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.

Rare Metastatic Sites of a Lung Adenocarcinoma.

We report a rare case of a lung adenocarcinoma presenting with chylothorax and metastases to the common bile duct and the rectum. From the radiological and endoscopic appearance of the tumors, the main differential diagnoses were metastatic lung cancer to multiple rare extra-thoracic sites and multiple synchronous primary oncological malignancies. Pathological examination of the biopsies with positive immunohistochemical staining for thyroid transcription factor-1 (TTF-1) played an important role in confirming metastatic pulmonary adenocarcinoma.

Factors associated with mortality among patients with active pulmonary tuberculosis requiring intensive care.

INTRODUCTION: The aim of this study was to identify patient characteristics and risk factors associated with in-hospital mortality of patients with pulmonary tuberculosis (PTB) requiring intensive care unit (ICU) management. METHODS: A retrospective chart review was conducted of all patients with active PTB admitted to the ICU at Singapore General Hospital, Singapore, between January 2005 and December 2010. RESULTS: There were 2,155 patients with active PTB diagnosed, of whom 83 (3.9%) patients were admitted to the ICU, but eight were excluded because their admission to the ICU was unrelated to PTB. The most common comorbidities were diabetes mellitus (n = 23, 30.7%) and immunocompromised host (n = 25, 33.3%). A few (n = 4, 5.3%) of the patients had HIV coinfection. A majority (n = 67, 89.3%) of patients required mechanical ventilation and the mean duration of mechanical ventilation was 8.05 ± 14.43 days. Mean duration of ICU stay and hospital stay were 10.23 ± 15.8 days and 33.7 ± 50.7 days, respectively. In-hospital mortality was 62.7% (n = 47), and 36 of these patients died while in the ICU (ICU mortality, 48.0%). Univariate analysis identified ischaemic heart disease, low albumin, Acute Physiology and Chronic Health Evaluation score, disseminated intravascular coagulation, shock and multiorgan failure as significantly associated with mortality. Multivariate analysis showed that low albumin on the day of ICU admission was the only significant independent predictor of death (p = 0.033). CONCLUSION: In-hospital mortality from active PTB requiring ICU admission was 62.7%, and low albumin was an independent predictor of mortality in this study.

Implementing electronic handover: interventions to improve efficiency, safety and sustainability.

PROBLEM: Effective handovers are critical for patient care and safety. Electronic handover tools are increasingly used today to provide an effective and standardized platform for information exchange. The implementation of an electronic handover system in tertiary hospitals can be a major challenge. Previous efforts in implementing an electronic handover tool failed due to poor compliance and buy-in from end-users. A new electronic handover tool was developed and incorporated into the existing electronic medical records (EMRs) for medical patients in Singapore General Hospital (SGH). INITIAL ASSESSMENT: There was poor compliance by on-call doctors in acknowledging electronic handovers, and lack of adherence to safety rules, raising concerns about the safety and efficiency of the electronic handover tool. Urgent measures were needed to ensure its safe and sustained use. SOLUTION: A quality improvement group comprising stakeholders, including end-users, developed multi-faceted interventions using rapid PDSA (P-Plan, D-Do, S-Study, A-Act ) cycles to address these issues. IMPLEMENTATION: Innovative solutions using media and online software provided cost-efficient measures to improve compliance. EVALUATION: The percentage of unacknowledged handovers per day was used as the main outcome measure throughout all PDSA cycles. Doctors were also assessed for improvement in their knowledge of safety rules and their perception of the electronic handover tool. LESSONS LEARNT: An electronic handover tool complementing daily clinical practice can be successfully implemented using solutions devised through close collaboration with end-users supported by the senior leadership. A combined 'bottom-up' and 'top-down' approach with regular process evaluations is crucial for its long-term sustainability.

Fibred confocal fluorescence microscopy in the diagnosis of interstitial lung diseases.

BACKGROUND: Accurate diagnosis is critical to both therapeutic decisions and prognostication in interstitial lung diseases (ILD). However, surgical lung biopsies carry high complication rates. Fibred confocal fluorescence microscopy (FCFM) offers an alternative as it can visualize lung tissue in vivo at the cellular level with minimal adverse events. We wanted to investigate the diagnostic utility, and safety of using FCFM for patients with ILD. METHODS: In patients with suspected ILD, FCFM images were obtained from multiple bronchopulmonary segments using a miniprobe inserted through the working channel of a flexible bronchoscope. The procedure was performed under moderate sedation in an outpatient setting. Morphometric measurements and fibre pattern analyses were co-related with computed tomography (CT) findings and patients' final diagnoses based on multi-disciplinary consensus. RESULTS: One hundred and eighty four segments were imaged in 27 patients (18 males) with a median age of 67 years (range, 24-79 years). They were grouped into chronic fibrosing interstitial pneumonia (16 patients) and other ILDs. Six distinct FCFM patterns were observed: normal, increased fibres, densely packed fibres, hypercellular, thickened fibres and others/non-specific. The pattern resembling densely packed fibres was seen in at least one segment in 68.8% patients with chronic fibrosing interstitial pneumonia, but only 36.4% in other ILD (P=0.097). An association between inflammatory patterns on CT and a hypercellular pattern on FCFM was also found (P<0.001). CONCLUSIONS: Our study shows the potential of FCFM in classifying ILD, but its role in further diagnosis remains limited.

Tuberculosis trends over a five-year period at a tertiary care university-affiliated hospital in Singapore.

