Patients with coronavirus disease 2019 (COVID-19), including those with mild or no symptoms, may readily transmit the disease given the high person-to-person infectivity in the latent period of COVID-19; this transmission could threaten public health.1 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of COVID-19, replicates efficiently in the upper respiratory tract and appears to cause delayed onset of symptoms; therefore, COVID-19 poses considerable challenges to the health system.2 3 Thus, there is a need to rapidly identify infected individuals who exhibit only mild symptoms. In March to April 2020, the Hospital Authority, Hong Kong, established a temporary test centre (TTC) at the AsiaWorld-Expo (AWE), which is within the Hong Kong International Airport complex on Lantau Island. The AWE TTC offered tests for individuals with mild symptoms among those arriving at the airport, as well as those engaged in home quarantine in Hong Kong, for the early detection of SARS-CoV-2 infection that could be managed by early isolation and intervention.4 Asymptomatic individuals were tested at a different facility within AWE operated by the Department of Health. This study reviewed the characteristics and outcomes of individuals who attended the AWE TTC for COVID-19 testing.

This retrospective cross-sectional study evaluated the characteristics and outcomes of individuals who attended the AWE TTC during its operation from 20 March 2020 to 19 April 2020. All individuals who attended the AWE TTC were included, with the exception of patients who were transferred out of the AWE TTC to accident and emergency departments before they could undergo COVID-19 testing. Infection control measures implemented at the AWE TTC were reported previously.5 Ethics approval was obtained from the Kowloon West Cluster Research Ethics Committee, Hospital Authority.

Clinical characteristics assessed in this study were fever, chills, cough, runny nose, sore throat, vomiting, diarrhoea, fatigue, myalgia, headache, anosmia, history of hypertension, history of diabetes mellitus, history of chronic respiratory disease, and history of malignancy. Epidemiological parameters assessed in this study were age, sex, district of residence, travel history, occupational exposure, contact history, and clustering history. These data were collected using a standard clinical assessment template by duty medical officers in the Clinical Management System of the Hospital Authority. The primary outcome was positive or negative SARS-CoV-2 test results, according to reverse transcription polymerase chain reaction analyses of pooled nasopharyngeal and throat swabs collected at the AWE TTC.

The positivity rate with 95% confidence interval (CI) was calculated. Demographic and clinical characteristics of individuals with positive and negative test results were compared using Pearson’s Chi squared test, Fisher’s exact test, or the Mann-Whitney U test, as appropriate. Adjusted odds ratios with 95% Wald CIs were derived using multivariable binary logistic regression to assess the associations of clinical characteristics with SARS-CoV-2 positive test results. Partially standardised beta coefficients were used to compare the strengths of associations between individual clinical characteristics and SARS-CoV-2 test results; a greater absolute value of the partially standardised beta coefficient was indicative of a stronger association. Ridge regression was performed to implement penalisation for management of the sparse data bias elicited by the low prevalences of some clinical characteristics.6 7 The tuning parameter λ was identified as the optimal value that resulted in minimal error via 10-fold cross-validation; as the tuning parameter λ became larger, the estimated odds ratio decreased towards a value of 1. Bootstrapping was used to construct 95% CIs with 100 bootstrap replications. Statistical analyses were performed using R version 3.6.1 with “glmnet” and “boot” packages. A P value of <0.05 was considered statistically significant.

In total, 1286 individuals attended the AWE TTC for COVID-19 testing (Table 1). Of these 1286 attendees, 1258 were included in the analysis after the exclusion of three attendees with important missing data and 25 attendees who were immediately referred to regional accident and emergency departments because of severe symptoms requiring investigation or therapy beyond the capacity of the AWE TTC. These severe symptoms included shortness of breath (n=8); high fever (n=5); chest discomfort (n=5); acute gastrointestinal symptoms (n=4); and acute ear, nose, throat symptoms (n=3). Finally, 1242 individuals were involved in the analysis because 16 individuals attended the AWE TTC twice due to ongoing or changing symptoms; the remaining 1226 individuals attended the AWE TTC only once for testing. Among the 1258 included tests, five showed indeterminate results during the first sampling, while subsequent re-tests revealed negative results; thus, there were 86 positive SARS-CoV-2 results with a positivity rate of 6.84% (95% CI=5.57%-8.37%). During the study period, the maximum number of attendees (n=79) was recorded on 30 March 2020 and the highest daily number of positive test results (n=8) was recorded on 6 April 2020. Attendees with positive test results were all admitted to public hospitals through central coordination for further clinical assessment and treatment.

Most attendees were aged 15 to 24 years (740/1258, 58.8%). Furthermore, most attendees (n=1190, 94.6%) were incoming travellers from the United Kingdom, the United States, Canada, Australia, and other parts of the world (Table 2). A history of travel to the United Kingdom was significantly associated with positive test results (69.8% of positive test results vs 51.9% of negative test results; P=0.001). Cluster or contact history was reported by 32.6% of attendees with positive test results and 10.7% of attendees with negative test results (P<0.001). The most frequently reported symptoms among all attendees were cough (60.8%), sore throat (46.9%), and runny nose (34.6%). Symptoms were reported by 86.0% and 96.3% of individuals with positive and negative test results, respectively.

The clinical characteristics most strongly associated with a positive test result were anosmia (ridge regression adjusted odds ratio [OR_adj]=8.30; 95% CI=1.12-127.09) and fever (OR_adj=1.32; 95% CI=1.02-3.28) [Table 3]. Sore throat was significantly associated with a negative test result (OR_adj= 0.86; 95% CI=0.36-0.99). Other characteristics (ie, cough, runny nose, fatigue, headache, myalgia, vomiting, chills, and diarrhoea) did not show significant associations with positive or negative test results, according to ridge regression analysis.

