Airway "Resistotypes" and Clinical Outcomes in Bronchiectasis.

Rationale: Chronic infection and inflammation shapes the airway microbiome in bronchiectasis. Utilizing whole-genome shotgun metagenomics to analyze the airway resistome provides insight into interplay between microbes, resistance genes, and clinical outcomes. Objectives: To apply whole-genome shotgun metagenomics to the airway microbiome in bronchiectasis to highlight a diverse pool of antimicrobial resistance genes: the "resistome," the clinical significance of which remains unclear. Methods: Individuals with bronchiectasis were prospectively recruited into cross-sectional and longitudinal cohorts (n = 280), including the international multicenter cross-sectional Cohort of Asian and Matched European Bronchiectasis 2 (CAMEB 2) study (n = 251) and two independent cohorts, one describing patients experiencing acute exacerbation and a further cohort of patients undergoing Pseudomonas aeruginosa eradication treatment. Sputum was subjected to metagenomic sequencing, and the bronchiectasis resistome was evaluated in association with clinical outcomes and underlying host microbiomes. Measurements and Main Results: The bronchiectasis resistome features a unique resistance gene profile and increased counts of aminoglycoside, bicyclomycin, phenicol, triclosan, and multidrug resistance genes. Longitudinally, it exhibits within-patient stability over time and during exacerbations despite between-patient heterogeneity. Proportional differences in baseline resistome profiles, including increased macrolide and multidrug resistance genes, associate with shorter intervals to the next exacerbation, whereas distinct resistome archetypes associate with frequent exacerbations, poorer lung function, geographic origin, and the host microbiome. Unsupervised analysis of resistome profiles identified two clinically relevant "resistotypes," RT1 and RT2, the latter characterized by poor clinical outcomes, increased multidrug resistance, and P. aeruginosa. Successful targeted eradication in P. aeruginosa-colonized individuals mediated reversion from RT2 to RT1, a more clinically favorable resistome profile demonstrating reduced resistance gene diversity. Conclusions: The bronchiectasis resistome associates with clinical outcomes, geographic origin, and the underlying host microbiome. Bronchiectasis resistotypes link to clinical disease and are modifiable through targeted antimicrobial therapy.

Low incidence of venous thrombosis but high incidence of arterial thrombotic complications among critically ill COVID-19 patients in Singapore.

BACKGROUND: Arterial and venous thrombosis are reported to be common in critically ill COVID-19 patients. METHOD AND RESULTS: This is a national multicenter retrospective observational study involving all consecutive adult COVID-19 patients who required intensive care units (ICU) admission between 23 January 2020 and 30 April 2020 in Singapore. One hundred eleven patients were included and the venous and arterial thrombotic rates in ICU were 1.8% (n = 2) and 9.9% (n = 11), respectively. Major bleeding rate was 14.8% (n = 16). CONCLUSIONS: Critically ill COVID-19 patients in Singapore have lower venous thromboembolism but higher arterial thrombosis rates and bleeding manifestations than other reported cohorts.

Choosing the right mask for your Asian patient with sleep apnoea: A randomized, crossover trial of CPAP interfaces.

