Systemic immune-inflammation index in predicting hospitalized bronchiectasis exacerbation risks and disease severity.

Background: Bronchiectasis is a common respiratory disease with neutrophilic inflammation being the predominant pathophysiology. Systemic immune-inflammation index (SII) is a simple and readily available biomarker being studied in various conditions including asthma, chronic obstructive pulmonary disease, and interstitial lung disease, but not in bronchiectasis. We aim to investigate the prognostic role of SII in bronchiectasis with this study. Methods: A retrospective cohort study in Chinese patients with non-cystic fibrosis (CF) bronchiectasis was conducted in Hong Kong, to investigate the association between baseline SII and of hospitalized bronchiectasis exacerbation risk over 4.5 years of follow-up, as well as correlating with disease severity in bronchiectasis. The baseline SII in 2018 was calculated based on stable-state complete blood count. Results: Among 473 Chinese patients with non-CF bronchiectasis were recruited, 94 of the patients had hospitalized bronchiectasis exacerbation during the follow-up period. Higher SII was associated with increased hospitalized bronchiectasis exacerbation risks with adjusted odds ratio (aOR) of 1.001 [95% confidence interval (CI): 1.000-1.001, P=0.003] for 1 unit (cells/µL) increase in SII count and aOR of 1.403 (95% CI: 1.126-1.748, P=0.003) for 1 standard deviation (SD) increase in SII. SII was found to have significant negative association with baseline forced expiratory volume in the first second (FEV1) (in litre and percentage predicted), forced vital capacity (FVC) in percentage; and significant positive correlation with the extent of bronchiectasis and baseline neutrophil to lymphocyte ratio (NLR). Conclusions: SII could serve as biomarker to predict the risks of hospitalized exacerbation in bronchiectasis patients, as well as correlating with the disease severity.

Real-World Effectiveness Study of Nirmatrelvir-Ritonavir or Molnupiravir in Hospitalized Unvaccinated Patients with Chronic Respiratory Diseases and Moderate COVID-19 at Presentation.

Introduction: Nirmatrelvir-ritonavir (NMV-r) and molnupiravir (MOL) were developed as out-patient anti-viral for mild COVID-19. There was limited data on their role in treating COVID-19 for hospitalized patients, especially among adult patients who are unvaccinated and had chronic respiratory diseases. Methods: A territory-wide retrospective study was conducted in Hong Kong to compare the efficacy of NMV-r and MOL against COVID-19 in unvaccinated adult patients with asthma, chronic obstructive pulmonary disease, bronchiectasis and interstitial lung diseases presenting with moderate COVID-19 from 16th February 2022 to 15th March 2023. Results: A total of 1354 patients were included, 738 received NMV-r and 616 received MOL. NMV-r was more effective in reducing 90-day mortality with adjusted hazard ratios (aHR) of 0.508 (95% confidence interval [CI] = 0.314-0.822, p = 0.006). Patients who received NMV-r also had significantly shorter length of stay (LOS) than those receiving MOL, with median LOS of 4 (Interquartile range [IQR] = 2-7) for NMV-r and 6 (IQR = 3-10) for MOL (p-value < 0.001). There was no statistically significant difference in the development of respiratory failure and severe respiratory failure in the two groups. Discussion: NMV-r was more effective than MOL among unvaccinated adults with chronic respiratory diseases who were hospitalized for moderate COVID-19 without hypoxaemia on admission.

