Assessment of long-term safety and efficacy of dupilumab in children with asthma (LIBERTY ASTHMA EXCURSION): an open-label extension study.

BACKGROUND: Dupilumab efficacy and safety in children aged 6-11 years with uncontrolled, moderate-to-severe asthma were shown in the VOYAGE study-a 52-week, multinational, multicentre, phase 3 randomised, double-blind, placebo-controlled trial. We aimed to evaluate the long-term safety and efficacy of dupilumab in children with moderate-to-severe asthma who previously participated in the VOYAGE study. METHODS: 365 of 408 children with moderate-to-severe asthma from VOYAGE enrolled in EXCURSION, a 52 week, open-label extension study conducted at 70 centres across 17 countries. 240 children continued with add-on dupilumab (dosed according to bodyweight: 100 mg for those weighing ≤30 kg and 200 mg for those weighing more than 30 kg at EXCURSION baseline) once every 2 weeks administered by subcutaneous injection (dupilumab/dupilumab group) and 125 children on placebo during VOYAGE initiated dupilumab (100 or 200 mg, according to bodyweight), once every 2 weeks administered by subcutaneous injection (placebo/dupilumab group). Following a protocol amendment, for a subset of children weighing 30 kg or less, the dose was changed to 300 mg once every 4 weeks. The primary endpoint for the open-label extension study was the number and proportion of patients with any treatment-emergent adverse event (TEAE) during the 52-week study period in the overall population (defined as children aged 6-11 years old with moderate-to-severe asthma who previously completed VOYAGE). Statistical analyses were descriptive. This study is registered with ClinicalTrials.gov (NCT03560466; EXCURSION). FINDINGS: Children who completed VOYAGE were eligible to enrol in EXCURSION between June 21, 2018 and Aug 18, 2020. During EXCURSION, the safety profile and proportion of patients reporting TEAEs were consistent with those observed during the parent study (VOYAGE). In the overall population, 232 (63·6%) of 365 patients experienced at least one TEAE (dupilumab/dupilumab: 147 [61·3%]; placebo/dupilumab: 85 [68·0%]). The most frequently reported TEAEs were nasopharyngitis, pharyngitis, and upper respiratory tract infections. INTERPRETATION: In EXCURSION, long-term treatment with dupilumab was well tolerated with an acceptable safety profile. FUNDING: Sanofi and Regeneron Pharmaceuticals.

Assessment of dupilumab in children with moderate-to-severe type 2 asthma with or without evidence of allergic asthma.

BACKGROUND: Cytokines, such as interleukins (IL)-4/5/13, play a key role in multiple type 2 inflammatory diseases, including allergic asthma. Dupilumab, a human monoclonal antibody, blocks the shared receptor component for IL-4/IL-13, inhibiting signaling. In this post hoc analysis of VOYAGE (NCT02948959), dupilumab efficacy was evaluated in patients aged 6-11 years with type 2 asthma with or without evidence of allergic asthma (baseline serum total IgE ≥30 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L). METHODS: Annualized severe exacerbation rates (AER) and changes in pre-bronchodilator (Pre-BD) forced expiratory volume in one second (FEV1 ), percent-predicted pre-BD FEV1 (ppFEV1 ), and Asthma Control Score (ACQ)-7 were assessed during the treatment period. RESULTS: 350 children (261 with and 89 without evidence of allergic asthma) were included. Dupilumab versus placebo significantly reduced AER in patients with (0.24 vs. 0.62, relative risk reduction [RRR]: 62% [95% CI, 39-76], P < .0001) and without (0.39 vs. 0.80, RRR: 51% [95% CI, 0-76], P < .05) evidence of allergic asthma. Significant improvements in ppFEV1 , pre-bronchodilator FEV1 , and ACQ-7 scores were observed in dupilumab versus placebo throughout the treatment period in patients with evidence of allergic asthma. In patients without evidence of allergic asthma, numerical improvements in pre-bronchodilator FEV1 and asthma control were observed by Week 52. CONCLUSION: Dupilumab versus placebo reduced asthma exacerbations in children with type 2 asthma irrespective of evidence of allergic asthma; similar trends were observed in changes in lung function. Significant improvement in asthma control was observed in patients with evidence of allergic asthma, but not in those without.

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

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.

Race, Ethnicity, Health Insurance, and Mortality in Older Survivors of Critical Illness.