BACKGROUND AND OBJECTIVE: A major challenge with the treatment of obstructive sleep apnoea (OSA) is adherence to continuous positive airway pressure (CPAP) therapy. Mask tolerability is an important determinant of adherence, however evidence to guide selection of mask interfaces is lacking. METHODS: We conducted a randomized crossover trial of mask interfaces in CPAP therapy for moderate-to-severe OSA to assess adherence and efficacy of CPAP therapy with nasal mask, nasal pillow and oronasal masks. Demographic data, Nasal Obstruction Symptom Evaluation (NOSE) scores and craniofacial measurements were also analysed for associations with adherence with oronasal masks. RESULTS: Eighty-five patients were included in the study (mean ± SD age: 46 ± 12 years; body mass index: 29.9 ± 5.6 kg/m2 ; apnoea-hypopnoea index (AHI): 53.6 ± 24.0 events/h). Patients had better adherence with nasal masks (average night use: 3.96 ± 2.26 h/night) compared to oronasal masks (3.26 ± 2.18 h/night, P < 0.001) and nasal pillows (3.48 ± 2.20 h/night, P = 0.007). Residual AHI was higher with oronasal masks (7.2 ± 5.2) compared to nasal masks (4.0 ± 4.2, P < 0.001) and nasal pillows (4.1 ± 3.3, P < 0.001). Twenty-two (25.9%) patients had the best adherence with oronasal masks (4.22 ± 2.14 vs 2.93 ± 2.12 h/night, P = 0.016). These patients had lower NOSE scores (15 (0-35) vs 40 (10-55), P = 0.024) and larger menton-labrale inferioris/biocular width ratios (31 ± 3% vs 28 ± 4%, P = 0.019). CONCLUSION: Nasal masks are the preferred interface during CPAP initiation. Patients with less nasal obstruction and a proportionally increased chin-lower lip distance to mid-face width may have better CPAP adherence with an oronasal mask interface.

Managing respiratory complications in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

In the recently published guidelines by the Society of Dermatology Hospitalists on the management of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), a brief section was included on airway management. These recommendations provide an easy reference on how to manage respiratory complications of the disease. Understanding the evidence that underlies these recommendations would offer physicians greater clarity on the considerations behind every decision and treatment offered. We present a review of the literature on respiratory manifestations associated with SJS and TEN. In addition, we aim to address specific concerns regarding the respiratory management of these patients. These include issues such as the indications and optimal timing of intubation, tracheostomy, role of flexible nasoendoscopy, bronchoscopy, ventilation strategies, and management of chronic respiratory complications.

Long-term outcomes in patients who received veno-venous extracorporeal membrane oxygenation and renal replacement therapy: a retrospective cohort study.

BACKGROUND: Acute kidney injury (AKI) is a frequent complication in patients with severe respiratory failure receiving extracorporeal membrane oxygenation (ECMO). However, little is known of long-term kidney function in ECMO survivors. We aimed to assess the long-term mortality and kidney outcomes in adult patients treated with veno-venous ECMO (VV-ECMO). METHODS: This was a single-centre retrospective study of adult patients (≥ 18 years old) who were treated with VV-ECMO at a commissioned ECMO centre in the UK between 1st September 2010, and 30th November 2016. AKI was defined and staged using the serum creatinine and urine output criteria of the Kidney Diseases: Improving Global Outcomes (KDIGO) classification. The primary outcome was 1-year mortality. Secondary outcomes were long-term mortality (up to March 2020), 1-year incidence of end-stage kidney disease (ESKD) or chronic kidney disease (CKD) among AKI patients who received renal replacement therapy (AKI-RRT), AKI patients who did not receive RRT (AKI-no RRT) and patients without AKI (non-AKI). RESULTS: A total of 300 patients [57% male; median age 44.5; interquartile range (IQR) 34-54] were included in the final analysis. Past medical histories included diabetes (12%), hypertension (17%), and CKD (2.3%). The main cause of severe respiratory failure was pulmonary infection (72%). AKI occurred in 230 patients (76.7%) and 59.3% received renal replacement therapy (RRT). One-year mortality was 32% in AKI-RRT patients vs. 21.4% in non-AKI patients (p = 0.014). The median follow-up time was 4.35 years. Patients who received RRT had a higher risk of 1-year mortality than those who did not receive RRT (adjusted HR 1.80, 95% CI 1.06, 3.06; p = 0.029). ESKD occurred in 3 patients, all of whom were in the AKI-RRT group. At 1-year, 41.2% of survivors had serum creatinine results available. Among these, CKD was prevalent in 33.3% of AKI-RRT patients vs. 4.3% in non-AKI patients (p = 0.004). CONCLUSIONS: VV-EMCO patients with AKI-RRT had high long-term mortality. Monitoring of kidney function after hospital discharge was poor. In patients with follow-up creatinine results available, the CKD prevalence was high at 1 year, especially in AKI-RRT patients. More awareness about this serious long-term complication and appropriate follow-up interventions are required.