Increased exacerbations of bronchiectasis following recovery from mild COVID-19 in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND AND OBJECTIVE: Respiratory viral infection is a common trigger of bronchiectasis exacerbation. Knowledge of the intermediate to long-term effect of COVID-19 on bronchiectasis is poor. METHODS: A retrospective cohort study of patient records was conducted to assess the frequency of bronchiectasis exacerbation following recovery from mild-to-moderate COVID-19. The exacerbation frequency at baseline, using 2019 and 2019-2021 data, was compared with that during the 1 year following recovery. RESULTS: A total of 234 adult patient records who had a confirmed diagnosis of bronchiectasis were identified, of whom 52 (22.2%) were classified as the COVID-19 group. Patients with COVID-19 had significantly more frequent annual exacerbations of bronchiectasis (total exacerbations and hospitalizations). Compared with 2019-2021 data, the total exacerbation frequency decreased by 0.1 ± 0.51 per year among non-COVID-19 patients but increased by 0.68 ± 1.09 per year among the COVID-19 group (p < 0.001). Compared with 2019 only data, exacerbation frequency decreased by 0.14 ± 0.79 per year among non-COVID-19 patients but increased by 0.76 ± 1.17 per year in the COVID-19 group, p < 0.001. The annual frequency of hospitalization for bronchiectasis increased by 0.01 ± 0.32 per year among non-COVID-19 patients and increased by 0.39 ± 1.06 per year in the COVID-19 group (p < 0.001) compared with 2019 to 2021 data. When compared with only 2019 data, it remained unchanged at 0 ± 0.43 per year among non-COVID-19 patients but increased to 0.38 ± 1.12 per year among COVID-19 patients (p < 0.001). CONCLUSION: Mild-to-moderate COVID-19 was associated with an increase in frequency of bronchiectasis exacerbation and frequency of hospitalizations following recovery.

The burden of systemic corticosteroid use in asthma management in Asia.

For most patients, asthma can be effectively managed using inhaled medications. However, patients who have severe and/or uncontrolled asthma, or who experience exacerbations, may require systemic corticosteroids (SCSs) to maintain asthma control. Although SCS are highly effective in this regard, even modest exposure to these medications can increase the risk for long-term, adverse health outcomes, such as type 2 diabetes, renal impairment, cardiovascular disease and overall mortality. Clinical and real-world data from studies investigating asthma severity, control and treatment practices around the globe have suggested that SCS are overused in asthma management, adding to the already substantial healthcare burden experienced by patients. Throughout Asia, although data on asthma severity, control and SCS usage are limited and vary widely among countries, available data strongly suggest a pattern of overuse consistent with the broader global trend. Coordinated changes at the patient, provider, institutional and policy levels, such as increasing disease awareness, promoting better adherence to treatment guidelines and increasing availability of safe and effective alternatives to SCS, are likely necessary to reduce the SCS burden for patients with asthma in Asia.

Blood eosinophil percentage as a predictor of response to inhaled corticosteroid in bronchiectasis.

INTRODUCTION: The role of inhaled corticosteroid (ICS) among patients with bronchiectasis remains controversial. There is limited evidence of using baseline eosinophil count (absolute and percentage) as a marker to predict the role of ICS among patients with bronchiectasis. METHODS: A retrospective case-control study was conducted in a major regional hospital and tertiary respiratory referral centre in Hong Kong, including 140 Chinese patients with noncystic fibrosis (CF) bronchiectasis, to investigate the exacerbation risks of bronchiectasis among ICS users and nonusers with different baseline eosinophil counts. RESULTS: ICS user had significantly lower risk to develop bronchiectasis exacerbation with adjusted odds ratio (OR) of 0.461 (95% confidence interval [CI] 0.225-0.945, p-value 0.035). Univariate logistic regression was performed for different cut-offs of blood eosinophil count (by percentage) from 2% to 4% (with a 0.5% grid each time). Baseline eosinophil 3.5% was found to be the best cut-off among all with adjusted OR of 0.138 (95% CI = 0.023-0.822, p-value = 0.030). CONCLUSION: Baseline eosinophil count of 3.5% might serve as a marker to predict the benefits of ICS on exacerbation risk among patients with non-CF bronchiectasis.

Prediction model on disease recurrence for low risk resected stage I lung adenocarcinoma.

BACKGROUND AND OBJECTIVE: Although stage I non-small cell lung carcinoma (NSCLC) typically carries a good prognosis following complete resection, early disease recurrence can occur. An accurate survival prediction model would help refine a follow-up strategy and personalize future adjuvant therapy. We developed a post-operative prediction model based on readily available clinical information for patients with stage I adenocarcinoma. METHODS: We retrospectively studied the disease-free survival (DFS) of 408 patients with pathologically confirmed low-risk stage I adenocarcinoma of lung who underwent curative resection from 2013 to 2017. A tree-based method was employed to partition the cohort into subgroups with distinct DFS outcome and stepwise risk ratio. These covariates were included in multivariate analysis to build a scoring system to predict disease recurrence. The model was subsequently validated using a 2011-2012 cohort. RESULTS: Non-smoker status, stage IA disease, epidermal-growth factor receptor mutants and female gender were associated with better DFS. Multivariate analysis identified smoking status, disease stage and gender as factors necessary for the scoring system and yielded 3 distinct risk groups for DFS [99.4 (95% CI 78.3-125.3), 62.9 (95% CI 48.2-82.0), 33.7 (95% CI 24.6-46.1) months, p < 0.005]. External validation yielded an area under the curve by receiver operating characteristic analysis of 0.863 (95% CI 0.755-0.972). CONCLUSION: The model could categorize post-operative patients using readily available clinical information, and may help personalize a follow-up strategy and future adjuvant therapy.

