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BACKGROUND Long-term survival after lung transplantation remains poor, yet modifiable risk factors for late-term morbidity and mortality have yet to be identified. Because psychiatric disorders increase risk for poor health outcomes in many nontransplant chronic disease populations, lung recipients with depression or anxiety before or early after transplantation may be at heightened risk for late-term transplant-related morbidity and mortality. METHODS Among 178 patients from a prospective study of mental health after lung transplantation, we identified 1-year survivors and examined whether they experienced major depression or anxiety disorders during that year as well as before transplantation. We used multivariable Cox regression to examine the relationship between these disorders and risk for subsequent bronchiolitis obliterans syndrome (BOS), mortality and graft loss for up to 15 years posttransplant, controlling for other known risk factors for the outcomes. RESULTS One hundred fifty-five recipients were studied. Recipients with posttransplant depression had an elevated risk of BOS (hazard ratio [HR], 1.91; 95% confidence interval [95% CI], 1.10-3.31), patient death (HR, 1.65; 95% CI, 1.01-2.71) and graft loss (HR, 1.75; 95% CI, 1.06-2.88). A trend toward reduced risk of BOS was observed in recipients with posttransplant anxiety (HR, 0.61; 95%CI, 0.37-1.00). Neither pretransplant disorder was related to risk for any outcome. CONCLUSIONS Early posttransplant depression increases risk for long-term transplant-related morbidity and mortality. Screening to identify depression should therefore be routine in posttransplant care. Although anxiety was not significantly associated with poor outcomes, screening for posttransplant anxiety should also be routine, to reduce patient distress. Research is needed to better understand mechanisms underlying depression-outcome associations.

BACKGROUND CXCL10 (IP-10) is a potent chemoattractant for T cells that has been postulated to play a role in infection and acute cellular rejection (ACR) in animal models. We measured CXCL10 (IP-10) (and other cytokines previously implicated in the pathogenesis of ACR) in the bronchoalveolar lavage (BAL) of lung transplant recipients (LTRs) to determine the association between CXCL10 (IP-10) and ACR in LTRs. METHODS In a prospective study of 85 LTRs, expression of cytokines (tumor necrosis factor, interferon-γ, interleukin [IL]-6, IL-8, IL-15, IL-16, IL-17, CXCL10 [IP-10], and MCP-1 [CCL2]) in BAL samples (n=233) from patients with episodes of ACR (n=44), infection ("Infect"; n=25), concomitant "Infect+ACR" (n=10), and "No Infect and No ACR" (n=154) were analyzed. RESULTS The levels of both CXCL10 (IP-10) and IL-16 were significantly increased in histologically proven ACR compared with the "No Infect and No ACR" group (CXCL10 [IP-10]: 107.0 vs. 31.9 pg/mL [P=0.001] and IL-16: 472.1 vs. 283.01 pg/mL [P=0.01]). However, in a linear mixed-effects model, significant association was found only between CXCL10 (IP-10) and ACR. A one-log increase of CXCL10 (IP-10) was associated with a 40% higher risk of ACR (odds ratio, 1.4; 95% confidence interval, 1.12-1.84). CONCLUSION Higher values of CXCL10 (IP-10) in BAL fluid are associated with ACR in LTRs, suggesting a potential mechanistic role in the pathogenesis of ACR in LTRs. These results suggest that therapeutic strategies to inhibit CXCL10 (IP-10) and or its cognate receptor, CXCR3, warrant investigation to prevent and/or treat ACR in clinical lung transplantation.

BACKGROUND Lung volume reduction surgery (LVRS) as a bridge to lung transplantation was first advocated in 1995 and published studies have supported the concept but with limited data. The risk-benefit tradeoffs of the combined procedure have not been thoroughly examined, although substantial information regarding LVRS has emerged. METHODS Of 177 patients who underwent lung transplantation for end-stage emphysema between 2002 and 2009 at our center, 25 had prior LVRS (22 bilateral and 3 unilateral). Lung transplantation was performed 22.9±15.9 months after LVRS. We compared in-hospital morbidity, functional capacity, and long-term outcomes of patients who underwent LVRS before lung transplantation with a matched cohort of patients without prior LVRS to assess the influence of LVRS on posttransplantation morbidity and mortality. RESULTS The incidence of postoperative bleeding requiring reexploration and the incidence of renal dysfunction requiring dialysis were higher in patients with LVRS before lung transplantation. Posttransplantation peak forced expiratory volume in 1 s was worse in patients with LVRS before lung transplantation (56.7% vs. 78.8%; P

