Insights into COVID-19 epidemiology and control from temporal changes in serial interval distributions in Hong Kong.

The serial interval distribution is used to approximate the generation time distribution, an essential parameter to infer the transmissibility (${R}_t$) of an epidemic. However, serial interval distributions may change as an epidemic progresses. We examined detailed contact tracing data on laboratory-confirmed cases of COVID-19 in Hong Kong during the five waves from January 2020 to July 2022. We reconstructed the transmission pairs and estimated time-varying effective serial interval distributions and factors associated with longer or shorter intervals. Finally, we assessed the biases in estimating transmissibility using constant serial interval distributions. We found clear temporal changes in mean serial interval estimates within each epidemic wave studied and across waves, with mean serial intervals ranged from 5.5 days (95% CrI: 4.4, 6.6) to 2.7 (95% CrI: 2.2, 3.2) days. The mean serial intervals shortened or lengthened over time, which were found to be closely associated with the temporal variation in COVID-19 case profiles and public health and social measures and could lead to the biases in predicting ${R}_t$. Accounting for the impact of these factors, the time-varying quantification of serial interval distributions could lead to improved estimation of ${R}_t$, and provide additional insights into the impact of public health measures on transmission.

Preliminary Findings From the Dynamics of the Immune Responses to Repeat Influenza Vaccination Exposures (DRIVE I) Study: A Randomized Controlled Trial.

BACKGROUND: Studies have reported that repeated annual vaccination may influence influenza vaccination effectiveness in the current season. METHODS: We established a 5-year randomized placebo-controlled trial of repeated influenza vaccination (Flublok; Sanofi Pasteur) in adults 18-45 years of age. In the first 2 years, participants were randomized to receive vaccine or saline placebo as follows: placebo-placebo (P-P), placebo-vaccine (P-V), or vaccine-vaccine (V-V). Serum samples were collected each year just before vaccination and after 30 and 182 days. A subset of serum samples collected at 5 time points from 95 participants were tested for antibodies against vaccine strains. RESULTS: From 23 October 2020 through 11 March 2021 we enrolled and randomized 447 adults. Among vaccinated individuals, antibody titers increased between days 0 and 30 against each of the vaccine strains, with smaller increases for repeat vaccinees who on average had higher prevaccination titers in year 2. There were statistically significant differences in the proportions of participants achieving ≥4-fold rises in antibody titer for the repeat vaccinees for influenza A(H1N1), B/Victoria, and B/Yamagata, but not for A(H3N2). Among participants who received vaccination in year 2, there were no significant differences between the P-V and V-V groups in geometric mean titers at day 30 or the proportions of participants with antibody titers ≥40 at day 30 for any of the vaccine strains. CONCLUSIONS: In the first 2 years, during which influenza did not circulate, repeat and first-time vaccinees had similar postvaccination geometric mean titers to all 4 vaccine strains, indicative of similar levels of clinical protection. Clinical Trials Registration. NCT04576377.

Preliminary findings from the Dynamics of the Immune Responses to Repeat Influenza Vaccination Exposures (DRIVE I) Study: a Randomized Controlled Trial.

Background: Studies have reported that repeated annual vaccination may influence the effectiveness of the influenza vaccination in the current season. The mechanisms underlying these differences are unclear but might include "focusing" of the adaptive immune response to older strains. Methods: We established a 5-year randomized placebo-controlled trial of repeated influenza vaccination (Flublok, Sanofi Pasteur) in adults 18-45 years of age. Participants were randomized equally between five groups, with planned annual receipt of vaccination (V) or saline placebo (P) as follows: P-P-P-P-V, P-P-P-V-V, P-P-V-V-V, P-V-V-V-V, or V-V-V-VV. Serum samples were collected each year just before vaccination and after 30 and 182 days. A subset of sera were tested by hemagglutination inhibition assays, focus reduction neutralization tests and enzyme-linked immunosorbent assays against vaccine strains. Results: From 23 October 2020 through 11 March 2021 we enrolled and randomized 447 adults. We selected sera from 95 participants at five timepoints from the first two study years for testing. Among vaccinated individuals, antibody titers increased between days 0 and 30 against each of the vaccine strains, with substantial increases for first-time vaccinees and smaller increases for repeat vaccinees, who had higher pre-vaccination titers in year 2. There were statistically significant reductions in the proportion of participants achieving a four-fold greater rise in antibody titer for the repeat vaccinees for A(H1N1), B/Victoria and B/Yamagata, but not for influenza A(H3N2). There were no statistically significant differences between groups in geometric mean titers at day 30 or the proportions of participants with antibody titers ≥40 at day 30 for any of the vaccine strains. Conclusions: In the first two years, repeat vaccinees and first-time vaccinees had similar post-vaccination geometric mean titers to all four vaccine strains, indicative of similar levels of clinical protection. The vaccine strains of A(H1N1) and A(H3N2) were updated in year 2, providing an opportunity to explore antigenic distances between those strains in humans in subsequent years.