To the best of our knowledge, this is the first study in Hong Kong to explore the clinical characteristics of attendees at a public TTC established by the Hospital Authority in response to a worldwide pandemic. Early identification and early containment have been critical strategies adopted by the Centre for Health Protection, Hong Kong to address the pandemic. Locally, the first imported case in an individual with a history of travel outside mainland China was reported on 4 March 2020. This was followed by a large number of imported cases involving returning travellers, including 245 students from the United Kingdom and the United States who had positive test results; the maximum number of cases (n=65) was reported on 27 March 2020.8 The establishment of a TTC was a crucial public health intervention to address the influx of returning overseas travellers during the worldwide spread of COVID-19 beginning in March 2020. Given the potential transmission of COVID-19 among individuals with relatively mild clinical symptoms, early identification of SARS-CoV-2 infection by reverse transcription polymerase chain reaction testing is crucial for reducing disease spread.9 The AWE TTC was equipped with extensive testing capacity for the target population of individuals with mild disease symptoms.

Among AWE TTC attendees, the majority of positive test results were recorded in young individuals (aged 15-24 years; 40 of 86 cases), who comprised 46.5% of total attendees with positive test results. Notably, this proportion was greater than the proportion reported by the Centre for Health Protection concerning individuals in the same age-group (289 of 1084 cases; 26.7%) among all COVID-19 cases in Hong Kong during the study period. This is potentially attributable to the targeted testing strategy that focused on incoming overseas students, which was implemented after the Hong Kong Government announced compulsory testing and quarantine for all arriving travellers beginning on 19 March 2020.10 We previously reported that most individuals could be tested on-site; moreover, the AWE TTC fulfilled its gatekeeping role by reducing the number of hospital admissions by 36 patients per day during its 31 days of operation.5

Primary care providers and emergency physicians have performed important gatekeeping roles in the early identification of individuals with COVID-19. However, a local Family Physician survey revealed that this gatekeeping task is challenging because of the non-specific and mild disease manifestations in many individuals with SARS-CoV-2 infections.11 In Hong Kong, among 1084 confirmed cases reported between January 2020 and May 2020, symptoms were reported by 859 (79.2%) affected patients. The five most common symptoms reported by Hong Kong patients with COVID-19 included cough (436, 50.8%), fever (428, 49.8%), sore throat (174, 20.3%), headache (98, 11.4%), and runny nose (97, 11.3%). The remaining 225 patients (20.8%) were asymptomatic.8 An early study of 41 patients in Wuhan, published in January 2020, revealed that the most common symptoms at onset of illness were fever (98%), cough (76%), and myalgia or fatigue (44%).12 A multicentre study in Shanghai reported that the most common symptoms among 1004 patients with positive test results were fever (84%), cough (62%), and fatigue (25%).13 Our study reviewed the clinical characteristics and outcomes of relatively healthy individuals in Hong Kong whose demographic characteristics were similar to those of the general practice population; we found that the three most common symptoms among infected individuals were cough, fever, and sore throat (Table 1), consistent with the findings in a local study by the Centre for Health Protection.6 In addition to the usual upper respiratory tract symptoms, our results showed that fever and anosmia were strongly associated with positive test results. These findings provide important guidance for gatekeeping physicians to carefully consider symptoms such as anosmia (a relatively uncommon symptom in primary care consultations), which was present in 22.1% of our attendees with positive test results and only 0.3% of attendees with negative test results. Evidence of such symptoms should alert clinicians to the potential presence of COVID-19. A study performed in South Korea revealed that acute olfactory disturbance was present in 15.3% of patients (488/3191) in the early stage of COVID-19. Its prevalence was significantly more common among female patients and younger individuals (P=0.01 and P<0.001, respectively).14 A study performed in the Netherlands showed that anosmia was present in 47% of individuals with positive test results and was strongly associated with SARS-CoV-2 positivity (odds ratio=23.0; 95% CI=8.2%-64.8%).15 In our study, the OR_adj for anosmia was 8.30 (95% CI=1.12-127.09), indicating a strong association between anosmia and a positive test result. However, this result should be interpreted cautiously, considering the potential for over- or under-reporting of the symptom at a cross-sectional encounter, the co-existence of other conditions that may lead to olfactory disturbance, and the timing of illness presentation. The probability of identifying an infected individual depends on the incubation period and the proportion of individuals with subclinical disease.16 Symptoms alone might not be reliable for diagnosis. Early testing is critical for the early identification of both symptomatic and asymptomatic individuals. This approach has been particularly essential with worsening disease spread, which has required stricter infection control measures since July 2020.17 18

Of the 1286 AWE TTC attendees, 25 (1.94%) with severe symptoms were immediately transferred to the accident and emergency departments; these attendees did not undergo testing at the AWE TTC. The inclusion and exclusion criteria used in this TTC could be useful for planning and implementation efforts (in terms of referral criteria) if similar centres must be established in future emergency circumstances. Notably, this type of centre is considered safe and efficient for screening to reduce community disease spread19 and could be more readily implemented to manage an infectious disease, compared with vaccination and effective antiviral therapy.20

The strengths of this study were its large sample size and centralised setting that allowed coverage of the entire Hong Kong population (regardless of residential location) with elevated COVID-19 risk, including those arriving at the airport and those under home quarantine; all AWE TTC attendees exhibited mild disease symptoms similar to those of potentially infected individuals encountered in primary care settings. The limitations of this study included its retrospective data collection based on electronic health records. Investigators could not verify the reported conditions of the AWE TTC attendees or recover any important missing data. Nevertheless, all AWE TTC attendees were assessed by physicians with a standard questionnaire for documentation of demographics and symptoms; they were also tested by reverse transcription polymerase chain reaction analyses of standard pooled nasopharyngeal and throat swabs, which provided clear positive and negative results that facilitated data analysis. Another limitation of the study involved its cross-sectional study design. The epidemiological information and clinical symptoms collected during patient assessment at the AWE TTC might not be identical to those of post-admission situations because the patients’ conditions might have changed in a manner dependent on the timing of presentation. For example, a study of 1099 patients in China found that fever was present in 43.8% of patients on admission, but was present in 88.7% of patients during hospitalisation.21 Importantly, the present study could not offer predictive value or relative risk projection on the basis of its epidemiological and clinical findings. Further studies with a longitudinal design may provide useful epidemiological and clinical insights.

