Burnout among doctors is increasingly recognised as a serious threat to medical and dental practice across all specialties; its prevalence is increasing worldwide.1 Burnout is a spectrum of clinical syndromes that were first categorised into three dimensions by Maslach as emotional exhaustion, depersonalisation, and a low sense of personal accomplishment.2 Subsequently, it was added to the International Classification of Diseases as a syndrome that results from poorly managed chronic workplace stress.3

Burnout among doctors can lead to decreased effectiveness and shortening of professional lifespan.4 Burnout exacerbates negative emotions, thereby impeding cognitive performance; it may result in biased decision making. Hence, the well-being of doctors is important for maintaining manpower, quality of care, and equity of care delivery. Multiple studies in different countries have shown that the incidence of burnout among doctors is rising. In the US, a Medscape nationwide survey showed that 59% of emergency medicine doctors experienced burnout symptoms, and the incidence had increased steadily over time.1 In Australia, the National Mental Health Survey found that the level of very high psychological distress was significantly greater in doctors (3.4%) than in the general population (2.6%) or other professionals (0.7%).5 A cross-sectional online survey in the United Kingdom also revealed a high rate of mental health disorders among junior doctors and medical students.6

To our knowledge, studies regarding well-being and burnout among doctors in Asia are limited. Gan et al7 performed a cross-sectional study of general practitioners in Hubei, China; they found a combined prevalence of 2.46% across all three dimensions of emotional exhaustion, depersonalisation, and personal accomplishment. However, that study only included doctors within a single specialty in one province. Huang et al8 found the prevalences of personal burnout and client-related burnout were 44.0% and 14.8%, respectively, among residents in Taiwan; however, they used a non-standardised questionnaire. In Hong Kong, a previous cross-sectional survey showed that 31.4% of respondents among doctors in the public sector had a high rate of burnout, but the sampling criteria were random and non-specific; moreover, that study did not include a substantial proportion of doctors who worked in the private sector.9 Another survey also suggested that burnout was prevalent among doctors in Hong Kong, but it only included graduates from one medical school in Hong Kong.10

Hence, this study aimed to evaluate the prevalence of burnout in the Hong Kong medical and dental workforce by administering standardised questionnaires to a broad population of residents-in-training and doctors within 10 years of their specialist registration. The study also explored well-being among doctors in terms of job satisfaction, depression, lifestyle behaviours, and factors associated with these states.

In this study, all doctors within 10 years of their specialist registration registered with the Hong Kong Academy of Medicine, as well as residents-in-training registered with one of the Academy’s 15 constituent Colleges, were invited to complete a voluntary cross-sectional survey between February 2019 and June 2019. The cut-off of 10 years was selected because the Hong Kong Academy of Medicine considers doctors within 10 years of their specialist registration to be “young Fellows”. The survey consisted of self-reported demographic data, year of entry into medical school, and current professional details. Burnout was assessed using the validated Copenhagen Burnout Inventory (CBI).11 Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9).12 Lifestyle factors were assessed with reference to the respondents’ drinking habits, sleep patterns, and levels of both exercise and activities. Items concerning job satisfaction and lifestyle behaviours were adapted from existing doctor questionnaires and health surveys.13 14

An online survey was developed in-house by the Hong Kong Jockey Club Innovative Learning Centre for Medicine of the Hong Kong Academy of Medicine, then administered electronically. The invitations to participate were sent via e-mail; two separate reminder emails were sent after the initial invitation. As an incentive, respondents were offered coffee or food coupons after completion of the survey. The study protocol was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (Ref No: UW 19-062).

PASS 2000 (NCSS, LLC., Kaysville [UT], US; www.ncss.com) power analysis software was used for sample size calculation. The prevalence of personal burnout among young doctors in Hong Kong was assumed to be similar to the prevalence of personal burnout among residents in Taiwan (44.0%)8; thus, to achieve a 95% confidence interval (CI) with a precision of 4.5%, 458 participants were required. Our final sample of 514 doctors was sufficient to achieve the desired statistical power.

This instrument consists of three scales that measure personal burnout, work-related burnout, and client-related burnout; the scales can be applied to workers in all industries and cultures. Personal burnout measures the degree of fatigue experienced by the respondent, irrespective of work experience or occupational status. Work-related burnout measures the degree of fatigue related to work; it explores how the respondent’s perception of work contributes to fatigue. Client-related burnout is the perceived degree of fatigue related to work with clients. The burnout level is calculated as a mean score; therefore, each scale has a value between 0 and 100. A score of ≥50 indicates a high degree of burnout.15 16 17 18

The PHQ-9 is a depression assessment tool, which scores each of the nine Diagnostic and Statistical Manual of Mental Disorders IV criteria for depression on a scale ranging from “0” (not at all) to “3” (nearly every day). A PHQ-9 score >9 has a reported sensitivity of 88% and specificity of 88% for major depression.19

The prevalence of burnout is shown using point estimates and 95% CIs. Descriptive statistics were presented concerning demographic characteristics and lifestyle behaviours. Bivariate logistic models were used to describe the distinct relationships of suicide, depression, and burnout with demographic, educational, and professional characteristics. The data were analysed using SPSS software (Windows version 26.0; IBM Corp, Armonk [NY], US). Statistical significance was set at P<0.05.

There were 746 total respondents; of these, 232 did not complete the entire survey and were excluded from the analysis. Of the included 514 respondents, 284 were doctors within 10 years of their specialist registration, while 230 were residents-in-training. The total number of doctors within 10 years of their specialist registration invited to participate in the survey was 2879; thus, the response rate was estimated as 9.9%. However, it was not possible to calculate the response rate for residents-in-training. The respondents included 277 women (54%); the mean age among all respondents was 33.7 ± 6.1 years. The respondents’ demographic data are summarised in Table 1; their current professional statuses are summarised in Table 2.

Overall, 24% (n=125) of respondents were “somewhat dissatisfied” with their present job position, while 4% (n=19) of respondents were “very dissatisfied” with their present job position. Furthermore, 15% (n=76) of respondents were “somewhat dissatisfied” with being a medical doctor, whereas 2% (n=10) of respondents were “very dissatisfied” with being a medical doctor. Finally, 3% (n=14) of respondents indicated they planned to stop practising medicine in the next 12 months, with stress or burnout (86%) cited as the most common reason for such plans.

As measured by the CBI, the mean personal burnout score was 59.6 ± 20.5, work-related burnout score was 57.3 ± 20.1, and client-related burnout score was 49.0 ± 22.3. Using a CBI subscale cut-off score of ≥50 (moderate and higher), 72.6% (n=373, 95% CI=68.5%-76.4%) of respondents reported personal burnout; 70.6% (n=363, 95% CI=66.4%-74.5%) of respondents reported work-related burnout; and 55.4% (n=285, 95% CI=51.0%-59.7%) of respondents reported client-related burnout (Table 3).

The mean physical component summary score of the 12-Item Short Form Survey was 49.6 ± 7.8; the mean mental component summary score of the 12-Item Short Form Survey was 42.3 ± 10.6 (Table 3).

As measured by the PHQ-9, the mean depression score was 6.2 ± 5.1. However, the prevalence of depression among respondents, defined as a score of ≥10, was 21% (n=110) [Table 3].

In total, 79% (n=404) of respondents did not report any suicidal ideation or attempt. The remaining respondents stated that life was “not worth living” or “wished he or she was dead”; some also reported a history of suicidal ideation or attempts. The most commonly cited source of stress in the past year was clinical responsibilities/job demands.

In terms of health conditions, there was a perception among respondents that their health status was “worse” (29%; n=148) or “much worse” (3%; n=17) than among other individuals of the same age. The mean duration of sleep each night was 6.2 ± 1.5 hours. However, most respondents frequently experienced inadequate sleep when at work; 70% (n=361) of respondents indicated that this occurred weekly or more often. In terms of personal habits, the prevalences of alcohol drinking, drug addiction, and smoking were low. However, the prevalences of regular physical activity and personal physical assessments were not high (Table 4).

Logistic regression modelling was performed to investigate bivariate associations of demographic and professional factors with burnout, the presence of depression, or suicide ideation and/or attempts.

The number of working hour(s) per week (odds ratio [OR]=1.02; 95% CI=1.01-1.04; P=0.001) was positively associated with depression (online supplementary Table 1); having children (OR=0.58; 95% CI=0.36-0.93; P=0.024) was negatively associated with suicidal ideation/attempts. Doctors who completed a project-based learning curriculum during undergraduate study were less likely to be depressed or report suicidal ideation/attempts (depression: OR=0.60; 95% CI=0.39-0.91; P=0.017; suicidal ideation/attempts: OR=0.65; 95% CI=0.43-1.00; P=0.049) [online supplementary Table 2].

Older age (OR=0.97; 95% CI=0.94-0.99; P=0.026), possession of a first university degree in medicine or dental surgery (OR=0.37; 95% CI=0.15-0.89; P=0.027), and possession of Academy fellowship status (OR=0.61; 95% CI=0.41-0.92; P=0.017) were associated with lower likelihood of personal burnout. Engagement in longer working hour(s) per week (OR=1.04; 95% CI=1.02-1.05; P<0.001) and working in Hospital Authority clinics (OR=1.95; 95% CI=1.05-3.62; P=0.034; compared with working in government clinics) were positively associated with personal burnout (online supplementary Table 3). Marital statuses of single, separated, or divorced (OR=1.71; 95% CI=1.16-2.53; P=0.007) and engagement in longer working hour(s) per week (OR=1.03; 95% CI=1.02-1.05; P<0.001) were positively associated with work-related burnout (online supplementary Table 4). Conversely, having children (OR=0.66; 95% CI=0.44-0.98; P=0.038), consultant seniority level (OR=0.27; 95% CI=0.09-0.88; P=0.029; compared with associate consultant seniority level), and working in the private sector (OR=0.40; 95% CI=0.17-0.94; P=0.035; compared with working in government) were negatively associated with work-related burnout. Provision of primary care (OR=1.5; 95% CI=1.04-2.16; P=0.031) was associated with client-related burnout (online supplementary Table 5).

This study attempted to quantify well-being and burnout in young doctors (both resident-in-training, and doctors within 10 years of their specialist registration) throughout Hong Kong; there were three main findings. First, the mean burnout score was high in this group of doctors; mean personal and work-related scores of ≥50 were observed on the CBI. Second, there was a high prevalence of job dissatisfaction (28%) in this group of doctors. Third, the self-perceived personal well-being and mental health were worse in this group of doctors than in members of the general population with similar ages.

Burnout is a well-known occupational hazard in people-oriented professions; doctors are at particular risk of burnout because of their frequent engagement in intense personal and emotional contact with patients. Although these therapeutic and service relationships are highly rewarding and engaging, they can also be a source of stress. Burnout among doctors has been recognised as a global crisis20; its effects on personal, patient, and institutional levels can be substantial. The expectation to meet job demands can lead to maladaptive practices which will ultimately compromise relationships with patients and colleagues, with long-term consequences on patient care.21 Hence, efforts to acknowledge that such a problem exists represents the first step in establishing a systematic strategy to address this crisis.

Although there have been multiple published reports regarding burnout among doctors, territory-wide data focusing on junior doctors in Hong Kong are lacking. Siu et al9 conducted a random sample survey of 226 public doctors in 2012; they found that 31.4% of respondents satisfied the criteria for high burnout. Moreover, young but moderately experienced doctors needing to work shifts were most vulnerable to high burnout. However, the questionnaire used in that study was not comprehensive, the random sampling method did not produce a representative cohort, and only public doctors were invited to the survey. More recently, a more comprehensive survey involving medical graduates of one university in Hong Kong found high prevalences of personal (63.1%) and 55.9% (work-related) burnout using the standardised CBI.10 The more comprehensive survey represents the most comprehensive and robust study in Hong Kong thus far, but it only included graduates from one university in Hong Kong; it did not include any doctors trained elsewhere.

The present study of young doctors throughout Hong Kong found high mean personal (59.6 ± 20.5) and work-related (57.3 ± 20.1) scores on the CBI. The mean client-related score was 49.0 ± 22.3, slightly below the score of 50 that constituted the threshold for burnout. These scores were higher than in the previous study performed in Hong Kong by Ng et al,10 which showed mean CBI scores of 57.4 ± 21.4 (personal), 48.9 ± 7.4 (work-related), and 41.5 ± 21.8 (client-related). Moreover, when compared with studies worldwide that used the CBI to measure burnout in doctors,15 16 18 22 the levels of burnout in the present study were among the highest. Contributing factors may differ among regional healthcare systems; causes of burnout and well-being in junior doctors may not be consistent worldwide. Our study attempted to identify sources of stress among junior doctors in Hong Kong; the most commonly cited sources were clinical responsibilities/job demands and professional examinations. Additional in-depth studies are necessary to determine how these factors can be modified to alleviate stress in junior doctors.

The respondents’ general health statuses (in terms of medical conditions) were not substantially worse than the general population, although 32% of the respondents indicated self-perceived health worse than their peers. The present study also showed that the prevalence of depression was 21%, according to the PHQ-9. This is more than double the prevalence previously reported in Hong Kong (8.4%).23 Despite the high prevalence of depression in the present study, respondents indicated low rates of suicidal ideation/attempts. Although a causal relationship could not be established because of the observational nature of the study, the number of working hours per week and having children were factors that affected risk of depression and suicidal ideation/attempts, respectively. The mean number of hours worked per week was 53.5 ± 14.8 hours. Junior doctors who work >55 hours per week are reportedly twofold more likely to have frequent health problems (OR=2.05, 95% CI=1.62-2.59; P<0.001) and suicidal ideation (OR=2.0, 95% CI=1.42-2.82; P<0.001).24 A previous systemic review showed an association between long working hours and a depressive state in other professions in general.25 Positive effects of reduced working hours among junior doctors have been found in some studies,26 27 but this relationship is not consistently observed. For example, in the United Kingdom, the Working Time Regulations were fully applied to junior doctors beginning in 2009; these comprised a limit of 48 hours per week, averaged across a reference period of 26 weeks, with additional minimum rest periods. However, implementation of the Working Time Regulations has not fully resolved the effects of long hours and fatigue.28 Furthermore, there are implications for professional training and manpower planning if rigid enforcement of such working hours is performed.

Our study did not find any substantial evidence that young doctors were reliant on alcohol, smoking, or drugs as coping mechanisms. This contrasts with findings from the US, which indicated that high levels of alcohol and substance abuse were associated with burnout among doctors.29 It was beyond the scope of the present study to explore other avenues that junior doctors in Hong Kong might use to alleviate their stress levels and burnout. Other health and lifestyle behaviours (eg, exercise levels and personal physical assessments) may be indicative of time constraints related to work or personal obligations; they may also be indicative of self-neglect caused by such constraints and work-related burnout.

This study had several limitations. First, it was a cross-sectional study with voluntary participation, and the results might not be representative of all doctors throughout public and private sectors in Hong Kong. However, to our knowledge, this study performed the most comprehensive survey regarding burnout among doctors in Hong Kong thus far. Second, the study was not designed to avoid selection bias concerning doctors who were more prone to burnout and therefore more interested to participate in such surveys. Third, because the survey did not allow free text entry in the questionnaire responses, more in-depth analysis was not possible in some instances. Fourth, because this was a cross-sectional survey, no causal relationships or risk factors could be established regarding the development of burnout or depression. Fifth, our definition of “young” was based on the 10 years of specialist registration, which included doctors with various levels of experience and responsibilities; thus, the results might not be representative of a specific subset of doctors.

The present study showed that junior doctors in Hong Kong had a high level of burnout, and there was a high prevalence of depression among the respondents. A substantial proportion of the respondents were dissatisfied with their present job position. Future studies to determine causal factors will allow the development and implementation of specific strategies to address these problems within Hong Kong. The maintenance of well-being in junior doctors is vital for sustaining a healthy medical workforce and long-term patient care.

Concept or design: All authors.
Acquisition of data: KYH Kwan, LWY Chan, PW Cheng.
Analysis or interpretation of data: KYH Kwan, LWY Chan, PW Cheng.
Drafting of the manuscript: KYH Kwan.
Critical revision of the manuscript for important intellectual content: All authors.

