Future Lung Function Research Articles

Identification of factors directly linked to incident chronic obstructive pulmonary disease: A causal graph modeling study.

Beyond exposure to cigarette smoking and aging, the factors that influence lung function decline to incident chronic obstructive pulmonary disease (COPD) remain unclear. Advancements have been made in categorizing COPD into emphysema and airway predominant disease subtypes; however, predicting which healthy individuals will progress to COPD is difficult because they can exhibit profoundly different disease trajectories despite similar initial risk factors. This study aimed to identify clinical, genetic, and radiological features that are directly linked-and subsequently predict-abnormal lung function. We employed graph modeling on 2,643 COPDGene participants (aged 45 to 80 years, 51.25% female, 35.1% African Americans; enrollment 11/2007-4/2011) with smoking history but normal spirometry at study enrollment to identify variables that are directly linked to future lung function abnormalities. We developed logistic regression and random forest predictive models for distinguishing individuals who maintain lung function from those who decline. Of the 131 variables analyzed, 6 were identified as informative to future lung function abnormalities, namely forced expiratory flow in the middle range (FEF25-75%), average lung wall thickness in a 10 mm radius (Pi10), severe emphysema, age, sex, and height. We investigated whether these features predict individuals leaving GOLD 0 status (normal spirometry according to Global Initiative for Obstructive Lung Disease (GOLD) criteria). Linear models, trained with these features, were quite predictive (area under receiver operator characteristic curve or AUROC = 0.75). Random forest predictors performed similarly to logistic regression (AUROC = 0.7), indicating that no significant nonlinear effects were present. The results were externally validated on 150 participants from Specialized Center for Clinically Oriented Research (SCCOR) cohort (aged 45 to 80 years, 52.7% female, 4.7% African Americans; enrollment: 7/2007-12/2012) (AUROC = 0.89). The main limitation of longitudinal studies with 5- and 10-year follow-up is the introduction of mortality bias that disproportionately affects the more severe cases. However, our study focused on spirometrically normal individuals, who have a lower mortality rate. Another limitation is the use of strict criteria to define spirometrically normal individuals, which was unavoidable when studying factors associated with changes in normalized forced expiratory volume in 1 s (FEV1%predicted) or the ratio of FEV1/FVC (forced vital capacity). This study took an agnostic approach to identify which baseline measurements differentiate and predict the early stages of lung function decline in individuals with previous smoking history. Our analysis suggests that emphysema affects obstruction onset, while airway predominant pathology may play a more important role in future FEV1 (%predicted) decline without obstruction, and FEF25-75% may affect both.

Mucus Plugs as Precursors to Exacerbation and Lung Function Decline in COPD Patients

BackgroundMucus plugs identified through chest computed tomography (CT) scans have emerged as potential prognostic factors in chronic obstructive pulmonary disease (COPD). This 5-year longitudinal study investigated their impact on exacerbations and FEV1 decline. MethodsCOPD patients with baseline chest CT and spirometric assessments were categorized based on mucus plug presence. Propensity-score matching yielded balanced groups. Exacerbation rates, time to exacerbation events, hazard ratio (HR) for exacerbations, and annual rates of FEV1 decline were evaluated. Sensitivity analysis was performed with stratification according to mucus plug scores of 0, 1–2, and ≥3. ResultsAmong 623 eligible patients, the mucus plug group was 44.3%. Through 1:1 propensity-score matching, each group was comprised of 187 individuals with balanced covariates. The mucus plug group showed higher rates of moderate-to-severe (0.51/year vs. 0.58/year, P=0.035), severe exacerbations (0.21/year vs. 0.24/year, P=0.032), and non-eosinophilic exacerbations (0.45/year vs. 0.52/year, P=0.008). Mucus plugs were associated with increased hazard of moderate-to-severe (adjusted HR=1.502 [95% CI 1.116–2.020]), severe (adjusted HR=2.106 [95% CI, 1.429–3.103]), and non-eosinophilic exacerbations (adjusted HR=1.551 [95% CI, 1.132–2.125]). Annual FEV1 decline was accelerated in the mucus plug group (β-coefficient=−62 [95% CI, −120 to −5], P=0.035). Sensitivity analysis showed higher risk of exacerbations and accelerated FEV1 decline in mucus plug score ≥3 compared to score 0. ConclusionsMucus plugs are associated with increased risks of exacerbations, particularly non-eosinophilic, and accelerated FEV1 declines over 5 years. Our study identified the potential prognostic value of mucus plugs on future exacerbation risks and lung function decline trajectories.

