Impact of the Use of Oral Antiviral Agents on the Risk of Hospitalization in Community Coronavirus Disease 2019 Patients (COVID-19).

BACKGROUND: We examined the effectiveness of molnupiravir and nirmatrelvir/ritonavir in reducing hospitalization and deaths in a real-world cohort of nonhospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: This was a territory-wide retrospective cohort study in Hong Kong. Nonhospitalized COVID-19 patients who attended designated outpatient clinics between 16 February and 31 March 2022 were identified. Patients hospitalized on the day of the first clinic appointment or used both oral antivirals were excluded. The primary endpoint was hospitalization. The secondary endpoint was a composite of intensive care unit admission, invasive mechanical ventilation use, and/or death. RESULTS: Of 93 883 patients, 83 154 (88.6%), 5808 (6.2%), and 4921 (5.2%) were oral antiviral nonusers, molnupiravir users, and nirmatrelvir/ritonavir users, respectively. Compared with nonusers, oral antiviral users were older and had more comorbidities, lower complete vaccination rate, and more hospitalizations in the previous year. Molnupiravir users were older and had more comorbidities, lower complete vaccination rate, and more hospitalizations in the previous year than nirmatrelvir/ritonavir users. At a median follow-up of 30 days, 1931 (2.1%) patients were hospitalized and 225 (0.2%) patients developed the secondary endpoint. After propensity score weighting, nirmatrelvir/ritonavir use (weighted hazard ratio 0.79; 95% confidence interval [CI], 0.65-0.95; P = .011) but not molnupiravir use (weighted hazard ratio 1.17; 95% CI, 0.99-1.39; P = .062) was associated with a reduced risk of hospitalization than nonusers. The use of molnupiravir or nirmatrelvir/ritonavir was not associated with a lower risk of the secondary endpoint as compared with nonusers. CONCLUSION: Use of nirmatrelvir/ritonavir but not molnupiravir was associated with a reduced risk of hospitalization in real-world nonhospitalized patients with COVID-19.

Sensitisation to recombinant Aspergillus fumigatus allergens and clinical outcomes in COPD.

BACKGROUND: Variable clinical outcomes are reported with fungal sensitisation in chronic obstructive pulmonary disease (COPD), and it remains unclear which fungi and what allergens associate with the poorest outcomes. The use of recombinant as opposed to crude allergens for such assessment is unknown. METHODS: A prospective multicentre assessment of stable COPD (n=614) was undertaken in five hospitals across three countries: Singapore, Malaysia and Hong Kong. Clinical and serological assessment was performed against a panel of 35 fungal allergens including crude and recombinant Aspergillus and non-Aspergillus allergens. Unsupervised clustering and topological data analysis (TDA) approaches were employed using the measured sensitisation responses to elucidate if sensitisation subgroups exist and their related clinical outcomes. RESULTS: Aspergillus fumigatus sensitisation was associated with increased exacerbations in COPD. Unsupervised cluster analyses revealed two "fungal sensitisation" groups. The first was characterised by Aspergillus sensitisation and increased exacerbations, poorer lung function and worse prognosis. Polysensitisation in this group conferred even poorer outcome. The second group, characterised by Cladosporium sensitisation, was more symptomatic. Significant numbers of individuals demonstrated sensitisation responses to only recombinant (as opposed to crude) A. fumigatus allergens f 1, 3, 5 and 6, and exhibited increased exacerbations, poorer lung function and an overall worse prognosis. TDA validated these findings and additionally identified a subgroup within Aspergillus-sensitised COPD of patients with frequent exacerbations. CONCLUSION: Aspergillus sensitisation is a treatable trait in COPD. Measuring sensitisation responses to recombinant Aspergillus allergens identifies an important patient subgroup with poor COPD outcomes that remains overlooked by assessment of only crude Aspergillus allergens.

Lysosome activation in peripheral blood mononuclear cells and prognostic significance of circulating LC3B in COVID-19.

Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, causing significant mortality. There is a mechanistic relationship between intracellular coronavirus replication and deregulated autophagosome-lysosome system. We performed transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients and identified the aberrant upregulation of genes in the lysosome pathway. We further determined the capability of two circulating markers, namely microtubule-associated proteins 1A/1B light chain 3B (LC3B) and (p62/SQSTM1) p62, both of which depend on lysosome for degradation, in predicting the emergence of moderate-to-severe disease in COVID-19 patients requiring hospitalization for supplemental oxygen therapy. Logistic regression analyses showed that LC3B was associated with moderate-to-severe COVID-19, independent of age, sex and clinical risk score. A decrease in LC3B concentration <5.5 ng/ml increased the risk of oxygen and ventilatory requirement (adjusted odds ratio: 4.6; 95% CI: 1.1-22.0; P = 0.04). Serum concentrations of p62 in the moderate-to-severe group were significantly lower in patients aged 50 or below. In conclusion, lysosome function is deregulated in PBMCs isolated from COVID-19 patients, and the related biomarker LC3B may serve as a novel tool for stratifying patients with moderate-to-severe COVID-19 from those with asymptomatic or mild disease. COVID-19 patients with a decrease in LC3B concentration <5.5 ng/ml will require early hospital admission for supplemental oxygen therapy and other respiratory support.

Respiratory admissions before and during the COVID-19 pandemic with mediation analysis of air pollutants, mask-wearing and influenza rates.

BACKGROUND AND OBJECTIVE: Decline in hospitalizations for various respiratory diseases has been reported during the COVID-19 pandemic, but what led to such an observation is uncertain. METHODS: This was a territory-wide, retrospective cohort study involving all public hospital admissions in Hong Kong from 1 January 2017 to 31 December 2020. Hospital admissions for respiratory diseases, including asthma, COPD and non-COVID pneumonia, were assessed. COVID-related admissions were excluded from this study. The time of commencement of the pandemic was taken from the fourth week of January 2020. The associations between air pollutant levels, influenza and mask-wearing rates with hospital admissions were assessed by mediation analyses. RESULTS: There were altogether 19,485, 78,693 and 238,781 admissions for asthma, COPD and non-COVID pneumonia from January 2017 to December 2020. There was a marked reduction in hospital admissions of asthma, COPD and non-COVID pneumonia (37%, 36% and 12% decrease in average daily admissions, respectively) during the COVID-19 pandemic compared to before. Air pollutant levels and influenza rate were decreased while mask-wearing rate was increased. Collinearity of mask-wearing rates and pandemic year was observed. For COPD, NO2 , SO2 , PM10 and influenza rates (4%, 11%, 4% and 4% of the total effect, respectively), while for non-COVID pneumonia, PM10 and influenza rates (11% and 52%, respectively) had significant mediation effect on changes in hospital admissions before and during the COVID-19 pandemic. CONCLUSION: During the COVID-19 pandemic, a decrease in air pollutant levels and influenza rate had mediation effect on the reduction in hospitalizations of COPD and non-COVID pneumonia.

Comparison of the 12-month impact of COVID-19 and SARS on physiological capacity and health-related quality of life.

