Lori Shah

Obesity and underweight are associated with an increased risk of death after lung transplantation.

RATIONALE Obesity is considered a relative contraindication to lung transplantation, based on studies that have not accounted for key confounders. Little is known about the risk of death for underweight candidates after transplantation. OBJECTIVES To examine the associations of pretransplant obesity and underweight with the risk of death after lung transplantation. METHODS We examined 5,978 adults with cystic fibrosis, chronic obstructive pulmonary disease, and diffuse parenchymal lung disease who underwent lung transplantation in the United States between 1995 and 2003. We used Cox models and generalized additive models to examine the association between pretransplant body mass index and the risk of death after lung transplantation with adjustment for donor and recipient factors. MEASUREMENTS AND MAIN RESULTS The median follow-up time was 4.2 years. Compared with normal weight recipients, the multivariable-adjusted rates of death were 15% higher for underweight recipients (95% confidence interval, 3 to 28%), 15% higher for overweight recipients (95% confidence interval, 6 to 26%), and 22% higher for obese recipients (95% confidence interval, 8 to 39%). These relationships persisted when stratified by diagnosis. The multivariable-adjusted population attributable fraction was 12% at 1 year and 8% at 5 years. CONCLUSIONS Both obesity and underweight are independent risk factors for death after lung transplantation, contributing to up to 12% of deaths in the first year after transplantation. Primary care providers and pulmonologists should promote a healthy weight for patients with lung disease long before transplantation is considered.

Frailty Phenotypes, Disability, and Outcomes in Adult Candidates for Lung Transplantation

RATIONALE Frailty is associated with morbidity and mortality in abdominal organ transplantation but has not been examined in lung transplantation. OBJECTIVES To examine the construct and predictive validity of frailty phenotypes in lung transplant candidates. METHODS In a multicenter prospective cohort, we measured frailty with the Fried Frailty Phenotype (FFP) and Short Physical Performance Battery (SPPB). We evaluated construct validity through comparisons with conceptually related factors. In a nested case-control study of frail and nonfrail subjects, we measured serum IL-6, tumor necrosis factor receptor 1, insulin-like growth factor I, and leptin. We estimated the association between frailty and disability using the Lung Transplant Valued Life Activities disability scale. We estimated the association between frailty and risk of delisting or death before transplant using multivariate logistic and Cox models, respectively. MEASUREMENTS AND MAIN RESULTS Of 395 subjects, 354 completed FFP assessments and 262 completed SPPB assessments; 28% were frail by FFP (95% confidence interval [CI], 24-33%) and 10% based on the SPPB (95% CI, 7-14%). By either measure, frailty correlated more strongly with exercise capacity and grip strength than with lung function. Frail subjects tended to have higher plasma IL-6 and tumor necrosis factor receptor 1 and lower insulin-like growth factor I and leptin. Frailty by either measure was associated with greater disability. After adjusting for age, sex, diagnosis, and transplant center, both FFP and SPPB were associated with increased risk of delisting or death before lung transplant. For every 1-point worsening in score, hazard ratios were 1.30 (95% CI, 1.01-1.67) for FFP and 1.53 (95% CI, 1.19-1.59) for SPPB. CONCLUSIONS Frailty is prevalent among lung transplant candidates and is independently associated with greater disability and an increased risk of delisting or death.

Body Composition and Mortality after Adult Lung Transplantation in the United States