The establishment of COPD organoids to study host-pathogen interaction reveals enhanced viral fitness of SARS-CoV-2 in bronchi.

Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation and infective exacerbations, however, in-vitro model systems for the study of host-pathogen interaction at the individual level are lacking. Here, we describe the establishment of nasopharyngeal and bronchial organoids from healthy individuals and COPD that recapitulate disease at the individual level. In contrast to healthy organoids, goblet cell hyperplasia and reduced ciliary beat frequency were observed in COPD organoids, hallmark features of the disease. Single-cell transcriptomics uncovered evidence for altered cellular differentiation trajectories in COPD organoids. SARS-CoV-2 infection of COPD organoids revealed more productive replication in bronchi, the key site of infection in severe COVID-19. Viral and bacterial exposure of organoids induced greater pro-inflammatory responses in COPD organoids. In summary, we present an organoid model that recapitulates the in vivo physiological lung microenvironment at the individual level and is amenable to the study of host-pathogen interaction and emerging infectious disease.

Heterogeneity of non-cystic-fibrosis bronchiectasis in multiethnic Singapore: A prospective cohort study at a tertiary pulmonology centre.

INTRODUCTION: Non-cystic fibrosis bronchiectasis (NCFB) is a highly heterogenous disease. We describe the clinical characteristics of NCFB patients and evaluate the performance of Bronchiectasis Severity Index (BSI) in predicting mortality. METHODS: Patients attending the bronchiectasis clinic between August 2015 and April 2020 with radiologically proven bronchiectasis on computed tomography were recruited. Clinical characteristics, spirometry, radiology, microbiology and clinical course over a median period of 2.4 years is presented. RESULTS: A total of 168 patients were enrolled in this prospective cohort study. They were predominantly women (67.8%), Chinese (87.5%) and never-smokers (76.9%). Median age of diagnosis was 64 years (interquartile range 56-71) and the most common aetiology was "idiopathic" bronchiectasis (44.6%). Thirty-nine percent had normal spirometries. Compared to female patients, there were more smokers among the male patients (53.8% versus 8.5%, P<0.001) and a significantly larger proportion with post-tuberculous bronchiectasis (37.0% vs 15.8%, P=0.002). Fifty-five percent of our cohort had a history of haemoptysis. Lower body mass index, presence of chronic obstructive pulmonary disease, ever-smoker status, modified Reiff score, radiological severity and history of exacerbations were risk factors for mortality. Survival was significantly shorter in patients with severe bronchiectasis (BSI>9) compared to those with mild or moderate disease (BSI<9). The hazard ratio for severe disease (BSI>9) compared to mild disease (BSI 0-4) was 14.8 (confidence interval 1.929-114.235, P=0.01). CONCLUSION: The NCFB cohort in Singapore has unique characteristics with sex differences. Over half the patients had a history of haemoptysis. The BSI score is a useful predictor of mortality in our population.

Cerebellar Stroke in a COVID-19 Infected Patient. a Case Report.