BACKGROUND: Little is known about the differences in medium to long-term recovery on spirometry, 6-minute walking distance (6MWD) and health-related quality of life (HRQoL) between COVID-19 and SARS. METHODS: We performed a 12-month prospective study on COVID-19 survivors. The changes in dynamic lung volumes at spirometry (%predicted FEV1, %predicted FVC), 6MWD and HRQoL at 1-3, 6 to 12 months were compared against a historical cohort of SARS survivors using the same study protocol. The residual radiological changes in HRCT in COVID-19 survivors were correlated with their functional capacity. RESULTS: 108 COVID-19 survivors of various disease severity (asymptomatic 2.9%, mild 33.3%, moderate 47.2%, severe 8.3%, critical 8.3%) were recruited. When compared with 97 SARS survivors, 108 COVID-19 survivors were older (48.1 ± 16.4 vs. 36.1 ± 9.5 years, p < 0.001) and required less additional support during hospitalization; with lower dynamic lung volumes, shorter 6MWD and better physical component score. Both groups of survivors had comparable changes in these parameters at subsequent follow-ups. Both COVID-19 and SARS survivors had similar mental component score (MCS) at 6 and 12 months. COVID-19 survivors initially experienced less (between-group difference, -3.1, 95% confidence interval [CI] -5.5 to -0.7, p = 0.012) and then more improvement (between-group difference 2.9, 95%, CI 0.8 to 5.1, p = 0.007) than SARS survivors in the MCS at 1-3 to 6 months and 6 to 12 months respectively. Forty (44.0%) out of 91 COVID-19 survivors had residual abnormalities on HRCT at 12 months, with a negative correlation between the severity scores of parenchymal changes and 6MWD (r=-0.239, p < 0.05). CONCLUSIONS: COVID-19 survivors demonstrated a similar recovery speed in dynamic lung volumes and exercise capacity, but different paces of psychological recovery as SARS survivors in the convalescent phase. The severity of parenchymal changes in HRCT is negatively correlated with the 6MWD of COVID-19 survivors. TRIAL REGISTRATION: This prospective study was registered at ClinicalTrials.gov on 2 November 2020 (Identifier: NCT04611243).

Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome.

BACKGROUND: Long-term complications after COVID-19 are common, but the potential cause for persistent symptoms after viral clearance remains unclear. OBJECTIVE: To investigate whether gut microbiome composition is linked to post-acute COVID-19 syndrome (PACS), defined as at least one persistent symptom 4 weeks after clearance of the SARS-CoV-2 virus. METHODS: We conducted a prospective study of 106 patients with a spectrum of COVID-19 severity followed up from admission to 6 months and 68 non-COVID-19 controls. We analysed serial faecal microbiome of 258 samples using shotgun metagenomic sequencing, and correlated the results with persistent symptoms at 6 months. RESULTS: At 6 months, 76% of patients had PACS and the most common symptoms were fatigue, poor memory and hair loss. Gut microbiota composition at admission was associated with occurrence of PACS. Patients without PACS showed recovered gut microbiome profile at 6 months comparable to that of non-COVID-19 controls. Gut microbiome of patients with PACS were characterised by higher levels of Ruminococcus gnavus, Bacteroides vulgatus and lower levels of Faecalibacterium prausnitzii. Persistent respiratory symptoms were correlated with opportunistic gut pathogens, and neuropsychiatric symptoms and fatigue were correlated with nosocomial gut pathogens, including Clostridium innocuum and Actinomyces naeslundii (all p<0.05). Butyrate-producing bacteria, including Bifidobacterium pseudocatenulatum and Faecalibacterium prausnitzii showed the largest inverse correlations with PACS at 6 months. CONCLUSION: These findings provided observational evidence of compositional alterations of gut microbiome in patients with long-term complications of COVID-19. Further studies should investigate whether microbiota modulation can facilitate timely recovery from post-acute COVID-19 syndrome.

Current and Past Infections of HBV Do Not Increase Mortality in Patients With COVID-19.