The authors have no conflicts of interest to disclose.

The authors thank all members of the Young Fellows Chapter of the Hong Kong Academy of Medicine for their active participation in this study; the secretariat and staff of the Hong Kong Academy of Medicine and its Hong Kong Jockey Club Innovative Learning Centre for Medicine for their administrative and information technology support; and the Council of the Hong Kong Academy of Medicine for their active support, encouragement, and funding of the coupons. The authors especially thank Dicken CC Chan for statistical assistance.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This study was approved by the Institutional Review Board of The University of Hong Kong/Hospital Authority Hong Kong West Cluster (Ref No: UW 19-062).

1. Kane L. Medscape national physician burnout and depression report 2019. Available from: https://www.medscape.com/slideshow/2019-lifestyle-burnout-depression-6011056. Accessed 2 Dec 2020.

2. Maslach C. What have we learned about burnout and health? Psychol Health 2001;16:607-11.Crossref

3. World Health Organization. International Classification of Diseases 11th Revision. QD85 Burnout. Available from: https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/129180281. Accessed 3 Dec 2020.

4. Lin M, Battaglioli N, Melamed M, Mott SE, Chung AS, Robinson DW. High prevalence of burnout among US emergency medicine residents: results from the 2017 National Emergency Medicine Wellness Survey. Ann Emerg Med 2019;74:682-90. Crossref

5. BeyondBlue. National Mental Health Survey of Doctors and Medical Students 2019. Available from: https://www.beyondblue.org.au/docs/default-source/beyond-blue-s-strategic-plan-2020-2023/research-project-files/bl1132-report---nmhdmss-full-report_web.pdf?sfvrsn=845cb8e9_14. Accessed 3 Dec 2020.

6. Bhugra D, Sauerteig SO, Bland D, et al. A descriptive study of mental health and wellbeing of doctors and medical students in the UK. Int Rev Psychiatry 2019;31:563-8. Crossref

7. Gan Y, Jiang H, Li L, et al. Prevalence of burnout and associated factors among general practitioners in Hubei, China: a cross-sectional study. BMC Public Health 2019;19:1607. Crossref

8. Huang EC, Pu C, Huang N, Chou YJ. Resident burnout in Taiwan Hospitals—and its relation to physician felt trust from patients. J Formos Med Assoc 2019;118:1438-49. Crossref

9. Siu CF, Yuen SK, Cheung A. Burnout among public doctors in Hong Kong: cross-sectional survey. Hong Kong Med J 2012;18:186-92.

10. Ng AP, Chin WY, Wan EY, Chen J, Lau CS. Prevalence and severity of burnout in Hong Kong doctors up to 20 years post-graduation: a cross-sectional study. BMJ Open 2020;10:e040178. Crossref

11. Kristensen TS, Borritz M, Villadsen E, Christensen KB. The Copenhagen Burnout Inventory: a new tool for the assessment of burnout. Work Stress 2005;19:192-207. Crossref

12. Rizzo R, Piccinelli M, Mazzi MA, Bellantuono C, Tansella M. The Personal Health Questionnaire: a new screening instrument for detection of ICD-10 depressive disorders in primary care. Psychol Med 2000;30:831-40. Crossref

13. Heponiemi T, Kouvonen A, Vänskä J, et al. Health, psychosocial factors and retirement intentions among Finnish physicians. Occup Med (Lond) 2008;58:406-12. Crossref

14. Taylor K, Lambert T, Goldacre M. Future career plans of a cohort of senior doctors working in the National Health Service. J R Soc Med 2008;101:182-90. Crossref

15. Benson S, Sammour T, Neuhaus SJ, Findlay B, Hill AG. Burnout in Australasian younger fellows. ANZ J Surg 2009;79:590-7. Crossref

16. Chou LP, Li CY, Hu SC. Job stress and burnout in hospital employees: comparisons of different medical professions in a regional hospital in Taiwan. BMJ Open 2014;4:e004185. Crossref

17. Creedy DK, Sidebotham M, Gamble J, Pallant J, Fenwick J. Prevalence of burnout, depression, anxiety and stress in Australian midwives: a cross-sectional survey. BMC Pregnancy Childbirth 2017;17:13. Crossref

18. Wright JG, Khetani N, Stephens D. Burnout among faculty physicians in an academic health science centre. Paediatr Child Health 2011;16:409-13. Crossref

19. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001;16:606-13. Crossref

20. Physician burnout: a global crisis [editorial]. Lancet 2019;394:93. Crossref

21. Graham J, Potts HW, Ramirez AJ. Stress and burnout in doctors. Lancet 2002;360:1975-6. Crossref

22. Thomas LR, Ripp JA, West CP. Charter on physician well-being. JAMA 2018;319:1541-2. Crossref

23. Cheng CM, Cheng M. To validate the Chinese version of the 2Q and PHQ-9 questionnaires in Hong Kong Chinese patients. HK Pract 2007;29:381-90.

24. Petrie K, Crawford J, LaMontagne AD, et al. Working hours, common mental disorder and suicidal ideation among junior doctors in Australia: a cross-sectional survey. BMJ Open 2020;10:e033525. Crossref

25. Bannai A, Tamakoshi A. The association between long working hours and health: a systematic review of epidemiological evidence. Scand J Work Environ Health 2014;40:5-18. Crossref

26. Kiernan M, Civetta J, Bartus C, Walsh S. 24 Hours on-call and acute fatigue no longer worsen resident mood under the 80-hour work week regulations. Curr Surg 2006;63:237-41. Crossref

27. Kort KC, Pavone LA, Jensen E, Haque E, Newman N, Kittur D. Resident perceptions of the impact of work-hour restrictions on health care delivery and surgical education: time for transformational change. Surgery 2004;136:861-71. Crossref

28. Morrow G, Burford B, Carter M, Illing J. Have restricted working hours reduced junior doctors' experience of fatigue? A focus group and telephone interview study. BMJ Open 2014;4:e004222. Crossref

29. Oreskovich MR, Shanafelt T, Dyrbye LN, et al. The prevalence of substance use disorders in American physicians. Am J Addict 2015;24:30-8. Crossref

Considerable physical and psychosocial benefits are associated with participation in sporting activities.1 2 Physical activity has been demonstrated to reduce the risks of coronary heart disease, some cancers, obesity, hypertension, and type 2 diabetes mellitus.2 3 4 5 6 Its obvious merits have prompted several national health programmes, including the health programme in Hong Kong, to promote sports to the general public.7 8 9 However, sports participation carries a risk of injury, especially traumatic brain injury (TBI). It has been estimated that 20% of all TBIs are sports-related.10 In addition, up to 20% of sports-related TBI survivors (usually adolescents or young adults) experience chronic symptoms including headache, fatigue, and cognitive and balance difficulties.11 There is a global trend of increasing sports-related TBI incidence: from 3.5 to 31.5 per 100 000 population in the past decade.12 13 Because many patients with mild TBI do not seek medical attention, these figures likely underestimate the total burden of this condition.13 Population-based studies reviewing sports-related TBI are sparse; most target specific groups of individuals (eg, professional athletes) or rely on self-reporting surveys that lack a uniform definition and comprehensive assessment of brain injury.14 For similar reasons, studies reviewing outcome predictors have also been inadequate, thus hindering the generation of meaningful conclusions to guide governmental policy initiatives.14

Hong Kong is highly urbanised with an established public transport system, such that cycling is mainly regarded as a recreational activity.15 16 In terms of fatality rate, Hong Kong is among the most dangerous areas for cycling, compared with other cities such as New York, the US, or countries such as France.17

This study was performed to document the epidemiology of sports-related TBI among patients who required inpatient care by adopting territory-wide uniform diagnostic coding criteria, clear data definitions, and systematic assessments of radiologic findings. Because cycling is a popular sport in Hong Kong, factors predictive of intracranial haemorrhage (eg, the effect of helmet use) and poor functional outcomes among cyclists hospitalised with TBI were determined.

Patients who required inpatient care at any Hospital Authority institution for sports-related TBI from 1 January 2015 to 31 December 2019 were reviewed. The Hospital Authority is a public health service highly subsidised by the Hong Kong SAR Government; it is responsible for 90% of inpatient bed days in the city. Patients were identified by the International Classification of Diseases, Tenth Revision, Clinical Modification code (ICD-10-CM) designation for TBI 854.0 secondary to a sports-related external cause (E codes: E006-10). Data from clinical records, operation notes, medication prescriptions, and computed tomography (CT) brain scans from a central digital imaging repository were reviewed. In particular, the type of sport played, the clinical presentation of symptoms, the Injury Severity Score (ISS), the need for neurosurgery, length of hospitalisation, and diagnosis of post-concussion syndrome were recorded. Head injury was classified into mild (presenting Glasgow Coma Scale [GCS] score, 14-15); moderate (presenting GCS score, 9-13), and severe (presenting GCS score, 3-8), in accordance with criteria established by the Neurotraumatology Committee of the World Federation of Neurosurgical Societies.18 Post-concussion syndrome was defined in accordance with ICD-10 criteria. This required a 4-week duration of symptoms from at least three categories following a traumatic loss of consciousness. The symptom categories were headache, irritability, concentration impairment, insomnia, and a preoccupation with the aforementioned symptoms. For neurosurgical patients with cycling related–TBI, the mechanism of injury and their experience level (ie, professional athlete or amateur rider) were documented. All CT scans were reviewed by an independent assessor with 6 months of neurosurgical training experience who was blinded to the patients’ clinical characteristics and outcomes. The scans were first evaluated using the Rotterdam CT score, a commonly utilised validated radiological assessment system for the prognosis of patients with TBI. The classification has four distinct elements that require the appraisal of the degree of basal cistern obliteration, degree of midline shift, the presence (or absence) of an epidural mass lesion, and the presence (or absence) of intraventricular or traumatic subarachnoid haemorrhage (Table 1). In addition, the scans were assessed for skull fractures, cerebral contusions, and acute subdural haematomas (ASDHs). The primary outcome of the study was the presence of intracranial haemorrhage on the admitting CT scan. All potential predictors were categorised into patient-related, trauma-related, and radiological factors. The secondary outcome was unfavourable functional performance, defined as a Glasgow Outcome Scale (GOS) score of 3 to 5 on discharge from the hospital (3, severe disability; 4, persistent vegetative state; and 5, death).

Statistical analyses utilised the Chi squared test and Fisher’s exact test were used for categorical data such as patient gender or the use of antiplatelet medication. Independent-samples t test was used for continuous data such as patient age or duration of hospitalisation. Multivariate binary logistic regression was used to identify independent factors for the presence (or absence) of traumatic intracranial haemorrhage. A P value of <0.05 was considered statistically significant. Statistical analysis was conducted using SPSS (Windows version 20.0; IBM Corp, Armonk [NY], US).

In total, 720 consecutive patients were hospitalised with sports-related TBI during the 5-year study period, and 705 (97.9%) of them were admitted under neurosurgical care. This was equivalent to a crude incidence of 1.9 per 100 000 general population. The mean (± standard deviation [SD]) age was 32 ± 19 years; 521 (72.4%) patients were adults (≥18 years) and 568 (78.9%) were male. The most common sport was cycling (59.2%), followed by football (21.3%) and basketball (7.5%) [Fig a]. On admission, most (86.1%) patients were fully conscious. Overall, 658 (91.4%) patients had mild TBI, 41 (5.7%) patients had moderate TBI, and 21 (2.9%) patients had severe TBI. Post-traumatic seizures occurred in 36 (5.0%) patients. Furthermore, 324 (45.0%) patients had a loss of consciousness and 269 (37.4%) patients experienced post-traumatic retrograde amnesia. Only 19 (2.6%) patients were taking either antiplatelet or anticoagulant medication. Extracranial injuries were sustained by 208 (28.9%) patients; among them, injuries were mainly either limb abrasions or contusions (62.1%). The median ISS was 2 (interquartile range=2-8).

Intracranial haemorrhage was noted in 283 (39.3%) patients with TBI; 166 (23.1%) patients exhibited traumatic subarachnoid haemorrhage and 157 (21.8%) exhibited ASDH. Skull fractures were detected in 179 (24.9%) patients, with a median Rotterdam CT score of 2 (interquartile range=2-2). In total, 59 (8.2%) patients required neurosurgical intervention; 32 (54.2%) of them had good recovery with a median GOS score of 5 on discharge from the hospital and at 6 months. The mean (± SD) duration of hospitalisation was 5 ± 28 days. Among 307 (42.6%) patients in whom 6-month GOS scores could be assessed, good recovery was observed in 260 (84.7%). Post-concussion syndrome was diagnosed in 30 (6.2%) of 482 patients who attended scheduled follow-up outpatient consultations.

The crude incidence of recreational cycling-related TBI requiring hospitalisation was 1.1 per 100 000 population. A comparison was performed between cyclists with sports-related TBI and patients who had TBI because of other sports (Table 2). Cyclists were significantly older (P<0.001) [Table 2; Fig b]. Among 426 cyclists, 306 (71.8%) were male and 120 (28.2%) were female. However, the proportion of patients who were female was significantly higher among those who had TBI because of cycling (28.2%) than among those who had TBI because of other sports (10.9%; P<0.001). Cyclists were likely to exhibit more severe TBI with an almost three-fold greater risk of sustaining extracranial injury (odds ratio [OR] 2.8; 95% CI: 1.9-4.0), resulting in a higher ISS (P<0.001). Of cyclists admitted for head injury, 201 (47.2%) had intracranial haemorrhage, which was radiologically more extensive in terms of the Rotterdam CT score, compared with haemorrhage in non-cyclists (P<0.01). As a consequence, a greater proportion of cyclists had a worse GOS score on discharge from hospital (OR 2.8; 95% CI: 1.3-6.2) and at 6 months (OR 4.7; 95% CI: 2.1-10.5). The cause of death for all cyclists with 30-day mortality was severe TBI with medically refractory intracranial hypertension. Although the overall incidence was low, cyclists also had a greater risk of post-concussion syndrome (OR 2.5; 95% CI: 1.2-5.4).

Among the 426 cyclists in this study, 128 (30.0%) experienced bicycle accidents during the weekend; 10 (2.3%) of the cyclists were professional athletes. Most cyclists (273; 64.1%) accidently fell off their bicycle on their own (ie, without colliding into another object) on level ground. Of the injuries, 103 (24.2%) were sustained when the cyclist was traveling downhill; for the 28 patients with records of self-reported velocities, the estimated mean (± SD) velocity at the moment before injury was 40 ± 15 km/h. At the time of injury, 361 (84.7%) cyclists had not been wearing a helmet. Among eight (1.9%) patients who subsequently died, none had been wearing protective head gear.

Risk factors for traumatic intracranial haemorrhage among cyclists are shown in Table 3. Univariate analysis identified the following risk factors: age ≥60 years, use of antiplatelet medication, involvement in a motor vehicle collision, presence of moderate to severe TBI, and skull fracture. In univariate analysis, helmet wearing was protective against intracranial haemorrhage. Multivariate logistic regression identified the following independent risk factors: age ≥60 years, antiplatelet medication intake, moderate or severe TBI, and the presence of a skull fracture. Table 4 shows independent significant predictors for unfavourable GOS score on discharge from hospital: age ≥60 years, antiplatelet intake, severe TBI, intracranial haemorrhage, and the need for neurosurgical operative intervention.

As shown in Table 2, 375 (88.0%) hospitalised cyclists had mild TBI, whereas only 36 (8.5%) cyclists had moderate TBI and 15 (3.5%) had severe TBI. No protective effect of helmet use was noted in terms of reducing TBI severity across these GCS-defined categories (Table 3). However, among cyclists with mild TBI, helmets were significantly protective against intracranial haemorrhage and skull fracture, regardless of age, antiplatelet medication intake, or mechanism of injury (Table 5). Although the median Rotterdam CT score was comparable between cyclists with mild TBI who did or did not wear helmets (P=0.68), significantly fewer patients with head protection had epidural haematoma or ASDH. For patients with mild TBI who had intracranial haemorrhage, this difference in radiological factors led to a significantly shorter mean (± SD) duration of hospitalisation for patients who wore helmets (2.6 ± 2.9 days), compared with patients who did not (7.1 ± 11.6 days, P<0.001). However, there was no difference in the need for neurosurgical intervention among patients with mild TBI who had intracranial haemorrhage according to head protection status (P=0.17). Similarly, unfavourable GOS scores on discharge from hospital (P=0.43) and at 6 months (P=0.71) were comparable among patients with mild TBI who had intracranial haemorrhage, regardless of head protection status (Table 5).