In some individuals, COVID-19 causes mild initial symptoms despite its high infectivity; thus, there is a need for early identification of individuals with SARS-CoV-2 infection who exhibit mild symptoms. The establishment of a TTC was successful in identifying infected individuals in a large-scale, high-turnover setting, thereby reducing the testing burden in secondary and tertiary healthcare facilities. Gatekeeping healthcare providers should carefully consider the epidemiological and clinical manifestations of COVID-19 and be vigilant in arranging appropriate early testing to reduce community spread.

Concept or design: WLH Leung, ELM Yu.
Acquisition of data: WLH Leung.
Analysis or interpretation of data: WLH Leung, ELM Yu.
Drafting of the manuscript: WLH Leung.
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.

The authors acknowledge all workers involved in the setup and operation of the temporary test centre at AsiaWorld-Expo, Hong Kong.

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 West Cluster Research Ethics Committee, Hospital Authority [Ref KW/EX-20-085(148-09)]. The Ethics Committee waived the need for patient consent for this retrospective study.

1. Bai Y, Yao L, Wei T, et al. Presumed asymptomatic carrier transmission of COVID-19. JAMA 2020;323:1406-7. Crossref

2. Heymann DL, Shindo N, WHO Scientific and Technical Advisory Group for Infectious Hazards. COVID-19: what is next for public health? Lancet 2020;395:542-5. Crossref

3. Chan JF, Yuan S, Kok KH, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2020;395:514-23. Crossref

4. Hong Kong SAR Government. Temporary test centres speed up tests for people upon arrival. Available from: https://www.info.gov.hk/gia/general/202003/19/P2020031900664.htm. Accessed 11 Jul 2020.

5. Wong SC, Leung M, Lee LL, Chung KL, Cheng VC. Infection control challenge in setting up a temporary test centre at Hong Kong International Airport for rapid diagnosis of COVID-19 due to SARS-CoV-2. J Hosp Infect 2020;105:571-3. Crossref

6. Greenland S, Mansournia MA, Altman DG. Sparse data bias: a problem hiding in plain sight. BMJ 2016;352:i1981. Crossref

7. Doerken S, Avalos M, Lagarde E, Schumacher M. Penalized logistic regression with low prevalence exposures beyond high dimensional settings. PloS One 2019;14:e0217057. Crossref

8. Lam HY, Lam TS, Wong CH, et al. The epidemiology of COVID-19 cases and the successful containment strategy in Hong Kong–January to May 2020. Int J Infect Dis 2020;98:51-8. Crossref

9. To KK, Yuen KY. Responding to COVID-19 in Hong Kong. Hong Kong Med J 2020;26:164-6. Crossref

10. Hong Kong SAR Government. Compulsory quarantine law gazetted. Available from: https://www.news.gov.hk/eng/20 20/03/20200318/20200318_211807_723.html. Accessed 11 Jul 2020.

11. Yu EY, Leung WL, Wong SY, Liu KS, Wan EY, HKCFP Executive and Research Committee. How are family doctors serving the Hong Kong community during the COVID-19 outbreak? A survey of HKCFP members. Hong Kong Med J 2020;26:176-83. Crossref

12. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. Crossref

13. Mao B, Liu Y, Chai YH, et al. Assessing risk factors for SARS-CoV-2 infection in patients presenting with symptoms in Shanghai, China: a multicentre, observational cohort study. Lancet Digit Health 2020;2:e323-30. Crossref

14. Lee Y, Min P, Lee S, Kim SW. Prevalence and duration of acute loss of smell or taste in COVID-19 patients. J Korean Med Sci 2020;35:e174. Crossref

15. Tostmann A, Bradley J, Bousema T, et al. Strong associations and moderate predictive value of early symptoms for SARS-CoV-2 test positivity among healthcare workers, the Netherlands, March 2020. Euro Surveill 2020;25:2000508. Crossref

16. Gostic K, Gomez AC, Mummah RO, Kucharski AJ, Lloyd-Smith JO. Estimated effectiveness of symptom and risk screening to prevent the spread of COVID-19. Elife 2020;9:e55570. Crossref

17. Hong Kong SAR Government. Social distancing rules to be tightened. Available from: https://www.news.gov.hk/eng/2020/07/20200709/20200709_175812_722.html. Accessed 11 Jul 2020.

18. Hong Kong SAR Government. Government further tightens social distancing measures. Available from: https://www.info.gov.hk/gia/general/202007/27/P2020072700650.htm. Accessed 27 Jul 2020.

19. Kwon KT, Ko JH, Shin H, Sung M, Kim JY. Drive-through screening center for COVID-19: a safe and efficient screening system against massive community outbreak. J Korean Med Sci 2020;35:e123. Crossref

20. Peto J. Covid-19 mass testing facilities could end the epidemic rapidly. BMJ 2020;368:m1163. Crossref

21. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708-20. Crossref

Paediatric glaucoma affects infants and children and may result in irreversible blindness that substantially diminishes productivity and quality of life over the entire lifetime of affected individuals. Prognosis is largely dependent on early, accurate diagnosis and timely treatment, comprising rigorous intraocular pressure (IOP) reduction to a level at which further progression is unlikely; the prevention of amblyopia is also a critical component of treatment.1 Paediatric glaucoma is classified as ‘primary’ when it involves an isolated idiopathic developmental abnormality of the anterior chamber angle, whereas it is classified as ‘secondary’ when aqueous outflow is reduced because of a congenital or acquired ocular disease or systemic disorder.2

Primary paediatric glaucoma includes primary congenital glaucoma (PCG, isolated trabeculodysgenesis) and juvenile open-angle glaucoma. Primary congenital glaucoma is the most common type of glaucoma in infants,3 4 with a variable incidence reported worldwide. Higher incidences have been observed in inbred populations where parental consanguinity is common.5 6 7 Primary congenital glaucoma occurs more frequently in boys than in girls8 9 10; it is bilateral in 70% to 80% of patients.11 12 Patients with familial PCG tend to have an equal sex distribution.10 11 13