BACKGROUND AND AIMS: We compared risk of acute liver injury and mortality in patients with COVID-19 and current, past, and no HBV infection. APPROACH AND RESULTS: This was a territory-wide retrospective cohort study in Hong Kong. Patients with COVID-19 between January 23, 2020, and January 1, 2021, were identified. Patients with hepatitis C or no HBsAg results were excluded. The primary outcome was mortality. Acute liver injury was defined as alanine aminotransferase or aspartate aminotransferase ≥2 × upper limit of normal (ULN; i.e., 80 U/L), with total bilirubin ≥2 × ULN (i.e., 2.2 mg/dL) and/or international normalized ratio ≥1.7. Of 5,639 patients included, 353 (6.3%) and 359 (6.4%) had current and past HBV infection, respectively. Compared to patients without known HBV exposure, current HBV-infected patients were older and more likely to have cirrhosis. Past HBV-infected patients were the oldest, and more had diabetes and cardiovascular disease. At a median follow-up of 14 (9-20) days, 138 (2.4%) patients died; acute liver injury occurred in 58 (1.2%), 8 (2.3%), and 11 (3.1%) patients with no, current, and past HBV infection, respectively. Acute liver injury (adjusted HR [aHR], 2.45; 95% CI, 1.52-3.96; P < 0.001), but not current (aHR, 1.29; 95% CI, 0.61-2.70; P = 0.507) or past (aHR, 0.90; 95% CI, 0.56-1.46; P = 0.681) HBV infection, was associated with mortality. Use of corticosteroid, antifungal, ribavirin, or lopinavir-ritonavir (adjusted OR [aOR], 2.55-5.63), but not current (aOR, 1.93; 95% CI, 0.88-4.24; P = 0.102) or past (aOR, 1.25; 95% CI, 0.62-2.55; P = 0.533) HBV infection, was associated with acute liver injury. CONCLUSION: Current or past HBV infections were not associated with more liver injury and mortality in COVID-19.

Risks of AKI and Major Adverse Clinical Outcomes in Patients with Severe Acute Respiratory Syndrome or Coronavirus Disease 2019.

BACKGROUND: Severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19) are closely related. The effect of AKI on the clinical outcomes of these two conditions is unclear. METHODS: This retrospective, territory-wide cohort study used an electronic public healthcare database in Hong Kong to identify patients with SARS or COVID-19 by diagnosis codes, virologic results, or both. The primary endpoint was a composite of intensive care unit admission, use of invasive mechanical ventilation, and/or death. RESULTS: We identified 1670 patients with SARS and 1040 patients with COVID-19 (median ages, 41 versus 35 years, respectively). Among patients with SARS, 26% met the primary endpoint versus 5.3% of those with COVID-19. Diabetes mellitus, abnormal liver function, and AKI were factors significantly associated with the primary endpoint among patients with either SARS or COVID-19. Among patients with SARS, 7.9%, 2.1%, and 3.7% developed stage 1, stage 2, and stage 3 AKI, respectively; among those with COVID-19, 6.6%, 0.4%, and 1.1% developed stage 1, stage 2, and stage 3 AKI, respectively. In both groups, factors significantly associated with AKI included diabetes mellitus and hypertension. Among patients with AKI, those with COVID-19 had a lower rate of major adverse clinical outcomes versus patients with SARS. Renal function recovery usually occurred within 30 days after an initial AKI event. CONCLUSIONS: AKI rates were higher among patients with SARS than those with COVID-19. AKI was associated with major adverse clinical outcomes for both diseases. Patients with diabetes mellitus and abnormal liver function were also at risk of developing severe consequences after SARS and COVID-19 infection.

Liver injury is independently associated with adverse clinical outcomes in patients with COVID-19.