SARS-CoV-2 infection aggravates cigarette smoke-exposed cell damage in primary human airway epithelia.

BACKGROUND: The coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide pandemic with over 627 million cases and over 6.5 million deaths. It was reported that smoking-related chronic obstructive pulmonary disease (COPD) might be a crucial risk for COVID-19 patients to develop severe condition. As cigarette smoke (CS) is the major risk factor for COPD, we hypothesize that barrier dysfunction and an altered cytokine response in CS-exposed airway epithelial cells may contribute to increased SARS-CoV-2-induced immune response that may result in increased susceptibility to severe disease. The aim of this study was to evaluate the role of CS on SARS-CoV-2-induced immune and inflammatory responses, and epithelial barrier integrity leading to airway epithelial damage. METHODS: Primary human airway epithelial cells were differentiated under air-liquid interface culture. Cells were then exposed to cigarette smoke medium (CSM) before infection with SARS-CoV-2 isolated from a local patient. The infection susceptibility, morphology, and the expression of genes related to host immune response, airway inflammation and damages were evaluated. RESULTS: Cells pre-treated with CSM significantly caused higher replication of SARS-CoV-2 and more severe SARS-CoV-2-induced cellular morphological alteration. CSM exposure caused significant upregulation of long form angiotensin converting enzyme (ACE)2, a functional receptor for SARS-CoV-2 viral entry, transmembrane serine protease (TMPRSS)2 and TMPRSS4, which cleave the spike protein of SARS-CoV-2 to allow viral entry, leading to an aggravated immune response via inhibition of type I interferon pathway. In addition, CSM worsened SARS-CoV-2-induced airway epithelial cell damage, resulting in severe motile ciliary disorder, junctional disruption and mucus hypersecretion. CONCLUSION: Smoking led to dysregulation of host immune response and cell damage as seen in SARS-CoV-2-infected primary human airway epithelia. These findings may contribute to increased disease susceptibility with severe condition and provide a better understanding of the pathogenesis of SARS-CoV-2 infection in smokers.

Real-World Study on Effectiveness of Molnupiravir and Nirmatrelvir-Ritonavir in Unvaccinated Patients with Chronic Respiratory Diseases with Confirmed SARS-CoV-2 Infection Managed in Out-Patient Setting.

While molnupiravir (MOV) and nirmatrelvir-ritonavir (NMV-r) were developed for treatment of mild to moderate COVID-19 infection, there has been a lack of data on the efficacy among unvaccinated adult patients with chronic respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD) and bronchiectasis. A territory-wide retrospective cohort study was conducted in Hong Kong to investigate the efficacy of MOV and NMV-r against severe outcomes of COVID-19 in unvaccinated adult patients with chronic respiratory diseases. A total of 3267 patients were included. NMV-r was effective in preventing respiratory failure (66.6%; 95% CI, 25.6-85.0%, p = 0.007), severe respiratory failure (77.0%; 95% CI, 6.9-94.3%, p = 0.039) with statistical significance, and COVID-19 related hospitalization (43.9%; 95% CI, -1.7-69.0%, p = 0.057) and in-hospital mortality (62.7%; 95% CI, -0.6-86.2, p = 0.051) with borderline statistical significance. MOV was effective in preventing COVID-19 related severe respiratory failure (48.2%; 95% CI 0.5-73.0, p = 0.048) and in-hospital mortality (58.3%; 95% CI 22.9-77.4, p = 0.005) but not hospitalization (p = 0.16) and respiratory failure (p = 0.10). In summary, both NMV-r and MOV are effective for reducing severe outcomes in unvaccinated COVID-19 patients with chronic respiratory diseases.