OBJECTIVES: To determine whether minority race or ethnicity is associated with mortality and mediated by health insurance coverage among older (≥ 65 yr old) survivors of critical illness. DESIGN: A retrospective cohort study. SETTING: Two New York City academic medical centers. PATIENTS: A total of 1,947 consecutive white (1,107), black (361), and Hispanic (479) older adults who had their first medical-ICU admission from 2006 through 2009 and survived to hospital discharge. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We obtained demographic, insurance, and clinical data from electronic health records, determined each patient's neighborhood-level socioeconomic data from 2010 U.S. Census tract data, and determined death dates using the Social Security Death Index. Subjects had a mean (SD) age of 79 years (8.6 yr) and median (interquartile range) follow-up time of 1.6 years (0.4-3.0 yr). Blacks and Hispanics had similar mortality rates compared with whites (adjusted hazard ratio, 0.92; 95% CI, 0.76-1.11 and adjusted hazard ratio, 0.92; 95% CI, 0.76-1.12, respectively). Compared to those with commercial insurance and Medicare, higher mortality rates were observed for those with Medicare only (adjusted hazard ratio, 1.43; 95% CI, 1.03-1.98) and Medicaid (adjusted hazard ratio, 1.30; 95% CI, 1.10-1.52). Medicaid recipients who were the oldest ICU survivors (> 82 yr), survivors of mechanical ventilation, and discharged to skilled-care facilities had the highest mortality rates (p-for-interaction: 0.08, 0.03, and 0.17, respectively). CONCLUSIONS: Mortality after critical illness among older adults varies by insurance coverage but not by race or ethnicity. Those with federal or state insurance coverage only had higher mortality rates than those with additional commercial insurance.

Survival Benefit of Lung Transplantation in the Modern Era of Lung Allocation.

RATIONALE: Lung transplantation is an accepted and increasingly employed treatment for advanced lung diseases, but the anticipated survival benefit of lung transplantation is poorly understood. OBJECTIVES: To determine whether and for which patients lung transplantation confers a survival benefit in the modern era of U.S. lung allocation. METHODS: Data on 13,040 adults listed for lung transplantation between May 2005 and September 2011 were obtained from the United Network for Organ Sharing. A structural nested accelerated failure time model was used to model the survival benefit of lung transplantation over time. The effects of patient, donor, and transplant center characteristics on the relative survival benefit of transplantation were examined. MEASUREMENTS AND MAIN RESULTS: Overall, 73.8% of transplant recipients were predicted to achieve a 2-year survival benefit with lung transplantation. The survival benefit of transplantation varied by native disease group (P = 0.062), with 2-year expected benefit in 39.2 and 98.9% of transplants occurring in those with obstructive lung disease and cystic fibrosis, respectively, and by lung allocation score at the time of transplantation (P < 0.001), with net 2-year benefit in only 6.8% of transplants occurring for lung allocation score less than 32.5 and in 99.9% of transplants for lung allocation score exceeding 40. CONCLUSIONS: A majority of adults undergoing transplantation experience a survival benefit, with the greatest potential benefit in those with higher lung allocation scores or restrictive native lung disease or cystic fibrosis. These results provide novel information to assess the expected benefit of lung transplantation at an individual level and to enhance lung allocation policy.

Donor lung assessment using selective pulmonary vein gases.