BACKGROUND Early major neurologic complications after lung transplantation represent a major source of morbidity for patients and compromise their quality of life; however, the mechanisms underlying neurologic complications and their impact on outcomes in lung transplantation remain largely unknown. METHODS Patients who received lung transplants at our institution between January 2004 and December 2010 were identified (n=759). Data on complications including occurrence, timing, management, and outcome were extracted from our transplant database and medical record review. Major neurologic complications were defined as those that were potentially life threatening, required urgent treatment/intubation, or required admission to the intensive care unit. RESULTS Seventy (9.2%) patients experienced major neurologic complications within 2 weeks after lung transplantation. Most common complications were stroke (41%) and severe toxic/metabolic encephalopathy (37%). Multivariate analysis demonstrated that advanced age, history of coronary artery disease, prolonged use of cardiopulmonary bypass, and severe primary graft dysfunction increased the risk for death in patients with early major neurologic complications (P

When selecting a donor for lung transplantation, it is generally believed that the best outcomes occur when the donor has no smoking history. Because we experienced unexpected adverse outcomes after transplant of lungs from teenaged donors with no smoking history, this study revisited the effects of donor smoking history in relation to age on transplant outcomes.We conducted a retrospective review of 532 consecutive lung transplants performed at our institution. Most donors (293, 55%) had a history of smoking; 239 donors were nonsmokers. The smoking donors were further subgrouped based on consumption (20, 20-40, or40 pack-years). The nonsmoking donors were subgrouped by age (20 years or ≥20 years). Recipients' characteristics and outcomes were compared.The recipients of lungs from donors with a smoking history showed better 5-year survival than recipients of lungs from nonsmokers (65.8% vs. 48.3%, P0.05), but recipients of lungs from heavy smokers (40 pack-years smoking history) exhibited a significantly higher incidence of severe primary graft dysfunction and higher short- and long-term mortality than the recipients of lungs from donors who smoked less. Surprisingly, recipients of lungs from teenaged donors with no smoking history exhibited a higher morbidity and mortality than recipients of lungs from adult nonsmoking donors but did not exhibit decreased posttransplant forced expiratory volume in 1 sec.In this large, single-center experience, the absence of smoking history in the donor did not result in better long-term outcomes after lung transplantation. Potential problems with lungs from teenaged donors with no smoking history were suggested.

Inhaled amphotericin preparations have been used for prophylaxis against invasive aspergillosis in lung transplant recipients. However, no published data exist regarding the pharmacokinetic profile of amphotericin B lipid complex in lung transplant recipients.We prospectively determined the concentrations of amphotericin B in the epithelial lining fluid (ELF) and plasma after aerosolized nebulization (AeroEclipse), of amphotericin B lipid complex at 1 mg/kg every 24 hr for 4 days in 35 lung transplant recipients. One brochoalveolar lavage sample and a simultaneous blood sample were collected at various time points after the fourth dose from each subject. High-performance liquid chromatography and high-performance liquid chromatography-MS-MS were used to measure amphotericin B.Concentrations of amphotericin B in ELF (median, 25-75 IQR) were at 4 hr (n=5) 7.20 μg/mL (1.3-17.6), 24 hr (n=6) 8.26 μg/mL (3.9-82.7), 48 hr (n=5) 2.15 μg/mL (1.4-5.5), 72 hr (n=4) 1.25 μg/mL (0.75-5.5), 96 hr (n=6) 0.86 μg/mL (0.55-1.4), 120 hr (n=4) 1.04 μg/mL (0.44-1.6), 144 hr (n=1), 4.25 μg/mL, 168 hr (n=3) 1.14 μg/mL, and 192 hr (n=1) 1 μg/mL. The plasma concentration of the drug remained below 0.08 μg/mL at all time points. During the study, the side effects noted included wheezing, coughing, and 12% decline in forced expiratory volume in 1 sec.We conclude that administration through aerosolized nebulization of amphotericin B lipid complex every 24 hr for 4 days in lung transplant recipients achieved amphotericin B concentrations in ELF above minimum inhibitory concentration of the Aspergillus nearly at 168 hr after the last inhaled dose and is well tolerated.

Background. Lung transplants, in particular, have the highest rate of infections among solid organ transplant recipients. However, there is no existing objective measure to predict the development of infections. We report the correlation between Cylex ImmuKnow (ng/mL ATP) values and various infectious syndromes in a large prospective cohort of lung transplant recipients. Methods. We followed up 175 lung transplants that developed 129 infectious episodes. Multiple logistic regression analysis was performed; generalized estimating equations were used to determine the odds ratio for infections. Results. The median ImmuKnow values in cytomegalovirus disease (49.3 ng/mL ATP), viral infection (70 ng/mL ATP), and bacterial pneumonia (92 ng/mL ATP) were significantly different from stable state (174.8 ng/mL ATP). The median ImmuKnow values of fungal disease (85 ng/mL ATP) and tracheobronchitis (123 ng/mL ATP) had a tendency to be lower than stable state (P=0.10), whereas patients with fungal colonization had comparable ImmunKnow values (167 vs. 174.8 ng/mL ATP). Of the patients colonized with fungus who subsequently developed fungal disease within 100 days, the median value of ImmuKnow was significantly lower than in those who did not develop fungal disease (22.5 vs. 183.5 ng/mL ATP; P