The incidence of sports-related TBI in Hong Kong is 2 per 100 000 general population; this is lower than in other countries (eg, the US, Australia, or Italy), where the incidences range from 4 to 32 per 100 000 population.12 The lower incidence in Hong Kong is consistent with a previous finding that Hong Kong residents (especially children and adolescents) have lower physical activity and fitness levels than in other regions, according to a global evidence-based evaluation of such indicators from 49 countries.19 Considering the health benefits of an active lifestyle, there is a clear need to promote sports engagement in Hong Kong. A survey of 5701 residents performed by the Transport Department of the Hong Kong SAR Government estimated that 10% of households had bicycles available for use; moreover, 69% (4 million) of residents aged 15 years or older knew how to ride one.16 In addition, most survey respondents (73%) cycled for recreational or fitness purposes.15

Previous epidemiological studies of sports-related brain injuries revealed that cycling was one of the most frequent activities involved.10 12 20 21 In 2019, 1738 road traffic accidents involving cyclists were reported to the Hong Kong Transport Department.22 Half of these accidents (50.6%, 879/1738) occurred in recreational areas such as cycling tracks, parks, or playgrounds; eight (0.5%) patients experienced fatal injuries.22 In the past 10 years, the number of cyclist injuries in Hong Kong has increased by 5.2% per year.17 Compared with other regions worldwide, Hong Kong is one of the most dangerous areas for cycling.17 The fatality rate (per billion minutes cycled) in the city was 34, substantially higher than the rates in Stockholm, Sweden (3), France (4), and other metropolitan areas (eg, New York City [18] and Los Angeles [8]).17 These studies included riders primarily involved in commuting and the causes of death were not elucidated, but they indicate a growing need to enhance the safety of vulnerable road users.

To our knowledge, this is the first multicentre study to comprehensively document the outcomes of inpatients with recreational cycling-related TBI using standard assessment criteria. By comparison with patients who had TBI because of other sports, we found that cyclists in Hong Kong exhibited greater risks of more severe injury, intracranial haemorrhage, unfavourable GOS score at discharge from hospital, and post-concussion syndrome. Despite these findings, our results suggest that cycling is generally safe and hospitalised patients had a high (92.7%) likelihood of favourable functional outcomes on discharge from hospital.

Single-centre reviews of cycling-related injuries among various suburban districts in Hong Kong found that limb injuries were the most common form of trauma followed by head injury (10%-39% of patients).23 24 25 26 Among patients with TBI, 16% to 53% exhibited “severe” injury; however, the studies did not provide explicit definitions to qualify this categorisation, and did not describe radiological data regarding the extent of injury or the need for neurosurgical intervention.23 26 In the present study, 12% of hospitalised cyclists with head injury had moderate to severe TBI. There was also a high incidence of intracranial haemorrhage involving almost half of the patients. Both these factors were independent predictors of poor GOS score on discharge from hospital. Our results are consistent with the findings in a previous study where 75% of all cycling-related deaths were caused by severe TBI.27 The lack of an independent association with motor vehicle collisions, which constituted only a minority of injuries in this cohort, suggests that recreational cycling at comparatively low speeds can be fatal. Notably, the mechanism of injury for four (50%) of the eight recreational cyclists who died in this study was a loss of balance, followed by a fall on level ground without colliding into another object, person, or motor vehicle.

Previous studies in Hong Kong, the most recent of which was performed >10 years ago, revealed that recreational cyclists rarely wore protective headgear (eg, frequencies of 0.2% to 2.2% among emergency department attendees).24 25 26 Our findings revealed that significantly more patients (15%) wore helmets at the time of injury. Governmental advocacy initiatives for promoting helmet wearing in recent years may have resulted in heightened public awareness regarding the risks of head trauma.28 There is little doubt that helmets are protective. In the past 30 years, several case-control and epidemiological studies have delivered compelling evidence to support the efficacy of bicycle helmet wearing in reducing the risk of life-threatening TBI.29 30 31 32 33 34 35 36 37 In a case-control prospective multicentre study of over 3000 patients, Thompson et al33 noted that helmets (irrespective of design) conferred up to a 74% reduction in TBI during accidents. A subsequent meta-analysis of five studies observed that helmets provided a 63% to 88% reduction in the risk of head, brain, and severe TBI for all ages of cyclists; this included equal levels of protection for collisions involving motor vehicles and collisions due to other causes.38 In the present study, helmet wearing did not reduce TBI severity according to our broadly predefined categories. However, among hospitalised recreational cyclists with mild head injury, helmets did provide significant protection against intracranial haemorrhage, including potentially life-threatening epidural haematomas and ASDHs, as well as skull fractures. Thus, our findings may have important public health implications with regard to introducing mandatory bicycle helmet wearing legislation in the city.

Whether such laws should exist is a particularly divisive issue among public health experts and interest groups.39 40 41 42 43 In Australia, a nation with all-age helmet wearing safety laws, an overall 46% decline in cyclist fatalities per 1 000 000 population has been reported, compared with the pre-legislation period.44 Similar findings were noted in New Zealand: a 67% decline in severe TBI was recorded after the introduction of helmet laws.45 In the US, a significant reduction in paediatric cyclist fatalities involving motor vehicles was observed in states with such laws.46 A meta-analysis of the effectiveness of bicycle helmet legislation revealed that it increased helmet usage, while significantly reducing head injuries and mortality.47 Several medical associations have expressed support for introducing such legislation; these include the World Health Organization, the British Medical Association, the American Medical Association, and the Royal Australasian College of Surgeons.48 49 50 51 However, critics of such compulsory policies have hypothesised that helmets could encourage risk-compensation behaviour, whereby cyclists may be more willing to engage in potentially injurious risks or for motorists to exercise less caution when encountering them.39 52 53 Other reasons for opposition include infringement on individual liberties; some public health scholars have theorised that such laws could discourage cyclists from participating in gainful physical activity.39 40 41 42 54 From a Hong Kong Transport Department survey (5701 respondents) regarding attitudes towards possible helmet law and enforcement measures, the majority of respondents (78%-90%) were in favour of introducing such legislation, especially when riding on carriageways.16 However, among respondents who knew how to ride a bicycle (3933 respondents), 23% declared they would ride less frequently if mandatory helmet wearing was required.16

An inherent limitation of a retrospective study of this nature was the likely under-reporting of the number of patients with sports-related head injuries. In the only existing population-based study of TBI epidemiology that included community-based injuries, 95% were considered mild and 28% of respondents did not seek medical attention.55 Among professional or university-level athletes, under-reporting is more apparent: questionnaire surveys reveal that 31% to 78% of respondents neglected to pursue medical care despite experiencing a concussion during the preceding 12 months.56 57 At the emergency department level, no territory-wide TBI registry exists in Hong Kong; moreover, diagnostic coding to facilitate data retrieval is typically not performed after consultations. Therefore, we could only identify hospitalised patients with sports-related TBI by means of an administrative database that utilised the ICD-10 coding system. However, the validity of such administrative data for research has been questioned.58 Studies have shown significantly lower TBI rates among young adults, men, and patients with less severe injuries when the ICD system was utilised, compared with thorough medical record review.59 Analysis of a population-based TBI sample showed that only 19% of individuals were assigned a TBI-related diagnostic ICD code.60 In addition, a degree of selection bias may have existed because some non-hospitalised helmet-wearing cyclists with mild head injury may have been discharged from the emergency department, mitigating the protective effects of helmet use. This may explain why no considerable differences in outcomes were detected for patients with moderate or severely injured patients. Despite the low rate of helmet use among recreational cyclists (15%), significant protective effects were detected among mildly injured patients with regard to intracranial haemorrhage and skull fracture. This limited participant identification approach also allowed for a pragmatic review of patients with clinically significant TBI who were hospitalised following evaluation by an emergency care physician. Computed tomography scans are generally performed only for hospitalised patients with head injury in our public healthcare system; this approach offered an opportunity to evaluate imaging data for intracranial haemorrhage. Because the ICD coding system for traumatic intracranial haemorrhage reportedly has high sensitivity and specificity (both >80%),59 we adopted this coding outcome as the study’s primary endpoint. Another important limitation was the definition of mild TBI, which affected most patients in this study. The definitions offered by several authorities range from conventional GCS-based criteria such as the US Centers for Disease Control and Prevention,61 and the American College of Surgeons62 to additional symptoms of confusion, memory impairment, transient loss of consciousness, and irritability proposed by the World Health Organisation and the American Congress of Rehabilitation Medicine.18 63 64 A better delineation of these symptoms would have enhanced the identification of patients with “high-risk” mild TBI; however, because these relevant symptoms were often not systematically documented in most medical records retrieved in our study, we used GCS-based criteria to reduce the overall rate of underdiagnosis. Using GOS score on discharge from hospital as a secondary study endpoint, we found that only 31 (7%) patients had unfavourable outcomes. Although statistically significant predictors for TBI were identified, the wide confidence intervals for these predictors suggest that the sample size was insufficient to draw robust conclusions. Finally, we could only retrospectively assess GOS score as a fundamental measure of functional outcome. More sensitive instruments (eg, the extended GOS or the Sport Concussion Assessment Tool65 66) might have been better for assessing the psychosocial and cognitive aspects of TBI, considering that a large proportion of mildly injured cyclists had intracranial haemorrhage.

The incidence of sports-related TBI in Hong Kong is low and cycling is the most frequently associated activity. Almost half of hospitalised recreational cyclists sustained intracranial haemorrhage. Compared with patients who had head injury because of other sports, cyclists are more likely to experience severe consequences. There is evidence that helmet use offers protection against intracranial haemorrhage and skull fracture among cyclists with mild head injury. Cycling is a safe physical activity, but further legislative measures should be introduced to promote and protect the welfare of individuals enjoying this sport.

Concept or design: PYM Woo, E Cheung.
Acquisition of data: PYM Woo, E Cheung, FWY Lau, NWS Law, CKY Mak, P Tan, B Siu, A Wong.
Analysis or interpretation of data: PYM Woo, E Cheung, CKY Mak.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This research has not been presented or published in any form prior to submission.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This study was approved by the Kowloon Central Cluster/Kowloon East Cluster research ethics committee (Ref KCC/KEC-2020-0331). All patients were treated in accordance with the Declaration of Helsinki. Informed consent was obtained from either the patient, next-of-kin, or their legal guardian.

1. Allender S, Cowburn G, Foster C. Understanding participation in sport and physical activity among children and adults: a review of qualitative studies. Health Educ Res 2006;21:826-35. Crossref

2. Warburton DE, Nicol CW, Bredin SS. Health benefits of physical activity: the evidence. CMAJ 2006;174:801-9. Crossref

3. Batty D, Thune I. Does physical activity prevent cancer? Evidence suggests protection against colon cancer and probably breast cancer. BMJ 2000;321:1424-5. Crossref

4. Batty GD, Lee IM. Physical activity and coronary heart disease. BMJ 2004;328:1089-90. Crossref

5. Aune D, Norat T, Leitzmann M, Tonstad S, Vatten LJ. Physical activity and the risk of type 2 diabetes: a systematic review and dose–response meta-analysis. Eur J Epidemiol 2015;30:529-42. Crossref

6. Liu X, Zhang D, Liu Y, et al. Dose-response association between physical activity and incident hypertension: a systematic review and meta-analysis of cohort studies. Hypertension 2017;69:813-20. Crossref

7. Malm C, Jakobsson J, Isaksson A. Physical activity and sports-real health benefits: a review with insight into the Public Health of Sweden. Sports (Basel) 2019;7:127. Crossref

8. Puckett M, Neri A, Underwood JM, Stewart SL. Nutrition and physical activity strategies for cancer prevention in current national comprehensive cancer control program plans. J Community Health 2016;41:1013-20. Crossref

9. Department of Health, Hong Kong SAR Government. Towards 2025: strategy and action plan to prevent and control non-communicable diseases in Hong Kong. 2018 Available from: https://www.chp.gov.hk/files/pdf/saptowards2025_fullreport_en.pdf. Accessed 2 Aug 2020.

10. Theadom A, Starkey NJ, Dowell T, et al. Sports-related brain injury in the general population: an epidemiological study. J Sci Med Sport 2014;17:591-6. Crossref

11. Manley G, Gardner AJ, Schneider KJ, et al. A systematic review of potential long-term effects of sport-related concussion. Br J Sports Med 2017;51:969-77. Crossref

12. Theadom A, Mahon S, Hume P, et al. Incidence of sports-related traumatic brain injury of all severities: a systematic review. Neuroepidemiology 2020;54:192-9. Crossref

13. Daneshvar DH, Nowinski CJ, McKee AC, Cantu RC. The epidemiology of sport-related concussion. Clin Sports Med 2011;30:1-17. Crossref

14. Selassie AW, Wilson DA, Pickelsimer EE, Voronca DC, Williams NR, Edwards JC. Incidence of sport-related traumatic brain injury and risk factors of severity: a population-based epidemiologic study. Ann Epidemiol 2013;23:750-6. Crossref

15. Transport Department, Hong Kong SAR Government. Cycling study. 2004. Available from: https://www.td.gov.hk/filemanager/en/publication/cyclingstudy.pdf. Accessed 22 Aug 2020.

16. Transport Department. Hong Kong SAR Government. Travel Characteristics Survey 2011 Final Report. Available from: https://www.td.gov.hk/filemanager/en/content_4652/tcs2011_eng.pdf. Accessed 22 Aug 2020.

17. Xu P, Dong N, Wong SC, Huang H. Cyclists injured in traffic crashes in Hong Kong: a call for action. PLoS One 2019;14:e0220785. Crossref

18. Servadei F, Teasdale G, Merry G, Neurotraumatology Committee of the World Federation of Neurosurgical Societies. Defining acute mild head injury in adults: a proposal based on prognostic factors, diagnosis, and management. J Neurotrauma 2001;18:657-64. Crossref

19. Huang WY, Wong SH, Sit CH, et al. Results from the Hong Kong’s 2018 report card on physical activity for children and youth. J Exerc Sci Fit 2019;17:14-9. Crossref

20. Harris AW, Jones CA, Rowe BH, Voaklander DC. A population-based study of sport and recreation-related head injuries treated in a Canadian health region. J Sci Med Sport 2012;15:298-304. Crossref

21. Beck AJ, Kee J. The epidemiology of sports head injuries in a rural population. Br J Sports Med 2011;45:A20. Crossref

22. Transport Department, Hong Kong SAR Government. Road Traffic Accident Statistics. Year 2019. Road traffic accidents involving bicycle by location and severity 2019. Available from: https://www.td.gov.hk/en/road_safety/road_traffic_accident_statistics/2019/index.html. Accessed 9 Aug 2020.

23. Lee LL, Yeung KL, Chan JT, Chen RC. A profile of bicycle-related injuries in Tai Po. Hong Kong J Emerg Med 2003;10:81-7.Crossref

24. Yeung JH, Leung CS, Poon WS, Cheung NK, Graham CA, Rainer TH. Bicycle related injuries presenting to a trauma centre in Hong Kong. Injury 2009;40:555-9. Crossref

25. Ng CP, Siu AY, Chung CH. Bicycle-related injuries: a local scene. Hong Kong J Emerg Med 2001;8:78-83. Crossref

26. Sze NN, Tsui KL, Wong SC, So FL. Bicycle-related crashes in Hong Kong: is it possible to reduce mortality and severe injury in the metropolitan area? Hong Kong J Emerg Med 2011;18:136-43. Crossref

27. Rivara FP, Thompson DC, Thompson RS. Epidemiology of bicycle injuries and risk factors for serious injury. Inj Prev 1997;3:110-4. Crossref

28. Transport Department, Hong Kong SAR Government. Be a smart cyclist. Wear bicycle helmet always. 2020. Available from: https://www.td.gov.hk/filemanager/en/content_4551/221201047_leaflet_a.pdf. Accessed 21 Aug 2020.

