First ever characterisation of the effects of short telomeres in a Singapore interstitial lung disease cohort.

BACKGROUND: Differences in disease behaviour and genotypes are described in Asian and Western interstitial lung disease (ILD) cohorts. Short leukocyte telomere length (LTL) correlates with poor outcomes in Western ILD cohorts but its significance in Asian populations is unknown. We aim to characterise the burden and clinical implications of short LTL in Singaporean ILD patients. METHODS: Patients diagnosed with ILD at Singapore General Hospital were prospectively recruited and compared against 36 healthy controls. The primary outcome was transplant-free survival. Genomic DNA from peripheral blood was extracted and LTL measured using quantitative polymerase chain reaction assay (qPCR). RESULTS: Amongst 165 patients, 37% had short LTL. There was a higher proportion of combined pulmonary fibrosis and emphysema (CPFE) patients with short LTL (n = 21, 34.4% vs n = 16, 15.4%; p < 0.001). Short LTL patients had reduced survival at 12-, 24- and 36-months and median survival of 24 months (p < 0.001) which remained significant following adjustment for smoking, GAP Stage and radiological UIP pattern (Hazard Ratio (HR), 2.74; 95%CI:1.46, 5.11; p = 0.002). They had increased respiratory-related mortality and acute exacerbation incidences. Despite similar baseline lung function, short LTL patients had a faster decline in absolute forced vital capacity (FVC) of -105.3 (95% CI: 151.4, -59.1) mL/year compared to -58.2 (95% CI: 82.9, -33.6) mL/year (p < 0.001) in normal LTL patients. CONCLUSION: Short LTL correlated with increased mortality and faster lung function decline in our Singaporean ILD cohort with a magnitude similar to that in Western ILD cohorts. Further research is needed to integrate LTL assessment into clinical practice.

Clinical Guidance on the Monitoring and Management of Trastuzumab Deruxtecan (T-DXd)-Related Adverse Events: Insights from an Asia-Pacific Multidisciplinary Panel.

Trastuzumab deruxtecan (T-DXd)-an antibody-drug conjugate targeting the human epidermal growth factor receptor 2 (HER2)-improved outcomes of patients with HER2-positive and HER2-low metastatic breast cancer. Guidance on monitoring and managing T-DXd-related adverse events (AEs) is an emerging unmet need as translating clinical trial experience into real-world practice may be difficult due to practical and cultural considerations and differences in health care infrastructure. Thus, 13 experts including oncologists, pulmonologists and a radiologist from the Asia-Pacific region gathered to provide recommendations for T-DXd-related AE monitoring and management by using the latest evidence from the DESTINY-Breast trials, our own clinical trial experience and loco-regional health care considerations. While subgroup analysis of Asian (excluding Japanese) versus overall population in the DESTINY-Breast03 uncovered no major differences in the AE profile, we concluded that proactive monitoring and management are essential in maximising the benefits with T-DXd. As interstitial lung disease (ILD)/pneumonitis is a serious AE, patients should undergo regular computed tomography scans, but the frequency may have to account for the median time of ILD/pneumonitis onset and access. Trastuzumab deruxtecan appears to be a highly emetic regimen, and prophylaxis with serotonin receptor antagonists and dexamethasone (with or without neurokinin-1 receptor antagonist) should be considered. Health care professionals should be vigilant for treatable causes of fatigue, and patients should be encouraged to use support groups and practice low-intensity exercises. To increase treatment acceptance, patients should be made aware of alopecia risk prior to starting T-DXd. Detailed monitoring and management recommendations for T-DXd-related AEs are discussed further.

Cluster phenotypes in a non-idiopathic pulmonary fibrosis fibrotic interstitial lung diseases cohort in Singapore.