Changes in Etiology and Clinical Outcomes of Pleural empyema during the COVID-19 Pandemic.

Healthcare-seeking behavior changed during the COVID-19 pandemic and might alter the epidemiology of pleural empyema. In this study, the incidence, etiology and outcomes of patients admitted for pleural empyema in Hong Kong in the pre-COVID-19 (January 2015-December 2019) and post-COVID-19 (January 2020-June 2022) periods were compared. Overall, Streptococcus pneumoniae was the predominant organism in <18-year-old patients, while Streptococcus anginosus, anaerobes and polymicrobial infections were more frequent in adults. In the post-COVID-19 period, a marked decline in the incidence of pleural empyema in children was observed (pre-COVID-19, 18.4 ± 4.8 vs. post-COVID-19, 2.0 ± 2.9 cases per year, p = 0.036), while the incidence in adults remained similar (pre-COVID-19, 189.0 ± 17.2 vs. post-COVID-19, 198.4 ± 5.0 cases per year; p = 0.23). In the post-COVID-19 period, polymicrobial etiology increased (OR 11.37, p < 0.0001), while S. pneumoniae etiology decreased (OR 0.073, p < 0.001). In multivariate analysis, clinical outcomes (length of stay, ICU admission, use of intrapleural fibrinolytic therapy, surgical intervention, death) were not significantly different in pre- and post-COVID-19 periods. In conclusion, an increase in polymicrobial pleural empyema was observed during the pandemic. We postulate that this is related to the delayed presentation of pneumonia to hospitals.

Worsening of asthma control after recovery from mild to moderate COVID-19 in patients from Hong Kong.

BACKGROUND: While there are postulations that asthma is potentially associated with severe coronavirus disease 2019 (COVID-19), there has been conflicting results from studies on the impact mild-to-moderate COVID-19 on asthma control after recovery. METHODS: A case control study on the association between mild-to-moderate COVID-19 and asthma control post infection was conducted. The primary outcome was a reduction in Asthma Control Test (ACT) score by ≥ 3 points post-COVID infection. The secondary outcomes included the change in ACT score, the proportion of patient with ACT score who dropped to ≤ 15 on enrolment visit and the need for escalation of asthma maintenance therapy. RESULTS: Out of the total of 221 adult patients with asthma recruited, 111 had mild-to-moderate COVID-19 within 30 to 270 days prior to study enrolment. The adjusted odds ratio (aOR) for a reduction in ACT score by ≥ 3 points after COVID-19 was 3.105 (95% CI = 1.385-6.959, p = 0.006). The odds of escalation of asthma maintenance therapy by at least 1 Global Initiative for Asthma (GINA) step was 4.733 (95% CI = 1.151-19.467, p = 0.031) and asthma patient are more likely to become uncontrolled after COVID-19 [aOR = 5.509 (95% CI = 1.061-28.600, p = 0.042)]. CONCLUSION: Mild-to-moderate COVID-19 among asthma patients, upon recovery, was associated with worsening of asthma symptom, lower ACT score, a higher need for escalation of asthma maintenance therapy and more uncontrolled asthma.

A Multi-Center Study of the Prevalence and Characteristics of Eosinophilic Phenotype and High IgE Levels Among Chinese Patients with Severe Asthma.