29. Attewell RG, Glase K, McFadden M. Bicycle helmet efficacy: a meta-analysis. Accid Anal Prev 2001;33:345-52. Crossref

30. Maimaris C, Summers CL, Browning C, Palmer CR. Injury patterns in cyclists attending an accident and emergency department: a comparison of helmet wearers and non-wearers. BMJ 1994;308:1537-40. Crossref

31. McDermott FT, Lane JC, Brazenor GA, Debney EA. The effectiveness of bicyclist helmets: a study of 1710 casualties. J Trauma 1993;34:834-44. Crossref

32. Thomas S, Acton C, Nixon J, Battistutta D, Pitt WR, Clark R. Effectiveness of bicycle helmets in preventing head injury in children: case-control study. BMJ 1994;308:173-6. Crossref

33. Thompson DC, Rivara FP, Thompson RS. Effectiveness of bicycle safety helmets in preventing head injuries. A case-control study. JAMA 1996;276:1968-73. Crossref

34. Thompson RS, Rivara FP, Thompson DC. A case-control study of the effectiveness of bicycle safety helmets. N Engl J Med 1989;320:1361-7. Crossref

35. Strotmeyer SJ, Behr C, Fabio A, Gaines BA. Bike helmets prevent pediatric head injury in serious bicycle crashes with motor vehicles. Inj Epidemiol 2020;7(Suppl 1):24. Crossref

36. Sethi M, Heidenberg J, Wall SP, et al. Bicycle helmets are highly protective against traumatic brain injury within a dense urban setting. Injury 2015;46:2483-90. Crossref

37. Persaud N, Coleman E, Zwolakowski D, Lauwers B, Cass D. Nonuse of bicycle helmets and risk of fatal head injury: a proportional mortality, case-control study. CMAJ 2012;184:E921-3. Crossref

38. Thompson DC, Rivara FP, Thompson R. Helmets for preventing head and facial injuries in bicyclists. Cochrane Database Syst Rev 2000;1999(2):CD001855. Crossref

39. Robinson DL. No clear evidence from countries that have enforced the wearing of helmets. BMJ 2006;332:722-5. Crossref

40. Hong Kong Cycling Alliance. Helmets. Available from: http://hkcyclingalliance.org/on-the-road/helmets. Accessed 21 Aug 2020.

41. Bateman-House A. Bikes, helmets, and public health: decision-making when goods collide. Am J Public Health 2014;104:986-92. Crossref

42. Goldacre B, Spiegelhalter D. Bicycle helmets and the law. BMJ 2013;346:f3817. Crossref

43. Rivara FP, Thompson DC, Patterson MQ, Thompson RS. Prevention of bicycle-related injuries: helmets, education, and legislation. Annu Rev Public Health 1998;19:293-318. Crossref

44. Olivier J, Boufous S, Grzebieta R. The impact of bicycle helmet legislation on cycling fatalities in Australia. Int J Epidemiol 2019;48:1197-203. Crossref

45. Tin Tin S, Woodward A, Ameratunga S. Injuries to pedal cyclists on New Zealand roads, 1988-2007. BMC Public Health 2010;10:655. Crossref

46. Meehan WP 3rd, Lee LK, Fischer CM, Mannix RC. Bicycle helmet laws are associated with a lower fatality rate from bicycle-motor vehicle collisions. J Pediatr 2013;163:726-9. Crossref

47. Macpherson A, Spinks A. Bicycle helmet legislation for the uptake of helmet use and prevention of head injuries. Cochrane Database Syst Rev 2008;2008(3):CD005401. Crossref

48. World Health Organisation. Why are helmets needed? 2006. Available from: https://www.who.int/roadsafety/projects/manuals/helmet_manual/1-Why.pdf. Accessed 13 Oct 2021.

49. British Medical Association. Healthy transport=healthy lives. 2012. Available from: https://thepep.unece.org/sites/default/files/2017-06/Healthy%20transport%20healthy%20lives%20Britsh%20Medical%20Association.pdf. Accessed 13 Oct 2021.

50. American Medical Association. Helmets for riders of motorized and non-motorized cycles H-10.964. Available from: https://policysearch.ama-assn.org/policyfinder/detail/bicycle helmets?uri=%2FAMADoc%2FHOD.xml-0-3.xml. Accessed 20 Sep 2021.

51. McDermott FT. Helmet efficacy in the prevention of bicyclist head injuries: Royal Australasian College of Surgeons initiatives in the introduction of compulsory safety helmet wearing in Victoria, Australia. World J Surg 1992;16:379-83. Crossref

52. Gamble T, Walker I. Wearing a bicycle helmet can increase risk taking and sensation seeking in adults. Psychol Sci 2016;27:289-94. Crossref

53. Walker I. Drivers overtaking bicyclists: objective data on the effects of riding position, helmet use, vehicle type and apparent gender. Accid Anal Prev 2007;39:417-25. Crossref

54. Hooper C, Spicer J. Liberty or death; don’t tread on me. J Med Ethics 2012;38:338-41. Crossref

55. Theadom A, Barker-Collo S, Feigin VL, et al. The spectrum captured: a methodological approach to studying incidence and outcomes of traumatic brain injury on a population level. Neuroepidemiology 2012;38:18-29. Crossref

56. Delaney JS, Lamfookon C, Bloom GA, Al-Kashmiri A, Correa JA. Why university athletes choose not to reveal their concussion symptoms during a practice or game. Clin J Sport Med 2015;25:113-25. Crossref

57. Meehan WP 3rd, Mannix RC, O’Brien MJ, Collins MW. The prevalence of undiagnosed concussions in athletes. Clin J Sport Med 2013;23:339-42. Crossref

58. van Walraven C, Bennett C, Forster AJ. Administrative database research infrequently used validated diagnostic or procedural codes. J Clin Epidemiol 2011;64:1054-9. Crossref

59. Carroll CP, Cochran JA, Guse CE, Wang MC. Are we underestimating the burden of traumatic brain injury? Surveillance of severe traumatic brain injury using Centers for Disease Control International Classification of Disease, Ninth Revision, Clinical Modification, traumatic brain injury codes. Neurosurgery 2012;71:1064-70. Crossref

60. Barker-Collo S, Theadom A, Jones K, Feigin VL, Kahan M. Accuracy of an International Classification of Diseases Code Surveillance System in the identification of traumatic brain injury. Neuroepidemiology 2016;47:46-52. Crossref

61. Centers for Disease Control and Prevention. Glasgow Coma Scale. Available from: https://www.cdc.gov/masstrauma/resources/gcs.pdf. Accessed 20 Sep 2021.

62. American College of Surgeons. Best practices in the management of traumatic brain injury. Available from: https://www.facs.org/-/media/files/quality-programs/trauma/tqip/tbi_guidelines.ashx. Accessed 20 Sep 2021.

63. Carroll LJ, Cassidy JD, Holm L, Kraus J, Coronado VG, WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. Methodological issues and research recommendations for mild traumatic brain injury: the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med 2004;(43 Suppl):113-25. Crossref

64. Kay T, Harrington DE, Adams R, et al. Definition of mild traumatic brain injury. J Head Trauma Rehabil 1993;8:86-7. Crossref

65. Kean J, Malec JF. Towards a better measure of brain injury outcome: new measures or a new metric? Arch Phys Med Rehabil 2014;95:1225-8. Crossref

66. McCrory P, Meeuwisse WH, Aubry M, et al. Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport, Zurich, November 2012. J Athl Train 2013;48:554-75. Crossref

Klebsiella pneumonia causes various clinically important infections. In 2017, K pneumoniae was the third most common isolate in intensive care units (ICUs) and second most common isolate in all patients in the Hong Kong East Cluster.1

The emergence of multidrug-resistant K pneumoniae infections is an increasing concern.2 There have been outbreaks of extended-spectrum beta-lactamase (ESBL)–producing strains, carbapenem-resistant (CR) and carbapenemase-producing (CP) strains, and hypervirulent K pneumoniae infections both in Hong Kong and worldwide.2 3 4 In Greece and Italy, CP K pneumoniae comprises 68.3% of all K pneumoniae strains.5

The importance of appropriate early empirical antibiotics has been repeatedly emphasised in the management of septic shock by the Surviving Sepsis Campaign 2016.6 Previously, we highlighted the importance of appropriate early antibiotics for successful patient outcomes.4 To the best of our knowledge, risk factors for receiving inappropriate empirical antibiotics have not yet been explored. Therefore, in the present study, we aimed to evaluate the impact of appropriate empirical antibiotics on outcomes in patients with K pneumoniae bacteraemia; we also performed subgroup analysis on ICU patients with K pneumoniae bacteraemia.

We conducted a retrospective analysis of adult patients with K pneumoniae bacteraemia who were admitted to Pamela Youde Nethersole Eastern Hospital within the period from 1 January 2009 to 30 June 2017. Pamela Youde Nethersole Eastern Hospital is a 1700-bed hospital in Hong Kong which provides extensive services except cardiothoracic surgery, transplant surgery, and burns. Patients were excluded if they were aged <18 years or had incomplete information. Patient medical records were reviewed, as were data in clinical management and clinical information systems (IntelliVue Clinical Information Portfolio; Philips Medical, Amsterdam, The Netherlands). The clinical management system is a database that stores patients’ demographics, laboratory results, and drug administration records for all public hospitals in Hong Kong. In the event of missing data, medical records were reviewed manually. Baseline demographics, clinical characteristics, and microbiological data for all included patients were identified from the above databases and medical records.

Disease severity was quantified using the maximum Sequential Organ Failure Assessment (SOFA) score.7 The following clinical outcome data were investigated: use of invasive organ supports (eg, inotropic use, mechanical ventilation, and renal replacement therapies), ICU and hospital lengths of stay (LOSs), ICU ventilator duration, and mortality. The primary outcome was 90-day all-cause mortality; secondary outcomes were ICU and hospital mortalities, ICU and hospital LOSs, and ICU ventilator duration.

Klebsiella pneumoniae bacteraemia was defined as the growth of K pneumoniae in one or more blood cultures. If more than one positive blood culture result was recorded, only the first sample was included. Empirical antibiotic treatment was defined as the antibiotic used within 24 hours after a culture sample was collected. The empirical antibiotic treatment was considered appropriate if at least one of the antibiotic agents was consistent with the in vitro susceptibility results.8 9 10 Community-acquired infection was defined as K pneumoniae identified in patients upon admission or within 48 hours after admission; hospital-acquired infection was defined as K pneumoniae identified in patients at >48 hours after admission.11 Hepatobiliary sepsis comprised liver abscess, cholangitis, and cholecystitis; gastrointestinal sepsis comprised spontaneous bacterial peritonitis, peritonitis caused by bowel perforation, and intra-abdominal abscesses (excluding liver abscess). Medical co-morbidities (eg, diabetes mellitus, cirrhosis, congestive heart failure, chronic renal impairment, haematological malignancy and solid tumour) were defined in accordance with the International Classification of Disease coding. Prior steroid use was defined as oral or intravenous steroid consumption within 30 days before the index positive blood culture result. Chemotherapy use was defined as oral or intravenous infusion of biological agents or chemotherapy administered within 30 days before the index positive blood culture result. Any antibiotics usage within 30 days before the index hospital admission was regarded as prior antibiotics usage.

Blood cultures were incubated and processed. Blood culture results were considered negative if no positive growth occurred after 5 to 7 days. Susceptibility interpretation was based on Clinical and Laboratory Standards Institute interpretive criteria. The ESBL testing was based on Clinical and Laboratory Standards Institute testing criteria12 13 14 15 16 17 18 or the double-disk synergy test described by Jarlier et al.19 Regarding CR K pneumoniae, the isolates were sent to the Public Health Laboratory Centre of Hong Kong if further genetic testing was required to confirm carbapenemase production. Multiplex real-time polymerase chain reaction assays were performed to detect Classes A, B, and D carbapenemase gene targets.

We compared the characteristics and clinical parameters between patients treated with appropriate and inappropriate empirical antibiotics, as well as between 90-day survivors and non-survivors. Results are expressed as the median ± interquartile range (IQR) or as the number (percentage) of patients, as appropriate.

Categorical variables were compared by the Pearson Chi squared test or Fisher’s exact test, as appropriate for univariate analysis. Continuous variables were compared by using the Mann–Whitney U test. Variables with P<0.2 in univariate analysis or with clinical significance from previous studies were included in the multivariate analysis. Independent predictors for 90-day mortality were assessed by Cox regression analysis. Logistic regression analysis was used to assess independent predictors for receiving appropriate and inappropriate empirical antibiotics. Post hoc analysis was performed for patients with chronic renal failure and resistant organisms.

The Statistical Package for Social Sciences (Windows version 24.0; IBM Corp, Armonk [NY], US) was used to perform statistical analyses.

During the 8.5-year study period, we identified 984 patients with K pneumoniae bacteraemia; of these, 686 (69.7%) and 298 (30.3%) received appropriate and inappropriate empirical antibiotics, respectively. Table 1 shows the baseline demographics of patients who received appropriate and inappropriate empirical antibiotics. The median patient age was 75 years (IQR=63-83 years). The most common types of infection were hepatobiliary tract infection (33.1%), urosepsis (24.4%), and respiratory tract infection (18.4%). The overall 90-day mortality was 32.7%, hospital mortality was 22.5%, and median hospital LOS was 10.68 days (5.38-22.81 days, P<0.001).

Univariate analysis (Table 1) revealed that the risk factors for receiving inappropriate empirical antibiotics were age >65 years (P=0.044), chronic renal impairment (P<0.001), respiratory tract infection (P=0.002), mechanical ventilation (P=0.001), CR or ESBL-producing isolates (both P<0.001), and higher total SOFA score (P=0.048). Hepatobiliary sepsis was associated with a higher rate of appropriate empirical antibiotic treatment (P=0.009).

Table 2 demonstrates the logistic regression analysis of the predictors for the appropriateness of empirical antibiotics for all patients and ICU subgroup. These include older patients (P=0.010), chronic kidney disease (P=0.007), mechanical ventilation (P=0.005), respiratory tract infection (P=0.034), and either carbapenem resistance or ESBL production (P<0.001). Table 1 shows that the 90-day and hospital mortalities were significantly higher in patients with inappropriate empirical treatment (both P<0.001). Moreover, the hospital LOS was shorter in patients who received inappropriate empirical antibiotics (P<0.001).

Receipt of inappropriate empirical antibiotics was associated with higher hospital mortality; this finding was consistent in ICU subgroup (56% vs 23%). The absolute risk increases in mortality associated with the receipt of inappropriate empirical antibiotics were 18.3% and 33% in ICU subgroup. The number of inappropriate empirical antibiotics associated with each mortality was five in the ICU subgroup and three in all patients.

Antibiograms showing the proportions of non-susceptible K pneumoniae isolates are described in the Online Supplementary Table 1. Twenty (2.0%) patients had CR K pneumoniae bacteraemia, but molecular tests in the Public Health Laboratory Centre of Hong Kong revealed that none of them had CP strains. Overall, 113 (11.5%) patients had ESBL-producing infections.

Post hoc analysis revealed that patients with chronic renal failure were more likely to have ESBL infections (18.3% vs 10.5%; P=0.011) and CR infections (0.056% vs 0.015%; P=0.003).

The 90-day all-cause mortalities were 32.7% in all patients with K pneumoniae bacteraemia and 34.6% in the ICU subgroup. Univariate analysis (Table 3) showed that 90-day non-survivors were more likely to be aged >65 years (P<0.001), admitted through the Department of Medicine (P<0.001), have septic shock (P=0.005), have a higher total SOFA score (P<0.001), receive inappropriate or no empirical antibiotics (P<0.001 and P<0.001, respectively), have solid tumour (P<0.001), have respiratory tract infection (P<0.001), be mechanically ventilated (P<0.001), have gastrointestinal infections (P<0.001), and require renal replacement therapy (P=0.044). Patients with diabetes (P=0.001), hepatobiliary sepsis (P<0.001), and urosepsis (P<0.001) had lower 90-day mortalities.