Background: Non-idiopathic pulmonary fibrosis fibrosing interstitial lung diseases (F-ILDs) may demonstrate a progressive disease trajectory similar to idiopathic pulmonary fibrosis (IPF). We aimed to identify novel F-ILD phenotypes in a multi-ethnic South-East Asian population. Methods: F-ILD subjects (n=201) were analysed using unsupervised hierarchical cluster analysis and their outcomes compared against IPF (n=86). Results: Four clusters were identified. Cluster 1 (n=53, 26.4%) comprised older Chinese males with high body mass index (BMI) and comorbidity burden, higher baseline forced vital capacity (FVC) percentage predicted and lower diffusing capacity of the lung for carbon monoxide (DLCO) percentage predicted. They had similar mortality to IPF. Cluster 2 (n=67, 33.3%) had younger female non-smokers with low comorbidity burden, groundglass changes on high-resolution chest computed tomography (HRCT) and a positive anti-nuclear antibody (ANA) titre ≥1:160. They had lower baseline FVC and higher DLCO, low mortality and slower lung function decline. Cluster 3 (n=42, 20.9%) consisted male smokers with low comorbidity burden, emphysema on HRCT and high baseline lung function. They had low mortality and slow lung function decline. Cluster 4 (n=39, 19.4%) was the highest risk and comprised of mainly Indians with high BMI. They had the highest proportion of ischemic heart disease (IHD) and previous pulmonary tuberculosis. Subjects had the lowest baseline lung function, highest mortality, and fastest lung function decline. Survival differences across clusters remained significant following adjustment for treatment. Conclusions: We identified four distinct F-ILD clinical phenotypes with varying disease trajectories. This demonstrates heterogeneity in F-ILD and the need for complementary approaches for classification and prognostication beyond ATS/ERS guideline diagnosis.

Clinical best practices in optimal monitoring, early diagnosis, and effective management of antibody-drug conjugate-induced interstitial lung disease or pneumonitis: a multidisciplinary team approach in Singapore.

INTRODUCTION: Interstitial lung disease (ILD) or pneumonitis remains an important adverse event identified with treatment with antibody-drug conjugates (ADCs). Drug-induced ILD (DILD) accounts for 3%-5% of common ILD cases and is a significant problem in clinical practice. Hence, with the anticipation of the widespread use of ADCs, it will be important for guidelines and recommendations to be established to direct and standardize the management of DILD by a multidisciplinary team (MDT). AREAS COVERED: A thorough literature search was conducted using PubMed to identify relevant articles related to ADCs published between 1 January 2010 and 31 November 2022. Based on the review of the literature combined with expert opinions, this review article offers an overview of incidences of ILDs associated with the use of newer anticancer therapies, specifically ADCs, and discusses local-regional best practices in optimal monitoring, early diagnosis, and management of DILD involving an MDT. EXPERT OPINION: Multidisciplinary input and consensus are crucial in the accurate diagnosis of DILD. The core group of essential attendees in the MDT are oncologists, pulmonologists, thoracic radiologists, and pathologists. This allows for the integration of expertise from different specialists to achieve a 'best fit' diagnosis and management.

Recurrent pneumothoraces with diffuse small ground-glass and solid nodules.

Multifocal micronodular pneumocyte hyperplasia (MMPH) is the lesser known pulmonary manifestation of tuberous sclerosis. It manifests radiologically as diffuse small ground-glass and solid nodules. Accurate diagnosis is essential as it can be mistaken for miliary tuberculosis or malignant lesions which necessitates specific treatment. Constellation of radiological features such as multicentric disease at onset and stability over time can help to distinguish MMPH from its differentials. Histologically, MMPH is characterized by hamartomatous proliferation of type II pneumocytes with a lack of high nuclear to cytoplasmic ratio. MMPH confers a benign prognosis unlike its differentials. Therefore, accurate diagnosis is paramount in ensuring appropriate care is delivered. Here, we describe the radiological and histological features of MMPH in a patient with genetically proven tuberous sclerosis complex and co-existing lymphangioleiomyomatosis.

Dysfunctional Bronchial Cilia Are a Feature of Chronic Obstructive Pulmonary Disease (COPD).

Impaired mucociliary clearance may increase COPD exacerbation risk. We aimed to compare bronchial ciliary function and epithelial ultrastructure of COPD patients to healthy controls and explore its relationship to exacerbator phenotypes (frequent [FE] and infrequent [IFE] exacerbator). In this cross-sectional study, 16 COPD patients and 12 controls underwent bronchial brushings. Ciliary beat frequency (CBF) and dyskinesia index (DI; % of dyskinetic cilia) were assessed using digital high-speed video microscopy, and epithelial ultrastructure using transmission electron microscopy (TEM). Bronchial epithelium in COPD showed lower CBF and higher DI, compared to controls (median [IQR] CBF: 6.8 (6.1-7.2) Hz vs 8.5 (7.7-8.9) Hz, p<0.001 and DI: 73.8 (60.7-89.8) % vs 14.5 (11.2-16.9) %, p<0.001, respectively). This was true for FE and IFE phenotypes of COPD, which were similar in terms of bronchial CBF or DI. Subgroup analyses demonstrated lower CBF and higher DI in FE and IFE COPD phenotypes compared to controls, irrespective of smoking status. TEM showed more loss of cilia, extrusion of cells, cytoplasmic blebs and dead cells in COPD patients versus controls. Profound dysfunction of bronchial cilia is a feature of COPD irrespective of exacerbation phenotype and smoking status, which is likely to contribute to poor mucus clearance in COPD.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1963695 .