Pursuing Clinical Predictors and Biomarkers for Progression in ILD: Analysis of the Pulmonary Fibrosis Foundation (PFF) Registry

IntroductionPulmonary fibrosis is a characteristic of various interstitial lung diseases (ILDs) with differing etiologies. Clinical trials in progressive pulmonary fibrosis (PPF) enroll patients based on previously described clinical criteria for past progression, which include a clinical practice guideline for PPF classification and inclusion criteria from the INBUILD trial. In this study, we compared the ability of past FVC (forced vital capacity) progression and baseline biomarker levels to predict future progression in a cohort of patients from the PFF Patient Registry.MethodsBiomarkers previously associated with pathobiology and/or progression in pulmonary fibrosis were selected to reflect cellular senescence (telomere length), pulmonary epithelium (SP-D, RAGE), myeloid activation (CXCL13, YKL40, CCL18, OPN) and fibroblast activation (POSTN, COMP, PROC3).ResultsPFF or INBUILD-like clinical criteria was used to separate patients into past progressor and non-past progressor groups, and neither clinical criterion appeared to enrich for patients with greater future lung function decline. All baseline biomarkers measured were differentially expressed in patient groups compared to healthy controls. Baseline levels of SP-D and POSTN showed the highest correlations with FVC slope over one year, though correlations were low.ConclusionsOur findings provide further evidence that prior decline in lung function may not predict future disease progression for ILD patients, and elevate the need for molecular definitions of a progressive phenotype. Across ILD subtypes, certain shared pathobiologies may be present based on the molecular profile of certain biomarker groups observed. In particular, SP-D may be a common marker of pulmonary injury and future lung function decline across ILDs.

Identification of Siglec-1-negative alveolar macrophages with proinflammatory phenotypes in chronic obstructive pulmonary disease.

Alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD) orchestrate persistent inflammation in the airway. However, subpopulations of AMs participating in chronic inflammation have been poorly characterized. We previously reported that Siglec-1 expression on AMs, which is important for bacteria engulfment, was decreased in COPD. Here, we show that Siglec-1-negative AMs isolated from COPD lung tissues exhibit a proinflammatory phenotype and are associated with poor clinical outcomes in patients with COPD. Using flow cytometry, we segregated three subsets of AMs based on the expression of Siglec-1 and their side scattergram (SSC) and forward scattergram (FSC) properties: Siglec-1+SSChiFSChi, Siglec-1-SSChiFSChi, and Siglec-1-SSCloFSClo subsets. The Siglec-1-SSCloFSClo subset number was increased in COPD. RNA sequencing revealed upregulation of multiple proinflammatory signaling pathways and emphysema-associated matrix metalloproteases in the Siglec-1-SSCloFSClo subset. Gene set enrichment analysis indicated that the Siglec-1-SSCloFSClo subset adopted intermediate phenotypes between monocytes and mature alveolar macrophages. Functionally, these cells produced TNF-α, IL-6, and IL-8 at baseline, and these cytokines were significantly increased in response to viral RNA. The increase in Siglec-1-negative AMs in induced sputum is associated with future exacerbation risk and lung function decline in patients with COPD. Collectively, the novel Siglec-1-SSCloFSClo subset of AMs displays proinflammatory properties, and their emergence in COPD airways may be associated with poor clinical outcomes.NEW & NOTEWORTHY Alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD) orchestrate persistent inflammation in the airway. We find that Siglec-1-negative alveolar macrophages have a wide range of proinflammatory landscapes and a protease-expressing phenotype. Moreover, this subset is associated with the pathogenesis of COPD and responds to viral stimuli.

Pulmonary function outcomes after tuberculosis treatment in children: a systematic review and meta-analysis

BackgroundDespite tuberculosis (TB) being a curable disease, current guidelines fail to account for the long-term outcomes of post-tuberculosis lung disease—a cause of global morbidity despite successful completion of effective treatment....