Background: Patients with severe asthma have higher total- and asthma-related health burden than those whose disease is not severe. Recent medical advances in biologic therapies allow better control of asthma characterized by type 2 inflammation. Objective: To study the prevalence of eosinophilic phenotype and IgE levels in Chinese with severe asthma, and the relationship of these type 2 characteristics with asthma control, exacerbations and lung function. Methods: This was a multicenter cross-sectional observational study in Hong Kong, in Chinese adults with asthma on Step 4 or 5 of GINA treatment. Their blood eosinophil counts and total IgE levels were measured, and the relationship of these phenotypic parameters to the number of exacerbations in the past 12 months, and to symptom control in the past 4 weeks, were investigated. Results: A total of 232 subjects were recruited from 6 centers. The mean age was 53.9±12.9 years, with 86 (37.1%) male, and the duration of diagnosed asthma was 26.2±15.7 years. A T-helper 2 (Th2) phenotype indicated by elevated eosinophils and/or IgE was present in 169 (72.8%) of patients. Of 232 patients, 43% had an eosinophilic phenotype (blood eosinophil count ≥300 cell/mm3), while 59% had high total IgE levels of >100 IU/mL (overlap with eosinophilic phenotype in 30%) and 44% had IgE levels of >150 IU/mL (overlap with eosinophilic phenotype in 22%). Subjects with eosinophilic phenotype and IgE >150 IU/mL had a higher rate (1.8 times) of uncontrolled asthma compared with those without such a combination. Conclusion: In Chinese adults with severe asthma defined by the use of conventional maintenance medication regimens, the prevalence of Th2 inflammation is comparable to that reported from other ethnic populations. Those with both eosinophil count ≥300 cell/mm3 and high IgE levels >150 IU/mL had a higher rate of uncontrolled asthma compared with those without a combination of these features.

Efficacy of mRNA and Inactivated Whole Virus Vaccines Against COVID-19 in Patients with Chronic Respiratory Diseases.

Background: While different COVID-19 vaccines have been developed, there has been lack of data on the efficacy comparison between mRNA and inactivated whole virus vaccine among patients with chronic respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis. Methods: This was a retrospective case control study on the efficacy of BNT162b2 (mRNA vaccine) and CoronaVac (inactivated whole virus vaccine) against COVID-19 in patients with chronic respiratory diseases. A total of 327 patients were included, with 109 patients infected with COVID-19 matched with 218 patients without COVID-19. The co-primary outcomes were vaccine effectiveness against symptomatic COVID-19, COVID-19-related hospitalization and COVID-19-related respiratory failure. Vaccine effectiveness was calculated using the formula (1-adjusted odds ratio) x 100. Results: Patients who received at least 2 doses of CoronaVac had lower risk of being hospitalized for COVID-19 and developing respiratory failure than those who did not have vaccination, with adjusted odds ratio (OR) of 0.189 (95% CI = 0.050-0.714, p = 0.014) and 0.128 (95% CI = 0.026-0.638, p = 0.012) respectively. Patients who received at least 2 doses of BNT162b2 had lower risk of being hospitalized for COVID-19 and developing respiratory failure than those who did not have vaccination with adjusted OR of 0.207 (95% CI = 0.043-0.962, p = 0.050) and 0.093 (95% CI = 0.011-0.827, p = 0.033) respectively. There was no statistically significant difference in the risks of being hospitalized for COVID-19 and developing respiratory failure between patients who received at least 2 doses of CoronaVac or BNT162b2. Conclusion: BNT162b2 and CoronaVac vaccines are effective in preventing hospitalization for COVID-19 and respiratory failure complicating COVID-19 among patients with chronic respiratory diseases. Patients with chronic respiratory diseases should be encouraged to have COVID-19 vaccination.

Cardiovascular outcomes in obstructive sleep apnoea and implications of clinical phenotyping on effect of CPAP treatment.

BACKGROUND: There is a growing awareness of the heterogeneity of obstructive sleep apnoea (OSA). Clinical trials of CPAP treatment on cardiovascular protection have been mostly negative. We aimed to assess the association between polysomnographic parameters and incident major adverse cardiovascular events (MACEs), and to investigate if the CPAP effect could be better delineated among clinical subgroups. METHODS: This sleep cohort study was conducted using a clinical database and territory-wide electronic health administration data in Hong Kong. Cox regressions were used to calculate HRs. Latent class analysis was used to cluster patients with OSA according to clinical and polysomnographic features. RESULTS: Of 1860 eligible Chinese subjects who underwent polysomnography (2006-2013), 1544 (83%) had OSA. Over median follow-up of 8.3 years, 278 (14.9%) experienced MACEs. Apnoea-hypopnoea index (AHI) did not predict MACEs (HR: 0.95; 95% CI 0.76 to 1.17), whereas sleep time with oxygen saturation <90% (TST90) (HR: 1.41; 95% CI 1.10 to 1.81) was an independent predictor of MACEs, as were wake and nocturnal heart rate. In moderate-severe OSA (n=1108) who were indicated for CPAP treatment, regular CPAP was not associated with reduction of incident MACEs. Further cluster analysis identified a subgroup (n=333) who was younger, more obese, had more severe OSA (higher AHI and TST90) and more cardiovascular risks, in whom regular CPAP was associated with a lower risk of MACEs (HR:0.49, 95% CI 0.25 to 0.95). CONCLUSIONS: OSA-related TST90 and mean heart rate, but not AHI, were robust predictors of MACEs. A clinical phenotype subgroup who demonstrated beneficial effect of CPAP treatment was identified.