Secondary paediatric glaucoma is commonly associated with anterior segment dysgenesis; 50% of patients develop glaucoma.14 Glaucoma associated with aniridia is usually caused by progressive angle closure; it presents often in childhood with an incidence of 6% to 75% in aniridic eyes.15 Aphakic glaucoma can occur soon or years after initial uneventful cataract extraction surgery in children with congenital cataract; its incidence ranges from 5% to 41%, depending on patient age at the time of surgery, corneal diameter, and surgical techniques.16 17 18 19 Phacomatoses commonly associated with glaucoma include Sturge–Weber syndrome20 and Klippel–Trenaunay–Weber syndrome. The glaucoma evident in patients with inflammatory disorders is multifactorial, with a reported incidence of up to 38% in children with juvenile idiopathic arthritis.21

The primary goal of treatment for both primary and secondary types of paediatric glaucoma is IOP reduction, for which medical treatment is often the first-line approach. Longer-term treatment involves surgery as the definitive approach for IOP control in the vast majority of patients with paediatric glaucoma. Available surgical procedures have various indications, with both advantages and disadvantages, as well as different success rates, among patient populations. Notably, the management approach and success rate also considerably vary among countries worldwide. Paediatric congenital glaucoma is a relatively uncommon disease, such that a consultant ophthalmologist in a general ophthalmology centre in the Western world is estimated to encounter a new patient with PCG approximately once every 5 years.22 Because of its relative rarity, PCG is sometimes misdiagnosed or not treated appropriately, especially in general ophthalmology centres, leading to irreversible corneal and optic nerve damage, as well as unnecessary irreversible visual loss. Consequently, PCG is present in a disproportionate percentage (up to 18%) of children in institutions for the blind worldwide.23 24 Furthermore, congenital glaucoma was reportedly present in 30% of paediatric patients attending a university low vision service.25 Overall, paediatric glaucoma is responsible for 5% of irreversible blindness in children worldwide.26 However, there is a paucity of contemporary epidemiologic and clinical data regarding paediatric glaucoma in Hong Kong.

We conducted the Hong Kong Paediatric Glaucoma Study as the first territory-wide analysis of the epidemiology, presentation, clinical interventions, and outcomes of paediatric glaucoma in Hong Kong. This study is expected to greatly enhance the understanding of this disease in our local community, while improving our disease management approaches and standards of clinical care. The findings will also provide our colleagues in Paediatrics and Family Medicine with a clearer overview of the clinical presentations of patients with paediatric glaucoma.

This study comprised a retrospective chart review of patients with confirmed paediatric glaucoma who were managed over a 10-year period (January 2006 to December 2015) in the ophthalmology departments of six regional clusters of the Hospital Authority in Hong Kong (ie, Hong Kong East, Kowloon West, Kowloon Central, Kowloon East, New Territories West, and New Territories East) and The Chinese University of Hong Kong. The Hospital Authority in Hong Kong provides a heavily government-subsidised public clinical service to all Hong Kong citizens, while the Hospital Authority ophthalmology service provides more than 90% of all clinical ophthalmology services delivered in Hong Kong. The six hospital clusters participating in this study had a total population of 6 889 400 in 2017, which represented 92.96% of the total population (7 411 300) in Hong Kong at the time of the study.27 This study was performed in accordance with the 1996 Declaration of Helsinki and ICH-GC; the study protocol was approved by the institutional review boards of all involved clusters.

Using the Hospital Authority’s Clinical Data Analysis and Reporting System, we identified patients aged ≤18 years on presentation, all of whom had either undergone glaucoma surgery or been prescribed glaucoma medication(s) continuously for >3 months. Patients identified through the Clinical Data Analysis and Reporting System were then verified through the Clinical Management System, which is an electronic medical records system in use throughout all hospitals and departments under the Hospital Authority in Hong Kong. Hard copies of medical records were also collected and reviewed to ensure the patients met the following criteria:

1. Age ≤18 years at presentation, with a diagnosis of primary or secondary glaucoma;
2. A combination of previous and/or current high IOP (>21 mm Hg), combined with disc cupping >0.3 or disc asymmetry >0.2, as well as one or more of the following signs: progressive disc cupping, buphthalmos (prominent, enlarged eye), enlarged corneal diameter (>11 mm in newborns, >12 mm in children aged <1 year, or >13 mm in children of any age), corneal oedema, Descemet’s membrane splitting (Haab’s striae), visual field defects, or progressive myopia.

Clinical data of all patients who met the above study criteria were retrospectively collected from medical records and the Clinical Management System, using standardised data sheets. The following data were collected: patient demographics including family history of glaucoma and parental consanguinity (defined as a union between two related individuals who were second cousins or closer), type of glaucoma (primary/secondary), presentation of disease/reason for referral, examination findings on presentation, subsequent management (eg, medications, laser interventions, and surgical interventions), and clinical outcomes at the final follow-up. Patients’ Hong Kong Identity Card numbers were used to identify duplicate entries at different hospitals; in such instances, the clinical data were combined prior to analysis.

The primary outcome measures were the epidemiological characteristics and clinical presentations of patients with paediatric glaucoma in Hong Kong. The secondary outcome measures were the subsequent management of these patients and their clinical outcomes at the final follow-up.

In this study, we identified 98 patients with paediatric glaucoma (150 eyes; 47 boys and 51 girls). Seventy eyes (46.7%) were right eyes, and the mean ± standard deviation (SD) presenting age was 5.2±5.7 years (range, 0-18 years). With the exception of two patients (one Japanese and one from mid-western Asia), all included patients were of Chinese ethnic origin. Three patients (3.1%) had a positive family history of glaucoma, while none had parental consanguinity. The mean ± SD duration of follow-up was 8.46±6.51 years (range, 0.2-25.5 years). While one patient had pigment dispersion syndrome (follow-up duration of 2 months) and one patient had persistent hyperplastic primary vitreous (follow-up duration of 5 months), all other included patients had a minimum follow-up duration of 6 months. The Hong Kong population aged <20 years was 1 378 912 in 2006,28 and it was 1 174 500 in 2015.29 The population covered by the involved six Hospital Authority clusters and The Chinese University of Hong Kong eye clinic constituted approximately 93% of the total population.27 Given that Hospital Authority ophthalmology departments provided services to 90% of our general population, the estimated annual incidence rate of paediatric glaucoma in our Hong Kong was 0.92 per 100 000 population aged <20 years.