Predicting Individualized Lung Disease Progression in Treatment-Naive Patients With Lymphangioleiomyomatosis

Lung function decline varies significantly in patients with lymphangioleiomyomatosis (LAM), impeding individualized clinical decision-making. Can we aid individualized decision-making in LAM by developing a dynamic prediction model that can estimate the probability of clinically relevant FEV1 decline in patients with LAM before treatment initiation? Patients observed in the US National Heart, Lung, and Blood Institute (NHLBI) Lymphangioleiomyomatosis Registry were included. Using routinely available variables such as age at diagnosis, menopausal status, and baseline lung function (FEV1 and diffusing capacity of the lungs for carbon monoxide [Dlco]), we used novel stochastic modeling and evaluated predictive probabilities for clinically relevant drops in FEV1. We formed predictive probabilities of transplant-free survival by jointly modeling longitudinal FEV1 and lung transplantation or death events. External validation used the UK Lymphangioleiomyomatosis Natural History cohort. Analysis of the NHLBI Lymphangioleiomyomatosis Registry and UK Lymphangioleiomyomatosis Natural History cohorts consisted of 216 and 185 individuals, respectively. We derived a joint model that accurately estimated the risk of future lung function decline and 5-year probabilities of transplant-free survival in patients with LAM not taking sirolimus (area under the receiver operating characteristic curve [AUC], approximately 0.80). The prediction model provided estimates of forecasted FEV1, rate of FEV1 decline, and probabilities for risk of prolonged drops in FEV1 for untreated patients with LAM with a high degree of accuracy (AUC > 0.80) for the derivation cohort as well as the validation cohort. Our tool is freely accessible at: https://anushkapalipana.shinyapps.io/testapp_v2/. Longitudinal modeling of routine clinical data can allow individualized LAM prognostication and assist in decision-making regarding the timing of treatment initiation.

Biomarkers of asthma relapse and lung function decline in adults with spontaneous asthma remission: A population-based cohort study.

The extent to which biomarkers of asthma activity persist in spontaneous asthma remission and whether such markers are associated with future respiratory outcomes remained unclear. We investigated the association between sub-clinical inflammation in adults with spontaneous asthma remission and future asthma relapse and lung function decline. The Tasmanian Longitudinal Health Study is a population-based cohort (n=8583). Biomarkers of systemic inflammation were measured on participants at age 45, and latent profile analysis was used to identify cytokine profiles. Bronchial hyperresponsiveness (BHR) and nitric oxide products in exhaled breath condensate (EBC NOx) were measured at age 50. Participants with spontaneous asthma remission at ages 45 (n=466) and 50 (n=318) were re-evaluated at age 53, and associations between baseline inflammatory biomarkers and subsequent asthma relapse and lung function decline were assessed. We identified three cytokine profiles in adults with spontaneous asthma remission: average (34%), Th2-high (42%) and Th2-low (24%). Compared to the average profile, a Th2-high profile was associated with accelerated decline in post-BD FEV1 /FVC (MD -0.18% predicted per-year; 95% CI -0.33, -0.02), while a Th2-low profile was associated with accelerated decline in both post-BD FEV1 (-0.41%; -0.75, -0.06) and post-BD FVC (-0.31%; -0.62, 0.01). BHR and high TNF-α during spontaneous remission were associated with an increased risk of asthma relapse. In contrast, we found no evidence of association between EBC NOx and either asthma relapse or lung function decline. BHR and serum inflammatory cytokines have prognostic value in adults with spontaneous asthma remission. At-risk individuals with BHR, Th2-high or Th2-low cytokine profiles may benefit from closer monitoring and on-going follow-up.

Bronchiectasis - Exercise as Therapy (BREATH): rationale and study protocol for a multi-center randomized controlled trial