RATIONALE Obesity and underweight are contraindications to lung transplantation based on their associations with mortality in studies performed before implementation of the lung allocation score (LAS)-based organ allocation system in the United States Objectives: To determine the associations of body mass index (BMI) and plasma leptin levels with survival after lung transplantation. METHODS We used multivariable-adjusted regression models to examine associations between BMI and 1-year mortality in 9,073 adults who underwent lung transplantation in the United States between May 2005 and June 2011, and plasma leptin and mortality in 599 Lung Transplant Outcomes Group study participants. We measured body fat and skeletal muscle mass using whole-body dual X-ray absorptiometry in 142 adult lung transplant candidates. MEASUREMENTS AND MAIN RESULTS Adjusted mortality rates were similar among normal weight (BMI 18.5-24.9 kg/m(2)), overweight (BMI 25.0-29.9), and class I obese (BMI 30-34.9) transplant recipients. Underweight (BMI < 18.5) was associated with a 35% increased rate of death (95% confidence interval, 10-66%). Class II-III obesity (BMI ≥ 35 kg/m(2)) was associated with a nearly twofold increase in mortality (hazard ratio, 1.9; 95% confidence interval, 1.3-2.8). Higher leptin levels were associated with increased mortality after transplant surgery performed without cardiopulmonary bypass (P for interaction = 0.03). A BMI greater than or equal to 30 kg/m(2) was 26% sensitive and 97% specific for total body fat-defined obesity. CONCLUSIONS A BMI of 30.0-34.9 kg/m(2) is not associated with 1-year mortality after lung transplantation in the LAS era, perhaps because of its low sensitivity for obesity. The association between leptin and mortality suggests the need to validate alternative methods to measure obesity in candidates for lung transplantation. A BMI greater than or equal to 30 kg/m(2) may no longer contraindicate lung transplantation.

Risk factors and outcomes of hypogammaglobulinemia after lung transplantation.

Background. Hypogammaglobulinemia (HGG) frequently occurs after solid organ transplantation; however, the prevalence and implications of HGG after lung transplantation are not well defined. The authors aimed to define the prevalence, risk factors, and outcomes of patients with severe HGG after lung transplantation. Methods. The authors performed a retrospective cohort study of 57 lung transplant recipients at their center. Quantitative total and subclass immunoglobulin (Ig) G levels were obtained from patients. Results. Thirty-four (60%; 95% confidence interval [CI], 46%–72%) patients had low IgG levels (IgG <700 mg/dL); of these, eight (14%; 95% CI, 6%–26%) had severe HGG (IgG <400 mg/dL). Female patients had a higher risk of severe HGG than male patients (25% vs. 0%, P=0.007), and patients who underwent transplantation for emphysema had a higher risk of severe HGG than others (P=0.04). Patients with bronchiolitis obliterans syndrome had a higher risk of severe HGG than those without (50% vs. 10%, P=0.03). Severe HGG was associated with an increased risk of pneumonia (P=0.01) and worse survival (P=0.04) but with neither the incidence of cytomegalovirus disease (P=0.54) nor a subsequent diagnosis of bronchiolitis obliterans syndrome (P=0.70). Conclusions. The authors have documented a high prevalence of HGG after lung transplantation. Emphysema, female gender, and bronchiolitis obliterans syndrome are risk factors for severe HGG. Patients with severe HGG had a higher cumulative incidence of pneumonia and worse survival. Studies of the efficacy and safety of IgG supplementation after lung transplantation should be pursued.

Donor Surfactant Protein D (SP‐D) Polymorphisms Are Associated With Lung Transplant Outcome

Chronic lung allograft dysfunction (CLAD) is the major factor limiting long‐term success of lung transplantation. Polymorphisms of surfactant protein D (SP‐D), an important molecule within lung innate immunity, have been associated with various lung diseases. We investigated the association between donor lung SP‐D polymorphisms and posttransplant CLAD and survival in 191 lung transplant recipients consecutively transplanted. Recipients were prospectively followed with routine pulmonary function tests. Donor DNA was assayed by pyrosequencing for SP‐D polymorphisms of two single‐nucleotide variations altering amino acids in the mature protein N‐terminal domain codon 11 (Met11Thr), and in codon 160 (Ala160Thr) of the C‐terminal domain. CLAD was diagnosed in 88/191 patients, and 60/191 patients have died. Recipients of allografts that expressed the homozygous Met11Met variant of aa11 had significantly greater freedom from CLAD development and better survival compared to those with the homozygous Thr11Th variant of aa11. No significant association was noted for SP‐D variants of aa160. Lung allografts with the SP‐D polymorphic variant Thr11Th of aa11 are associated with development of CLAD and reduced survival. The observed genetic differences of the donor lung, potentially with their effects on innate immunity, may influence the clinical outcomes after lung transplantation.