Among the patients in this study, 57 eyes of 30 patients had primary glaucoma (35 eyes of 18 patients had PCG and 22 eyes of 12 patients had juvenile open-angle glaucoma). Furthermore, 93 eyes of 68 patients had secondary glaucoma (Table 1). The most prevalent type of secondary glaucoma was lens-related glaucoma after cataract extraction for congenital cataract (27 eyes of 17 patients, 18.0% of all involved eyes), which included aphakic glaucoma (13.3%) and pseudophakic glaucoma (4.7%). Other types of secondary glaucoma were Axenfeld–Rieger anomaly (8 eyes, 5.3%), uveitis (intermediate/anterior, 8 eyes, 5.3%), Sturge–Weber syndrome (7 eyes, 4.7%), and traumatic (5 eyes, 3.3%).

The main presenting symptoms are summarised in Table 2. Common clinical presentations were parental concerns (31 eyes of 21 patients, 20.7% of all involved eyes) including cloudy cornea (19 eyes of 13 patients, 12.7%) and tearing/photophobia (12 eyes of 8 patients, 8.0%); other presentations that warranted referral to an ophthalmologist included poor visual acuity (27 eyes, 18.0%), high IOP (20 eyes, 13.3%), and strabismus (9 eyes, 6.0%). The mean ± SD IOP on presentation to the attending ophthalmologist was 25.3±10.2 mm Hg (range, 7-53 mm Hg). Notably, one eye had an iris cyst and underwent penetrating keratoplasty; although its IOP was 7 mm Hg, it showed an increased cup-to-disc ratio (0.5) and was therefore included in the cohort. The mean ± SD visual acuity was 0.6±0.7 logarithm of the minimum angle of resolution (LogMAR; range, -0.08 to 3.00), the mean ± SD spherical equivalent was -2.5±5.6 (range, -12.6 to 13.3), and the mean ± SD cup-to-disc ratio was 0.59±0.22 (range, 0.2-1.0).

Among the 78 eyes which underwent surgical or laser interventions, 38 (48.7%) had primary glaucoma and 40 (51.3%) had secondary glaucoma. The first glaucoma intervention for each eye is indicated in Table 3. The most commonly performed surgery was trabeculectomy with antimetabolites (26 eyes, 33.3%) followed by goniotomy (23 eyes, 29.5%) and glaucoma drainage device implantation (6 eyes, 7.7%). The most commonly performed laser procedure was transscleral cyclophotocoagulation (9 eyes, 11.5%). The mean ± SD number of glaucoma interventions per eye was 1.37±1.90 (range, 0-9). Of the 78 eyes which underwent surgical or laser interventions, 31 (39.7%) received one intervention during the study period while 47 (60.3%) received more than one intervention.

In all, 63.2% of eyes with primary glaucoma were treated surgically during the follow-up period; 54.8% of eyes with secondary glaucoma were treated by medications alone during the follow-up period. Among the 35 eyes of 18 patients with PCG, 23 eyes (66%) were managed surgically and only six of them (17.1%) were medication-free on the final follow-up. Among the 22 eyes of 12 patients with juvenile open-angle glaucoma, 15 eyes (68%) were managed surgically and only six of them (27.3%) were medication-free on the final follow-up. Among the 93 eyes of 68 patients with secondary glaucoma, 40 eyes (43.0%) were managed surgically during follow-up and 14 (15.1%) were medication-free on the final follow-up.

The mean ± SD LogMAR visual acuity at the final follow-up was 0.90±0.98 (range, -0.19 to 3.00, ie, no light perception). Among 111 eyes for which visual acuity was determined, 10 (9.0%) had no light perception at the final follow-up, four (3.6%) had light perception, five (4.5%) could perceive hand movement, and four (3.6%) could perceive finger counting. The mean ± SD IOP at the final follow-up was 18.4±6.6 mm Hg (range, 6-43 mm Hg), while the mean ± SD number of glaucoma medications at the final follow-up was 2.22±1.61 (range, 0-5). The mean ± SD spherical equivalent was -3.4±6.6 (range, -18.25 to 13.1), whereas the mean ± SD cup-to-disc ratio was 0.68±0.20 (range, 0.3-1.0). Clinical parameters among the different types of glaucoma (ie, PCG, juvenile open-angle glaucoma, and secondary glaucoma) are described in Table 4. As expected, PCG manifested at an earlier age, compared with other types of glaucoma. Patients with secondary glaucoma had a wider range of refraction because some exhibited hyperopia, such as in aphakic glaucoma. Other parameters (eg, IOP, cup-to-disc ratio, number of glaucoma interventions, and number of medications) were similar among the different types of glaucoma.

To our knowledge, this is the first epidemiological report concerning paediatric glaucoma in Hong Kong. Hong Kong had a population of 7.4 million in 2018,30 of which 92.0% were of Chinese ethnic origin, while there were 2.5% Filipinos, 2.1% Indonesians, and 0.8% Caucasians.29 In this study, we included patients with confirmed paediatric glaucoma who were managed in the ophthalmology departments of six regional clusters of the Hospital Authority in Hong Kong (Hong Kong East, Kowloon West, Kowloon Central, Kowloon East, New Territories West, and New Territories East) and The Chinese University of Hong Kong. In this study, we estimated the annual incidence rate of paediatric glaucoma in Hong Kong to be 0.92 per 100 000 population <20 years of age. The reported incidence rates have varied among previous studies, presumably because of differences in the ethnicity of the study population. In the British Infantile and Childhood Glaucoma Eye Study, Papadopoulos et al31 concluded that the incidence of PCG was nearly ninefold greater among children of Pakistani origin, compared with Caucasian children; other groups with high incidences of PCG included those of Bangladeshi and Indian origin. Notably, only one Chinese child (among 99 paediatric patients with newly diagnosed glaucoma) was diagnosed with PCG during the 1-year surveillance period. In total, 67% of all Pakistani children in that study were from consanguineous marriages. Although South Asians remain a minority in Hong Kong, local census data29 showed that the population increased from 47 505 to 80 028 from 2006 to 2016 (68% increase). Thus, clinicians should be aware of the potential for this condition among babies and children of specific ethnic origins.