BackgroundGlobally, bronchiectasis (BE) unrelated to cystic fibrosis (CF) is recognized as a major cause of respiratory morbidity, mortality, and healthcare utilization. Children with BE regularly experience exacerbations of their condition resulting in frequent hospitalizations and decreased health-related quality of life (HR-QoL). Guidelines for the treatment and management of BE call for regular exercise as a means of improving aerobic fitness and HR-QoL. Moreover, research in adults with BE has shown that exercise can reduce the frequency of exacerbations, a potent predictor of future lung function decline and respiratory morbidity. Yet, to date, the health benefits resulting from therapeutic exercise have not been investigated in children with BE. The BREATH, Bronchiectasis - Exercise as Therapy, trial will test the efficacy of a novel 8-week, play-based therapeutic exercise program to reduce the frequency of acute exacerbations over 12 months in children with BE (aged ≥ 4 and < 13 years). Secondary aims are to determine the cost-effectiveness of the intervention and assess the program’s impact on aerobic fitness, fundamental movement skill (FMS) proficiency, habitual physical activity, HR-QoL, and lung function.MethodsThis multi-center, observer-blinded, parallel-group (1:1 allocation), randomized controlled trial (RCT) will be conducted at three sites. One hundred and seventy-four children ≥ 4 and < 13 years of age with BE will be randomized to a developmentally appropriate, play-based therapeutic exercise program (eight, 60-min weekly sessions, supplemented by a home-based program) or usual care. After completing the baseline assessments, the number of exacerbations and secondary outcomes will be assessed immediately post-intervention, after 6 months of follow-up, and after 12 months of follow-up. Monthly, parental contact and medical review will document acute respiratory exacerbations and parameters for cost-effectiveness outcomes.DiscussionThe BREATH trial is the first fully powered RCT to test the effects of a therapeutic exercise on exacerbation frequency, fitness, movement competence, and HR-QoL in children with bronchiectasis. By implementing a developmentally appropriate, play-based exercise program tailored to the individual needs of children with bronchiectasis, the results have the potential for a major paradigm shift in the way in which therapeutic exercise is prescribed and implemented in children with chronic respiratory conditions. The exercise program can be readily translated. It does not require expensive equipment and can be delivered in a variety of settings, including the participant’s home. The program has strong potential for translation to other pediatric patient groups with similar needs for exercise therapy, including those with obesity, childhood cancers, and neurological conditions such as cerebral palsy.Trial registrationAustralian and New Zealand Clinical Trials Register (ANZCTR) ACTRN12619001008112

Prognostic Value of First Post-Transplant Lung Function

<h3>Purpose</h3> Normalization of lung function after transplant is an important milestone and determinant of survival. We tested the relationship between first post-transplant lung function and the maximal (baseline) function, as well the association with future lung dysfunction phenotypes, survival and potential pretransplant predictors. <h3>Methods</h3> We analyzed patients who underwent double lung transplant at our center between 2004 and 2016, assessing their first and maximum (baseline) forced expiratory volume in 1 second (FEV1) percent predicted. We tested the relationship between first and maximum FEV1% predicted via correlation coefficient. We secondarily analyzed the relationship between first FEV1% predicted and the future risk of baseline lung allograft dysfunction (BLAD) via logistic regression and time to chronic lung allograft dysfunction (CLAD) onset and overall survival via Cox regression. We assessed for pretransplant factors associated with first FEV1% predicted by t-tests and correlation coefficients. <h3>Results</h3> We analyzed 446 patients with a mean first FEV1 of 2.14L (SD 0.70) and FEV1% predicted of 63.8% (SD 16.8), performed at a median of 23 days post-transplant (IQR 16-38). First function was strongly associated with maximal baseline function (corr coeff 0.5955, p<0.0001; figure 1). First FEV1% < 80% predicted strongly increased the risk of BLAD (odds ratio 7.89 (95% CI 3.91-18.20, p<0.0001), but not of death or time to CLAD onset. Grade 3 PGD and longer ventilation, ICU stay and hospitalization were all associated with lower first function, but time to first function was not. Pre- and peritransplant factors associated with first function < 80% predicted were: younger recipient age, older and female donors, use of cardiopulmonary bypass and use of IL2RA induction. <h3>Conclusion</h3> First FEV1% predicted is an important milestone associated with future baseline lung function, but not with future risk of death or CLAD onset. Future work into whether this early value is modifiable would be of use.

A personalized biomedical risk assessment infographic for people who smoke with COPD: a qualitative study

