Late infantile Batten disease (CLN2 disease) is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations in the
gene encoding tripeptidyl peptidase 1 (TPP1). We tested ...intraparenchymal delivery of AAVrh.10hCLN2, a nonhuman serotype rh.10 adeno-associated virus vector encoding human
, in a nonrandomized trial consisting of two arms assessed over 18 months: AAVrh.10hCLN2-treated cohort of 8 children with mild to moderate disease and an untreated, Weill Cornell natural history cohort consisting of 12 children. The treated cohort was also compared to an untreated European natural history cohort of CLN2 disease. The vector was administered through six burr holes directly to 12 sites in the brain without immunosuppression. In an additional safety assessment under a separate protocol, five children with severe CLN2 disease were treated with AAVrh.10hCLN2. The therapy was associated with a variety of expected adverse events, none causing long-term disability. Induction of systemic anti-AAVrh.10 immunity was mild. After therapy, the treated cohort had a 1.3- to 2.6-fold increase in cerebral spinal fluid TPP1. There was a slower loss of gray matter volume in four of seven children by MRI and a 42.4 and 47.5% reduction in the rate of decline of motor and language function, compared to Weill Cornell natural history cohort (
< 0.04) and European natural history cohort (
< 0.0001), respectively. Intraparenchymal brain administration of AAVrh.10hCLN2 slowed the progression of disease in children with CLN2 disease. However, improvements in vector design and delivery strategies will be necessary to halt disease progression using gene therapy.
Since early in the HIV epidemic, emphysema has been identified among people with HIV (PWH) and has been associated with increased mortality. Smoking cessation is key to risk reduction. Health ...maintenance for PWH and emphysema should ensure appropriate vaccination and lung cancer screening. Treatment should adhere to inhaler guidelines for the general population, but inhaled corticosteroid (ICS) should be used with caution. Frontiers in treatment include targeted therapeutics. Major knowledge gaps exist in the epidemiology of and optimal care for PWH and emphysema, particularly in low and middle-income countries (LMIC).
Topics addressed include risk factors, pathogenesis, current treatment and prevention strategies, and frontiers in research.
There are limited data on the epidemiology of emphysema in LMIC, where more than 90% of deaths from COPD occur and where the morbidity of HIV is most heavily concentrated. The population of PWH is aging, and age-related co-morbidities such as emphysema will only increase in salience. Over the next 5 years, the authors anticipate novel trials of targeted therapy for emphysema specific to PWH, and we anticipate a growing body of evidence to inform optimal clinical care for lung health among PWH in LMIC.
People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) ...trials and lack evidence-based therapies.
To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS).
SPIROMICS II was an extension of SPIROMICS I, a multicenter study of persons aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without COPD and controls without tobacco exposure or airflow obstruction. Participants were enrolled in SPIROMICS I and II from November 10, 2010, through July 31, 2015, and followed up through July 31, 2021.
Participants in SPIROMICS I underwent spirometry, 6-minute walk distance testing, assessment of respiratory symptoms, and computed tomography of the chest at yearly visits for 3 to 4 years. Participants in SPIROMICS II had 1 additional in-person visit 5 to 7 years after enrollment in SPIROMICS I. Respiratory symptoms were assessed with the COPD Assessment Test (range, 0 to 40; higher scores indicate more severe symptoms). Participants with symptomatic TEPS had normal spirometry (postbronchodilator ratio of forced expiratory volume in the first second FEV1 to forced vital capacity >0.70) and COPD Assessment Test scores of 10 or greater. Participants with asymptomatic TEPS had normal spirometry and COPD Assessment Test scores of less than 10. Patient-reported respiratory symptoms and exacerbations were assessed every 4 months via phone calls.
The primary outcome was assessment for accelerated decline in lung function (FEV1) in participants with symptomatic TEPS vs asymptomatic TEPS. Secondary outcomes included development of COPD defined by spirometry, respiratory symptoms, rates of respiratory exacerbations, and progression of computed tomographic-defined airway wall thickening or emphysema.
