 95% CI, 0.126−0.789; P = 0.009). Changes from baseline up to Month 12 in assessments of dyspnea and QOL favored treatment with bosentan. No unexpected adverse events were reported.

Conclusions: Bosentan treatment in patients with IPF did not show superiority over placebo on 6MWD. A trend in delayed time to death or disease progression, and improvement in QOL, was observed with bosentan. The more pronounced treatment effect in patients with biopsy-proven IPF warrants further investigation.

Clinical trial registered with www.clinicaltrials.gov (NCT 00071461).

Authors: Khalid Puthawala; Nicos Hadjiangelis; Steven C. Jacoby; Emmanuel Bayongan; Zhicheng Zhao; Zhiwei Yang; Mary Louise Devitt; Gerald S. Horan; Paul H. Weinreb; Matvey E. Lukashev; Shelia M. Violette; Kristen S. Grant; Cristina Colarossi; Silvia C. Formenti; John S. Munger

Rationale: In experimental models, lung fibrosis is dependent on transforming growth factor (TGF)-β signaling. TGF-β is secreted in a latent complex with its propeptide, and TGF-β activators release TGF-β from this complex. Because the integrin αvβ6 is a major TGF-β activator in the lung, inhibition of αvβ6-mediated TGF-β activation is a logical strategy to treat lung fibrosis.

Objectives: To determine, by genetic and pharmacologic approaches, whether murine radiation-induced lung fibrosis is dependent on αvβ6.

Methods: Wild-type mice, αvβ6-deficient (Itgb6^−/−) mice, and mice heterozygous for a Tgfb1 mutation that eliminates integrin-mediated activation (Tgfb1^+/RGE) were exposed to 14 Gy thoracic radiation. Some mice were treated with an anti-αvβ6 monoclonal antibody or a soluble TGF-β receptor fusion protein. αvβ6 expression was determined by immunohistochemistry. Fibrosis, inflammation, and gene expression patterns were assessed 20–32 weeks postirradiation.

Measurements and Main Results: β6 Integrin expression increased within the alveolar epithelium 18 weeks postirradiation, just before onset of fibrosis. Itgb6^−/− mice were completely protected from fibrosis, but not from late radiation-induced mortality. Anti-αvβ6 therapy (1–10 mg/kg/wk) prevented fibrosis, but only higher doses (6–10 mg/kg/wk) caused lung inflammation similar to that in Itgb6^−/− mice. Tgfb1-haploinsufficient mice were also protected from fibrosis.

Conclusions: αvβ6-Mediated TGF-β activation is required for radiation-induced lung fibrosis. Together with previous data, our results demonstrate a robust requirement for αvβ6 in distinct fibrosis models. Inhibition of αvβ6-mediated TGF-β activation is a promising new approach for antifibrosis therapy.

Authors: Charlie Strange; Marcy B. Bolster; Michael D. Roth; Richard M. Silver; Arthur Theodore; Jonathan Goldin; Philip Clements; Joanie Chung; Robert M. Elashoff; Robert Suh; Edwin A. Smith; Daniel E. Furst; Donald P. Tashkin

Rationale: The presence of inflammatory cells on bronchoalveolar lavage is often used to predict disease activity and the need for therapy in systemic sclerosis–associated interstitial lung disease.

Objectives: To evaluate whether lavage cellularity identifies distinct subsets of disease and/or predicts cyclophosphamide responsiveness.

Methods: Patients underwent baseline lavage and/or high-resolution computed tomography as part of a randomized placebo-controlled trial of cyclophosphamide versus placebo (Scleroderma Lung Study) to determine the effect of therapy on forced vital capacity. Patients with 3% or greater polymorphonuclear and/or 2% or greater eosinophilic leukocytes on lavage and/or ground-glass opacification on computed tomography were eligible for enrollment.

Measurements and Main Results: Lavage was performed in 201 individuals, including 141 of the 158 randomized patients. Abnormal cellularity was present in 101 of these cases (71.6%) and defined a population with a higher percentage of men (P = 0.04), more severe lung function, including a worse forced vital capacity (P = 0.003), worse total lung capacity (P = 0.005) and diffusing capacity of the lung for carbon monoxide (P = 0.004), more extensive ground-glass opacity (P = 0.005), and more extensive fibrosis in the right middle lobe (P = 0.005). Despite these relationships, the presence or absence of an abnormal cell differential was not an independent predictor of disease progression or response to cyclophosphamide at 1 year (P = not significant).

Conclusions: The presence of an abnormal lavage in the Scleroderma Lung Study defined patients with more advanced interstitial lung disease but added no additional value to physiologic and computed tomography findings as a predictor of progression or treatment response.

Clinical trial registered with www.clinicaltrials.gov (NCT 000004563).

Authors: Barbara O. Meyrick; David B. Friedman; D. Dean Billheimer; Joy D. Cogan; Melissa A. Prince; John A. Phillips; James E. Loyd

Rationale: Not all family members with BMPR2 mutations develop pulmonary arterial hypertension (PAH), implying that additional modifier genes or proteins are necessary for full expression of the disease.

Objectives: To determine whether protein expression is altered in patients with familial PAH (FPAH) compared with obligate carriers and nondiseased control subjects.