OBJECTIVE: Data on serial liver biochemistries of patients infected by different human coronaviruses (HCoVs) are lacking. The impact of liver injury on adverse clinical outcomes in coronavirus disease 2019 (COVID-19) patients remains unclear. DESIGN: This was a retrospective cohort study using data from a territory-wide database in Hong Kong. COVID-19, severe acute respiratory syndrome (SARS) and other HCoV patients were identified by diagnosis codes and/or virological results. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation was defined as ALT/AST ≥2 × upper limit of normal (ie, 80 U/L). The primary end point was a composite of intensive care unit (ICU) admission, use of invasive mechanical ventilation and/or death. RESULTS: We identified 1040 COVID-19 patients (mean age 38 years, 54% men), 1670 SARS patients (mean age 44 years, 44% men) and 675 other HCoV patients (mean age 20 years, 57% men). ALT/AST elevation occurred in 50.3% SARS patients, 22.5% COVID-19 patients and 36.0% other HCoV patients. For COVID-19 patients, 53 (5.1%) were admitted to ICU, 22 (2.1%) received invasive mechanical ventilation and 4 (0.4%) died. ALT/AST elevation was independently associated with primary end point (adjusted OR (aOR) 7.92, 95% CI 4.14 to 15.14, p<0.001) after adjusted for albumin, diabetes and hypertension. Use of lopinavir-ritonavir ±ribavirin + interferon beta (aOR 1.94, 95% CI 1.20 to 3.13, p=0.006) and corticosteroids (aOR 3.92, 95% CI 2.14 to 7.16, p<0.001) was independently associated with ALT/AST elevation. CONCLUSION: ALT/AST elevation was common and independently associated with adverse clinical outcomes in COVID-19 patients. Use of lopinavir-ritonavir, with or without ribavirin, interferon beta and/or corticosteroids was independently associated with ALT/AST elevation.

Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19.

OBJECTIVE: Although COVID-19 is primarily a respiratory illness, there is mounting evidence suggesting that the GI tract is involved in this disease. We investigated whether the gut microbiome is linked to disease severity in patients with COVID-19, and whether perturbations in microbiome composition, if any, resolve with clearance of the SARS-CoV-2 virus. METHODS: In this two-hospital cohort study, we obtained blood, stool and patient records from 100 patients with laboratory-confirmed SARS-CoV-2 infection. Serial stool samples were collected from 27 of the 100 patients up to 30 days after clearance of SARS-CoV-2. Gut microbiome compositions were characterised by shotgun sequencing total DNA extracted from stools. Concentrations of inflammatory cytokines and blood markers were measured from plasma. RESULTS: Gut microbiome composition was significantly altered in patients with COVID-19 compared with non-COVID-19 individuals irrespective of whether patients had received medication (p<0.01). Several gut commensals with known immunomodulatory potential such as Faecalibacterium prausnitzii, Eubacterium rectale and bifidobacteria were underrepresented in patients and remained low in samples collected up to 30 days after disease resolution. Moreover, this perturbed composition exhibited stratification with disease severity concordant with elevated concentrations of inflammatory cytokines and blood markers such as C reactive protein, lactate dehydrogenase, aspartate aminotransferase and gamma-glutamyl transferase. CONCLUSION: Associations between gut microbiota composition, levels of cytokines and inflammatory markers in patients with COVID-19 suggest that the gut microbiome is involved in the magnitude of COVID-19 severity possibly via modulating host immune responses. Furthermore, the gut microbiota dysbiosis after disease resolution could contribute to persistent symptoms, highlighting a need to understand how gut microorganisms are involved in inflammation and COVID-19.

Significantly Lower Case-fatality Ratio of Coronavirus Disease 2019 (COVID-19) than Severe Acute Respiratory Syndrome (SARS) in Hong Kong-A Territory-Wide Cohort Study.

BACKGROUND: The case-fatality ratios (CFR) of coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) appeared to differ substantially. We aimed to compare the CFR and its predictors of COVID-19 and SARS patients using a territory-wide cohort in Hong Kong. METHODS: This was a territory-wide retrospective cohort study using data captured from all public hospitals in Hong Kong. Laboratory-confirmed COVID-19 and SARS patients were identified. The primary endpoint was a composite endpoint of intensive care unit admission, use of mechanical ventilation, and/or death. RESULTS: We identified 1013 COVID-19 patients (mean age, 38.4 years; 53.9% male) diagnosed from 23 January to 14 April 2020 and 1670 SARS patients (mean age, 44.4 years; 44.0% male) from March to June 2003. Fifty-five (5.4%) COVID-19 patients and 432 (25.9%) SARS patients had reached the primary endpoint in 30 days. By 30 June 2003, 286 SARS patients had died (CFR, 17.1%). By 7 June 2020, 4 COVID-19 patients had died (CFR, 0.4%). After adjusting for demographic and clinical parameters, COVID-19 was associated with a 71% lower risk of primary endpoint compared with SARS (adjusted hazard ratio, 0.29; 95% confidence interval, .21-.40; P < .0001). Age, diabetes mellitus, and laboratory parameters (high lactate dehydrogenase, high C-reactive protein, and low platelet count) were independent predictors of the primary endpoint in COVID-19 patients, whereas use of antiviral treatments was not associated with primary endpoint. CONCLUSIONS: The CFR of COVID-19 was 0.4%. Age and diabetes were associated with worse outcomes, whereas antiviral treatments were not.