Table 4 shows the Cox regression analysis of predictors for 90-day mortality. Independent predictors for increased 90-day mortality were respiratory tract infection (P<0.001), gastrointestinal infection (P<0.001), inappropriate empirical antibiotics (P<0.001), older age (P<0.001), solid tumour (P<0.001), patients admitted through the Department of Medicine (P=0.012), and higher total SOFA score (P<0.001). Patients with diabetes had lower 90-day mortality (P=0.001). The Figure shows the Kaplan–Meier survival plot and according to log rank analysis, the results demonstrated a statistically significant improvement in survival among patients who received appropriate empirical antibiotics (P<0.001).

Online Supplementary Table 2 shows the demographics for inappropriate empirical antibiotics by logistic regression analysis in ICU subgroup. Overall, 205 (20.8%) patients required intensive care; among them, 148 (72.2%) received appropriate empirical antibiotics, while 57 (27.8%) received inappropriate or no empirical antibiotics. The median patient age was 68 years (IQR=58-78 years). The commonest infection was hepatobiliary infections (42.9%), followed by respiratory tract (23.4%) and urosepsis (14.6%). Furthermore, 82.4% of the patients had septic shock, 33.2% received renal replacement therapy, 60% received mechanical ventilation, and 78.5% had vasopressor use. The ICU and overall 90-day mortalities were 18.5% and 34.6%, respectively. The receipt of inappropriate empirical antibiotics was significantly associated with higher 90-day mortality (59.6% vs 25.0%; P<0.001), higher ICU mortality (35.1% vs 12.2%; P<0.001), higher hospital mortality (56.1% vs 23.0%; P<0.001), and longer ventilator duration (2 d vs 1 d, P=0.026).

Cox regression analysis showed that the receipt of inappropriate or no empirical antibiotics (P<0.001; Table 4) was the strongest independent predictor of 90-day mortality in critically ill patients with K pneumoniae bacteraemia. Other independent predictors were congestive heart failure (P=0.02), admitted through the Department of Medicine (P=0.016), and a higher total SOFA score (P<0.001). Ninety-day non-survivors had longer hospital LOS (P<0.001).

Among all patients in this study, 686 (69.7%) received appropriate empirical antibiotics. Furthermore, 148 (72.2%) critically ill patients received appropriate empirical antibiotics. Importantly, 93 (9.5%) patients did not receive any empirical antibiotics. The median hospital LOS for these 93 patients was significantly shorter than the LOS for all patients in the study. We performed event-free survival analysis and found that the LOSs were similar in both groups; these findings suggested that patients who received inappropriate antibiotics had more severe disease and earlier death, leading to a shorter hospital LOS.

Micek et al20 found that prior antibiotic exposure was a risk factor for inappropriate empirical therapy. Lautenbach et al21 described a positive correlation between the total cumulative dose of antibiotics and ESBL K pneumoniae infection. In our cohort, prior antibiotics exposure was not significantly correlated with inappropriate empirical antibiotic treatment; furthermore, prior antibiotics exposure was not associated with ESBL infections. We examined the presence of prior antibiotics use 30 days prior to positive blood culture results, but information regarding the total cumulative antibiotics exposure in terms of dosing and duration were not available. Other information was unavailable regarding antibiotics prescribed outside hospital settings.

Patients with chronic renal failure are reportedly more prone to developing resistant infections.22 They were at greater risk of receiving inappropriate antibiotics. Additionally, hospital-acquired infection has been associated with a higher rate of inappropriate empirical antibiotic treatment and higher 90-day mortality.11

The rates of CR and CP K pneumoniae bacteraemia were much lower than the rates reported in other endemic countries.5 A study from Shanghai reported that approximately 22% of all patients with K pneumoniae bacteraemia had CR infections; moreover, approximately 59% of the isolates were CR infections in patients who required intensive care.23

The prevalence of ESBL K pneumoniae bacteraemia in Hong Kong is low.4 The ESBL infection rate in our cohort was 11.5%, similar to previous local studies.1 24 Another study in China demonstrated a much higher rate of ESBL infections (approximately 39%).25 Both ESBL and CR infections were not associated with increased mortality in our study in either the overall patient population or the ICU subgroup. However, ESBL and CR infections were significantly associated with longer hospital LOS.

The antibiotics sensitivity in our cohorts was comparable with the antibiogram data in the IMPACT guideline.1 Ampicillin-sulbactam or amoxicillin-clavulanate is recommended as the drug of choice for treatment of K pneumomiae infections in local guidelines.1 In our cohort, more than 80% of K pneumomiae isolates were susceptible to amoxicillin-clavulanate, indicating that it is a reasonable option for broad empirical coverage. Add-on therapy with aminoglycoside improves the coverage of this regimen, because more than 90% of the isolates in our cohort were sensitive to either gentamicin or amikacin. While combination therapy improves the chance of successful empirical therapy, routine use of combination therapy remains controversial.6

The 90-day all-cause mortalities in our study were comparable with the findings in previous studies.24 26 Respiratory tract infections and gastrointestinal infections have consistently been associated with a worse outcome and greater mortality.27 28 In contrast, urosepsis and hepatobiliary sepsis have repeatedly associated with better survival outcomes.29 These sources of infections may be amendable to percutaneous, endoscopic, or surgical drainage, allowing more rapid and definitive control of sepsis, which leads to better survival.28

A greater proportion of patients with respiratory tract infection did not receive any empirical antibiotics, which might explain the worse outcomes in these patients. The symptoms and signs of respiratory tract infection may overlap with other diseases (eg, heart failure) and treatment may be delayed while waiting for laboratory results and imaging. Given the greater proportion of patients with respiratory tract infections who did not receive any empirical antibiotics, there is a need for early consideration of empirical antibiotics in patients with signs and symptoms of respiratory tract infections.

Consistent with the findings of previous studies, we found that older age, solid tumour, and admission through the Department of Medicine were factors associated with higher 90-day mortality.30 31 Patients with these factors were more likely to have other pre-existing co-morbidities, worse premorbid functional status, and be institutionalised. They may also have received a more conservative approach to treatment overall.

Diabetes mellitus is well-known to predispose patients to infections, such that affected patients are reportedly 4.4-fold more likely to develop bloodstream infection.32 Similar to the findings by Peralta et al,32 we did not find increased mortality among patients with diabetes. In our cohort, diabetic patients were more likely to had urosepsis than respiratory tract infections. Greater frequency of urosepsis and smaller frequency of respiratory tract infection may have an overall positive effect on survival. Moreover, advances in diabetes care in recent decades (eg, newer generations of medication and integrated multidisciplinary care) have led to neutral effects of diabetes on short-term mortality in patients undergoing major operations and patients with sepsis.34 34 35 Glycaemic status, haemoglobin A1c levels, and diabetes severity were not available in the present study; thus, we could not delineate how diabetes control affected bacteraemia outcomes. Our results are limited to demonstrating that 90-day mortality and diabetes have a greater impact on long-term survival, although this conclusion may not be apparent in the current study.33

In addition to mortality, we demonstrated that the inappropriate use of empirical antibiotics was associated with longer ICU ventilator duration, which leads to greater costs and more extensive use of ICU resources. A large retrospective cohort from the US regarding Enterobacteriaceae infections showed that each additional day without appropriate antibiotics was associated with an increased hospital expenditure of US$750 and an increased risk of 30-day readmission.36

To the best of our knowledge, the appropriateness of empirical antibiotics has consistently been identified as one of the strongest independent predictors of 90-day mortality in all affected patients and in critically ill patients.37 38 39 Kumar et al8 demonstrated a fivefold increase in mortality among patients with sepsis who received inappropriate initial antibiotics. In this study, we demonstrated a twofold increase in mortality in all patients with K pneumoniae bacteraemia, as well as a threefold increase in mortality in critically ill patients with K pneumoniae bacteraemia. Furthermore, receipt of inappropriate initial antibiotics was the strongest independent predictor of 90-day mortality in the ICU subgroup. Zilberberg et al40 found that the detrimental effect of inappropriate empirical antibiotic treatment could not be corrected despite subsequent targeted antibiotic treatments. A meta-analysis revealed a slower rate of bacterial clearance and increased treatment failure rate when patients were administered inappropriate empirical antibiotic therapy.41 Appropriate early antibiotics allow rapid reduction of bacterial load and modulate host defences, thus alleviating some organ dysfunction.42 A more pragmatic approach would be the early administration of broader-spectrum empirical antibiotics and timely de-escalation, according to bacterial sensitivity and the patient’s clinical progression.

The chain of sepsis management begins during the first encounter in the Emergency Department and in general hospital wards, rather than in the ICU. Early administration of antibiotics within 3 hours of hospital admission and aggressive sepsis care (beginning in the Emergency Department) can improve survival.42 Another prospective observational study demonstrated that the adequate use of empirical antibiotics prior to ICU admission was the strongest independent factor associated with survival.29 Extensive efforts are needed to facilitate early, appropriate use of empirical antibiotics, including the use of a current antibiogram, implementation of multidisciplinary sepsis management guidelines, and establishment of protocols among pharmacists, microbiologists, clinicians, and nurses.

To the best of our knowledge, this is the largest study of K pneumoniae bacteraemia in Hong Kong and in the Asia-Pacific region. By including both ICU and general ward patients, we achieved clarity regarding the diverse characteristics of K pneumoniae bacteraemia. We also identified many potential predictors of K pneumoniae bacteraemia–related mortality, based on our extensive literature review and previous publications, then tested these predictors using real-world patient data. By evaluating 90-day mortality, hospital LOS, and ventilator duration, our study more comprehensively evaluated immediate and longer-term complications of bacteraemia; it also provided information for future studies of cost-effectiveness in terms of empirical antibiotics and resource utilisation. Finally, we used the maximum total SOFA score for severity assessment. This score has been repeatedly validated in determining disease severity and predicting mortality in critically ill patients.43 44 45

This retrospective study was subject to potential confounding factors, including selection bias that could not be completely eliminated from the analysis. Notably, the results of this single-centre study may not be generalisable to other countries with higher CR or CP K pneumoniae infections. Furthermore, this study encompassed a long duration, in which the definitions of sepsis or septic shock might have changed.45 The care of patients with sepsis evolved over time, including advances in source control by percutaneous and endoscopic means that potentially improved patient survival. Nonetheless, the role of empirical antibiotics in patients with sepsis remains an essential sepsis consideration.

Antibiotic pharmacodynamics also has a fundamental role in bacteraemia treatment. In this study, we could not collect information regarding the timing of first-dose antibiotics, time to appropriate antibiotics, duration of antibiotics, or time to surgical treatments. Moreover, antibiotic stewardship and therapeutic de-escalation efforts, as well as their impacts on patient outcomes, were not assessed in the present study. Future studies may be needed concerning the prolonged infusion of beta-lactam antibiotics, use of combination therapies, duration of antibiotics, and serum monitoring of antibiotics.

The receipt of inappropriate empirical antibiotics led to twofold greater 90-day mortality in patients with K pneumoniae bacteraemia. In critically ill patients, inappropriate use of empirical antibiotics was the strongest independent predictor of mortality. Early identification of high-risk patients and administration of appropriate empirical antibiotics can improve patient outcomes.

Concept or design: MY Man, HP Shum.
Acquisition of data: MY Man, HP Shum.
Analysis or interpretation of data: MY Man, HP Shum.
Drafting of the manuscript: MY Man.
Critical revision of the manuscript for important intellectual content: WW Yan.

All authors read and approved the final manuscript. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This research was presented by KC Li as an abstract at the 31st Annual Congress of the European Society of Intensive Care Medicine (ESICM), 21-24 October 2018, Paris, France.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This study was approved by the Hong Kong Easter Cluster Ethics Committee of the Hospital Authority (HKECREC-2018-018). The requirement for written informed consent was waived because of the retrospective nature of the study.

1. Ho PL, Wu TC, Chao DV, et al, editors. Reducing bacterial resistance with IMPACT. Interhospital multi-disciplinary programme on antimicrobial chemotherapy. 5th edition. 2017. Available from: https://www.chp.gov.hk/files/pdf/reducing_bacterial_resistance_with_impact.pdf. Accessed 7 Jun 2020.

2. Ben-David D, Kordevani R, Keller N, et al. Outcome of carbapenem resistant Klebsiella pneumoniae bloodstream infections. Clin Microbiol Infect 2012;18:54-60. Crossref

3. Wong MH, Shum HP, Chen JH, et al. Emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae. Lancet Infect Dis 2018;18:24. Crossref

4. Man MY, Shum HP, Chan YH, et al. Clinical predictors and outcomes of Klebsiella pneumoniae bacteraemia in a regional hospital in Hong Kong. J Hosp Infect 2017;97:35-41.Crossref

5. Alicino C, Giacobbe DR, Orsi A, et al. Trends in the annual incidence of carbapenem-resistant Klebsiella pneumoniae bloodstream infections: a 8-year retrospective study in a large teaching hospital in northern Italy. BMC Infect Dis 2015;15:415. Crossref

6. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017;43:304-77.Crossref

7. Ferreira FL, Bota DP, Bross A, Mélot C, Vincent JL. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 2001;286:1754-8. Crossref

8. Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009;136:1237-48. Crossref

9. Vazquez-Guillamet C, Scolari M, Zilberberg MD, Shorr AF, Micek ST, Kollef M. Using the number needed to treat to assess appropriate antimicrobial therapy as a determinant of outcome in severe sepsis and septic shock. Crit Care Med 2014;42:2342-9. Crossref

10. Micek ST, Welch EC, Khan J, et al. Empiric combination antibiotic therapy is associated with improved outcome against sepsis due to Gram-negative bacteria: a retrospective analysis. Antimicrob Agents Chemother 2010;54:1742-8. Crossref

11. Juan CH, Chuang C, Chen CH, Li L, Lin YT. Clinical characteristics, antimicrobial resistance and capsular types of community-acquired, healthcare-associated, and nosocomial Klebsiella pneumoniae bacteremia. Antimicrob Resist Infect Control 2019;8:1. Crossref

12. Clinical and Laboratory Standards Institute. M100-S16 Performance Standards for Antimicrobial Susceptibility Testing; Sixteenth Informational Supplement. Clinical and Laboratory Standards Institute, Wayne, PA; January 2006.

13. Clinical and Laboratory Standards Institute. M100-S17 Performance Standards for antimicrobial susceptibility testing; Seventeenth Informational Supplement. Clinical and Laboratory Standards Institute, Wayne, PA; January 2007.

14. Clinical and Laboratory Standards Institute. M100-S19 Performance Standards for antimicrobial susceptibility testing; Nineteenth Informational Supplement. Clinical and Laboratory Standards Institute, Wayne, PA; January 2009.

15. Clinical and Laboratory Standards Institute. M100-S20 Performance Standards for Antimicrobial Susceptibility Testing; Twentieth Informational Supplement. Clinical and Laboratory Standards Institute, Wayne, PA; January 2010.

16. Clinical and Laboratory Standards Institute. M100-S23 Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Third Informational Supplement. Clinical and Laboratory Standards Institute, Wayne, PA; January 2013.

17. Clinical and Laboratory Standards Institute. M100-S25 Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Fifth Informational Supplement. Clinical and Laboratory Standards Institute, Wayne, PA; January 2015.

18. Clinical and Laboratory Standards Institute. M100-S26 Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Sixth Informational Supplement. Clinical and Laboratory Standards Institute, Wayne, PA; January 2016.

19. Jarlier V, Nicolas MH, Fournier G, Philippon A. Extended broad-spectrum beta-lactamases conferring transferable resistance to newer beta-lactam agents in Enterobacteriaceae: hospital prevalence and susceptibility patterns. Rev Infect Dis 1988;10:867-78. Crossref

20. Micek ST, Hampton N, Kollef M. Risk factors and outcomes for ineffective empiric treatment of sepsis caused by Gram-negative pathogens: stratification by onset of infection. Antimicrob Agents Chemother 2017;62:e01577-17.