INTRODUCTION: Tuberculosis (TB), a potentially fatal infectious disease, poses significant health problems. The objective of this study was to analyse trends among newly diagnosed TB patients seen at the Singapore General Hospital (SGH). METHODS: This study was a retrospective case record review of notified TB patients at SGH between 2006 and 2010 (inclusive). RESULTS: A total of 1,979 cases of TB were notified over the five years. The number increased from 368 in 2006 to 407 in 2010 (p = 0.51), in tandem with the increasing number of patients seen at the hospital and the rising population in Singapore. Singaporean residents accounted for 82.8% of the cases, while non-Singaporean residents and non-residents made up the remainder. The year-to-year percentage of non-Singaporean residents and non-residents notified remained stable throughout the five years (p = 0.783). The number of male Singaporean residents (70.7%) notified was more than twice that of female Singaporean residents (29.3%). The majority of patients infected with TB (31.9%) were elderly patients aged > 65 years. Although testing for the human immunodeficiency virus increased from 43.8% (2006) to 64.2% (2010), the number detected with coinfection remained stable (14 and 12 patients in 2006 and 2010, respectively). Mortality rates also remained stable at 12.0%. CONCLUSION: We cannot afford complacency, as there was no downward trend in the number of notified TB cases at SGH from 2006 to 2010. As the elderly contribute significantly to the TB burden, increased efforts are required to manage this vulnerable population.

Radial endobronchial ultrasound in diagnosing peripheral lung lesions in a high tuberculosis setting.

BACKGROUND: Current data for the utility of radial endobronchial ultrasound (EBUS) in investigating peripheral lung lesions (PLLs) has been restricted to populations with low pulmonary tuberculosis (TB) incidence. The aim of this study was to assess the diagnostic utility of radial EBUS with guide sheath in the diagnosis of peripheral lung lesions in Singapore, a high TB incidence setting. METHODS: A post-hoc database analysis was performed. 123 consecutive patients with computed tomographic evidence of PLLs who underwent radial EBUS guided bronchoscopy were included. RESULTS: The final diagnosis was malignancy in 76 cases and benign in 44 cases. Radial EBUS guided bronchoscopy had a sensitivity of 65.8 % for malignancy, positive predictive value of 100 %, negative predictive value of 62.9 %, and a diagnostic accuracy of 82.5 %. 22 patients had a final diagnosis of pulmonary TB. The diagnostic sensitivity for pulmonary TB was 77.3 %, with a positive predictive value of 100 %, negative predictive value of 95.2 % and a diagnostic accuracy of 95.8 %. Overall, 58.8 % of pulmonary TB cases relied on histology to make an early diagnosis. CONCLUSION: Radial EBUS guided bronchosopy is useful in investigating PLLs in a high TB incidence setting. Our data also suggests that radial EBUS is a more rapid diagnosis technique for tuberculous lesions.

Pulmonary alveolar proteinosis.

We report a 68-year-old female who presented with chronic cough and progressive dyspnoea. Computed tomography of the thorax and subsequent bronchoscopy confirmed the diagnosis of pulmonary alveolar proteinosis (PAP), which was treated with whole lung lavage. This case is reported in view of the low incidence of PAP.

Use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of granulomatous mediastinal lymphadenopathy.

INTRODUCTION: This study assessed the clinical utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the diagnosis of suspected granulomatous mediastinal lymphadenopathy. MATERIALS AND METHODS: Retrospective chart review of all patients who underwent EBUS-TBNA for suspected granulomatous mediastinal lymphadenopathy at Singapore General Hospital between December 2008 and December 2011 inclusive. RESULTS: Over a period of 3 years, a total of 371 patients underwent EBUS-TBNA of whom 33 (9%) had the procedure performed for evaluation of suspected granulomatous mediastinal lymphadenopathy - 18 for suspected tuberculosis (TB) and non-tuberculous mycobacterial (NTM) lymphadenitis, and 15 for suspected sarcoidosis. EBUS-TBNA was diagnostic in 9 of the 13 patients with a final diagnosis of TB/NTM. EBUS-TBNA cultures were positive in 6 of them (46%), 1 showed acid-fast bacilli (AFB) although cultures were negative, and 2 had necrotising granulomatous inflammation from EBUS-TBNA biopsies and sputum cultures grew TB. EBUS-TBNA was diagnostic in 9 of the 14 patients with a final diagnosis of sarcoidosis through histology showing non-caseating granulomatous inflammation. The sensitivities of EBUS-TBNA for diagnosis of TB/NTM, sarcoidosis and overall granulomatous mediastinal lymphadenopathy were 69%, 64%, 64%; the negative predictive values were 56%, 17%, 33%; and accuracies were 78%, 67%, 70%, respectively. CONCLUSION: EBUS-TBNA can be useful in the diagnosis of suspected granulomatous mediastinal lymphadenopathy with sensitivities and accuracies of >60%.

Role of endobronchial ultrasound in the diagnosis of bronchogenic cysts.

Diagnosis of bronchogenic cysts is possible with computed tomography, but half of all cases present as soft tissue densities. Two such cases are highlighted where asymptomatic bronchogenic cysts that presented as soft tissue masses were evaluated by endobronchial ultrasound (EBUS). After studying the ultrasound image characteristics, the diagnosis was confirmed using EBUS-guided transbronchial needle aspiration (EBUS-TBNA). The first case had ultrasound findings of an anechoic collection, and the aspirate was serous with negative microbiologic cultures. The second was an echogenic collection within a hyperechoic wall. Needle aspirate was purulent and cultured Haemophilus influenza. The diagnosis of a bronchogenic cyst complicated by infection was made, and the lesion was surgically resected. This potential for EBUS in the diagnosis of bronchogenic cysts and in identifying complications such as infection should be considered in the management of such cases.