BackgroundChronic obstructive pulmonary disease (COPD) causes 3 million deaths each year, yet 38% of COPD patients continue to smoke. Despite proof of effectiveness and universal guideline recommendations, smoking cessation interventions are underused in practice. We sought to develop an infographic featuring personalized biomedical risk assessment through future lung function decline prediction (with vs without ongoing smoking) to both prompt and enhance clinician delivery of smoking cessation advice and pharmacotherapy, and augment patient motivation to quit.MethodsWe recruited patients with COPD and pulmonologists from a quaternary care center in Toronto, Canada. Infographic prototype content and design was based on best evidence. After face validation, the prototype was optimized through rapid-cycle design. Each cycle consisted of: (1) infographic testing in a moderated focus group and a clinician interview (recorded/transcribed) (with questionnaire completion); (2) review of transcripts for emergent/critical findings; and (3) infographic modifications to address findings (until no new critical findings emerged). We performed iterative transcript analysis after each cycle and a summative qualitative transcript analysis with quantitative (descriptive) questionnaire analysis.ResultsStopping criteria were met after 4 cycles, involving 20 patients (58% male) and 4 pulmonologists (50% male). The following qualitative themes emerged: Tool content (infographic content preferences); Tool Design (infographic design preferences); Advantages of Infographic Messaging (benefits of an infographic over other approaches); Impact of Tool on Determinants of Smoking Cessation Advice Delivery (impact on barriers and enablers to delivery of smoking cessation advice in practice); and Barriers and Enablers to Quitting (impact on barriers and enablers to quitting). Patient Likert scale ratings of infographic content and format/usability were highly positive, with improvements in scores for 20/21 questions through the design process. Providers scored the infographic at 77.8% (“superior”) on the Suitability Assessment of Materials questionnaire.ConclusionsWe developed a user preference-based personalized biomedical risk assessment infographic to drive smoking cessation in patients with COPD. Our findings suggest that this tool could impact behavioural determinants of provider smoking-cessation advice delivery, while increasing patient quit motivation. Impacts of the tool on provider care, patient motivation to quit, and smoking cessation success should now be evaluated in real-world settings.

Inhaled Corticosteroids Alone and in Combination With Long-Acting β2 Receptor Agonists to Treat Reduced Lung Function in Preterm-Born Children

Decreases in future lung function are a hallmark of preterm birth, but studies for management of decreased lung function are limited. To determine whether 12 weeks of treatment with inhaled corticosteroids (ICS) alone or in combination with long-acting β2 agonists (LABA) improves spirometry and exercise capacity in school-aged preterm-born children who had percent predicted forced expiratory volume in 1 second (%FEV1) less than or equal to 85% compared with inhaled placebo treatment. A double-blind, randomized, placebo-controlled trial was conducted to evaluate ICS and ICS/LABA against placebo. Preterm-born children (age, 7-12 years; gestation ≤34 weeks at birth) who did not have clinically significant congenital, cardiopulmonary, or neurodevelopmental abnormalities underwent spirometry, exercise testing, and measurement of fractional exhaled nitric oxide before and after treatment. A total of 144 preterm-born children at the Children's Hospital for Wales in Cardiff, UK, were identified and enrolled between July 1, 2017, and August 31, 2019. Each child was randomized to 1 of 3 cohorts: fluticasone propionate, 50 μg, with placebo; fluticasone propionate, 50 μg, with salmeterol, 25 μg; or placebo inhalers, all given as 2 puffs twice daily for 12 weeks. Children receiving preexisting ICS treatment underwent washout prior to randomization to ICS or ICS/LABA. The primary outcome was between-group differences assessed by adjusted pretreatment and posttreatment differences of %FEV1 using analysis of covariance. Intention-to-treat analysis was conducted. Of 144 preterm-born children who were identified with %FEV1 less than or equal to 85%, 53 were randomized. Treatment allocation was 20 children receiving ICS (including 5 with prerandomization ICS), 19 children receiving ICS/LABA (including 4 with prerandomization ICS), and 14 children receiving placebo. The mean (SD) age of children was 10.8 (1.2) years, and 29 of the randomized children (55%) were female. The posttreatment %FEV1 was adjusted for sex, gestation, bronchopulmonary dysplasia, intrauterine growth restriction, pretreatment corticosteroid status, treatment group, and pretreatment values. Posttreatment adjusted means for %FEV1, using analysis of covariance, were 7.7% (95% CI, -0.27% to 15.72%; P = .16) higher in the ICS group and 14.1% (95% CI, 7.3% to 21.0%; P = .002) higher in the ICS/LABA group compared with the placebo group. Active treatment decreased the fractional exhaled nitric oxide and improved postexercise bronchodilator response but did not improve exercise capacity. One child developed cough when starting inhaler treatment; no other adverse events reported during the trial could be attributed to the inhaler treatment. The results of this randomized clinical trial suggest that combined ICS/LABA treatment is beneficial for prematurity-associated lung disease in children. EudraCT number: 2015-003712-20.