Our study showed that PCG was the most prevalent type of glaucoma in our patient population, present in 23.3% of the included eyes; other common types were juvenile open-angle glaucoma (14.7%) and aphakic glaucoma (13.3%). The reported prevalences have varied among types of paediatric glaucoma in previous studies. Taylor et al3 described a population of Canadian patients with paediatric glaucoma, in which congenital glaucoma was the most common subtype (38% of patients). In the British Infantile and Childhood Glaucoma Eye Study,31 45 of 95 patients (47.4%) were diagnosed with PCG during the 1-year surveillance period. In mainland China, two hospital-based studies revealed the epidemiology of paediatric glaucoma in Chinese populations.32 33 Both studies concluded that congenital glaucoma was the most common subtype. Aponte et al34 reported the 40-year incidence and clinical characteristics of childhood glaucoma among patients in the region of Rochester, United States. They concluded that acquired and secondary forms of glaucoma were the most common, while congenital and juvenile forms of glaucoma were rare. Thus, we presume that variations in prevalence among different types of glaucoma are related to ethnicity.

Among patients with secondary glaucoma, the most commonly associated conditions were lens-related: aphakia (13.3% of eyes) and pseudophakia (4.7%) after cataract extraction for congenital cataract. Although the exact mechanisms of glaucoma in young patients with aphakia and pseudophakia are not well known, Beck et al35 suggested the following aetiologies based on their findings in the Infant Aphakia Treatment Study: congenital angle anomalies, postoperative inflammation leading to angle dysfunction or progressive synechial closure, corticosteroid-induced mechanisms, and some unknown influences of the aphakic state or vitreous interaction with developing angle structures that cause reduced outflow.

Congenital conditions, such as anterior segment dysgenesis (11.4%) and Sturge–Weber syndrome (4.7%), were also associated with glaucoma in our patients. Clinicians could occasionally discern irregular pupils or abnormal red reflex from the fundi in patients with anterior segment dysgenesis; Sturge–Weber syndrome is associated with the presence of a facial port-wine stain.

The mechanisms of uveitic glaucoma are not clearly known, they may involve inflammatory substances/cellular components that cause trabecular damage and blockage, as well as a response to steroid treatment in young patients, which causes high IOP.36 In addition to uveitis, 2.7% of eyes had steroid-induced glaucoma related to the chronic use of topical steroid treatment for other ophthalmic conditions (eg, allergy and chalazion) or systemic conditions (eg, eczema). Therefore, medication history concerning steroid use is an important consideration in paediatric patients; steroid self-medication and/or long-term steroid use without close IOP monitoring could carry a risk of glaucoma.37

Trauma-related glaucoma was also observed in 3.3% of included eyes; four of the five patients with traumatic glaucoma exhibited angle recession. Therefore, IOP should generally be measured in young patients after ocular trauma and the angle structure should be examined via gonioscopy whenever possible.

Parental concerns of tearing, photophobia, and cloudy cornea comprised approximately 21.5% of the reasons for referral in this cohort (20.7% of total eyes). High IOP comprised only 12.2% of the reasons for referral (13.3% of eyes); other ophthalmic complaints leading to referral included poor visual acuity (18.0% of eyes), strabismus (6.0% of eyes), and nystagmus (4.7% of eyes); these complaints could be related to the presence of unilateral or bilateral amblyopia. Buphthalmia is a finding of glaucoma in infancy as the young eye increases in size from elevated IOP due to corneal and scleral collagen immaturity (Fig).2 Therefore, a subset of patients presented with ocular asymmetry, buphthalmos, increased or early myopia, or increased cup-to-disc ratio with or without elevated IOP. Furthermore, although visual acuity may not be fully assessed in babies and young children, there is a need to actively screen for and treat amblyopia in this patient group. Amblyopia remains the main cause of poor visual acuity in patients with paediatric glaucoma. Appropriate correction of refractive error and eye patching are essential components of clinical management for these patients.

Family doctors and paediatricians are usually the first clinicians to examine paediatric patients with suspected glaucoma in the healthcare setting in Hong Kong. Early detection and diagnosis are important for preventing the loss of vision. Appropriate referral is based on the detection of signs and symptoms of paediatric glaucoma. Clinical signs include epiphora, conjunctival erythema, corneal enlargement, corneal clouding, Haabs striae, abnormally deep anterior chamber, myopia and/or astigmatism, and enlarged optic nerve cupping. The classic triad of epiphora, photophobia, and blepharospasm is usually evident in patients with congenital glaucoma. Other symptoms of paediatric glaucoma often include a cloudy and enlarged cornea or large eye, ocular asymmetry (ie, one eye larger than the other), blurring, frequent eye rubbing, pain and discomfort; moreover, the child may become irritable and fussy, and may exhibit a poor appetite. Family doctors and paediatricians may assess vision in older babies or young children; measure IOP using non-contact tonometry in older children (although there is no established range of normal IOP in paediatric patients, an IOP ≥21 mm Hg would merit referral to an ophthalmologist); and may detect manifestations of strabismus, nystagmus, ocular asymmetry, cloudy cornea, irregular pupil, and/or conjunctival injection. Prompt and early referrals are important for minimising visual loss and preventing amblyopia.