The hallmark of humoral rejection is the presence of subendothelial C4d in the allograft. A simultaneous determination of vascular C4d with soluble C4d in broncho-alveolar lavage fluid (BAL) and circulating anti-human leukocyte antigen (HLA) antibodies (HLA-Ab) has not been reported in lung transplantation.Forty-two consecutive lung-transplant patients were included in this cross-sectional study. The presence and specificity of HLA-Ab was determined at the same frequency with transbronchial biopsies. Soluble C4d levels were measured by enzyme-linked immunosorbent assay in all 42 patients. In a subgroup of 32 patients with available timely matched paraffin-embedded tissue sections, the vascular C4d deposition was also assessed.The presence of HLA-Ab in 16 patients was associated with biopsy-proven acute rejection (10/16 vs. 3/16, P0.01) and increased immunosuppression (13/16 vs. 4/16, P0.005). Pulmonary function was also decreased in patients with HLA-Ab (mean forced expiratory volume in 1 second=49%) when compared with the control group (mean forced expiratory volume in 1 second=66%, P0.05). Nine patients exhibited specific vascular C4d deposition and in eight of nine (89%) cases HLA-Ab were detected, versus 8 of 23 (35%) in C4d-negative patients (P0.05). Soluble C4d in BAL was highly (0.5 microg/mL) elevated in patients with HLA-Ab and vascular C4d and was moderately (0.2 microg/mL) increased in patients with antibodies but C4d-negative. In contrast, only a slight elevation of soluble C4d (0.1 microg/mL) was detected in patients without HLA-specific antibodies.The association of HLA-specific antibodies with vascular C4d deposition and soluble C4d in BAL, in addition to the reduced pulmonary function, might constitute a diagnostic triad for antibody-mediated rejection in lung transplant patients.

The clinical utility of Platelia Aspergillus enzyme immunoassay (EIA) for galactomannan (GM) antigen detection in bronchoalveolar lavage (BAL) for the diagnosis of invasive aspergillosis (IA) in lung transplant recipients is not known.BAL fluid samples from consecutive lung transplant recipients who underwent bronchoscopy were prospectively analyzed for GM.A total of 333 BAL samples from 116 patients were tested. Invasive aspergillosis was documented in 5.2% (6/116) of the patients. Samples analyzed included 9 BALs from two patients with proven IA, 19 BALs from four patients with probable IA, and 305 BALs from 110 patients without IA. At the index cutoff value ofor =0.5, the sensitivity was 60%; specificity was 95%, with positive and negative likelihood ratios of 14 and 0.41, respectively. Increasing the index cutoff value toor =1.0 yielded a sensitivity of 60%, a specificity of 98%, and the positive and negative likelihood ratios of 28 and 0.40, respectively. Two of six patients with IA receiving antifungal prophylaxis had false-negative results.A Platelia EIA index cut-offor =1.0 in the BAL fluid in a lung transplant recipient with a compatible clinical illness may be considered as suggestive of IA.

Background. Simkania negevensis is a novel organism closely related to chlamydiae. The organism has been associated with community acquired pneumonia and acute exacerbation of chronic obstructive pulmonary disease. The prevalence and pathogenic potential of S. negevensis is not known in lung transplant recipients. Methods. In this multicenter study comparative analysis of bronchoalveolar lavage (BAL) in lung transplants (Tx) and kidney Tx, immunocompromised and nasopharyngeal (NP) washes of immunocompetent patients was done. The BAL specimens were tested by nested polymerase chain reaction (PCR) for C. pneumoniae and S. negevensis. Selected S. negevensis positive PCR cases were confirmed by culture. Results. In the initial 41 BAL samples S. negevensis was detected in 97.5% (40/41) of lung transplant recipients as compared to 14.1% (1/7) in other organ transplant recipients (P

In recent years, several functions of the cystic fibrosis transmembrane conductance regulator have been discovered, yet the pathophysiology of the pulmonary disease in cystic fibrosis remains unclear. At the cellular level, functions of this protein include regulation of chloride and sodium transport at the cell membrane and in intracellular organelles, regulation of protein trafficking, and posttranslational processing of glycoconjugates. Elucidation of these functions has led to several hypotheses to account for how defects in the cystic fibrosis transmembrane conductance regulator produce pulmonary disease, but a clear understanding of the pathophysiologic links between the cellular functions of the cystic fibrosis transmembrane conductance regulator and organ dysfunction has been hampered by the lack of ideal model systems. Current evidence suggests that defects in the cystic fibrosis transmembrane conductance regulator lead to alterations in periciliary fluid homeostasis, mucus hydration, mucin secretion, and apical membrane protein structure. In turn, these alterations impair mucociliary clearance and promote bacterial infection, which then leads to chronic airway inflammation and the development of bronchiectasis.