Recent advances in airway imaging using micro-computed tomography and computed tomography for chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a complex lung disease characterized by a combination of airway disease and emphysema. Emphysema is classified as centrilobular emphysema (CLE), paraseptal emphysema (PSE), or panlobular emphysema (PLE), and airway disease extends from the respiratory, terminal, and preterminal bronchioles to the central segmental airways. Although clinical computed tomography (CT) cannot be used to visualize the small airways, micro-CT has shown that terminal bronchiole disease is more severe in CLE than in PSE and PLE, and micro-CT findings suggest that the loss and luminal narrowing of terminal bronchioles is an early pathological change in CLE. Furthermore, the introduction of ultra-high-resolution CT has enabled direct evaluation of the proximal small (1 to 2-mm diameter) airways, and new CT analytical methods have enabled estimation of small airway disease and prediction of future COPD onset and lung function decline in smokers with and without COPD. This review discusses the literature on micro-CT and the technical advancements in clinical CT analysis for COPD. Hopefully, novel micro-CT findings will improve our understanding of the distinct pathogeneses of the emphysema subtypes to enable exploration of new therapeutic targets, and sophisticated CT imaging methods will be integrated into clinical practice to achieve more personalized management.

Sex-specific longitudinal association of DNA methylation with lung function.

Investigating whether DNA methylation (DNA-M) at an earlier age is associated with lung function at a later age and whether this relationship differs by sex could enable prediction of future lung function deficit.A training/testing-based technique was used to screen 402 714 cytosine-phosphate-guanine dinucleotide sites (CpGs) to assess the longitudinal association of blood-based DNA-M at ages 10 and 18 years with lung function at 18 and 26 years, respectively, in the Isle of Wight birth cohort (IOWBC). Multivariable linear mixed models were applied to the CpGs that passed screening. To detect differentially methylated regions (DMRs), DMR enrichment analysis was conducted. Findings were further examined in the Avon Longitudinal Study of Parents and Children (ALSPAC). Biological relevance of the identified CpGs was assessed using gene expression data.DNA-M at eight CpGs (five CpGs with forced expiratory volume in 1 s (FEV1) and three CpGs with FEV1/forced vital capacity (FVC)) at an earlier age was associated with lung function at a later age regardless of sex, while at 13 CpGs (five CpGs with FVC, three with FEV1 and five with FEV1/FVC), the associations were sex-specific (pFDR<0.05) in IOWBC, with consistent directions of association in ALSPAC (IOWBC-ALSPAC consistent CpGs). cg16582803 (WNT10A) and cg14083603 (ZGPAT) were replicated in ALSPAC for main and sex-specific effects, respectively. Among IOWBC-ALSPAC consistent CpGs, DNA-M at cg01376079 (SSH3) and cg07557690 (TGFBR3) was associated with gene expression both longitudinally and cross-sectionally. In total, 57 and 170 DMRs were linked to lung function longitudinally in males and females, respectively.CpGs showing longitudinal associations with lung function have the potential to serve as candidate markers in future studies on lung function deficit prediction.

Atelectasis in primary graft dysfunction survivors after lung transplantation.

Primary graft dysfunction (PGD) is an important contributor to early mortality in lung transplant recipients and is associated with impaired lung function. The radiographic sequelae of PGD on computed tomography (CT) have not been characterized. We studied adult double lung transplant recipients from 2010 to 2016 for whom protocol 3-month post-transplant CT scans were available. We assessed CTs for changes including pleural effusions, ground glass opacification, atelectasis, centrilobular nodularity, consolidation, interlobular septal thickening, air trapping and fibrosis, and their relationship to prior post-transplant PGD, future lung function, post-transplant baseline lung allograft dysfunction (BLAD), and chronic lung allograft dysfunction (CLAD). Of 237 patients studied, 50 (21%) developed grade 3 PGD (PGD3) at 48 or 72h. PGD3 was associated with increased interlobular septal thickening (p=.0389) and atelectasis (p=.0001) at 3months, but only atelectasis remained associated after correction for multiple testing. Atelectasis severity was associated with lower peak forced expiratory volume in 1s (FEV1) and increased risk of BLAD (p=.0014) but not with future CLAD onset (p=.7789). Severe PGD was associated with atelectasis on 3-month post-transplant CT in our cohort. Atelectasis on routine CT may be an intermediary identifiable stage between PGD and future poor lung function.

Increased serum SP-D in identification of high-risk smokers at high risk of COPD.