Estimation of the Time-Varying Effective Reproductive Number of COVID-19 Based on Multivariate Time Series of Severe Health Outcomes.

The time-varying effective reproduction number (Rt at time t) measures the transmissibility of SARS-CoV-2 and is conventionally based on daily case counts, which may suffer from time-varying ascertainment. We analyzed Rt estimates from case counts and severe COVID-19 (intensive care unit admissions, severe or critical cases, and mortality) across 2022 in Hong Kong's fifth and sixth waves of infection. Within the fifth wave, the severe disease-based Rt (3.5) was significantly higher than the case-based Rt (2.4) but not in the sixth wave. During periods with fluctuating underreporting, data based on severe diseases may provide more reliable Rt estimates.

Comparison of control and transmission of COVID-19 across epidemic waves in Hong Kong: an observational study.

Background: Hong Kong contained COVID-19 for two years but experienced a large epidemic of Omicron BA.2 in early 2022 and endemic transmission of Omicron subvariants thereafter. We reflected on pandemic preparedness and responses by assessing COVID-19 transmission and associated disease burden in the context of implementation of various public health and social measures (PHSMs). Methods: We examined the use and impact of pandemic controls in Hong Kong by analysing data on more than 1.7 million confirmed COVID-19 cases and characterizing the temporal changes non-pharmaceutical and pharmaceutical interventions implemented from January 2020 through to 30 December 2022. We estimated the daily effective reproductive number (Rt) to track changes in transmissibility and effectiveness of community-based measures against infection over time. We examined the temporal changes of pharmaceutical interventions, mortality rate and case-fatality risks (CFRs), particularly among older adults. Findings: Hong Kong experienced four local epidemic waves predominated by the ancestral strain in 2020 and early 2021 and prevented multiple SARS-CoV-2 variants from spreading in the community before 2022. Strict travel-related, case-based, and community-based measures were increasingly tightened in Hong Kong over the first two years of the pandemic. However, even very stringent measures were unable to contain the spread of Omicron BA.2 in Hong Kong. Despite high overall vaccination uptake (>70% with at least two doses), high mortality was observed during the Omicron BA.2 wave due to lower vaccine coverage (42%) among adults ≥65 years of age. Increases in antiviral usage and vaccination uptake over time through 2022 was associated with decreased case fatality risks. Interpretation: Integrated strict measures were able to reduce importation risks and interrupt local transmission to contain COVID-19 transmission and disease burden while awaiting vaccine development and rollout. Increasing coverage of pharmaceutical interventions among high-risk groups reduced infection-related mortality and mitigated the adverse health impact of the pandemic. Funding: Health and Medical Research Fund.

Standard-dose versus MF59-adjuvanted, high-dose or recombinant-hemagglutinin influenza vaccine immunogenicity in older adults: comparison of A(H3N2) antibody response by prior season's vaccine status.

