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ObjectiveTo assess survival and identify predictors of survival in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) who participated in the Scleroderma Lung Studies (SLS) I and II.MethodsSLS I randomised 158 patients with SSc-ILD to 1  year of oral cyclophosphamide (CYC) vs placebo. SLS II randomised 142 patients to 1 year of oral CYC followed by 1 year of placebo vs 2 years of mycophenolate mofetil. Counting process Cox proportional hazard modelling identified variables associated with long-term mortality in SLS I and II. Internal validation was performed using joint modelling.ResultsAfter a median follow-up of 8 years, 42% of SLS I patients died, and when known the cause of death was most often attributable to SSc. There was no significant difference in the time to death between treatment arms in SLS I or II. Higher baseline skin score, older age, and a decline in the forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) over 2 years were independently associated with an increased risk of mortality in SLS I. The Cox model identified the same mortality predictor variables using the SLS II data.ConclusionIn addition to identifying traditional mortality risk factors in SSc (skin score, age), this study demonstrated that a decline in FVC and DLCO over 2 years was a better predictor of mortality than baseline FVC and DLCO. These findings suggest that short-term changes in surrogate measures of SSc-ILD progression may have important effects on long-term outcomes.

Objective To investigate whether an early rehabilitation intervention initiated during acute admission for exacerbations of chronic respiratory disease reduces the risk of readmission over 12 months and ameliorates the negative effects of the episode on physical performance and health status.Design Prospective, randomised controlled trial.Setting An acute cardiorespiratory unit in a teaching hospital and an acute medical unit in an affiliated teaching district general hospital, United Kingdom.Participants 389 patients aged between 45 and 93 who within 48 hours of admission to hospital with an exacerbation of chronic respiratory disease were randomised to an early rehabilitation intervention (n=196) or to usual care (n=193).Main outcome measures The primary outcome was readmission rate at 12 months. Secondary outcomes included number of hospital days, mortality, physical performance, and health status. The primary analysis was by intention to treat, with prespecified per protocol analysis as a secondary outcome.Interventions Participants in the early rehabilitation group received a six week intervention, started within 48 hours of admission. The intervention comprised prescribed, progressive aerobic, resistance, and neuromuscular electrical stimulation training. Patients also received a self management and education package.Results Of the 389 participants, 320 (82%) had a primary diagnosis of chronic obstructive pulmonary disease. 233 (60%) were readmitted at least once in the following year (62% in the intervention group and 58% in the control group). No significant difference between groups was found (hazard ratio 1.1, 95% confidence interval 0.86 to 1.43, P=0.4). An increase in mortality was seen in the intervention group at one year (odds ratio 1.74, 95% confidence interval 1.05 to 2.88, P=0.03). Significant recovery in physical performance and health status was seen after discharge in both groups, with no significant difference between groups at one year.Conclusion Early rehabilitation during hospital admission for chronic respiratory disease did not reduce the risk of subsequent readmission or enhance recovery of physical function following the event over 12 months. Mortality at 12 months was higher in the intervention group. The results suggest that beyond current standard physiotherapy practice, progressive exercise rehabilitation should not be started during the early stages of the acute illness.Trial registration Current Controlled Trials ISRCTN05557928.

Background The forced vital capacity (FVC) is the most commonly used endpoint in registrational trials for systemic sclerosis-associated interstitial lung disease (SSc-ILD). However, the FVC has known methodological pitfalls, is affected by extra-pulmonary SSc manifestations and may not be clinically meaningful to patients. Combining individual outcomes into a composite endpoint is an attractive alternative for measuring treatment response and augmenting statistical efficiency in SSc-ILD trials. Methods We previously developed a composite endpoint for SSc-ILD using data from the Scleroderma Lung Study (SLS) I (comparing cyclophosphamide versus placebo for SSc-ILD), which included physiological (FVC), radiological (quantitative extent of fibrosis in the zone of maximum involvement) and patient-reported outcomes (transitional dyspnea index and health assessment disability questionnaire), which demonstrated a more robust treatment effect of cyclophosphamide than the FVC alone. The purpose of this post-hoc analysis was to validate this composite endpoint in an external clinical trial cohort (SLS II [cyclophosphamide versus mycophenolate for SSc-ILD). A secondary goal was to determine whether the composite endpoint predicted long-term mortality in SLS I and II. Results Seventy-two of the 142 randomized participants in SLS II had all composite endpoint components at 24 months and were included in this analysis. In both SLS I and II, the standardized effect size (Cohen’s d) was greater when the composite endpoint model was applied than when the FVC alone model was applied. In SLS I and II, the composite endpoint was a better predictor of long-term survival (HR 0.76 vs. 0.98 and 0.59 vs. 0.98, for the composite index vs. FVC Cox proportional hazards models in SLS I and II, respectively). Patients with high composite outcomes scores in both SLS I and II had significantly worse long-term survival than patients with low scores ( p  = 0.039 for log-rank test). Conclusion The results of this post-hoc analysis provide further evidence that a composite endpoint comprised of physiological, radiological and patient-reported outcomes is a promising endpoint for SSc-ILD trials. Future validation studies are needed. Trial registration SLS II: NCT00883129 (Date of registration April 17, 2009); SLS I: NCT00004563 (Date of registration: February 10, 2000).