Pulmonary surfactant protein D (SP-D) is an important component of the pulmonary innate immune system with the ability to dampen cigarette smoke-induced lung inflammation. However, cigarette smoking mediates translocation of SP-D from the lung to the blood, and serum SP-D (sSP-D) has therefore previously been suggested as marker for smoke-induced lung injury. In support of this notion, associations between high sSP-D and low lung function measurements have previously been demonstrated in smokers and in chronic obstructive lung disease (COPD). The present investigations employ a 12-yr longitudinal Danish twin study to test the hypothesis that baseline sSP-D variation has the capacity to identify smokers with normal baseline lung function who are at high risk of significant future smoke-induced lung function decline. We find that sSP-D is significantly increased in those with normal lung function at baseline who develop lung function decline during follow-up compared with those who stay lung healthy. Moreover, we demonstrate that it is the smoke-induced baseline sSP-D level, and not the constitutional level, which has capacity as biomarker, and which is linearly increased with the decline in lung function during follow-up. In conclusion, we here present first observation of increased sSP-D for identification of high-risk smokers.

Quantitative CT metrics are associated with longitudinal lung function decline and future asthma exacerbations: Results from SARP-3

Currently, there is limited knowledge regarding which imaging assessments of asthma are associated with accelerated longitudinal decline in lung function. We aimed to assess whether quantitative computed tomography (qCT) metrics are associated with longitudinal decline in lung function and morbidity in asthma. We analyzed 205 qCT scans of adult patients with asthma and calculated baseline markers of airway remodeling, lung density, and pointwise regional change in lung volume (Jacobian measures) for each participant. Using multivariable regression models, we then assessed the association of qCT measurements with the outcomes of future change in lung function, future exacerbation rate, and changes in validated measurements of morbidity. Greater baseline wall area percent (β= -0.15 [95% CI= -0.26 to -0.05]; P< .01), hyperinflation percent (β= -0.25 [95% CI= -0.41 to -0.09]; P < .01), and Jacobian gradient measurements (cranial-caudal β= 10.64 [95% CI= 3.79-17.49]; P< .01; posterior-anterior β= -9.14, [95% CI= -15.49 to -2.78]; P< .01) were associated with more severe future lung function decline. Additionally, greater wall area percent (rate ratio= 1.06 [95% CI= 1.01-1.10]; P= .02) and air trapping percent (rate ratio=1.01 [95% CI= 1.00-1.02]; P= .03), as well as lower decline in the Jacobian determinant mean (rate ratio= 0.58 [95% CI= 0.41-0.82]; P< .01) and Jacobian determinant standard deviation (rate ratio= 0.52 [95% CI= 0.32-0.85]; P= .01), were associated with a greater rate of future exacerbations. However, imaging metrics were not associated with clinically meaningful changes in scores on validated asthma morbidity questionnaires. Baseline qCT measures of more severe airway remodeling, more small airway disease and hyperinflation, andless pointwise regional change in lung volumes were associated with future lung function decline and asthma exacerbations.

Unsupervised phenotypic clustering for determining clinical status in children with cystic fibrosis.

Cystic fibrosis (CF) is a multisystem disease in which the assessment of disease severity based on lung function alone may not be appropriate. The aim of the study was to develop a comprehensive machine-learning algorithm to assess clinical status independent of lung function in children. A comprehensive prospectively collected clinical database (Toronto, Canada) was used to apply unsupervised cluster analysis. The defined clusters were then compared by current and future lung function, risk of future hospitalisation, and risk of future pulmonary exacerbation treated with oral antibiotics. A k-nearest-neighbours (KNN) algorithm was used to prospectively assign clusters. The methods were validated in a paediatric clinical CF dataset from Great Ormond Street Hospital (GOSH). The optimal cluster model identified four (A-D) phenotypic clusters based on 12 200 encounters from 530 individuals. Two clusters (A and B) consistent with mild disease were identified with high forced expiratory volume in 1 s (FEV1), and low risk of both hospitalisation and pulmonary exacerbation treated with oral antibiotics. Two clusters (C and D) consistent with severe disease were also identified with low FEV1. Cluster D had the shortest time to both hospitalisation and pulmonary exacerbation treated with oral antibiotics. The outcomes were consistent in 3124 encounters from 171 children at GOSH. The KNN cluster allocation error rate was low, at 2.5% (Toronto) and 3.5% (GOSH). Machine learning derived phenotypic clusters can predict disease severity independent of lung function and could be used in conjunction with functional measures to predict future disease trajectories in CF patients.