21. Lautenbach E, Patel JB, Bilker WB, Edelstein PH, Fishman NO. Extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes. Clin Infect Dis 2001;32:1162-71. Crossref

22. Eilertson B, Cober E, Richter SS, et al. Carbapenem-resistant Enterobacteriaceae infections in patients on renal replacement therapy. Open Forum Infect Dis 2017;4:ofx216.

23. Tian L, Tan R, Chen Y, et al. Epidemiology of Klebsiella pneumoniae bloodstream infections in a teaching hospital: factors related to the carbapenem resistance and patient mortality. Antimicrob Resist Infect Control 2016;5:48. Crossref

24. Pau CK, Ma FF, Ip M, You JH. Characteristics and outcomes of Klebsiella pneumoniae bacteraemia in Hong Kong. Infect Dis (Lond) 2015;47:283-8. Crossref

25. Li L, Huang H. Risk factors of mortality in bloodstream infections caused by Klebsiella pneumonia: a singlecenter retrospective study in China. Medicine (Baltimore) 2017;96:e7924.

26. Melot B, Colot J, Guerrier G. Bacteremic community-acquired infections due to Klebsiella pneumoniae: clinical and microbiological presentation in New Caledonia, 2008-2013. Int J Infect Dis 2015;41:29-31. Crossref

27. Russo A, Falcone M, Gutiérrez-Gutiérrez B, et al. Predictors of outcome in patients with severe sepsis or septic shock due to extended-spectrum beta-lactamase-producing Enterobacteriaceae. Int J Antimicrob Agents 2018;52:577-85.Crossref

28. Zilberberg MD, Shorr AF, Micek ST, Vazquez-Guillamet C, Kollef MH. Multi-drug resistance, inappropriate initial antibiotic therapy and mortality in Gram-negative severe sepsis and septic shock: a retrospective cohort study. Crit Care 2014;18:596. Crossref

29. Garnacho-Montero J, Gutiérrez-Pizarraya A, Escoresca-Ortega A, Fernández-Delgado E, López-Sánchez JM. Adequate antibiotic therapy prior to ICU admission in patients with severe sepsis and septic shock reduces hospital mortality. Crit Care 2015;19:302. Crossref

30. Antonio M, Gudiol C, Royo-Cebrecos C, Grillo S, Ardanuy C, Carratalà J. Current etiology, clinical features and outcomes of bacteremia in older patients with solid tumors. J Geriatr Oncol 2019;10:246-51. Crossref

31. Tseng CP, Wu HS, Wu TH, Lin YT, Fung CP. Clinical characteristics and outcome of patients with community-onset Klebsiella pneumoniae bacteremia requiring intensive care. J Microbiol Immunol Infect 2013;46:217-23. Crossref

32. Peralta G, Sánchez MB, Roiz MP, Garrido JC, Teira R, Mateos F. Diabetes does not affect outcome in patients with Enterobacteriaceae bacteremia. BMC Infect Dis 2009;9:94. Crossref

33. Filsoufi F, Rahmanian PB, Castillo JG, Mechanick JI, Sharma SK, Adams DH. Diabetes is not a risk factor for hospital mortality following contemporary coronary artery bypass grafting. Interact Cardiovasc Thorac Surg 2007;6:753-8. Crossref

34. Teo BJ, Chong HC, Yeo W, Tan AH. The impact of diabetes on patient outcomes after total knee arthroplasty in an Asian population. J Arthroplasty 2018;33:3186-9. Crossref

35. Stegenga ME, Vincent JL, Vail GM, et al. Diabetes does not alter mortality or hemostatic and inflammatory responses in patients with severe sepsis. Crit Care Med 2010;38:539-45. Crossref

36. Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. 30-day readmission, antibiotics costs and costs of delay to adequate treatment of Enterobacteriaceae UTI, pneumonia, and sepsis: a retrospective cohort study. Antimicrob Resist Infect Control 2017;6:124. Crossref

37. Gutiérrez-Gutiérrez B, Salamanca E, de Cueto M, et al. Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study. Lancet Infect Dis 2017;17:726-34. Crossref

38. Cheng WL, Hsueh PR, Lee CC, et al. Bacteremic pneumonia caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: appropriateness of empirical treatment matters. J Microbiol Immunol Infect 2016;49:208-15. Crossref

39. Kohler PP, Volling C, Green K, Uleryk EM, Shah PS, McGeer A. Carbapenem resistance, initial antibiotic therapy, and mortality in Klebsiella pneumoniae bacteremia: a systematic review and meta-analysis. Infect Control Hosp Epidemiol 2017;38:1319-28. Crossref

40. Zilberberg MD, Shorr AF, Micek ST, Mody SH, Kollef MH. Antimicrobial therapy escalation and hospital mortality among patients with health-care-associated pneumonia: a single-center experience. Chest 2008;134:963-8. Crossref

41. Raman G, Avendano E, Berger S, Menon V. Appropriate initial antibiotic therapy in hospitalized patients with gram-negative infections: systematic review and meta-analysis. BMC Infect Dis 2015;15:395. Crossref

42. Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 2017;376:2235-44. Crossref

43. Moreno R, Vincent JL, Matos R, et al. The use of maximum SOFA score to quantify organ dysfunction/failure in intensive care. Results of a prospective, multicentre study. Working Group on Sepsis related Problems of the ESICM. Intensive Care Med 1999;25:686-96. Crossref

44. Minne L, Abu-Hanna A, de Jonge E. Evaluation of SOFA-based models for predicting mortality in the ICU: a systematic review. Crit Care 2008;12:R161.

45. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016;315:801-10. Crossref

Viral hepatitis is a major public health burden worldwide and is the predominant aetiology of liver cirrhosis and/or liver cancer.1 2 At least 325 million individuals were reported to be infected with viral hepatitis B (HBV) and/or C (HCV).2 3 Hong Kong is considered an endemic area with intermediate incidence of HBV infection.4 In a local epidemiological study conducted between 2015 and 2016, the seroprevalence of hepatitis B surface antigen (HBsAg) was estimated at 7.8% among the general population.5 In contrast, the prevalence rate of HCV infection in Hong Kong has remained low.6 The seroprevalence of anti-HCV positivity among new blood donors was 0.06% in 2017, compared with 0.11% in 2008.6 The local HCV prevalence among the general population between 2015 and 2016 was estimated at 0.5%,5 which has remained relatively unchanged since 1992.7

In 2016, the World Health Organization (WHO) implemented a global elimination strategy targeted to achieve at least a 90% diagnosis rate of all viral hepatitis cases, an 80% treatment rate for all diagnosed cases, and a 90% reduction in the incidence of viral hepatitis cases.3 Recent epidemiological studies in Hong Kong revealed that the diagnosis and treatment uptake rates within the community were significantly lacking, hovering around 50% compared with the WHO’s 90%/80% targets.5 8 It has been suggested that inadequate knowledge and awareness about viral hepatitis B and C within Hong Kong’s community might be driving this deficiency.5 8 9 10 In other parts of the world, social stigma arising from poor knowledge has been reported to reduce diagnosis and treatment rates among high-risk individuals.11 12 13

In 2020, the Hong Kong Viral Hepatitis Action Plan (HKVHAP) 2020-2024 was launched to facilitate achieving the WHO’s eradication target goals by 2030. The action plan outlined four major strategies: (1) Awareness, (2) Surveillance, (3) Prevention, and (4) Treatment to monitor and implement local efforts towards achieving the WHO’s 2030 elimination target.14

In the present study, we aimed to explore the knowledge, attitudes, and behaviour within Hong Kong’s general population pertaining to viral hepatitis and related risk factors. Furthermore, in this study, we sought to identify potential gaps in existing knowledge, attitudes, and behaviour related to the WHO’s global viral hepatitis elimination strategy to optimise local efforts towards the WHO’s target goal.

Potential respondents were recruited through an existing, general purpose (ie, not healthcare-specific) web-based consumer panel via email in February 2020. Respondents who were aged ≥18 years, had access to online or comfort with web-based administration, and were able to read English or traditional Chinese were eligible to participate in the study. There were no exclusion criteria for this study. All eligible respondents explicitly agreed to join the panel and provided informed online consent to participate in the study.

Assuming 95% confidence intervals and 50% response distribution, responses collected from 500 adult individuals were deemed sufficient to provide descriptive estimates with 4.33% margin of error.

Items pertaining to awareness and perceptions of liver diseases among the general public were explored using a self-administered web-based survey. The survey questionnaire was developed in English and translated into traditional Chinese. The translation was validated by a linguist from a translation company who is a native speaker of the language. The developed questionnaire was reviewed and finalised by a steering committee comprising gastroenterology and/or hepatology experts from 11 countries/territories as part of a regional liver index study (Lee Mei-hsuan et al, unpublished). All respondents completed the questionnaire in either English or Chinese. Only de-identified data were collected.

The internal consistency of the questionnaire from the regional liver index study was assessed by Cronbach’s alpha (threshold: alpha >0.7). As part of this study’s objective to explore the knowledge, attitudes, and behaviour of Hong Kong’s public towards viral hepatitis-related liver diseases, seven items were extracted from the questionnaire used in a regional liver index study. These items pertained to the awareness and knowledge of liver diseases as well as the respondents’ attitudes and behaviours towards screening and diagnosis of liver diseases (online supplementary Appendix 1; Q1-7).

Seven screener questions (online supplementary Appendix 1; S1-7) pertaining to the respondents’ socio-demographic characteristics, including age, sex, education, monthly household income, and their awareness of different types of hepatitis were also included in this study.

Respondents who indicated their awareness of ‘hepatitis B’ or ‘hepatitis C’ in screener item S7 proceeded to answer Q1(I)-Q2(I) or Q1(II)-Q2(II). Female respondents who correctly recognised the statement ‘from a pregnant mother to her baby’ in Q2f(I) or Q2f(II) proceeded to answer Q3c.

This study was exploratory and descriptive in nature. Respondents’ characteristics and responses to the survey questions were summarised and are presented as frequencies and percentages. No statistical analyses were performed.

Missing data were random; all data were reported, including those of respondents who declined to answer certain screener questions, such as on monthly household income. Missing data for any question were excluded from analysis of that question only, not from the whole study.

Among the respondents, 68.0% were aged ≥35 years, and 56.0% were female. Among the respondents, 59.0% had completed university or higher education, and 76.0% possessed private insurance. About 70% of respondents had a monthly household income of ≥HK$30 000. The respondents’ sex, age, education level, and household income were reflective of Hong Kong’s population.15 Approximately half of the respondents (55.8%) self-reported having attended health screenings within the last 2 years, and about 32.4% of them were aware of their family history pertaining to liver diseases (Table 1).

A higher proportion of respondents were aware of hepatitis B (93.0%, 465/500) than hepatitis C (46.4%, 232/500) [online supplementary Appendix 2]. The majority (>80%) were aware that hepatitis B and C can cause liver failure and increase the risks of developing liver cirrhosis and liver cancer (Fig 1a).

About 60% of respondents who were aware of hepatitis B knew that HBV is not airborne (61.5%) and can be prevented by a vaccine (62.4%). Only approximately 40% (186/465) of the respondents were aware that hepatitis B is not hereditary (Fig 1a). In contrast, only 19.0% (n=44/232) of those aware of hepatitis C knew that it cannot be prevented by vaccination, and about half knew that it is neither airborne (54.3%) nor hereditary (41.8%) [Fig 1a].

About half of the respondents aged <25 years (58.2%) and 55 to 64 years (46.9%) were not aware that hepatitis B is preventable by vaccination. More than half of the respondents across all age-groups were unaware that hepatitis B is not hereditary, with the highest proportion aged <25 years (80.0%). A substantial proportion of respondents (>35%) with either secondary or university education misperceived hepatitis B to be airborne (38.5%; 39.8%) or hereditary (62.0%; 59.7%) [online supplementary Appendix 3].

More than 70% of respondents across all age-groups and >80% with secondary school or university education misperceived that a vaccine could prevent hepatitis C. About half of subjects aged 25 to 44 years and ≥65 years were not aware that hepatitis C is not airborne, whereas >70% of those aged 25 to 34 years and ≥65 years misperceived hepatitis C to be hereditary. More than half of respondents with university (61.0%) or postgraduate (51.9%) education misperceived hepatitis C as hereditary (online supplementary Appendix 4).

At least 30% of respondents rightly perceived that (1) touching an infected person (HBV: 29.9%; HCV: 31.5%), (2) the faecal-oral route (21.9%; 28.4%); or (3) dining with an infected person (42.2%; 38.4%) were not possible modes of transmission of viral hepatitis B and C (Fig 1b). More than half of the respondents were aware of the mother-to-child transmission risk of HBV (68.4%) and HCV (53.9%) [Fig 1b]. Awareness of other transmission modes of HBV and HCV are detailed in online supplementary Appendix 2.

More than 60% of respondents across all age-groups and those with at least secondary school education did not correctly identify the transmission risks of HBV (online supplementary Appendix 5): more than half with secondary or university education misperceived touching (73.3%; 70.4%) or dining with an infected person (60.4%; 56.2%) as HBV transmission risks.

With regard to hepatitis C, more than half of the respondents aged ≥35 years and at least 60% of individuals with at least secondary-level education were unaware or incorrectly identified with the statements regarding social interaction and food contamination as HCV transmission risks. Notably, no respondents with the primary school education level were aware of hepatitis C (online supplementary Appendix 6).

Among the 280 female respondents, 65% correctly identified mother-to-child transmission as a transmission risk of viral hepatitis B and/or C (Fig 2). Among these respondents, 70.3% expressed that they were extremely likely or likely to seek a doctor’s consultation to get tested if they were or intended to become pregnant (Fig 2).

About one-fifth of the respondents with university (25.3%) or postgraduate (21.4%) education indicated that they were unlikely (neutral, unlikely, or extremely unlikely) to get tested for viral hepatitis in the event of pregnancy planning. About 40% of the respondents aged <25 years (46.7%) expressed that they were unlikely to seek screening if they wanted to become or became pregnant (Table 2).

The top three disease information topics that the respondents stated that they would like to understand more were disease prevention (84.2%), disease symptoms and complications (60.2%), and treatment (59.4%) [Fig 3a].

Among the various information dissemination channels, about half of the respondents preferred TV (conventional media [52.4%]), internet search (digital/social media [47.8%]) and doctor’s consultation (face-to-face/interpersonal interactions [50.8%]) [Fig 3b].

There was an improved general awareness (>80%) about the sequelae of HBV and HCV compared with that observed in 2010 (>70%).16 However, a substantial proportion (>60%) of respondents across all age-groups and education levels in Hong Kong held misconceptions about HBV and HCV and their transmission risks.

The local awareness of HBV vaccination among Hong Kong respondents (62.4%) was higher than that of Nigeria (31.9%)17 but lower than that of Singapore (75.1%).18 Among those unaware of hepatitis B vaccination in Hong Kong, the majority were aged ≥25 years. This is concerning because these respondents were born before the rollout of the local vaccination programme in 1988. Extensive global and local studies have reported that the implementation of HBV vaccination effectively reduced the incidence and seroprevalence of HBV-associated viral hepatitis.3 6 14 19 20 A recent study in Nigeria showed a relationship between HBV vaccination and knowledge about viral hepatitis,17 suggesting an unmet need to improve knowledge about HBV to increase HBV vaccination uptake, particularly in older adults.

Moreover, in this study, we observed a general local misperception that a vaccine is available for HCV, which has been similarly observed globally,18 21 although we observed a slightly higher local awareness rate (19.0%) than that in Singapore (15.0%).18 This lack of awareness pertaining to HCV might impede the adoption of correct preventive measures against hepatitis C infection.22

Both the WHO’s hepatitis elimination strategy and HKVHAP 2020-2024 emphasised the importance of combating any forms of stigmatisation or discrimination in the implementation of awareness and communication strategies to improve health outcomes among high-risk individuals.3 14 Social stigmatisation and discrimination stem from the lack of knowledge within society12 23 and among healthcare practitioners.10 Misperceptions such as the idea that hepatitis can be spread by sharing of food or eating utensils, the faecal-oral route, or touching an infected person (perceived by >60% of the study’s respondents) often underlie the social stigmatisation surrounding viral hepatitis.16 18 23 24 These often result in the avoidance of casual contact, self-isolation,11 23 or denial of potential employment or professional advancement,25 26 as experienced by infected individuals across the world. Many respondents without HBV infection in China expressed discomfort about being in close contact or sharing meals with HBV-infected individuals and felt that they should not be allowed to work in restaurants or with children.25 Similarly, 55.2% respondents in a 2019 Korean survey thought HCV patients should use separate towels and dishes,27 which is an indication of the misperception of HCV transmission by causal contact.