Clinical efficacy and safety of pemetrexed with or without either Bevacizumab or Pembrolizumab in patients with metastatic nonsquamous non-small cell carcinoma.

BACKGROUND: Pemetrexed was approved by United States Food and Drug Administration (US FDA) in combination with platinum for the treatment of advanced nonsquamous non-small cell lung carcinoma (NSCLC) and malignant mesothelioma. Bevacizumab and pembrolizumab can be added to chemotherapy for patients with nonsquamous NSCLC with benefits but there has not been any dedicated head-to-head comparison between pembrolizumab-pemetrexed-platinum (PAC) and bevacizumab-pemetrexed-platinum (BAC) on their efficacy and safety. METHODS: This was a retrospective single-center cohort study conducted in Queen Mary Hospital in Hong Kong. The study included 451 patients with advanced stage nonsquamous NSCLC that received first-line pemetrexed and platinum with or without bevacizumab or pembrolizumab. Patients who received pemetrexed-platinum (AC) were compared with those who received PAC and BAC. The primary endpoint was the progression-free survival (PFS). RESULTS: The median PFS for patients that received PAC was significantly longer than those who received BAC and AC (9 months vs. 6.8 months vs. 4.8 months, p < 0.05 among all three groups), with OR of 0.578 (95% CI, 0.343-0.976; p = 0.040) and 0.430 (95% CI, 0.273-0.675; p < 0.001) when compared to BAC and AC, respectively. Patients who received PAC also had a higher disease control rate and higher likelihood to receive continuation maintenance therapy than those on AC. There is no statistically significant difference in the grade 3 to 4 toxicity among the three treatment groups. CONCLUSIONS: Although both regimens are superior to pemetrexed-platinum alone, data from this retrospective single center study suggested a better PFS in  advanced stage nonsquamous NSCLC patient treated with first-line pembrolizumab-pemetrexed-platinum than bevacizumab-pemetrexed-platinum without an obvious increase in significant toxicity.

The effects of intermittent hypoxia on hepatic expression of fatty acid translocase CD36 in lean and diet-induced obese mice.

BACKGROUND: Both obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) are prevalent within obese individuals. We aimed to investigate the effects of intermittent hypoxia (IH), a clinical feature of OSA, on hepatic expression of fatty acid translocase (CD36) in relation to liver injury in lean and diet-induced obese mice. METHODS: Four-week-old male C57BL/6J mice were randomized to standard diet (SD) or high fat (HF) diet groups. At 13-week-old, all mice were exposed to either air or IH (IH30; thirty hypoxic episodes per hour) for four weeks. We assessed liver injury through lipid profile, oxidative and inflammatory stress, histological scoring and hepatic CD36 expression. RESULTS: In lean mice, IH elevated serum and hepatic triglyceride and free fatty acid (FFA) levels, in line with upregulation of hepatic CD36 expression and myeloperoxidase (MPO)-positive cells in support of inflammatory infiltrates along with increase in serum malondialdehyde (MDA), C-X-C motif chemokine ligand 1(CXCL-1) and monocyte chemoattractant protein-1 (MCP-1). In diet-induced obese mice, an increase in hepatic alanine transaminase (ALT) activity, serum and hepatic levels of lipid parameters and inflammatory markers, serum MDA level, hepatic expressions of CD36 and α-smooth muscle actin (α-SMA), and MPO-positive cells was observed. IH potentiated hepatic ALT activity, serum CXCL-1 and hepatic interleukin-6 (IL-6), in line with inflammatory infiltrates, but paradoxically, reduced hepatic FFA level and hepatic CD36 expression, compared to obese mice without IH exposure. However, IH further augmented diet-induced liver steatosis and fibrosis as shown by histological scores. CONCLUSION: This study contributes to support that IH featuring OSA may lead to liver injury via differential regulation of hepatic CD36 expression in lean and diet-induced obese mice.