In interstitial lung disease complicating systemic sclerosis (SSc-ILD), the optimal prognostic use of baseline pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) is uncertain. To construct a readily applicable prognostic algorithm in SSc-ILD, integrating PFTs and HRCT. The prognostic value of baseline PFT and HRCT variables was quantified in patients with SSc-ILD (n = 215) against survival and serial PFT data. Increasingly extensive disease on HRCT was a powerful predictor of mortality (P < 0.0005), with an optimal extent threshold of 20%. In patients with HRCT extent of 10-30% (termed indeterminate disease), an FVC threshold of 70% was an adequate prognostic substitute. On the basis of these observations, SSc-ILD was staged as limited disease (minimal disease on HRCT or, in indeterminate cases, FVC >or= 70%) or extensive disease (severe disease on HRCT or, in indeterminate cases, FVC < 70%). This system (hazards ratio [HR], 3.46; 95% confidence interval [CI], 2.19-5.46; P < 0.0005) was more discriminatory than an HRCT threshold of 20% (HR, 2.48; 95% CI, 1.57-3.92; P < 0.0005) or an FVC threshold of 70% (HR, 2.11; 95% CI, 1.34-3.32; P = 0.001). The system was evaluated by four trainees and four practitioners, with minimal and severe disease on HRCT defined as clearly < 20% or clearly > 20%, respectively, and the use of an FVC threshold of 70% in indeterminate cases. The staging system was predictive of mortality for all scorers, with prognostic separation higher for practitioners (HR, 3.39-3.82) than trainees (HR, 1.87-2.60). An easily applicable limited/extensive staging system for SSc-ILD, based on combined evaluation with HRCT and PFTs, provides discriminatory prognostic information.

New treatments are required for severe breathlessness in advanced disease. We conducted a randomised feasibility trial of mirtazapine over 28 days in adults with a modified medical research council breathlessness scale score ≥3. Sixty-four patients were randomised (409 screened), achieving our primary feasibility endpoint of recruitment. Most patients had COPD or interstitial lung disease; 52 (81%) completed the trial. There were no differences between placebo and mirtazapine in tolerability or safety, and blinding was maintained. Worst breathlessness ratings at day 28 (primary clinical activity endpoint) were, 7.1 (SD 2.3, placebo) and 6.3 (SD 1.8, mirtazapine). A phase III trial of mirtazapine is indicated. Trial registration: ISRCTN 32236160; European Clinical Trials Database (EudraCT no: 2015-004064-11).

Abstract Rationale Palliative care has been focused largely on patients with cancer, and yet patients with chronic lung diseases also have high morbidity and mortality. The majority of deaths in intensive care units (ICUs) follow decisions to withhold or withdraw life-sustaining treatments, suggesting that palliative care is critically important in this setting. Objectives We explored differences in receipt of elements of palliative care among patients with interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD) who die in ICUs compared with patients with cancer. Methods We identified patients with COPD, ILD, or metastatic cancer who died in the ICUs of 15 Seattle-area hospitals between 2003 and 2008. We used robust multivariable logistic and linear regression to compare differences in receipt of elements of palliative care and length of stay. Measurements and Main Results: Compared with patients with cancer, patients with COPD were more likely to receive cardiopulmonary resuscitation before death and patients with ILD were less likely to have documentation of pain assessment in the last day of life. Patients with ILD and COPD were less likely to have a do-not-resuscitate order in place at the time of death and less likely to have documentation of discussions about prognosis than patients with cancer. Patients with COPD had longer hospital lengths of stay, and patients with COPD and ILD had longer ICU lengths of stay. Conclusions Among patients who die in the ICU, patients with ILD and COPD receive fewer elements of palliative care and have longer lengths of stay than patients with cancer. These findings identify areas for improvement in caring for patients with chronic lung diseases. Clinical trial registered with www.clinicaltrials.gov (NCT00685893).

Objective Long-term oxygen therapy (LTOT) during 15 h/day or more prolongs survival in patients with chronic obstructive pulmonary disease (COPD) and severe hypoxemia. No randomized controlled trial has evaluated the net effects (benefits or harms) from LTOT 24 h/day compared with 15 h/day or the effect in conditions other than COPD. We describe a multicenter, national, phase IV, non-superiority, registry-based, randomized controlled trial (R-RCT) of LTOT prescribed 24 h/day compared with 15 h/day. The primary endpoint is all-cause-mortality at 1 year. Secondary endpoints include cause-specific mortality, hospitalizations, health-related quality of life, symptoms, and outcomes in interstitial lung disease. Methods/design Patients qualifying for LTOT are randomized to LTOT 24 h/day versus 15 h/day during 12 months using the Swedish Register for Respiratory Failure (Swedevox). Planned sample size in this pragmatic study is 2126 randomized patients. Clinical follow-up and concurrent treatments are according to routine clinical practice. Mortality, hospitalizations, and incident diseases are assessed using national Swedish registries with expected complete follow-up. Patient-reported outcomes are assessed using postal questionnaire at 3 and 12 months. Discussion The R-RCT approach combines the advantages of a prospective randomized trial and large clinical national registries for enrollment, allocation, and data collection, with the aim of improving the evidence-based use of LTOT. Trial registration Clinical Trial registered with www.clinicaltrials.gov , Title: REgistry-based Treatment Duration and Mortality in Long-term OXygen Therapy (REDOX); ID: NCT03441204.