Epidemiology, clinical spectrum, viral kinetics and impact of COVID-19 in the Asia-Pacific region.

COVID-19 has hit the world by surprise, causing substantial mortality and morbidity since 2020. This narrative review aims to provide an overview of the epidemiology, induced impact, viral kinetics and clinical spectrum of COVID-19 in the Asia-Pacific Region, focusing on regions previously exposed to outbreaks of coronavirus. COVID-19 progressed differently by regions, with some (such as China and Taiwan) featured by one to two epidemic waves and some (such as Hong Kong and South Korea) featured by multiple waves. There has been no consensus on the estimates of important epidemiological time intervals or proportions, such that using them for making inferences should be done with caution. Viral loads of patients with COVID-19 peak in the first week of illness around days 2 to 4 and hence there is very high transmission potential causing community outbreaks. Various strategies such as government-guided and suppress-and-lift strategies, trigger-based/suppression approaches and alert systems have been employed to guide the adoption and easing of control measures. Asymptomatic and pre-symptomatic transmission is a hallmark of COVID-19. Identification and isolation of symptomatic patients alone is not effective in controlling the ongoing outbreaks. However, early, prompt and coordinated enactment predisposed regions to successful disease containment. Mass COVID-19 vaccinations are likely to be the light at the end of the tunnel. There is a need to review what we have learnt in this pandemic and examine how to transfer and improve existing knowledge for ongoing and future epidemics.

Effect of short-course exercise training on the frequency of exacerbations and physical activity in patients with COPD: A randomized controlled trial.

BACKGROUND AND OBJECTIVE: Previous studies have suggested that early pulmonary rehabilitation (PR) programmes post-AECOPD are an effective and safe intervention for reducing hospital admissions and improving quality of life. This study assessed whether a short course of exercise training post-AECOPD with periodic reinforcement exercise training and phone call reminders reduces readmissions and increases physical activity in COPD patients. METHODS: Subjects were randomized into either the (i) intervention group (IG), consisting of 4-8 weeks of training supervised by a physiotherapist and phone contact every 2 weeks by a case manager providing support and reinforcement of continuous exercise at home or (ii) usual care group (UG), which had no input by a physiotherapist or case manager. Readmissions were assessed at 12 months. Activities of all patients were assessed by an activity monitor at baseline, 3 and 12 months. RESULTS: Altogether, 136 subjects were included and randomized (68 in IG and 68 in UG). The age, gender and FEV1 % predicted were 75.0 ± 6.7 years, 132 males and 47.0 ± 16.2%, respectively. The mean number of readmissions for AECOPD (1.06 vs 1.72 times, P = 0.014) was less and time to first readmission was increased (146.8 vs 122.4 days, P = 0.005) in the IG versus UG at 12 months. At 12 months, there was no change in activity measured by activity monitor between the two groups. CONCLUSION: This programme decreased exacerbation frequency and increased the time of readmissions for AECOPD. It did not improve physical activities and exercise tolerance at 12 months.

Evolving Epidemiological Characteristics of COVID-19 in Hong Kong From January to August 2020: Retrospective Study.