This study had some notable limitations. First, paediatric glaucoma is a rare and diverse condition with heterogeneous manifestations. Thus, there are no widely established diagnostic criteria and no standardised management protocol in use among different hospitals. Second, clinical data were collected retrospectively from the patients’ medical records in this study. Because the ophthalmology departments in most Hospital Authority service clusters have not fully implemented the use of electronic medical records for both out-patients and in-patients, the retrospective collection of handwritten clinical data from hard-copy medical records might have led to the unintentional exclusion of patients or data. Furthermore, missing data and recall bias may have influenced the findings, especially with respect to symptom presentation at the first clinical visit. Among patients who had not received surgical interventions, diagnostic information might have been omitted for some patients in some clusters. Finally, patients with paediatric glaucoma managed in the Hong Kong West Cluster and in the private sector were not included in this study; thus, the findings may not have been entirely representative of the whole territory, although this remains the largest cohort study of patients with paediatric glaucoma in Hong Kong.

Paediatric glaucoma remains an important and irreversible blinding eye disease among children. Children are often unable to complain of specific symptoms and the signs of paediatric glaucoma are often subtle; thus, parents, family doctors, and paediatricians should be familiar with the common manifestations of this disease. Family doctors and paediatricians should have a very high level of suspicion for paediatric glaucoma, combined with a lower threshold for referring patients to ophthalmologists for further evaluation and early treatment. Among the known types of paediatric glaucoma, PCG is the most common. Children with unexplained cloudy corneas, tearing, photophobia, diminished visual acuity, and signs of squinting should be promptly referred for further assessment.

Concept or design: NB Baig and CC Tham.
Acquisition of data: JJ Chan, JC Ho, GC Tang, S Tsang, KH Wan, WK Yip.
Analysis or interpretation of data: NB Baig and CC Tham.
Drafting of the manuscript: NB Baig and CC Tham.
Critical revision of the manuscript for important intellectual content: NB Baig and CC Tham.

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

The study obtained ethics approval from the following ethics committees:

Research Ethics Committee (Kowloon Central/Kowloon East) (Ref: KC/KE-15-0013/ER-2);

Research Ethics Committee, Kowloon West Cluster (Ref: KW/EX-15-056[85-09]);

Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (Ref: 2015.100);

New Territories West Cluster Clinical & Research Ethics Committee (Ref: NTWC/CREC/15010);

Hong Kong East Cluster Research Ethics Committee (Ref: HKEC-2015-033).

The participants (or a legal guardian) gave informed consent before the study.

1. Richardson KT Jr, Ferguson WJ Jr, Shaffer RN. Long-term functional results in infantile glaucoma. Trans Am Acad Ophthalmol Otolaryngol 1967;71:833-7.

2. Papadopoulos M, Khaw PT. Childhood glaucoma. In: Taylor D, Hoyt CS, editors. Pediatric Ophthalmology and Strabismus. 3rd ed. Philadelphia: Elsevier Saunders; 2005: 458-71.

3. Taylor RH, Ainsworth JR, Evans AR, Levin AV. The epidemiology of pediatric glaucoma: the Toronto experience. J AAPOS 1999;3:308-15. Crossref

4. Shaffer RN, Weiss DI. Infantile glaucoma: diagnosis and differential diagnosis. Congenital and Pediatric Glaucomas. St. Louis: CV Mosby; 1970: 37-59.

5. Elder MJ. Congenital glaucoma in the West Bank and Gaza Strip. Br J Ophthalmol 1993;77:413-6. Crossref

6. Genĉík A. Epidemiology and genetics of primary congenital glaucoma in Slovakia. Description of a form of primary congenital glaucoma in gypsies with autosomal-recessive inheritance and complete penetrance. Dev Ophthalmol 1989;16:76-115.

7. Turaçli ME, Aktan SG, Sayli BS, Akarsu N. Therapeutic and genetical aspects of congenital glaucomas. Int Ophthalmol 1992;16:359-62. Crossref

8. McGinnity FG, Page AB, Bryars JH. Primary congenital glaucoma: twenty years experience. Ir J Med Sci 1987;156:364-5. Crossref

9. Jay MR, Rice NS. Genetic implications of congenital glaucoma. Metab Ophthalmol 1978;2:257-8.

10. Barsoum-Homsy M, Chevrette L. Incidence and prognosis of childhood glaucoma. A study of 63 cases. Ophthalmology 1986;93:1323-7. Crossref

11. François J. Congenital glaucoma and its inheritance. Ophthalmologica 1980;181:61-73. Crossref

12. Morin JD, Merin S, Sheppard RW. Primary congenital glaucoma—a survey. Can J Ophthalmol 1974;9:17-28.

13. Sarfarazi M, Stoilov I. Molecular genetics of primary congenital glaucoma. Eye (Lond) 2000;14:422-8. Crossref

14. Idrees F, Vaideanu D, Fraser SG, Sowden JC, Khaw PT. A review of anterior segment dysgeneses. Surv Ophthalmol 2006;51:213-31. Crossref

15. Nelson LB, Spaeth GL, Nowinski TS, Margo CE, Jackson L. Aniridia. A review. Surv Ophthalmol 1984;28:621-42.Crossref

16. Francois J. Late results of congenital cataract surgery. Ophthalmology 1979;86:1586-98. Crossref

17. Simon JW, Mehta N, Simmons ST, Catalano RA, Lininger LL. Glaucoma after pediatric lensectomy/vitrectomy. Ophthalmology 1991;98:670-4. Crossref

18. Rabiah PK. Frequency and predictors of glaucoma after pediatric cataract surgery. Am J Ophthalmol 2004;137:30-7. Crossref

19. Vishwanath M, Cheong-Leen R, Taylor D, Russell-Eggitt I, Rahi J. Is early surgery for congenital cataract a risk factor for glaucoma? Br J Ophthalmol 2004;88:905-10. Crossref

20. Sullivan TJ, Clarke MP, Morin JD. The ocular manifestations of the Sturge-Weber syndrome. J Pediatr Ophthalmol Strabismus 1992;29:349-56.

21. Sijssens KM, Rothova A, Berendschot TT, de Boer JH. Ocular hypertension and secondary glaucoma in children with uveitis. Ophthalmology 2006;113:853-9.e2. Crossref

22. Walton DS. Primary congenital open-angle glaucoma. In: Chandler PA, Grant WM, editors. Glaucoma. 2nd ed. Philadelphia: Lea & Febiger; 1979: 329-43.