This study aimed to compare the therapeutic effects of single umbilical cord blood transplantation (UCBT) and unmanipulated haploidentical hematopoietic SCT (haplo-HSCT) in childhood hematologic malignances. We enrolled 410 consecutive children who received either single UCBT ( n =37) or haplo-HSCT from a family donor ( n =373) during the same time period. For each UCBT recipient, three recipients matched for year of HSCT, underlying diseases, disease status and the length of follow-up were randomly selected from the haplo-HSCT cohort. Hematopoietic recovery was significantly faster in haplo-HSCT recipients than in UCBT recipients. The incidence of chronic GVHD was significantly higher in haplo-HSCT recipients. The incidence of CMV-related interstitial pneumonia was higher in UCBT recipients. The haplo-HSCT recipients had better 1-year OS (73.0% vs 56.8%, P =0.048), lower 1-year non-relapse mortality (NRM, 18.0% vs 35.1%, P =0.026) and lower 2-year NRM rates (19.9% vs 35.1%, P =0.044). The relapse- and disease-free survival rates did not differ significantly between the groups. Our results showed that compared with UCBT, unmanipulated haplo-HSCT can improve the outcomes of children with hematologic malignances.

Background: Acute exacerbation of chronic fibrosing interstitial pneumonia (AE-CFIP) is an often fatal condition with no established treatment. Recently, macrolides were found to be beneficial in cases of acute lung injury. Objectives: To examine the clinical effectiveness and safety of intravenous azithromycin in patients hospitalized for AE-CFIP. Methods: A prospective, open-label study with historical controls was conducted. Twenty consecutive patients with AE-CFIP received azithromycin. They were compared with a historical cohort treated with fluoroquinolone (n = 56). All patients received high-dose steroid pulse therapy. The primary end point was mortality at 60 days. The secondary end point was safety of intravenous azithromycin in patients with AE-CFIP. Inverse probability of treatment weighting (IPTW) using the propensity score was performed to investigate the relationship between azithromycin use and survival time. Results: Mortality was significantly lower in the patients treated with azithromycin than in those treated with fluoroquinolone (mortality rate at 60 days: 20 vs. 69.6%, p < 0.001; median survival time: not reached vs. 29.5 days, p < 0.001). The IPTW adjusted hazard of mortality at 60 days in patients receiving azithromycin was 0.17 (95% CI 0.05-0.61). No serious adverse events were observed. Conclusions: Azithromycin was associated with improved outcomes in patients with AE-CFIP. Further studies are needed to verify this finding (Clinical trial JMA-IIA00095).

Abstract Rationale Interstitial lung abnormalities (ILA) are radiologic abnormalities on chest computed tomography scans that have been associated with an early or mild form of pulmonary fibrosis. Although ILA have been associated with radiologic progression, it is not known if specific imaging patterns are associated with progression or risk of mortality. Objectives To determine the role of imaging patterns on the risk of death and ILA progression. Methods ILA (and imaging pattern) were assessed in 5,320 participants from the AGES-Reykjavik Study, and ILA progression was assessed in 3,167 participants. Multivariable logistic regression was used to assess factors associated with ILA progression, and Cox proportional hazards models were used to assess time to mortality. Measurements and Main Results Over 5 years, 327 (10%) had ILA on at least one computed tomography, and 1,435 (45%) did not have ILA on either computed tomography. Of those with ILA, 238 (73%) had imaging progression, whereas 89 (27%) had stable to improved imaging; increasing age and copies of MUC5B genotype were associated with imaging progression. The definite fibrosis pattern was associated with the highest risk of progression (odds ratio, 8.4; 95% confidence interval, 2.7–25; P = 0.0003). Specific imaging patterns were also associated with an increased risk of death. After adjustment, both a probable usual interstitial pneumonia and usual interstitial pneumonia pattern were associated with an increased risk of death when compared with those indeterminate for usual interstitial pneumonia (hazard ratio, 1.7; 95% confidence interval, 1.2–2.4; P = 0.001; hazard ratio, 3.9; 95% confidence interval, 2.3–6.8;P < 0.0001), respectively. Conclusions In those with ILA, imaging patterns can be used to help predict who is at the greatest risk of progression and early death.