BACKGROUND: Recent studies have reported that COVID-19 infected patients with stroke, who were often in the older age group, had a higher incidence of vascular risk factors, and more severe infection related respiratory symptoms. These observations provided little evidence to suggest that COVID-19 infection is a potential causative factor for stroke. This report describes a young patient with a cerebellar stroke secondary to COVID-19 infection. CASE PRESENTATION: A 45-year old male presented at a hospital, reporting a two-day history of headache, vertigo, persistent vomiting, and unsteady gait. Physical examination revealed gaze-evoked nystagmus on extraocular movement testing, left-sided dysmetria and dysdiadochokinesia. He was diagnosed with a left cerebellar stroke. An external ventricular drain was inserted, and sub-occipital craniectomy was performed to manage the effects of elevated intracranial pressure due to the extent of oedema secondary to the infarct. He also underwent screening for the COVID-19 infection, which was positive on SARS-COV-2 polymerase chain reaction testing of his endotracheal aspirate. Blood and cerebrospinal fluid samples were negative. After the surgery, the patient developed atrial fibrillation and had prolonged vomiting symptoms, but these resolved eventually with symptomatic treatment. He was started on aspirin and statin therapy, but anticoagulation was withheld due to bleeding concerns. The external ventricular drain was removed nine days after the surgery. He continued with active rehabilitation. CONCLUSIONS: Young patients with COVID-19 infection may be more susceptible to stroke, even in the absence of risk factors. Standard treatment with aspirin and statins remains essential in the management of COVID-19 related stroke. Anticoagulation for secondary prevention in those with atrial fibrillation should not be routine and has to be carefully evaluated for its benefits compared to the potential harms of increased bleeding associated with COVID-19 infection.

Potential role of statins in COVID-19.

Patients with COVID-19 infection have an increased risk of cardiovascular complications and thrombotic events. Statins are known for their pleiotropic anti-inflammatory, antithrombotic and immunomodulatory effects. They may have a potential role as adjunctive therapy to mitigate endothelial dysfunction and dysregulated inflammation in patients with COVID-19 infection.

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.

Impact of an Extracorporeal Membrane Oxygenation Intensivist-Led Multidisciplinary Team on Venovenous Extracorporeal Membrane Oxygenation Outcomes.

OBJECTIVES: Venovenous extracorporeal membrane oxygenation is increasingly being established as a treatment option for severe acute respiratory failure. We sought to evaluate the impact of a dedicated specialist team-based approach on patient outcomes. DESIGN: Retrospective cohort study. SETTING: Single-center medical ICU in an academic tertiary hospital. PATIENTS: Adult patients initiated on venovenous extracorporeal membrane oxygenation for severe acute respiratory failure. INTERVENTIONS: Initiation of an extracorporeal membrane oxygenation intensivist-led multidisciplinary team; critical decisions on extracorporeal membrane oxygenation management were jointly made by a dedicated team of extracorporeal membrane oxygenation intensivists, together with the multidisciplinary team. MEASUREMENTS AND MAIN RESULTS: Eighty-one patients (75%) and 27 patients (35%) were initiated on venovenous extracorporeal membrane oxygenation in the preextracorporeal membrane oxygenation intensivist-led multidisciplinary team (before January 2018) and postextracorporeal membrane oxygenation intensivist-led multidisciplinary team period (after January 2018), respectively. Inhospital (14.8% vs 44.4%, p = 0.006) and ICU mortality (11.1% vs 40.7%, p = 0.005) were significantly lower in the postextracorporeal membrane oxygenation intensivist-led multidisciplinary team period. On multivariate analysis correcting for possible confounding factors (ICU severity and extracorporeal membrane oxygenation-specific mortality prediction scores, body mass index, preextracorporeal membrane oxygenation vasopressor support, preextracorporeal membrane oxygenation cardiac arrest, and days on mechanical ventilation before extracorporeal membrane oxygenation initiation), management by an extracorporeal membrane oxygenation intensivist-led multidisciplinary team remained associated with improved hospital survival (odds ratio, 5.06; 95% CI, 1.20-21.28). Patients in the postextracorporeal membrane oxygenation intensivist-led multidisciplinary team period had less nosocomial infections (18.5% vs 46.9%, p = 0.009), a shorter ICU stay (12 days [interquartile range, 6-16 d] vs 15 days [interquartile range, 10-24 d]; p = 0.049), and none suffered an intracranial hemorrhage or nonhemorrhagic stroke. CONCLUSIONS: An extracorporeal membrane oxygenation intensivist-led multidisciplinary team approach is associated with improved outcomes in patients initiated on venovenous extracorporeal membrane oxygenation for severe acute respiratory failure.