BACKGROUND: Annual influenza vaccination is recommended for older adults but repeated vaccination with standard-dose influenza vaccine has been linked to reduced immunogenicity and effectiveness, especially against A(H3N2) viruses. METHODS: Community-dwelling Hong Kong adults aged 65-82 years were randomly allocated to receive 2017/18 standard-dose quadrivalent, MF59-adjuvanted trivalent, high-dose trivalent, and recombinant-HA quadrivalent vaccination. Antibody response to unchanged A(H3N2) vaccine antigen was compared among participants with and without self-reported prior year (2016/17) standard-dose vaccination. RESULTS: Mean fold rise (MFR) in antibody titers from Day 0 to Day 30 by hemagglutination inhibition and virus microneutralization assays were lower among 2017/18 standard-dose and enhanced vaccine recipients with (range, 1.7-3.0) vs. without (range, 4.3-14.3) prior 2016/17 vaccination. MFR was significantly reduced by about one half to four fifths for previously vaccinated recipients of standard-dose and all three enhanced vaccines (ß range, 0.21-0.48). Among prior-year vaccinated older adults, enhanced vaccines induced higher 1.43 to 2.39-fold geometric mean titers and 1.28 to 1.74-fold MFR vs. standard-dose vaccine by microneutralization assay. CONCLUSIONS: In the context of unchanged A(H3N2) vaccine strain, prior-year vaccination was associated with reduced antibody response among both standard-dose and enhanced influenza vaccine recipients. Enhanced vaccines improved antibody response among older adults with prior-year standard-dose vaccination.

Residential Clustering of Coronavirus Disease 2019 Cases and Efficiency of Building-Wide Compulsory Testing Notices as a Transmission Control Measure in Hong Kong.

We described the frequency of residential case clusters and the efficiency of compulsory testing in identifying cases using buildings targeted in compulsory testing and locally infected coronavirus disease 2019 (COVID-19) cases matched by residence in Hong Kong. Most of the buildings (4246 of 7688, 55.2%) with COVID-19 cases identified had only 1 reported case, and 13% of the daily reported cases were detected through compulsory testing. Compulsory testing notices could be essential in attempting to eliminate infections ("zero COVID") and have an impact early in an epidemic, but they appear to be relatively inefficient in response to sustained community transmission.

Accounting for the Potential of Overdispersion in Estimation of the Time-varying Reproduction Number.

BACKGROUND: The time-varying reproduction number, Rt, is commonly used to monitor the transmissibility of an infectious disease during an epidemic, but standard methods for estimating Rt seldom account for the impact of overdispersion on transmission. METHODS: We developed a negative binomial framework to estimate Rt and a time-varying dispersion parameter (kt). We applied the framework to COVID-19 incidence data in Hong Kong in 2020 and 2021. We conducted a simulation study to compare the performance of our model with the conventional Poisson-based approach. RESULTS: Our framework estimated an Rt peaking around 4 (95% credible interval = 3.13, 4.30), similar to that from the Poisson approach but with a better model fit. Our approach further estimated kt <0.5 at the start of both waves, indicating appreciable heterogeneity in transmission. We also found that kt decreased sharply to around 0.4 when a large cluster of infections occurred. CONCLUSIONS: Our proposed approach can contribute to the estimation of Rt and monitoring of the time-varying dispersion parameters to quantify the role of superspreading.

Incorporating temporal distribution of population-level viral load enables real-time estimation of COVID-19 transmission.

Many locations around the world have used real-time estimates of the time-varying effective reproductive number ([Formula: see text]) of COVID-19 to provide evidence of transmission intensity to inform control strategies. Estimates of [Formula: see text] are typically based on statistical models applied to case counts and typically suffer lags of more than a week because of the latent period and reporting delays. Noting that viral loads tend to decline over time since illness onset, analysis of the distribution of viral loads among confirmed cases can provide insights into epidemic trajectory. Here, we analyzed viral load data on confirmed cases during two local epidemics in Hong Kong, identifying a strong correlation between temporal changes in the distribution of viral loads (measured by RT-qPCR cycle threshold values) and estimates of [Formula: see text] based on case counts. We demonstrate that cycle threshold values could be used to improve real-time [Formula: see text] estimation, enabling more timely tracking of epidemic dynamics.

Restaurant-Based Measures to Control Community Transmission of COVID-19, Hong Kong.

Controlling transmission in restaurants is an important component of public health and social measures for coronavirus disease. We examined the effects of restaurant measures in Hong Kong. Our findings indicate that shortening operating hours did not have an effect on time-varying effective reproduction number when capacity was already reduced.

Universal Community Nucleic Acid Testing for Coronavirus Disease 2019 (COVID-19) in Hong Kong Reveals Insights Into Transmission Dynamics: A Cross-Sectional and Modeling Study.