Over time, these social behaviours arising from misperceptions could result in a paradox for those infected with viral hepatitis, as stigma and shame could lead them to conceal their condition and avoid seeking the necessary medical treatment.26 28 Therefore, there is a need to adopt a comprehensive approach to raise community awareness and knowledge to tackle stigmatisation against infected individuals.

The belief that viral hepatitis is hereditary (ie, it could be inherited through ‘bad genes’29) could potentially result in the misunderstanding that there are no preventive measures against viral hepatitis. In fact, mother-to-child transmission is a major route of hepatitis B transmission in Asia. The potential confusion between a vertically transmitted disease and a hereditary one could impede efforts to reduce community transmission of viral hepatitis, as many might not bother to find out more information or proactively seek screening.

The HBsAg seropositivity screening during pregnancy and neonatal vaccination are integral parts of HKVHAP and the WHO’s hepatitis elimination strategy to prevent mother-to-child transmission.3 14 Prevention of perinatal transmission of HBV in Hong Kong includes an additional viral load screening of HBsAg-seropositive mothers to guide maternal antiviral therapy. Approximately 70% of pregnant women in Hong Kong (between May 2017 and December 2019) reportedly did not undergo viral load testing or regular hepatological surveillance before pregnancy.30 This is an important public health issue, as viral load in mothers who are hepatitis B carriers is a key influencing factor of immunoprophylaxis success in their babies.31 Among the 280 female respondents, only 128 (45.7%) were aware of the risk of mother-to-child transmission and likely to seek medical consultation in the event of pregnancy, suggesting a gap in women’s awareness and knowledge about viral hepatitis in Hong Kong.

Besides vertical transmission, horizontal spread is also an important means of HBV infection. In this study, 67.6% of respondents were unaware of their family’s history of liver disease(s), and only 50% knew that sexual contact is a transmission risk of HBV and HCV (online supplementary Appendix 2). This suggests an unmet need to educate the community about not only mother-to-child transmission, but also other transmission risks. More robust education efforts are needed to raise the population’s level of knowledge and awareness about viral hepatitis to work towards the WHO’s elimination goal. Such outreach efforts could be aligned with the respondents’ preferences for information media channels such as TV, internet search, and doctor’s consultation to optimise community reception.

This study has some limitations. Being a self-administered cross-sectional study based on self-reported data, the study is subject to recall bias. As such, data validation could not be performed, and no causal associations could be made. Respondents who lack internet access or comfort with online administration could be underrepresented. Furthermore, this study did not consider factors that could influence respondents’ levels of knowledge and/or awareness or attitudes towards HBV and HCV (eg, respondents’ health consciousness or vaccination or hepatitis status). With <60% having attended a health screening in the past 2 years and <70% expressing a high likelihood of medical consultation when exposed to risk factors, it would be insightful to explore the reasons for these gaps in proactive health-seeking behaviours. This would facilitate addressing and dispelling concerns to promote precautionary measures and health-seeking behaviours to reduce community transmission.

As this study is exploratory and descriptive in nature, statistical analyses were not performed to evaluate factors associated with the gaps in knowledge, awareness, and/or practices pertaining to hepatitis B and C; thus, the associations of respondents’ characteristics could not be identified in this study. Additional analyses would be warranted in future studies to confirm any independent factors associated with the community’s levels of knowledge and awareness.

In this study, we found that respondents had a general awareness of hepatitis B and C. However, our findings revealed gaps in respondents’ knowledge and understanding of the transmission risks of hepatitis B and C as well as awareness of their family history related to liver disease(s). The findings suggest that there may be social stigmatisation or discrimination against people with HBV and HCV within the community, which may deter some from undergoing screening and diagnosis.

It is essential to develop targeted education strategies with special attention towards addressing misperceptions relevant to social stigmatisation or discrimination and raise the importance of preventive measures such as vaccination and screening when exposed to risk factors. Outreach of such targeted education efforts should be aligned with the community’s preferred information channels to maximise information accessibility.

Concept or design: All authors.
Acquisition of data: S Singh.
Analysis or interpretation of data: All authors.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

HLY Chan is an advisor to AbbVie, Aligos, Arbutus, Gilead Sciences, GSK, Hepion, Janssen, Merck, Roche, Vaccitech, Venatorx, and Vir Biotechnology; and a speaker for Gilead Sciences, Mylan, and Roche.

GLH Wong has served as an advisory committee member for Gilead Sciences; as a speaker for Abbott, Abbvie, Bristol-Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen and Roche; and received a research grant from Gilead Sciences.

VWS Wong served as a consultant or advisory board member for 3V-BIO, AbbVie, Allergan, Boehringer Ingelheim, the Center for Outcomes Research in Liver Diseases, Echosens, Gilead Sciences, Hanmi Pharmaceutical, Intercept, Inventiva, Merck, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, ProSciento, Sagimet Biosciences, TARGET PharmaSolutions, and Terns; and a speaker for AbbVie, Bristol-Myers Squibb, Echosens, and Gilead Sciences. He has received a grant from Gilead Sciences for fatty liver research. He is also a Co-founder of Illuminatio Medical Technology Limited.

As an editor of the Journal, MCS Wong was not involved in the peer review process for this article.

The authors acknowledge valuable support from Dr Vince Grillo of Kantar Health overseeing the development of the project. The authors thank Dr Amanda Woo of Kantar Health for providing medical writing and editorial support, which was funded by Gilead Sciences, Hong Kong, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). The translation of the questionnaire from English to traditional Chinese was performed by GlobaLexicon Limited, United Kingdom and funded by Gilead Sciences, Hong Kong. The authors acknowledge the members of the steering committee for their contribution in reviewing and finalising the questionnaire: Dr Mei-hsuan Lee, National Yang Ming Chiao Tung University (Taiwan); Dr Sang-hoon Ahn, Yonsei University College of Medicine (South Korea); Dr Henry LY Chan, Union Hospital (Hong Kong); Dr Asad Choudhry, Chaudhry Hospital (Pakistan); Dr Rino Alvani Gani, University of Indonesia (Indonesia); Dr Rosmawati Mohamed, University of Malaya (Malaysia), Dr Janus P Ong, University of the Philippines (Philippines); Dr Akash Shukla, King Edward Memorial Hospital, Global Hospital (India); Dr Chee-kiat Tan, Singapore General Hospital (Singapore); Dr Tawesak Tanwandee, Siriraj Hospital, Mahidol University (Thailand); and Dr Pham-thi Thu Thuy, Ho Chi Minh Medic Medical Center (Vietnam).

This study was funded by Gilead Sciences, Hong Kong. Kantar Health, Singapore, received funding from Gilead Sciences, Hong Kong, for the conduct of the study and development of the manuscript.

All eligible respondents explicitly agreed to join the panel and provided informed online consent to participate in the study.

1. Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol 2019;70:151-71. Crossref

2. World Health Organization. Hepatitis in the Western Pacific. Available from: https://www.who.int/westernpacific/health-topics/hepatitis. Accessed 3 Aug 2020.

3. World Health Organization. Global Health Sector Strategy on Viral Hepatitis, 2016-2021: towards ending viral hepatitis. Available from: https://apps.who.int/iris/bitstream/handle/10665/246177/WHO-HIV-2016.06-eng.pdf;jsessionid=F5934335456A761C7349258535E3E5EC?sequence=1. Accessed 14 Dec 2020.

4. Lin AW, Wong KH. Surveillance and response of hepatitis B virus in Hong Kong Special Administrative Region, 1988-2014. Western Pac Surveill Response J 20163;7:24-8. Crossref

5. Liu KS, Seto WK, Lau EH, et al. A territory-wide prevalence study on blood-borne and enteric viral hepatitis in Hong Kong. J Infect Dis 2019;219:1924-33. Crossref

6. Viral Hepatitis Control Office, Special Preventive Programme, Centre for Health Protection, Department of Health, Hong Kong SAR Government. Surveillance of viral hepatitis in Hong Kong—2017 update report. Available from: https://www.chp.gov.hk/files/pdf/viral_hepatitis_report.pdf. Accessed 14 Jan 2021.

7. Chan GC, Lim W, Yeoh EK. Prevalence of hepatitis C infection in Hong Kong. J Gastroenterol Hepatol 1992;7:117-20. Crossref

8. Hui YT, Wong GL, Fung JY, et al. Territory-wide population-based study of chronic hepatitis C infection and implications for hepatitis elimination in Hong Kong. Liver Int 2018;38:1911-9. Crossref

9. Lao TT, Sahota DS, Suen SS, Lau TK, Leung, TY. Chronic hepatitis B virus infection and rubella susceptibility in pregnant women. J Viral Hepat 2010;17:737-41. Crossref

10. Paterson BL, Backmund M, Hirsch G, Yim C. The depiction of stigmatization in research about hepatitis C. Int J Drug Policy 2007;18:364-73. Crossref

11. Zacks S, Beavers K, Theodore D, et al. Social stigmatization and hepatitis C virus infection. J Clin Gastroenterol 2006;40:220-4. Crossref

12. Mokaya J, McNaughton AL, Burbridge L, et al. A blind spot? Confronting the stigma of hepatitis B virus (HBV) infection—a systematic review. Wellcome Open Res 2018;3:29. Crossref

13. Marinho RT, Barreira DP. Hepatitis C, stigma and cure. World J Gastroenterol 2013;19:6703-9. Crossref

14. Viral Hepatitis Control Office, Department of Health, Hong Kong SAR Government. Hong Kong Viral Hepatitis Action Plan 2020-2024. Available from: https://www.hepatitis.gov.hk/english/document_cabinet/action_plan.html. Accessed 4 Dec 2020.

15. Census and Statistics Department, Hong Kong SAR Government. Population and Household Statistics Analysed by District Council District. Available from: https://www.statistics.gov.hk/pub/B11303012019AN19B0100.pdf. Accessed 14 Jan 2021.

16. Leung CM, Wong WH, Chan KH, et al. Public awareness of hepatitis B infection: a population-based telephone survey in Hong Kong. Hong Kong Med J 2010;16:463-9.

17. Eni AO, Soluade MG, Oshamika OO, Efekemo OP, Igwe TT, Onile-ere OA. Knowledge and awareness of hepatitis B virus infection in Nigeria. Ann Glob Health 2019;85:56. Crossref

18. Tan CK, Goh GB, Youn J, Yu JC, Singh S. Public awareness and knowledge of liver health and diseases in Singapore. J Gastroenterol Hepatol 2021 Mar 18. Epub ahead of print. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/jgh.15496. Accessed 2 May 2021. Crossref

19. Meireles LC, Marinho RT, Van Damme P. Three decades of hepatitis B control with vaccination. World J Hepatol 2015;7:2127-32. Crossref

20. Posuwan N, Wanlapakorn N, Sintusek P, et al. Towards the elimination of viral hepatitis in Thailand by the year 2030. J Virus Erad 2020;6:100003. Crossref

21. Ha S, Timmerman K. Awareness and knowledge of hepatitis C among health care providers and the public: a scoping review. Can Commun Dis Rep 2018;44:157-65. Crossref

22. Wait S, Kell E, Hamid S, et al. Hepatitis B and hepatitis C in southeast and southern Asia: challenges for governments. Lancet Gastroenterol Hepatol 2016;1:248-55. Crossref

23. Lee H, Fawcett J, Kim D, Yang JH. Correlates of hepatitis B virus-related stigmatization experienced by Asians: a scoping review of literature. Asia-Pac J Oncol Nurs 2016;3:324-34. Crossref

24. Smith-Palmer J, Cerri K, Sbarigia U, et al. Impact of stigma on people living with chronic hepatitis B. Patient Relat Outcome Meas 2020;11:95-107. Crossref

25. Huang J, Guan ML, Balch J, et al. Survey of hepatitis B knowledge and stigma among chronically infected patients and uninfected persons in Beijing, China. Liver Int 2016;36:1595-603. Crossref

26. Northrop JM. A dirty little secret: stigma, shame and hepatitis C in the health setting. Med Humanit 2017;43:218-24. Crossref

27. Choi GH, Jang ES, Kim JW, Jeong SH. A survey of the knowledge of and testing rate for hepatitis C in the general population in South Korea. Gut Liver 2020;14:808-16. Crossref

28. Gautier RL, Wallace J, Richmond JA, Pitts M. The personal and social impact of chronic hepatitis B: a qualitative study of Vietnamese and Chinese participants in Australia. Health Soc Care Community. 2020. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/hsc.13197. Accessed 27 Jan 2021. Crossref

29. Haga SB, Barry WT, Mills R, et al. Public knowledge of and attitudes toward genetics and genetic testing. Genet Test Mol Biomarkers 2013;17:327-35. Crossref

30. Hui PW, Ng C, Cheung KW, Lai CL. Acceptance of antiviral treatment and enhanced service model for pregnant patients carrying hepatitis B. Hong Kong Med J 2020;26:318-22. Crossref

31. Cheung KW, Seto MT, Wong SF. Towards complete eradication of hepatitis B infection from perinatal transmission: review of the mechanisms of in utero infection and the use of antiviral treatment during pregnancy. Eur J Obstet Gynecol Reprod Biol 2013;169:17-23. Crossref

Carrier screening aims to identify couples at risk of conceiving children affected by recessive genetic diseases. Carrier couples of most recessive genetic conditions are typically asymptomatic, and the only way to identify them is by carrier screening. If a couple are both carriers of the same autosomal recessively inherited condition, their offspring have a 1 in 4 chance of being affected. The risk is as high as 1 in 2 in male offspring if the mother is an X-linked recessive carrier. Carrier screening facilitates informed prenatal testing options such as pre-implantation genetic diagnosis, prenatal invasive testing, and other reproductive options such as donor gametes and adoption for carrier couples. Prenatal genetic diagnosis could provide parents with more information, appropriate counselling, and preparation to take care of the child.1

Various carrier screening programmes targeting specific populations have been developed for single gene diseases such as cystic fibrosis, thalassaemia, and Tay-Sachs disease.2 3 The American College of Obstetrics and Gynecology (ACOG) published guidelines on ethnically based carrier screening programmes, eg, screening for haemoglobinopathies in individuals of Southeast Asian, African and Mediterranean descent and screening for cystic fibrosis, Tay-Sachs disease, familial dysautonomia, and Canavan disease for individuals of Ashkenazi Jewish descent.2 4 However, race and ethnicity can only be determined by patient self-report, and measures to ascertain ethnicity are restrictive.5 Ancestry-based screening could also lead to unequal distribution of genetic testing and may miss diagnosis of diseases in populations without screening.3 Thus, both the American College of Medical Genetics and Genomics (ACMG) and ACOG recommended carrier screening for cystic fibrosis in all couples in 2001.6 7 The ACMG and ACOG have also recommended carrier screening for spinal muscular atrophy (SMA) in all couples since 2008 and 2017, respectively.8 9

With advancements in genomic technology providing access to next-generation sequencing (NGS), expanded screening panels that cover a wide variety of disorders could be offered to individuals regardless of ethnic background.9

The common mutations in the screening panel are mainly chosen based on studies performed in the Caucasian and Ashkenazi Jewish populations. Those known common mutations may not be ethnicity-specific and may not cover all mutations present in the Chinese population. Thus, the approach of sequencing the entire disease-causing gene would be more useful than the targeted common mutations approach for the Chinese population.

Studies that evaluate carrier frequencies and common mutations in the Chinese population are lacking in our locality. Further study to review carrier frequency and the identified variants in the Chinese population is essential to guide the future design of carrier screening platforms specific to the Chinese population and improve the cost-effectiveness of carrier screening for genetic diseases.

Expanded carrier screening testing was offered to women who attended the subfertility clinic and pre-pregnancy counselling clinic of the study unit between March 2016 and March 2017. They were counselled about the prevalence and inheritance of recessive conditions, and the chance of having affected offspring for a silent carrier couple, using examples and figures. The purpose, testing methods, interpretation of results, potential benefits, risks, and limitations of the expanded carrier screening were also explained.