BACKGROUND: COVID-19 has plagued the globe, with multiple SARS-CoV-2 clusters hinting at its evolving epidemiology. Since the disease course is governed by important epidemiological parameters, including containment delays (time between symptom onset and mandatory isolation) and serial intervals (time between symptom onsets of infector-infectee pairs), understanding their temporal changes helps to guide interventions. OBJECTIVE: This study aims to characterize the epidemiology of the first two epidemic waves of COVID-19 in Hong Kong by doing the following: (1) estimating the containment delays, serial intervals, effective reproductive number (Rt), and proportion of asymptomatic cases; (2) identifying factors associated with the temporal changes of the containment delays and serial intervals; and (3) depicting COVID-19 transmission by age assortativity and types of social settings. METHODS: We retrieved the official case series and the Apple mobility data of Hong Kong from January-August 2020. The empirical containment delays and serial intervals were fitted to theoretical distributions, and factors associated with their temporal changes were quantified in terms of percentage contribution (the percentage change in the predicted outcome from multivariable regression models relative to a predefined comparator). Rt was estimated with the best fitted distribution for serial intervals. RESULTS: The two epidemic waves were characterized by imported cases and clusters of local cases, respectively. Rt peaked at 2.39 (wave 1) and 3.04 (wave 2). The proportion of asymptomatic cases decreased from 34.9% (0-9 years) to 12.9% (≥80 years). Log-normal distribution best fitted the 1574 containment delays (mean 5.18 [SD 3.04] days) and the 558 serial intervals (17 negative; mean 4.74 [SD 4.24] days). Containment delays decreased with involvement in a cluster (percentage contribution: 10.08%-20.73%) and case detection in the public health care sector (percentage contribution: 27.56%, 95% CI 22.52%-32.33%). Serial intervals decreased over time (6.70 days in wave 1 versus 4.35 days in wave 2) and with tertiary transmission or beyond (percentage contribution: -50.75% to -17.31%), but were lengthened by mobility (percentage contribution: 0.83%). Transmission within the same age band was high (18.1%). Households (69.9%) and social settings (20.3%) were where transmission commonly occurred. CONCLUSIONS: First, the factors associated with reduced containment delays suggested government-enacted interventions were useful for achieving outbreak control and should be further encouraged. Second, the shorter serial intervals associated with the composite mobility index calls for empirical surveys to disentangle the role of different contact dimensions in disease transmission. Third, the presymptomatic transmission and asymptomatic cases underscore the importance of remaining vigilant about COVID-19. Fourth, the time-varying epidemiological parameters suggest the need to incorporate their temporal variations when depicting the epidemic trajectory. Fifth, the high proportion of transmission events occurring within the same age group supports the ban on gatherings outside of households, and underscores the need for residence-centered preventive measures.

Environmental fungal sensitisation associates with poorer clinical outcomes in COPD.

INTRODUCTION: Allergic sensitisation to fungi such as Aspergillus are associated to poor clinical outcomes in asthma, bronchiectasis and cystic fibrosis; however, clinical relevance in COPD remains unclear. METHODS: Patients with stable COPD (n=446) and nondiseased controls (n=51) were prospectively recruited across three countries (Singapore, Malaysia and Hong Kong) and screened against a comprehensive allergen panel including house dust mites, pollens, cockroach and fungi. For the first time, using a metagenomics approach, we assessed outdoor and indoor environmental allergen exposure in COPD. We identified key fungi in outdoor air and developed specific-IgE assays against the top culturable fungi, linking sensitisation responses to COPD outcomes. Indoor air and surface allergens were prospectively evaluated by metagenomics in the homes of 11 COPD patients and linked to clinical outcome. RESULTS: High frequencies of sensitisation to a broad range of allergens occur in COPD. Fungal sensitisation associates with frequent exacerbations, and unsupervised clustering reveals a "highly sensitised fungal predominant" subgroup demonstrating significant symptomatology, frequent exacerbations and poor lung function. Outdoor and indoor environments serve as important reservoirs of fungal allergen exposure in COPD and promote a sensitisation response to outdoor air fungi. Indoor (home) environments with high fungal allergens associate with greater COPD symptoms and poorer lung function, illustrating the importance of environmental exposures on clinical outcomes in COPD. CONCLUSION: Fungal sensitisation is prevalent in COPD and associates with frequent exacerbations representing a potential treatable trait. Outdoor and indoor (home) environments represent a key source of fungal allergen exposure, amenable to intervention, in "sensitised" COPD.