BACKGROUND: Testing of an entire community has been used as an approach to control coronavirus disease 2019 (COVID-19). In Hong Kong, a universal community testing program (UCTP) was implemented at the fadeout phase of a community epidemic in July to September 2020. We described the utility of the UCTP in finding unrecognized infections and analyzed data from the UCTP and other sources to characterize transmission dynamics. METHODS: We described the characteristics of people participating in the UCTP and compared the clinical and epidemiological characteristics of COVID-19 cases detected by the UCTP versus those detected by clinical diagnosis and public health surveillance (CDPHS). We developed a Bayesian model to estimate the age-specific incidence of infection and the proportion of cases detected by CDPHS. RESULTS: In total, 1.77 million people, 24% of the Hong Kong population, participated in the UCTP from 1 to 14 September 2020. The UCTP identified 32 new infections (1.8 per 100000 samples tested), consisting of 29% of all local cases reported during the two-week UCTP period. Compared with the CDPHS, the UCTP detected a higher proportion of sporadic cases (62% vs 27%, P<.01) and identified 6 (out of 18) additional clusters during that period. We estimated that 27% (95% credible interval: 22%, 34%) of all infections were detected by the CDPHS in the third wave. CONCLUSIONS: We reported empirical evidence of the utility of population-wide COVID-19 testing in detecting unrecognized infections and clusters. Around three quarters of infections have not been identified through existing surveillance approaches including contact tracing.

The differential importation risks of COVID-19 from inbound travellers and the feasibility of targeted travel controls: A case study in Hong Kong.

BACKGROUND: Many countries/regions implemented strict border measures (e.g., 14-day quarantines) as a blanket policy to prevent COVID-19 importations, while proposed "travel bubbles" as an alternative to reduce the impact of border controls. We aim to examine the differential importation risks with departure origins and post-arrival controls. METHODS: We developed a Bayesian framework to model disease progress of COVID-19 and the effectiveness of travel measures and inferred the origin-specific disease prevalence among inbound travellers, using data on passengers arriving in Hong Kong and laboratory-confirmed imported cases. We estimated the origin-specific risks of releasing infectious travellers under different control strategies and traveller volumes. We also estimated the risk of having released infectious travellers when a resurgence occurs in departure locations with no imported cases during a certain period. FINDINGS: Under the then strict controls of 14-day quarantine and testing on day 12, the Philippines imposed the greatest importation risk among the studied countries/regions (95.8% of releasing at least one infectious traveller, 95% credible interval (CrI), 94.8-96.6%). This was higher than that from low prevalence countries/regions (e.g., 23.4%, 95% CrI, 21.6-25.3% for Taiwan) if controls relaxed (i.e., 7-day quarantine and test on day 5). Increased traveller volumes and resurgence in departure locations with low prevalence under relaxed controls did not impose a greater importation risk than high prevalence locations under stricter controls. INTERPRETATION: Moderate relaxation of control measures for travellers arriving from low prevalence locations did not impose higher risks of community outbreaks than strict controls on travellers from high prevalence locations. FUNDING: Health and Medical Research Fund, Hong Kong.

Changing Disparities in Coronavirus Disease 2019 (COVID-19) Burden in the Ethnically Homogeneous Population of Hong Kong Through Pandemic Waves: An Observational Study.

BACKGROUND: Disparities were marked in previous pandemics, usually with higher attack rates reported for those in lower socioeconomic positions and for ethnic minorities. METHODS: We examined characteristics of laboratory-confirmed coronavirus disease 2019 (COVID-19) cases in Hong Kong, assessed associations between incidence and population-level characteristics at the level of small geographic areas, and evaluated relations between socioeconomics and work-from-home (WFH) arrangements. RESULTS: The largest source of COVID-19 importations switched from students studying overseas in the second wave to foreign domestic helpers in the third. The local cases were mostly individuals not in formal employment (retirees and homemakers) and production workers who were unable to WFH. For every 10% increase in the proportion of population employed as executives or professionals in a given geographic region, there was an 84% (95% confidence interval [CI], 1-97%) reduction in the incidence of COVID-19 during the third wave. In contrast, in the first 2 waves, the same was associated with 3.69 times (95% CI, 1.02-13.33) higher incidence. Executives and professionals were more likely to implement WFH and experienced frequent changes in WFH practice compared with production workers. CONCLUSIONS: Consistent findings on the reversed socioeconomic patterning of COVID-19 burden between infection waves in Hong Kong in both individual- and population-level analyses indicated that risks of infections may be related to occupations involving high exposure frequency and WFH flexibility. Contextual determinants should be taken into account in policy planning aiming at mitigating such disparities.