Of 1397 study participants, 226 had symptomatic TEPS (mean age, 60.1 SD, 9.8 years; 134 were women 59%) and 269 had asymptomatic TEPS (mean age, 63.1 SD, 9.1 years; 134 were women 50%). At a median follow-up of 5.76 years, the decline in FEV1 was -31.3 mL/y for participants with symptomatic TEPS vs -38.8 mL/y for those with asymptomatic TEPS (between-group difference, -7.5 mL/y 95% CI, -16.6 to 1.6 mL/y). The cumulative incidence of COPD was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio, 1.05 95% CI, 0.76 to 1.46). Participants with symptomatic TEPS had significantly more respiratory exacerbations than those with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; rate ratio, 2.38 95% CI, 1.71 to 3.31, P < .001).
Participants with symptomatic TEPS did not have accelerated rates of decline in FEV1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.
Objectives
To investigate effects of older age, comorbidities, and physiological measures on outcomes of elderly adults requiring prolonged mechanical ventilation (PMV).
Design
Retrospective cohort ...study.
Setting
Public long‐term acute care hospital (LTACH) with an active program for ventilator weaning from PMV.
Participants
Chronically seriously ill individuals with PMV aged 65 and older divided into six cohorts (65–69, 70–74, 75–79, 80–84, 85–89, ≥90) for comparative purposes (n = 540).
Measurements
Main outcomes were weaning criteria met, weaning success, discharge dispositions, and long‐term survival. Other outcomes included weaning duration, LTACH days, discharge physical function, tracheostomy decannulation, and relapses to ventilator support. Weaning success was defined as 4 weeks or longer entirely free from mechanical ventilator support.
Results
The main finding from age cohort comparisons was that the likelihood of meeting weaning criteria (P = .001) and subsequent successful weaning (P = .002) decreased with age. Best predictors for weaning success in multivariable analysis were lower comorbidity burden (P < .001) and less‐severe illness (P = .001). Other clinically important predictors were more‐normal values in the respiratory physiology measures of rapid shallow breathing (P = .001) and static compliance (P = .003). Successful weaning was also associated with a 62% lower risk of death (P < .001).
Conclusion
Although meeting weaning criteria and being successfully weaned decreased with increasing age, age was not the dominant factor in predicting outcomes. More importantly, individuals with PMV with better respiratory physiology and lower comorbidity burdens were more likely to be weaned and have longer survival, no matter their age.
Airway remodelling in chronic obstructive pulmonary disease (COPD) originates, in part, from smoking-induced changes in airway basal stem/progenitor cells (BCs). Based on the knowledge that bone ...morphogenetic protein 4 (BMP4) influences epithelial progenitor function in the developing and adult mouse lung, we hypothesised that BMP4 signalling may regulate the biology of adult human airway BCs relevant to COPD.BMP4 signalling components in human airway epithelium were analysed at the mRNA and protein levels, and the differentiation of BCs was assessed using the BC expansion and air-liquid interface models in the absence/presence of BMP4, BMP receptor inhibitor and/or small interfering RNAs against BMP receptors and downstream signalling.The data demonstrate that in cigarette smokers, BMP4 is upregulated in ciliated and intermediate undifferentiated cells, and expression of the BMP4 receptor BMPR1A is enriched in BCs. BMP4 induced BCs to acquire a smoking-related abnormal phenotype
mediated by BMPR1A/Smad signalling, characterised by decreased capacity to differentiate into normal mucociliary epithelium, while generating squamous metaplasia.Exaggerated BMP4 signalling promotes cigarette smoking-relevant airway epithelial remodelling by inducing abnormal phenotypes in human airway BCs. Targeting of BMP4 signalling in airway BCs may represent a novel target to prevent/treat COPD-associated airway disease.
Objective:
To determine whether burdens of chronic comorbid illnesses can predict the clinical course of prolonged mechanical ventilation (PMV)patients in a long-term, acute-care hospital (LTACH).