Long-term outcomes of tracheobronchial stenosis due to tuberculosis (TSTB) in symptomatic patients: airway intervention vs. conservative management.

BACKGROUND: Patients with tracheobronchial stenosis due to tuberculosis (TSTB) have a variable clinical course and response to treatment including airway intervention. There are no clear guidelines on the best approach to manage such patients. This study examines long-term outcomes of patients with TSTB and factors associated with recurrent symptoms or need for repeat airway intervention following initial bronchoscopic intervention. METHODS: This is a retrospective analysis of patients with TSTB over an 18-year period. Symptoms, radiological, bronchoscopic findings, airway interventions and complications were obtained. Multivariate logistic regression analysis was performed to identify factors predictive of recurrence of symptoms or need for repeat airway intervention. RESULTS: A total of 131 patients with mean age 50±18 years and median follow-up 5 (interquartile range, 2-10) years were included. Nineteen (29.7%) patients underwent balloon dilatation alone, 22 (34.4%) had additional resection or stenting, and 19 (29.7%) underwent all 3 procedures. Among patients conservatively managed, a larger proportion (55.6%) of patients with no recurrence of symptoms had active TB. Patients who developed recurrent symptoms had longer symptom duration (12 vs. 3 months, P=0.025), and more had recurrent lower respiratory tract infections (50% vs. 5.6%, P=0.003), lung collapse (90.0% vs. 41.7%, P=0.011) or linear fibrosis (70.0% vs. 30.6%, P=0.033) compared to those without recurrent symptoms. Bronchomalacia (OR =17.18; 95% CI, 3.43-86.18) and prior bronchoscopic airway resection (OR =4.97; 95% CI, 1.20-20.60) were strongly associated with the recurrence of symptoms or need for repeat airway intervention on multivariate logistic regression analysis. CONCLUSIONS: Bronchomalacia and prior bronchoscopic airway resection are associated with the recurrence of symptoms despite airway intervention. Patients who are diagnosed with TSTB early in the course of active TB may be conservatively managed.

Validation of the ILD-GAP Model and a Local Nomogram in a Singaporean Cohort.

BACKGROUND: The ILD-GAP model was developed and validated in a Western cohort to predict 1-, 2- and 3-year mortality in chronic interstitial lung disease (ILD). OBJECTIVES: We aimed to validate the ILD-GAP model and identify predictors of mortality to derive a nomogram to predict mortality in our local Asian population. METHODS: Characteristics of patients on follow-up in a tertiary ILD referral center were retrospectively reviewed. RESULTS: There were 181 patients and 48 mortalities. 29.8% had idiopathic pulmonary fibrosis, 2.8% unclassifiable ILD, 33.1% connective tissue disease-associated interstitial lung disease (CTD-ILD), 28.7% idiopathic nonspecific interstitial pneumonia and 5.5% chronic hypersensitivity pneumonitis. Univariable analysis showed that a higher ILD-GAP index, unclassified ILD, males, older age, higher pulmonary artery systolic pressure, lower forced vital capacity percent predicted and carbon monoxide diffusion capacity (DLCO) correlated with increased mortality, and CTD had lower mortality. Multivariable analysis utilizing Akaike's information criterion stopping rule showed males and a lower DLCO predicted increased mortality, while CTD predicted lower mortality. These were used to generate a nomogram which predicted overall mortality better (C index 0.817, adequacy index 99.5%) than ILD-GAP (C index 0.777, adequacy index 60.7%) and provided superior estimates based on likelihood ratio testing. Calibration plots showed the nomogram predicted 1-year mortality better, whilst the ILD-GAP model predicted 2- and 3-year mortality closer to actual mortality rates but underpredicted 1-year mortality. CONCLUSION: The nomogram performed better than ILD-GAP in predicting overall mortality and 1-year mortality. Both demonstrated good performance in predicting mortality risk.