OBJECTIVES: Standard donor lung assessment relies on imaging, challenge gases and subjective interpretation of bronchoscopic findings, palpation and visual assessment. Central gases may not accurately represent true quality of the lungs. We report our experience using selective pulmonary vein gases to corroborate the subjective judgement. METHODS: Starting, January 2012, donor lungs have been assessed by intraoperative bronchoscopy, palpation and visual judgement of lung collapse upon temporary disconnection from ventilator, central gases from the aorta and selective pulmonary vein gases. Partial pressure of oxygen (pO2) <300 mmHg on FiO2 of 1.0 was considered low. The results of the chest X-ray and last pO2 in the intensive care unit were also collected. Post-transplant primary graft dysfunction and survival were monitored. RESULTS: To date, 259 consecutive brain-dead donors have been assessed and 157 transplants performed. Last pO2 in the intensive care unit was poorly correlated with intraoperative central pO2 (Spearman's rank correlation rs = 0.29). Right inferior pulmonary vein pO2 was associated (Mann-Whitney, P < 0.001) with findings at bronchoscopy [clean: median pO2 443 mmHg (25th-75th percentile range 349-512) and purulent: 264 mmHg (178-408)]; palpation [good: 463 mmHg (401-517) and poor: 264 mmHg (158-434)] and visual assessment of lung collapse [good lung collapse: 429 mmHg (320-501) and poor lung collapse: 205 mmHg (118-348)]. Left inferior pulmonary pO2 was associated (P < 0.001) with findings at bronchoscopy [clean: 419 mmHg (371-504) and purulent: 254 mmHg (206-367)]; palpation [good: 444 mmHg (400-517) and poor 282 mmHg (211-419)] and visual assessment of lung collapse [good: 420 mmHg (349-496) and poor: 246 mmHg (129-330)]. At 72 h, pulmonary graft dysfunction 2 was in 21/157 (13%) and pulmonary graft dysfunction 3 in 17/157 (11%). Ninety-day and 1-year mortalities were 6/157 (4%) and 13/157 (8%), respectively. CONCLUSIONS: Selective pulmonary vein gases provide corroborative objective support to the findings at bronchoscopy, palpation and visual assessment. Central gases do not always reflect true function of the lungs, having high false-positive rate towards the individual lower lobe gas exchange. Objective measures of donor lung function may optimize donor surgeon assessment, allowing for low pulmonary graft dysfunction rates and low 90-day and 1-year mortality.

Short Stature and Access to Lung Transplantation in the United States. A Cohort Study.

RATIONALE: Anecdotally, short lung transplant candidates suffer from long waiting times and higher rates of death on the waiting list compared with taller candidates. OBJECTIVES: To examine the relationship between lung transplant candidate height and waiting list outcomes. METHODS: We conducted a retrospective cohort study of 13,346 adults placed on the lung transplant waiting list in the United States between 2005 and 2011. Multivariable-adjusted competing risk survival models were used to examine associations between candidate height and outcomes of interest. The primary outcome was the time until lung transplantation censored at 1 year. MEASUREMENTS AND MAIN RESULTS: The unadjusted rate of lung transplantation was 94.5 per 100 person-years among candidates of short stature (<162 cm) and 202.0 per 100 person-years among candidates of average stature (170-176.5 cm). After controlling for potential confounders, short stature was associated with a 34% (95% confidence interval [CI], 29-39%) lower rate of transplantation compared with average stature. Short stature was also associated with a 62% (95% CI, 24-96%) higher rate of death or removal because of clinical deterioration and a 42% (95% CI, 10-85%) higher rate of respiratory failure while awaiting lung transplantation. CONCLUSIONS: Short stature is associated with a lower rate of lung transplantation and higher rates of death and respiratory failure while awaiting transplantation. Efforts to ameliorate this disparity could include earlier referral and listing of shorter candidates, surgical downsizing of substantially oversized allografts for shorter candidates, and/or changes to allocation policy that account for candidate height.

Idiopathic Pulmonary Fibrosis in United States Automated Claims. Incidence, Prevalence, and Algorithm Validation.

RATIONALE: Estimates of idiopathic pulmonary fibrosis (IPF) incidence and prevalence from electronic databases without case validation may be inaccurate. OBJECTIVES: Develop claims algorithms to identify IPF and assess their positive predictive value (PPV) to estimate incidence and prevalence in the United States. METHODS: We developed three algorithms to identify IPF cases in the HealthCore Integrated Research Database. Sensitive and specific algorithms were developed based on literature review and consultation with clinical experts. PPVs were assessed using medical records. A third algorithm used logistic regression modeling to generate an IPF score and was validated using a separate set of medical records. We estimated incidence and prevalence of IPF using the sensitive algorithm corrected for the PPV. MEASUREMENTS AND MAIN RESULTS: We identified 4,598 patients using the sensitive algorithm and 2,052 patients using the specific algorithm. After medical record review, the PPVs of these algorithms using the treating clinician's diagnosis were 44.4 and 61.7%, respectively. For the IPF score, the PPV was 76.2%. Using the clinical adjudicator's diagnosis, the PPVs were 54 and 57.6%, respectively, and for the IPF score, the PPV was 83.3%. The incidence and period prevalences of IPF, corrected for the PPV, were 14.6 per 100,000 person-years and 58.7 per 100,000 persons, respectively. CONCLUSIONS: Sensitive algorithms without correction for false positive errors overestimated incidence and prevalence of IPF. An IPF score offered the greatest PPV, but it requires further validation.