Molecular detection of respiratory pathogens and typing of human rhinovirus of adults hospitalized for exacerbation of asthma and chronic obstructive pulmonary disease.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and asthma are associated with a variety of precipitating factors including infection. This study assessed the infective viral etiologies by real-time multiplex polymerase chain reaction of patients hospitalized with AECOPD and asthma exacerbations. In addition, infective etiologies were assessed for association with the clinical outcome of the patients. METHODS: Adults admitted with AECOPD and asthma exacerbations between August 2016 and July 2017 were recruited. Nasopharyngeal aspirate (NPA) samples were obtained from the patients within 1-2 days of admission and subjected to pathogen detection and human rhinovirus (HRV) typing. RESULTS: Altogether 402 patients with AECOPD, 80 stable COPD, 100 asthma exacerbation and 21 stable asthma subjects were recruited. Among those admitted for AECOPD and asthma exacerbations, 141(35.1%) and 45(45.0%) respectively had pathogens identified in the NPA specimens. The commonest virus identified was influenza A followed by HRV. HRV typing identified HRV-A and HRV-C as the more common HRV with a wide variety of genotypes. Identification of pathogens in NPA or HRV typing otherwise did not affect clinical outcomes including the hospital length of stay, readmission rates and mortality except that identification of pathogens in asthma exacerbation was associated with a lower rate of readmissions at 30 and 60 days. CONCLUSIONS: Many respiratory viruses were associated with AECOPD and asthma exacerbation. HRV-A and HRV-C were the more common HRV associated with exacerbations. Identification of pathogens in NPA was associated with less readmissions for asthma patients at 30 and 60 days. TRIAL REGISTRATION: ClinicalTrials.gov NCT02866357 .

IFITM3, TLR3, and CD55 Gene SNPs and Cumulative Genetic Risks for Severe Outcomes in Chinese Patients With H7N9/H1N1pdm09 Influenza.

Background: We examined associations between single-nucleotide polymorphisms (SNPs) of IFITM3, TLR3, and CD55 genes and influenza clinical outcomes in Chinese. Methods: A multicenter study was conducted on 275 adult cases of avian (H7N9) and pandemic (H1N1pdm09) influenza. Host DNA was extracted from diagnostic respiratory samples; IFITM3 rs12252, TLR3 rs5743313, CD55 rs2564978, and TLR4 rs4986790/4986791 were targeted for genotyping (Sanger sequencing). The primary outcome analyzed was death. Results: IFITM3 and TLR3 SNPs were in Hardy-Weinberg equilibrium; their allele frequencies (IFITM3/C-allele 0.56, TLR3/C-allele 0.88) were comparable to 1000 Genomes Han Chinese data. We found over-representation of homozygous IFITM3 CC (54.5% vs 33.2%; P = .02) and TLR3 CC (93.3% vs 76.9%; P = .04) genotypes among fatal cases. Recessive genetic models showed their significant independent associations with higher death risks (adjusted hazard ratio [aHR] 2.78, 95% confidence interval [CI] 1.29-6.02, and aHR 4.85, 95% CI 1.11-21.06, respectively). Cumulative effects were found (aHR 3.53, 95% CI 1.64-7.59 per risk genotype; aHR 9.99, 95% CI 1.27-78.59 with both). Results were consistent for each influenza subtype and other severity indicators. The CD55 TT genotype was linked to severity. TLR4 was nonpolymorphic. Conclusions: Host genetic factors may influence clinical outcomes of avian and pandemic influenza infections. Such findings have important implications on disease burden and patient care in at-risk populations.