Associations of sleep apnea risk and oxygen desaturation indices with cerebral small vessel disease burden in patients with stroke.

Background: Obstructive sleep apnea (OSA) is associated with cerebral small vessel disease (CSVD). Nonetheless, whether OSA-risk determined by a simple screening questionnaire or indices quantifying nocturnal hypoxemia other than the conventional apnea-hypopnea index (AHI) by the home sleep apnea test (HSAT) associated with CSVD burden remains uncertain. Methods: From 2018 to 2021, we recruited patients with transient ischemic attack (TIA)/minor stroke from the Queen Mary Hospital Acute Stroke Unit and TIA/Stroke Outpatient Clinics. Logistic regression models were applied to determine the association of baseline OSA-risk (on STOP-BANG questionnaire) or HSAT-derived indices quantifying nocturnal hypoxemia with global burden/individual markers of CSVD on MRI. Indices included oxygen desaturation (≥3%) index (ODI), minimum oxygen saturation (SpO2), percentage of total sleep time with an oxygen saturation <90% (CT90%), and desaturation duration (≥3%, DesDur). Results: In 283 patients with TIA/minor stroke (mean age 65 years, 64% men), OSA-risk was significantly associated with total CSVD score (multivariate-adjusted odds ratio: 1.23, 95% confidence interval 1.01-1.51), presence of lacunes [1.39 (1.09-1.79)] and burden of basal ganglia PVSs [1.32 (1.06-1.67)]. In 85/283 patients who completed HSAT, neither AHI, minimum SpO2 nor CT90% was associated with CSVD burden. Nonetheless, ODI and DesDur remained significantly associated with total CSVD score after covariate adjustment: ODI [1.04 (1.01-1.07)] and DesDur [1.04 (1.01-1.08)]. Conclusion: In patients with TIA/minor stroke, high OSA-risk was associated with a greater CSVD burden. Oxygen desaturation indices (ODI and DesDur) rather than AHI were independently associated with global CSVD burden, indicating that longer and more severe desaturations may contribute to the pathogenesis of CSVD.

Association of genetic polymorphisms of CYP3A4 and CYP2D6 with gefitinib-induced toxicities.

Dermatological, gastrointestinal and hepatic toxicities are the most common adverse events associated with gefitinib use. Gefitinib is metabolized by cytochrome P450. Inconsistent associations of single nucleotide genetic polymorphisms of CYP450 and gefitinib-induced adverse effects were reported. We aim to investigate the association between CYP450 genetic polymorphism and the development of gefitinib-associated adverse events. A retrospective cohort study of Chinese patients with metastatic nonsmall cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations who received first-line gefitinib treatment was conducted. Single nucleotide polymorphisms (SNPs) of CYP2D6, CYP3A4 and CYP3A5 were assayed using a multiplex SNP microarray. Risks of development of gefitinib-induced toxicities associated with different SNPs were determined. Among the 152 patients treated with gefitinib, 52 (34.2%) had gefitinib-induced hepatotoxicity, 113 (74.3%) had cutaneous reactions and 53 (34.9%) had gastrointestinal adverse effects. CYP2D6*41 CT, CYP2D6*10 AA and CYP3A4*1/*1G TT genotypes were significantly associated with hepatic, cutaneous and gastrointestinal adverse effects [odds ratio (OR) 3.773; (95% confidence interval {CI},1.046-13.610; P = 0.043), 3.368 (95% CI, 1.000-11.345; P = 0.050) and 20.000 (95% CI, 2.381-167.965; P = 0.006), respectively]. CYP2D6*41 CT, CYP2D6*10 AA and CYP3A4*1/*1G TT genotypes may be associated with increased risks of gefitinib-induced toxicities in the liver, skin and gastrointestinal tract.

Long-term spill-over impact of COVID-19 on health and healthcare of people with non-communicable diseases: a study protocol for a population-based cohort and health economic study.