...Methods:
Retrospective study of 866 consecutive PMV patients whose burdens of chronic comorbid illnesses were quantified using the Cumulative Illness Rating Scale (CIRS). Based on increasing CIRS scores, 6 groups were formed and compared: group A (≤25; n = 97), group B (26-28; n = 105), group C (29-31; n = 181), group D (32-34; n = 208), group E (35-37; n = 173), and group F (>37; n = 102).
Results:
As CIRS scores increased from group A to group F, rates of weaning success, home discharges, and LTACH survival declined progressively from 74% to 17%, 48% to 0%, and 79% to 21%, respectively (all P < .001). Negative correlations between the mean score of each CIRS group and correspondent outcomes also supported patients’ group allocation and an accurate prediction of their clinical course (all P < .01). Long-term survival progressively declined from a median survival time of 38.9 months in group A to 3.2 months in group F (P < .001). Compared to group A, risk of death was 75% greater in group F (P = .03). Noteworthy, PMV patients with CIRS score <25 showed greater ability to recover and a low likelihood of becoming chronically critically ill. Diagnostic accuracy of CIRS to predict likelihood of weaning success, home discharges, both LTACH and long-term survival was good (area under the curves ≥0.71; all P <.001).
Conclusions:
The burden of chronic comorbid illnesses was a strong prognostic indicator of the clinical course of PMV patients. Patients with lower CIRS values showed greater ability to recover and were less likely to become chronically critically ill. Thus, CIRS can be used to help guide clinicians caring for PMV patients in transfer decisions to and from postacute care setting.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) considers blood eosinophil counts < 100 cells/μL (BEC≤100) in people with COPD to predict poor inhaled corticosteroid (ICS) ...responsiveness. However, the BEC≤100 phenotype is inadequately characterized, especially in advanced COPD.
Are there differences between GOLD group D patients with high BEC and those with low BEC regarding baseline characteristics and longitudinal outcomes?
We used multivariable mixed models and logistic regression to contrast clinical characteristics and outcomes of BEC≤100 vs BEC > 100 (BEC100+) in all subjects with COPD (n = 1,414) and GOLD group D subjects (n = 185) not receiving ICS.
We identified n = 485 with BEC≤100 (n = 61 GOLD group D) and n = 929 people with BEC100+ (n = 124 GOLD group D). BEC≤100 status was stable at 6 weeks and approximately 52 weeks (intraclass correlations of 0.78 and 0.71, respectively). Compared with BEC100+, BEC≤100 comprised more women, with greater current smoking, and less frequent childhood asthma. Among all analyzed participants, the two BEC-defined subsets showed similar rates of lung function decline (mean slope, BEC≤100 vs BEC100+, –50 vs –39 mL/y; P = .140), exacerbations (0.40 vs 0.36/y; P = .098), subsequent ICS initiation (2.5% vs 4.4%; P = .071), and mortality (7.8% vs 8.4%; P = .715). However, in GOLD group D, people with BEC≤100 showed higher exacerbation rates within 365 days of enrollment (0.62 vs 0.33/y; P = .002) and total follow-up (1.16 vs 0.83/y; P = .014). They also had greater lung function decline (mean slope of –68 mL/y vs –23 mL/y; P = .036) and had greater emphysema at baseline (voxels < 950 Hounsfield units at total lung capacity of 7.46% vs 4.61%; P = .029).
In non-ICS-treated GOLD group D COPD, people with BEC≤100 had more baseline emphysema, prospective exacerbations, and lung function decline. Our analysis has identified a particularly vulnerable subpopulation of people with COPD, suggesting the need for studies focused specifically on their therapeutic treatment.
ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov
In addition to rare genetic variants and the
locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the
locus for IPF ...and interstitial lung abnormalities (ILAs) is unknown.
We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the
region on IPF, ILA, and ILA progression.
We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the
region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression.
We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio OR per SD of the score, 3.1;
= 7.1 × 10
) and PRS-NO-M5B (OR per SD, 2.8;
= 2.5 × 10
) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants.
A common genetic variant risk score complements the
variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.
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