A generic consent form for the expanded carrier screening testing prepared by the laboratory was used. Consent for the use of data obtained for research or audit purposes was also obtained. The test was then ordered by the clinician as self-financed testing. The expanded carrier screening test was offered to both members of the couple separately during pre-test counselling. During post-test counselling, if a woman was identified to be a carrier of an autosomal recessive disease, but her partner had not completed the test, her partner was also counselled for carrier testing using the same method as self-financed testing. If both the male and female members of the couple were carriers of a same autosomal recessive disorder or the female was the carrier of an X-linked recessive disorder, they were identified as at-risk couples having the possibility of an affected pregnancy. Genetic counselling was arranged for at-risk couples to discuss reproductive options such as preimplantation genetic testing and prenatal diagnostic testing. Finally, the carrier frequencies of individual diseases and the identified variants were reviewed. STROBE reporting guidelines were implemented in this manuscript.

The expanded carrier screening panel consisted of 104 conditions inherited in autosomal recessive or X-linked manner (online supplementary Appendix). The severity of these conditions ranged from debilitating diseases with neurological impairment (eg, SMA), reduced lifespan (eg, thalassaemia), or intellectual disability (eg, fragile X syndrome) to diseases requiring early intervention in the prenatal or early neonatal period (eg, 21-hydroxylase deficient congenital adrenal hyperplasia [CAH]).

The screening platform (Family Prep Screen 2.0; Counsyl, South San Francisco [CA], United States), which was reported by Lazarin et al,10 uses NGS techniques to analyse the listed exons, as well as selected intergenic and intronic regions, of the genes responsible for the recessive conditions. The selected regions were sequenced to high coverage and compared with standards and references of normal variation. High-throughput sequencing detects approximately 94% of known clinically significant variants according to the test provider. Variants classified as ‘predicted’ or ‘likely’ pathogenic have been reported.11 Fragile X specific polymerase chain reaction assay was used to determine the CGG repeat size in the 5' untranslated region of the FMR1 gene. Targeted copy number analysis was used to determine the copy number of exon 7 of the SMN1 gene. g.27134T>G variant testing for identification of silent SMA carriers is not included in this platform.12 The turnaround time of the test was approximately 3 weeks.

A total of 123 Chinese women (age range, 20-45 years) opted for expanded carrier screening, and 69 (56.1%) of them were found to be carriers of at least one disease. Twenty of the women’s partners (29.0%, 20/69) were willing to complete the screening test after genetic counselling. Screening for possible carrier status before contemplating pregnancy was the indication in all individuals. Excluding one woman who was positive for fragile X syndrome, 48 women who screened positive opted not to screen their partners. Seventeen of them were solely carriers of alpha- or beta-thalassaemia (10 and 7, respectively), which could be accurately screened by mean corpuscular volume. The results also included 20 GJB2 carriers, especially the c.109G>A (p.Val37Ile) mutation, which has low penetrance and is prevalent in the Chinese population.13 14 Carrier status for CAH, SMA, Pendred’s syndrome, and other very rare diseases was found in three, one, one, and six individuals, respectively. After integrating partners’ data, 84 subjects (58.7%) were found to be carriers for at least one recessive disease, including thalassaemias. Excluding thalassaemias, 68 subjects (47.6%) were found to be carriers of at least one disease (Tables 1 and 2).

A total of 24 recessive diseases were identified in 84 (58.7%) of the 143 subjects. The data are summarised in Table 1. The most common condition identified was GJB2-related hearing loss (frequency: 1 in 4). One subject was also found to be a homozygote for the p.V37I mutation in the GJB2 gene. The subject was aged 34 years and did not complain of hearing impairment at the time of recruitment. Both alpha- and beta-thalassaemia were prevalent in this cohort (1 in 7 and 1 in 14, respectively), as shown in Table 1. Eleven subjects (1 in 13) were identified as carriers of the 21-hydroxylase deficient type of CAH. Four subjects were heterozygous carriers of Pendred’s syndrome (1 in 36), and three subjects were heterozygous carriers for each of SMA and Krabbe’s disease (1 in 48). Two carriers were identified for both CLN5-related neuronal ceroid lipofuscinosis and Fanconi’s anaemia type C, and one carrier was identified for each of 15 other recessive conditions (Table 1).

The frequency of multiple-disease carriers is shown in Table 2. Carrier status of at least two recessive conditions was identified in 24 subjects (24/143, 16.8%) including thalassaemias and 11 subjects (7.7%) excluding thalassaemias.

One woman was a fragile X syndrome premutation carrier, and 20 women had positive results for carrier status, and their male partners were sequentially tested. After integrating the sequential testing results, we identified nine at-risk couples, including three of alpha-thalassaemia, two of CAH, two of GJB2-related hearing loss, one of Pendred’s syndrome, and one of fragile X syndrome (Table 3). The rate of at-risk couples was 12.0% (9/75) overall and 8.0% (6/75) excluding thalassaemias.

Forty three variants were identified by the NGS panel (Table 4). Of the 43 variants, 29 (67.4%) were not included in the ACMG or ACOG guidelines.9 11

This study demonstrated the application of NGS to investigate carrier frequency status of members of the Chinese population in Hong Kong. The overall positive yield of this expanded carrier screening panel in our cohort was 58.7%. Not surprisingly, both alpha- and beta-thalassaemia account for a significant proportion of them. However, even after excluding thalassaemias that could be screened by mean corpuscular volume, the positive yield using NGS was still as high as 47.6%, with 6 out of 75 at-risk couples (8.0%) identified and potentially benefiting from further pre-conception genetic counselling.

Although NGS has been increasingly used for genetic carrier screening in Western countries in recent years, there is a scarcity of data about the carrier frequency of various recessive diseases in the Chinese population. In 2013, Lazarin et al10 reported the carrier frequencies of a sample of approximately 20 000 people from different ethnic groups using a targeted mutation panel. East Asians had the lowest carrier frequency (8.5%) compared with Ashkenazi Jews (43.6%) or Caucasians (21%-32.6%). The most common genetic disease identified among East Asians was GJB2-related hearing loss (1 in 22), followed by beta-thalassaemia/sickle cell disease (1 in 78) and SMA (1 in 85). However, the assay used by Lazarin et al10 was partially based on targeted genotyping, so carriers of variants other than the included common mutations were not detected. Thus, the reported carrier frequencies are likely underestimated, particularly among East Asians, as the common mutation panel was mainly based on the Caucasian and Ashkenazi Jewish populations. In particular, alpha-thalassaemia and CAH are not included in their panel.

Recently, Guo and Gregg15 investigated the carrier prevalence of 415 recessive diseases using an exome sequencing database of approximately 120 000 samples. The consistent finding is that Ashkenazi Jews had the highest carrier frequency (62.9%), followed by Caucasians, Africans, and Hispanics; South and East Asians had the lowest carrier frequency, but that frequency rose to 32.6% with a more comprehensive panel. However, because neither alpha-thalassaemia nor SMA was included in the panel, the most common diseases for which carrier status was found among East Asians were autoimmune polyendocrinopathy syndrome type 1, beta-thalassaemia, Usher’s syndrome type IIa, and CAH. The carrier frequency of each of those diseases was 1% to 2%. In 2018, Zhao et al16 reported >10 000 mainland Chinese couples in whom NGS was used to screen for 11 recessive diseases. That study showed a high carrier frequency of 27.49%, and 2.4% of couples were carriers of the same genetic disease. The authors found that the diseases with the highest carrier frequencies were alpha-thalassaemia (15.1%), beta-thalassaemia (4.8%), phenylketonuria (3.6%), Wilson’s disease (2.0%), GJB2-related hearing loss (1.7%), and Pendred’s syndrome (1.6%). However, that study excluded SMA, CAH, and fragile X syndrome.16 Our study’s findings are distinguished from those of Lazarin et al,10 Guo and Gregg,15 and Zhao et al16 in that we observed a much higher carrier rate for GJB2-related hearing loss (28.0%), which is consistent with our previous report (15.9%) using target-enriched massively parallel sequencing.14 In addition, we found higher carrier frequencies for CAH (7.7%) and Pendred’s syndrome (2.8%). Our study observed carrier frequency for SMA (2.1%) is similar to that found in Western populations,17 18 19 20 21 indicating that SMA affects all ethnic groups.

One of the major limitations of our study was the small sample size. More data are required before we can draw precise conclusions regarding the carrier frequency of individual recessive conditions in the Chinese population. Second, patients in this cohort were referred for subfertility or pre-pregnancy counselling for genetic conditions, and give out of this 123-patient cohort had a positive family history, including thalassaemias, balanced translocation carriers, family history of autism, neonatal death, and previous pregnancy with structural abnormality. Thus, some of the results might have been over-represented. For example, one woman who presented with subfertility was discovered to be a fragile X permutation carrier, and this may have elevated the carrier frequency of fragile X in our cohort of 123 women. In our previous study, in which we used a robust polymerase chain reaction–based assay to quantify fragile X CGG repeats for screening of 3000 low-risk Chinese pregnant women, the permutation frequency was approximately 1 in 800.22 Another couple in the present study had a previous baby with neonatal death of unknown cause in Mainland China and were found to be 21-hydroxylase deficient CAH carriers. Nonetheless, even after excluding these two CAH cases, the CAH carrier frequency in our study (1 in 16) remains high.

Currently, both the ACOG and ACMG recommend carrier screening for SMA and cystic fibrosis only in individuals of East Asian ethnicity.7 9 If those ethnic-based carrier screening strategies advocated by the guidelines had been followed, many carriers and all five carrier couples identified in our cohort would have been missed. The results of our pilot study suggest that recessive genetic conditions may not be as uncommon as previously thought. Many of the diseases identified in our cohort are debilitating conditions that are associated with progressive neurological derangement and reduced life span, such as SMA, Krabbe’s disease, and biotinidase deficiency. More importantly, some conditions such as CAH may require intervention during the early prenatal or early neonatal periods to avoid irreversible complications. Hence, public and professional awareness of expanded carrier screening should be improved, and genetic counselling and expanded carrier screening should be an option for the Chinese population, especially in the setting of subfertility clinics.

Yet, genetic carrier screening has not been popular among the Chinese population or in Hong Kong because of the high cost of the test and the perceived low carrier rate in Chinese people. As the cost for NGS has dropped recently, and our pilot study demonstrated an overall high yield of 8.0% of couples at risk of conceiving foetuses with genetic diseases (even after excluding thalassaemias), further studies of couples are warranted. Potential candidates for expanded carrier screening in Hong Kong also include couples in consanguineous marriages, which are common in minor ethnic groups such as Pakistani and Indian. A recent local study showed that they had a higher prevalence of congenital abnormality (10.5%), unexplained intrauterine foetal demise (4.2%), and unexplained neonatal death (4.6%).23

In our cohort, NGS was used to analyse the listed exons, as well as selected intergenic and intronic regions, of the genes responsible for certain recessive conditions. The high-throughput sequencing technique was able to detect approximately 94% of known clinically significant variants irrespective of ethnicity. Of 43 variants identified using NGS, 29 (67.4%) were not included in the ACMG or ACOG guidelines. Thus, our study demonstrated that the NGS technique increased the detection rate of carrier status for recessive conditions in the Chinese population. Yet, further study with a larger sample size should be conducted to study the prevalence of carrier status, which conditions should be included, and ethical issues related to carrier screening testing such as reproductive options.

The observed carrier frequency in the Chinese population was 58.7% overall (47.6% after excluding thalassaemias) and was higher than previously reported. Expanded carrier screening using NGS should be provided to Chinese people to improve the detection rate of carrier status and facilitate optimal pregnancy planning.

All authors contributed to the concept or design of the study, acquisition of data, analysis or interpretation of the data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

As an editor of the journal, JPW Chung was not involved in the peer review process. Other authors have disclosed no conflicts of interest.

This research project was partially funded by the Liauw’s Family Reproductive Genomics Programme.

This study obtained ethical approval from The Joint Chinese University of Hong Kongew Territories East Cluster Clinical Research Ethics Committee (Ref CREC2019.138). All participants gave informed consent before the study.

1. Edwards JG, Feldman G, Goldberg J, et al. Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. Obstet Gynecol 2015;125:653-62. Crossref

2. ACOG Committee on Obstetrics. ACOG Practice Bulletin No. 78: hemoglobinopathies in pregnancy. Obstet Gynecol 2007;109:229-37. Crossref

3. Bajaj K, Gross SJ. Carrier screening: past, present and future. J Clin Med 2014;3:1033-42. Crossref

4. ACOG Committee on Genetics. ACOG Committee Opinion No. 442: preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol 2009;114:950-3. Crossref

5. Eisenhower A, Suyemoto K, Lucchese F, Canenguez K. “Which box should I check?”: examining standard check box approaches to measuring race and ethnicity. Health Serv Res 2014;49:1034-55. Crossref

6. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 486: update on carrier screening for cystic fibrosis. Obstet Gynecol 2011;117:1028-31. Crossref

7. Watson MS, Cutting GR, Desnick RJ, et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med 2004;6:387-91. Crossref

8. Prior TW, Professional Practice and Guidelines Committee. Carrier screening for spinal muscular atrophy. Genet Med 2008;10:840-2. Crossref

9. Committee on Genetics. Committee Opinion No. 691: carrier screening for genetic conditions. Obstet Gynecol 2017;129:e41-55. Crossref

10. Lazarin GA, Haque IS, Nazareth S, et al. An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. Genet Med 2013;15:178-86. Crossref

11. Haque IS, Lazarin GA, Kang HP, Evans EA, Goldberg JD, Wapner RJ. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA 2016;316:734-42. Crossref

12. Feng Y, Ge X, Meng L, et al. The next generation of population-based spinal muscular atrophy carrier screening: comprehensive pan-ethnic SMN1 copy-number and sequence variant analysis by massively parallel sequencing. Genet Med 2017;19:936-44. Crossref

13. Shen J, Oza AM, Del Castillo I, et al. Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel. Genet Med 2019;21:2442-52. Crossref

14. Choy KW, Cao Y, Lam ST, Lo FM, Morton CC, Leung TY. Target-enriched massively parallel sequencing for genetic diagnosis of hereditary hearing loss in patients with normal array CGH result. Hong Kong Med J 2018;24 Suppl 3:11-4.

15. Guo MH, Gregg AR. Estimating yields of prenatal carrier screening and implications for design of expanded carrier screening panels. Genet Med 2019;21:1940-7. Crossref

16. Zhao S, Xiang J, Fan C, et al. Pilot study of expanded carrier screening for 11 recessive diseases in China: results from 10,476 ethnically diverse couples. Eur J Hum Genet 2019;27:254-62. Crossref

17. Li C, Geng Y, Zhu X, et al. The prevalence of spinal muscular atrophy carrier in China: evidences from epidemiological surveys. Medicine (Baltimore) 2020;99:e18975. Crossref

18. Evans M, McCarthy M, Moore R, Karbassi I, Alagia DP, Lacbawan F. A comprehensive analysis of allele frequencies from 476,930 spinal muscular atrophy test results [23M]. Obstet Gynecol 2019;133:147S. Crossref

19. Park JE, Yun S, Roh EY, Yoon JH, Shin S, Ki CS. Carrier frequency of spinal muscular atrophy in a large-scale Korean population. Ann Lab Med 2020;40:326-30. Crossref

20. Dejsuphong D, Taweewongsounton A, Khemthong P, et al. Carrier frequency of spinal muscular atrophy in Thailand. Neurol Sci 2019;40:1729-32. Crossref

21. Chen X, Sanchis-Juan A, French CE, et al. Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data. Genet Med 2020;22:945-53. Crossref

22. Kwok YK, Wong KM, Lo FM, et al. Validation of a robust PCR-based assay for quantifying fragile X CGG repeats. Clin Chim Acta 2016;456:137-43. Crossref

23. Siong KH, Au Yeung SK, Leung TY. Parental consanguinity in Hong Kong. Hong Kong Med J 2019;25:192-200. Crossref