Refining Low Physical Activity Measurement Improves Frailty Assessment in Advanced Lung Disease and Survivors of Critical Illness

&NA; Rationale: The frail phenotype has gained popularity as a clinically relevant measure in adults with advanced lung disease and in critical illness survivors. Because respiratory disease and chronic illness can greatly limit physical activity, the measurement of participation in traditional leisure time activities as a frailty component may lead to substantial misclassification of frailty in pulmonary and critical care patients. Objectives: To test and validate substituting the Duke Activity Status Index (DASI), a simple 12‐item questionnaire, for the Minnesota Leisure Time Physical Activity (MLTA) questionnaire, a detailed questionnaire covering 18 leisure time activities, as the measure of low activity in the Fried frailty phenotype (FFP) instrument. Methods: In separate multicenter prospective cohort studies of adults with advanced lung disease who were candidates for lung transplant and older survivors of acute respiratory failure, we assessed the FFP using either the MLTA or the DASI. For both the DASI and MLTA, we evaluated content validity by testing floor effects and construct validity through comparisons with conceptually related factors. We tested the predictive validity of substituting the DASI for the MLTA in the FFP assessment using Cox models to estimate associations between the FFP and delisting/death before transplant in those with advanced lung disease and 6‐month mortality in older intensive care unit (ICU) survivors. Results: Among 618 adults with advanced lung disease and 130 older ICU survivors, the MLTA had a substantially greater floor effect than the DASI (42% vs. 1%, and 49% vs. 12%, respectively). The DASI correlated more strongly with strength and function measures than did the MLTA in both cohorts. In models adjusting for age, sex, comorbidities, and illness severity, substitution of the DASI for the MLTA led to stronger associations of the FFP with delisting/death in lung transplant candidates (FFP‐MLTA hazard ratio [HR], 1.42; 95% confidence interval [CI], 0.55‐3.65; FFP‐DASI HR, 2.99; 95% CI, 1.03‐8.65) and with mortality in older ICU survivors (FFP‐MLTA HR, 2.68; 95% CI, 0.62‐11.6; FFP‐DASI HR, 5.71; 95% CI, 1.34‐24.3). Conclusions: The DASI improves the construct and predictive validity of frailty assessment in adults with advanced lung disease or recent critical illness. This simple questionnaire should replace the more complex MLTA in assessing the frailty phenotype in these populations.

Frailty phenotypes and mortality after lung transplantation: A prospective cohort study

Frailty is associated with increased mortality among lung transplant candidates. We sought to determine the association between frailty, as measured by the Short Physical Performance Battery (SPPB), and mortality after lung transplantation. In a multicenter prospective cohort study of adults who underwent lung transplantation, preoperative frailty was assessed with the SPPB (n = 318) and, in a secondary analysis, the Fried Frailty Phenotype (FFP; n = 299). We tested the association between preoperative frailty and mortality following lung transplantation with propensity score–adjusted Cox models. We calculated postestimation marginalized standardized risks for 1‐year mortality by frailty status using multivariate logistic regression. SPPB frailty was associated with an increased risk of both 1‐ and 4‐year mortality (adjusted hazard ratio [aHR]: 7.5; 95% confidence interval [CI]: 1.6‐36.0 and aHR 3.8; 95%CI: 1.8‐8.0, respectively). Each 1‐point worsening in SPPB was associated with a 20% increased risk of death (aHR: 1.20; 95%CI: 1.08‐1.33). Frail subjects had an absolute increased risk of death within the first year after transplantation of 12.2% (95%CI: 3.1%‐21%). In secondary analyses, FFP frailty was associated with increased risk of death within the first postoperative year (aHR: 3.8; 95%CI: 1.1‐13.2) but not over longer follow‐up. Preoperative frailty is associated with an increased risk of death after lung transplantation.