Osteopontin Links Myeloid Activation and Disease Progression in Systemic Sclerosis

SummaryProgressive lung fibrosis is a major cause of mortality in systemic sclerosis (SSc) patients, but the underlying mechanisms remain unclear. We demonstrate that immune complexes (ICs) activate human monocytes to promote lung fibroblast migration partly via osteopontin (OPN) secretion, which is amplified by autocrine monocyte colony stimulating factor (MCSF) and interleukin-6 (IL-6) activity. Bulk and single-cell RNA sequencing demonstrate that elevated OPN expression in SSc lung tissue is enriched in macrophages, partially overlapping with CCL18 expression. Serum OPN is elevated in SSc patients with interstitial lung disease (ILD) and prognosticates future lung function deterioration in SSc cohorts. Serum OPN levels decrease following tocilizumab (monoclonal anti-IL-6 receptor) treatment, confirming the connection between IL-6 and OPN in SSc patients. Collectively, these data suggest a plausible link between autoantibodies and lung fibrosis progression, where circulating OPN serves as a systemic proxy for IC-driven profibrotic macrophage activity, highlighting its potential as a promising biomarker in SSc ILD.

Heterogeneity of Mild to Moderate Persistent Asthma in Children: Confirmation by Latent Class Analysis and Association with 1-Year Outcomes

Compared with adults, phenotypic characterization of children with asthma is still limited and it remains difficult to predict which children with asthma are at highest risk for poor outcomes. To identify latent classes in a large population of treatment-adherent children with mild to moderate asthma enrolled in clinical trials and determine whether latent class assignment predicts future lung function abnormalities and exacerbation rate. Latent class analysis was performed on 2593 children with mild to moderate asthma aged 5 18 years, with 19 variables encompassing demographic characteristics, medical history, symptoms, lung function, allergic sensitization, and type 2 inflammation. Outcomes included lung function and the annualized exacerbation rate at 12 months of follow-up. Five latent classes were identified with differing demographic features, asthma control, sensitization, type 2 inflammatory markers, and lung function. Exacerbation rates were 1.30 ± 0.12 for class 1 (multiple sensitization with partially reversible airflow limitation), 0.90 ± 0.05 for class 2 (multiple sensitization with reversible airflow limitation), 0.87 ± 0.08 for class 3 (lesser sensitization with reversible airflow limitation), 0.87 ± 0.05 for class 4 (multiple sensitization with normal lung function), and 0.71 ± 0.06 for class 5 (lesser sensitization with normal lung function). Lung function abnormalities persisted in class 1 at 12 months. Children with mild to moderate asthma are a heterogeneous group. Allergic sensitization and lung function may be particularly useful in identifying children at the greatest risk for future exacerbation. Additional studies are needed to determine whether latent classes correspond to meaningful phenotypes for the purpose of personalized treatment.

An Individualized Prediction Model for Long-term Lung Function Trajectory and Risk of COPD in the General Population

Prediction of future lung function will enable the identification of individuals at high risk of developing COPD, but the trajectory of lung function decline varies greatly among individuals. This study involved the development and validation of an individualized prediction model of lung function trajectory and risk of airflow limitation in the general population. Data were obtained from the Framingham Offspring Cohort, which included 4,167 participants≥ 20 years of age and who had≥ 2 valid spirometry assessments. The primary outcome was prebronchodilator FEV1; the secondary outcome was the risk of airflow limitation (defined as FEV1/FVC less than the lower limit of normal). Mixed effects regression models were developed for individualized prediction, and a machine learning algorithm was used to determine essential predictors. The model was validated in two large, independent multicenter cohorts (N= 2,075 and 12,913, respectively). With 20 common predictors, the model explained 79%of the variation in FEV1 decline in the derivation cohort. In two validation datasets, the model had low error in predicting FEV1 decline (root mean square error range, 0.18-0.22 L) and high discriminative power in predicting risk of airflow limitation (C-statistic range, 0.86-0.87). This model was implemented in a freely accessible website-based application, which allows prediction based on flexible sets of predictors (http://resp.core.ubc.ca/ipress/FraminghamFEV1). The individualized predictor is an accurate tool to predict long-term lung function trajectories and risk of airflow limitation in the general population. This model enables identifying individuals at higher risk of COPD, who can then be targeted for preventive therapies.