Removal of distal fragments of liquid embolic agents during arteriovenous malformation embolization using the TIGERTRIEVER 13: a technical report.

BACKGROUND: Arteriovenous malformations (AVMs) are vascular lesions that may be treated by an endovascular approach using liquid embolic agents but the control of the liquid embolic agent remains poor and a potential complication may be distal migration of embolic material. The TIGERTRIEVER 13 is a new stent retriever designed for stroke thrombectomy and has a version ideal for distal occlusions. We report our experience in the removal of embolic agent which had migrated into the distal vessels using the TIGERTRIEVER during PHIL/Onyx embolization of AVMs. CLINICAL PRESENTATIONS: Three patients with brain and spinal AVMs underwent endovascular embolization. During trans-arterial embolization of the AVM with PHIL/Onyx, retrograde filling of distal arterial feeders was followed by migration into the normal arterial branches (cortical middle cerebral artery, distal posterior cerebral artery, and anterior spinal artery). This resulted in occlusion or sluggish distal flow in these branches with potential significant neurological deficits. In all three cases, a Headway Duo microcatheter was navigated distally in the occluded vessel beyond the embolic material using a Traxcess microwire. The TIGERTRIEVER 13 was deployed with recanalization of the vessel after a single attempt. In all three patients there were no complications related to the retrieval of embolic agent. CONCLUSION: Distal migrated embolic agents such as PHIL or Onyx can be removed from various arterial vascular territories using stent retrievers dedicated to small vessels.

Clinically important difference of Stroke-Specific Quality of Life Scale for aneurysmal subarachnoid hemorrhage.

Health-related quality of life measurements, are commonly used to quantify burden of disease, to evaluate treatment method, and to facilitate benchmarking. The aim of the current study was to determine the Clinically Important Difference (CID) for a Chinese version of Stroke-specific Quality of Life (SS-QOL) in an aneurysmal subarachnoid hemorrhage (SAH) patient cohort. The study recruited SAH patients in a neurosurgical unit in Hong Kong. SAH patients who completed both 3-month and 1-year assessments were included in the analysis. The study received ethical approvals from the joint CUHK-NTEC Clinical Ethics Committee and written informed consent was obtained from all participants or their next of kins. Over a 2-year period, 65 eligible patients were included in the study. Employing the anchor-based approach with global rating of change, the CID estimate of SS-QOL total score was 4.7 (95% confidence interval [CI]: 2.5-5.3), the CID estimate for SSQOL physical subscore was 2.1 (95% CI: 0.3-2.4), and the CID estimate for SS-QOL psychosocial subscore change was 2.8 (95% CI: 1.8-3.7). In conclusion, our study defined the CID for SS-QOL applied to SAH patients and should be further validated in another SAH patient population.

Location, Infarct Load, and 3-Month Outcomes of Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage is a serious disease with high case fatality and morbidity. Delayed cerebral infarction (DCI) is an important surrogate marker. How location and infarct load affected outcomes was unclear. We aimed to assess the effects of load and location of DCI on outcomes of aneurysmal subarachnoid hemorrhage at 3 months. METHODS: We prospectively enrolled patients with subarachnoid hemorrhage presenting to an academic neurosurgical unit in Hong Kong during a 3-year period. DCI was defined by new hypoattenuation on computed tomography at 4 to 6 weeks, which was not present in the postaneurysm-treatment computed tomography at 24 to 48 hours. DCI was assessed for location according to cerebral artery territories and load semiquantitatively. Cognitive and functional outcome assessments were carried out 3 months after ictus. RESULTS: One hundred twenty-six patients with subarachnoid hemorrhage consented for this study. DCI occurred in 56 (44%) patients and was associated with poorer cognitive and functional outcomes (Montreal Cognitive Assessment, Mini-Mental State Examination, modified Rankin Scale, and Lawton Instrumental Activity of Daily Living) at 3 months. In patients with DCI, the presence of perforator zone infarct was associated with poorer cognitive and functional outcomes, and cortical middle cerebral artery infarct was associated with poorer modified Rankin Scale. After adjustment for age, admission World Federation of Neurosurgical Societies Grade and mode of aneurysm treatment, both middle cerebral artery cortical infarct load and perforator infarct load were independently associated with poor cognitive outcomes (Montreal Cognitive Assessment and Mini-Mental State Examination) and modified Rankin Scale. CONCLUSIONS: Middle cerebral artery cortical and perforator zone infarct loads are potential surrogate marker to assess the severity of delayed cerebral ischemia.