Methods: Protein extracts from transformed blood lymphocytes from four patients with FPAH, three obligate carriers, and three married-in control subjects from one family with a known BMPR2 mutation (exon 3 T354G) were labeled with either Cy3 or Cy5. Cy3/5 pairs were separated by standard two-dimensional differential gel electrophoresis using a Cy2-labeled internal standard of all patient samples. Log volume ratios were analyzed using a linear mixed-effects model. Proteins were identified by matrix-assisted laser desorption ionization, time-of-flight mass spectrometry (MALDI-TOF MS) and tandem TOF/TOF MS/MS.

Measurements and Main Results: Hierarchical clustering, heat-map, and principal components analysis revealed marked changes in protein expression in patients with FPAH when compared with obligate carriers. Significant changes were apparent in expression of 16 proteins (P < 0.05) when affected patients were compared with obligates: nine showed a significant increase and seven showed a significant reduction.

Conclusions: A series of novel proteins with altered expression were found that could distinguish affected patients from obligate carriers and married-in controls in a single family with a BMPR2 mutation. These differences provide new information highlighting proteins that may be involved in the mechanism(s) that differentiates those individuals with a BMPR2 mutation who develop FPAH from those who do not.

Authors: Olivier Sitbon; Caroline Lascoux-Combe; Jean-François Delfraissy; Patrick G. Yeni; François Raffi; Dominique De Zuttere; Virginie Gressin; Pierre Clerson; Daniel Sereni; Gérald Simonneau

Rationale: The prevalence of HIV-associated pulmonary arterial hypertension (PAH) has not been evaluated since introduction of combined, highly active antiretroviral treatments.

Objectives: To establish the current prevalence of PAH in a large HIV-positive population.

Methods: Prospective study conducted in 7,648 consecutive HIV-positive adults in 14 HIV clinics in France. PAH was identified through screening with a predefined algorithm. Patients with dyspnea unexplained by other causes underwent transthoracic Doppler echocardiography. PAH was suspected if peak velocity of tricuspid regurgitation was greater than 2.5 m/second and was confirmed by right heart catheterization.

Measurements and Main Results: PAH was diagnosed if mean pulmonary arterial pressure at rest was 25 mm Hg or greater (with pulmonary capillary wedge pressure  15 mm Hg) or 30 mm Hg or greater on exercise. A total of 739 patients had dyspnea, of which 312 met exclusion criteria and 150 refused to participate. Among the remaining 277, 30 had known PAH and 247 had unexplained dyspnea and underwent echocardiography; PAH was suspected in 18 and confirmed in 5, to give a total of 35 cases. The prevalence was thus 0.46% (95% confidence interval, 0.32–0.64%). All new cases had relatively milder PAH.

Conclusions: The prevalence of HIV-associated PAH is about the same as it was in the early 1990s. Given the current good long-term prognosis of patients with HIV, the severity of PAH in HIV-infected patients, and the absence of predictive factors, careful screening for PAH is warranted for patients with unexplained dyspnea.

Authors: Steven M. Kawut; David J. Lederer; Shaf Keshavjee; Jessie S. Wilt; Theresa Daly; Frank D'Ovidio; Joshua R. Sonett; Selim M. Arcasoy; Mark L. Barr

Rationale: Characteristics of and survival estimates for recipients of lung retransplantation in the modern era are unknown.

Objectives: To compare lung retransplant patients in the modern era with historical retransplant patients, to compare retransplant patients with initial transplant patients in the modern era, and to determine the predictors of the risk of death after lung retransplantation.

Methods: We performed a retrospective cohort study of patients who underwent lung retransplantation between January 2001 and May 2006 in the United States (modern retransplant cohort). The characteristics and survival of this cohort were compared with those of patients who underwent first lung retransplantation between January 1990 and December 2000 (historical retransplant cohort) and patients who underwent initial lung transplantation between January 2001 and May 2006 (modern initial transplant cohort).

Measurements and Main Results: Modern retransplant recipients (n = 205) had a lower risk of death compared with that of the historical retransplant cohort (n = 184) (hazard ratio, 0.7; 95% confidence interval, 0.5–0.9; P = 0.006). However, modern retransplant recipients had a higher risk of death than that of patients who underwent initial lung transplantation (n = 5,657) (hazard ratio, 1.3; 95% confidence interval, 1.2–1.5; P = 0.001), which appeared to be explained by a higher prevalence of certain comorbidities. Retransplantation at less than 30 days after the initial transplant procedure was associated with worse survival.

Conclusions: Outcomes after lung retransplantation have improved; however, retransplantation continues to pose an increased risk of death compared with the initial transplant procedure. Retransplantation early after the initial transplant poses a particularly high mortality risk.

Authors: Ronan A. M. Breen; Robert F. Miller; Marc C. I. Lipman

Authors: Payam Nahid; Bouke C. de Jong; Charles L. Daley

Authors: Ramon C. J. Langen; Annemie M. W. J. Schols

Authors: Mariève Doucet; Aaron Russell; Denis R. Joanisse; François Maltais

Author: Akashdeep Singh

Authors: Hari Dandapantula; Vishnuvardhan Reddy; J. Richard Spears

Authors: Adrian R. Martineau; Robert J. Wilkinson; Christopher J. Griffiths