INTRODUCTION: The COVID-19 pandemic has a significant spill-over effect on people with non-communicable diseases (NCDs) over the long term, beyond the direct effect of COVID-19 infection. Evaluating changes in health outcomes, health service use and costs can provide evidence to optimise care for people with NCDs during and after the pandemic, and to better prepare outbreak responses in the future. METHODS AND ANALYSIS: This is a population-based cohort study using electronic health records of the Hong Kong Hospital Authority (HA) CMS, economic modelling and serial cross-sectional surveys on health service use. This study includes people aged ≥18 years who have a documented diagnosis of diabetes mellitus, hypertension, cardiovascular disease, cancer, chronic respiratory disease or chronic kidney disease with at least one attendance at the HA hospital or clinic between 1 January 2010 and 31 December 2019, and without COVID-19 infection. Changes in all-cause mortality, disease-specific outcomes, and health services use rates and costs will be assessed between pre-COVID-19 and-post-COVID-19 pandemic or during each wave using an interrupted time series analysis. The long-term health economic impact of healthcare disruptions during the COVID-19 pandemic will be studied using microsimulation modelling. Multivariable Cox proportional hazards regression and Poisson/negative binomial regression will be used to evaluate the effect of different modes of supplementary care on health outcomes. ETHICS AND DISSEMINATION: The study was approved by the institutional review board of the University of Hong Kong, the HA Hong Kong West Cluster (reference number UW 21-297). The study findings will be disseminated through peer-reviewed publications and international conferences.

Serum protein level as a predictor of therapeutic response and adverse effects associated with afatinib use.

Background: Afatinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with significant serum protein binding. Total protein level was found to be associated with plasma afatinib level. The trough serum concentration was shown to be associated with development of adverse effects. This study aims to explore the association between serum protein levels and clinical responses and adverse effects in advanced stage non-small cell lung cancer (NSCLC) treated with afatinib. Methods: This was a retrospective cohort study of Chinese patients with metastatic NSCLC harboring EGFR mutations who received first or second line afatinib treatment. The association of serum protein and album levels, as well as their ratio, and the development of adverse effects was investigated. Results: Among 217 patients included, 91 were on afatinib as first line treatment and 126 as second line treatment. Higher serum protein levels, albumin levels and albumin to globulin ratio, were found to be associated with clinical response to afatinib among patients on first or second line setting. Among patients on first line afatinib with Eastern Cooperative Oncology Group Performance State (ECOG PS) at 1 or above, those with lower serum protein levels at baseline had higher risks of developing grade 2 or above gastrointestinal adverse effects. Among patients on second line afatinib and with ECOG PS at 1 or above, patients with lower serum protein levels at baseline had higher risks of developing grade 3 or above cutaneous adverse effects. Lower serum albumin to globulin ratio at baseline was associated with increased risks of grade 3 or above gastrointestinal adverse effects among patients with ECOG PS at 1 or above and no prior systemic chemotherapy. Conclusions: Serum protein, albumin level and serum albumin to globulin ratio may predict the response to afatinib and occurrence of adverse effects with afatinib treatment.

Survival benefits from afatinib compared with gefitinib and erlotinib among patients with common EGFR mutation in first-line setting.

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are recommended as first-line treatment in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations. The sequential use of different EGFR-TKIs has been reported to demonstrate improvement in overall survival of NSCLC patients with EGFR mutations. There are limited reports on comparisons between regimens with first-line use of afatinib, gefitinib or erlotinib, followed by osimertinib upon disease progression with acquired T790M mutation. METHODS: A retrospective cohort study of Chinese patients with metastatic NSCLC harboring EGFR mutations who received first-line gefitinib, erlotinib or afatinib treatment, followed by osimertinib upon disease progression with acquired T790M mutation, was conducted. The differences in overall survival (OS) and progression-free survival (PFS) with first-line EGFR-TKI (PFS1) and time to second objective disease progression (PFS2) were compared among patients on different first-line EGFR-TKIs. RESULTS: Among 155 patients, 101 (65.2%), 38 (24.5%) and 16 (10.3%) patients were on first-line gefitinib, erlotinib or afatinib, respectively. Patients treated with afatinib in the first-line setting had significantly longer OS compared with those on gefitinib or erlotinib, while the PFS1 and PFS2 were longer for patients on afatinib but did not reach statistical significance. CONCLUSIONS: First-line afatinib, followed by osimertinib upon disease progression with T790M mutation, demonstrated significantly longer OS compared to that using other EGFR-TKI in the first-line setting.