The beginning of medical education in Hong Kong 125 years ago...its unique features in comparison with similar efforts in China.

Medical education in Hong Kong began with the inauguration of the College of Medicine for Chinese in 1887. Although training in western medicine for Chinese had been started half a century earlier in the mainland of China, with a few exceptions, much of it was in the form of apprenticeships without a formal course of study, such that by the end of the 19th century medical education in China was still on the whole poorly developed. This paper presents some examples of significant efforts in western medical education on the Chinese mainland during the 19th century. It compares the Hong Kong College with these efforts, and examines those features which, together, made the College unique. These included its independent status as an educational institution, its use of English as a medium of instruction together with the attendant advantages that brings, the availability of students with the requisite language skills to undertake such studies, the availability of teachers, support of the public, and access to autopsies and dissection. Moreover, opportunities for employment in the public sector and in private practice gradually became available for its graduates, thus accelerating the acceptance of western medicine by the Chinese population and the development of these services in Hong Kong. The College, at its inception, could rightfully claim a leading position in these various aspects. Its story should be a source of inspiration and pride, and of encouragement for the local medical profession to continue this 125-year-old tradition of service and leadership.

Functional survival after acute care for severe head injury at a designated trauma center in Hong Kong.

BACKGROUND: Severe head injury is known to be a major cause of early mortalities and morbidities. Patients' long-term outcome after acute care, however, has not been widely studied. We aim to review the outcome of severely head-injured patients after discharge from acute care at a designated trauma center in Hong Kong. MATERIALS AND METHODS: This is a retrospective study of prospectively collected data of patients admitted with severe head injuries between 2004 and 2008. Patients' functional status post-discharge was assessed using the Extended Glasgow Outcome Score (GOSE). RESULTS: Of a total of 1565 trauma patients, 116 had severe head injuries and 41 of them survived acute hospital care. Upon the last follow-up, 23 (56.1%) of the acute-care survivors had improvements in their GOSE, six (11.8%) experienced deteriorations, and 12 (23.5%) did not exhibit any change. The greatest improvement was observed in patients with GOSE of 5 and 6 upon discharge, but two of the 16 patients with GOSE 2 or 3 also had a good recovery. On logistic regression analysis, old age and prolonged acute hospital stay were found to be independent predictors of poor functional outcome after a mean follow-up duration of 42 months. CONCLUSION: Multidisciplinary neurorehabilitation service is an important component of comprehensive trauma care. Despite significant early mortalities, a proportion of severely head-injured patients who survive acute care may achieve good long-term functional recovery.

Western medicine in a Chinese cultural setting.

Hong Kong's unique medical heritage stems from its development as a city with a predominantly Chinese population and a long history of exposure to the influence of Western cultural and scientific ideas and practices. This heritage is preserved and displayed in the Hong Kong Museum of Medical Sciences, where exhibits of both Traditional Chinese Medicine and Western medicine, particularly those aspects with special relevance to Hong Kong, are featured. This paper also describes the significance of the plague outbreak of 1894 in shaping Hong Kong's medical history, and in bringing about the existence of the building which houses the museum, a 100 year-old protected monument originally named the Bacteriological Institute. The museum's role in society, by providing programmes on health and heritage for the public's education and enjoyment, and the need to preserve and identify both tangible and intangible aspects of our cultural heritage is also briefly explored.