High burden of palliative needs among older intensive care unit survivors transferred to post-acute care facilities. a single-center study.

RATIONALE: Adults with chronic critical illness (tracheostomy after ≥ 10 d of mechanical ventilation) have a high burden of palliative needs, but little is known about the actual use and potential need of palliative care services for the larger population of older intensive care unit (ICU) survivors discharged to post-acute care facilities. OBJECTIVES: To determine whether older ICU survivors discharged to post-acute care facilities have potentially unmet palliative care needs. METHODS: We examined electronic records from a 1-year cohort of 228 consecutive adults ≥ 65 years of age who had their first medical-ICU admission in 2009 at a single tertiary-care medical center and survived to discharge to a post-acute care facility (excluding hospice). Use of palliative care services was defined as having received a palliative care consultation. Potential palliative care needs were defined as patient characteristics suggestive of physical or psychological symptom distress or anticipated poor prognosis. We examined the prevalence of potential palliative needs and 6-month mortality. MEASUREMENTS AND MAIN RESULTS: The median age was 78 years (interquartile range, 71-84 yr), and 54% received mechanical ventilation for a median of 7 days (interquartile range, 3-16 d). Six subjects (2.6%) received a palliative care consultation during the hospitalization. However, 88% had at least one potential palliative care need; 22% had chronic wounds, 37% were discharged on supplemental oxygen, 17% received chaplaincy services, 23% preferred to not be resuscitated, and 8% were designated "comfort care." The 6-month mortality was 40%. CONCLUSIONS: Older ICU survivors from a single center who required postacute facility care had a high burden of palliative care needs and a high 6-month mortality. The in-hospital postcritical acute care period should be targeted for palliative care assessment and intervention.

Assessment of kidney function in lung transplant candidates.

BACKGROUND: Glomerular filtration rate (GFR) is the best measure of kidney function; however, 24-hour creatinine clearance (CrCl) is the initial screening test used for lung transplant candidates at most centers. Although creatinine-based formulas that estimate GFR have been derived, none have been validated in patients with severe lung disease. METHODS: We performed a retrospective cohort study of patients evaluated for lung transplantation at Columbia Presbyterian Medical Center and compared the GFR estimated from the Modification of Diet in Renal Disease (MDRD) and other formulas to the CrCl. We then validated these results in a cohort of patients evaluated at the Hospital of the University of Pennsylvania. RESULTS: There were strong and statistically significant direct correlations between estimated GFR and CrCl. An estimated GFR of <95 ml/min by the MDRD was very sensitive at detecting kidney dysfunction by CrCl in the derivation cohort. In the validation cohort, the negative predictive value of this cut-off was 97%. CONCLUSIONS: Established formulas for estimating GFR are highly discriminating for kidney dysfunction in patients being evaluated for lung transplantation and may actually have greater validity than CrCl in some instances.

Racial differences in waiting list outcomes in chronic obstructive pulmonary disease.

RATIONALE: Blacks with chronic illness have poorer outcomes than whites in the United States. The health outcomes of minorities with chronic obstructive pulmonary disease (COPD) on the lung transplant waiting list have not been studied. OBJECTIVES: To compare outcomes of black and white patients with COPD after listing for lung transplantation in the United States. METHODS: Retrospective cohort study of all 280 non-Hispanic black and 5,272 non-Hispanic white adults 40 years and older with COPD listed for lung transplantation in the United States between 1995 and 2004. MEASUREMENTS AND MAIN RESULTS: Blacks with COPD were more likely to have pulmonary hypertension, obesity, and diabetes; to lack private health insurance; and to live in poorer neighborhoods than whites. Blacks were less likely to undergo transplantation after listing compared with whites, despite adjustment for age, lung function, pulmonary hypertension, cardiovascular risk factors, insurance coverage, and poverty level (adjusted hazard ratio, 0.83; 95% confidence interval, 0.70-0.98; P = 0.03). This was accompanied by a greater risk of dying or being removed from the list among blacks (unadjusted hazard ratio, 1.31; 95% confidence interval, 1.05-1.63; P = 0.02). CONCLUSIONS: After listing for lung transplantation, black patients with COPD were less likely to undergo transplantation and more likely to die or be removed from the list compared with white patients. Unequal access to care may have contributed to these differences.