23. Tabbara KF, Badr IA. Changing pattern of childhood blindness in Saudi Arabia. Br J Ophthalmol 1985;69:312-5. Crossref

24. Gilbert CE, Canovas R, Kocksch de Canovas R, Foster A. Causes of blindness and severe visual impairment in children in Chile. Dev Med Child Neurol 1994;36:326-33. Crossref

25. Haddad MA, Lobato FJ, Sampaio MW, Kara-José N. Pediatric and adolescent population with visual impairment: study of 385 cases. Clinics (Sao Paulo) 2006;61:239-46. Crossref

26. Gilbert CE, Rahi JS, Quinn GE. Visual impairment and blindness in children. In: Johnson GJ, Minassian DC, Weale RA, West SK, editors. The Epidemiology of Eye Disease. 2nd ed. London: Edward Arnold Ltd; 2003: 260-86.

27. Planning Department, Hong Kong SAR Government. Projections of Population Distribution 2015-2024. Hong Kong: Planning Department, Hong Kong SAR Government; 2015.

28. Census and Statistics Department, Hong Kong SAR Government. Hong Kong 2006 Population By-Census (Report). Hong Kong: Census and Statistics Department, Hong Kong SAR Government; 2006.

29. Census and Statistics Department, Hong Kong SAR Government. Hong Kong 2016 Population By-Census (Report). Hong Kong: Census and Statistics Department, Hong Kong SAR Government; 2016.

30. Census and Statistics Department, Hong Kong SAR Government. Hong Kong Monthly Digest of Statistics (Report). Hong Kong: Census and Statistics Department, Hong Kong SAR Government; 2018.

31. Papadopoulos M, Cable N, Rahi J, Khaw PT, BIG Eye Study Investigators. The British Infantile and Childhood Glaucoma (BIG) Eye Study. Invest Ophthalmol Vis Sci 2007;48:4100-6. Crossref

32. Qiao CY, Wang LH, Tang X, Wang T, Yang DY, Wang NL. Epidemiology of hospitalized pediatric glaucoma patients in Beijing Tongren Hospital. Chin Med J (Engl) 2009;122:1162-6.

33. Fang Y, Long Q, Guo W, Sun X. Profile of pediatric glaucoma patients in Shanghai Eye, Ear, Nose and Throat Hospital. Chin Med J (Engl) 2014;127:1429-33.

34. Aponte EP, Diehl N, Mohney BG. Incidence and clinical characteristics of childhood glaucoma: a population-based study. Arch Ophthalmol 2010;128:478-82. Crossref

35. Beck AD, Freedman SF, Lynn MJ, Bothun E, Neely DE, Lambet SR, Infant Aphakia Treatment Study Group. Glaucoma-related adverse events in the Infant Aphakia Treatment Study: 1-year results. Arch Ophthalmol 2012;130:300-5. Crossref

36. Sen ES, Dick AD, Ramanan AV. Uveitis associated with juvenile idiopathic arthritis. Nat Rev Rheumatol 2015;11:338-48. Crossref

37. Nuyen B, Weinreb RN, Robbins SL. Steroid-induced glaucoma in the pediatric population. J AAPOS 2017;21:1-6. Crossref

Cross-border reproductive care (CBRC) is an increasingly popular global trend in reproductive medicine, whereby patients travel out of their home country to receive fertility treatment.1 2

This phenomenon has also been referred to as “reproductive tourism”, “reproductive travel”, “health travel”, and “reproductive exile”.3 4 Among these terms, CBRC has a relatively neutral meaning and is used in the present study to avoid stigmatisation. Thus far, CBRC has been described in Europe, North America, Middle East, Australia, and Japan.1 2 3 4 5 6 7 8 9 10 11

A survey in Europe in 2010 showed that there were 24 000 to 30 000 cycles of CBRC annually, which involved 11 000 to 14 000 patients.12 13 Because 525 640 total treatment cycles were performed during the same period, approximately 5% of the fertility care was estimated to involve CBRC. In the US, nearly 4% of all fertility treatment provided was delivered to non-US residents; this comprised approximately 6000 cycles.13 14 The reasons for CBRC use in Europe12 included avoidance of legal restrictions at home (eg, fertility treatment for single and lesbian women in France and pre-implantation genetic testing in Germany), avoidance of lengthy waiting lists at home (eg, for egg donation in the United Kingdom), lower treatment cost, and treatment within a more favourable framework (eg, gamete donation with donor anonymity).

The aim of the present study was to evaluate the use of CBRC and its influencing factors in Hong Kong.

Women with infertility who attended infertility clinics in the Hospital Authority (ie, Queen Mary Hospital, Pamela Youde Nethersole Eastern Hospital, Kwong Wah Hospital, and Prince of Wales Hospital) and the Family Planning Association (FPA) from 1 February 2017 to 31 March 2019 were recruited to participate in the study. Women who could not read English or Chinese were excluded from the study. All participants provided written informed consent to participate. The study was approved by the Institutional Review Boards of all participating centres, including the Hong Kong East Cluster Ethics Committee (HKECREC-2018-014); The University of Hong Kong Hong Kong West Cluster Clinical Research Ethics Committee (UW 18-266); Kowloon Central/Kowloon East Cluster Clinical Research Ethics Committee (KC/KE-18-0073/ER-4); North Territories East Cluster Clinical Research Ethics Committee (NTEC-2018-0384); and the Ethics Panel and the Health Services Subcommittee of the FPAHK (OA1-2).

A search of the literature was conducted using PubMed using the terms “cross border reproductive care”, “reproductive travel”, “infertility”, and “Hong Kong”. It revealed no existing validated questionnaires concerning CBRC use in Hong Kong. Most questions in our questionnaire were adapted from another questionnaire focused on CBRC.5 The questionnaire content focused on three main areas: (1) demographic information, (2) reproductive history and attitudes concerning fertility, and (3) factors affecting the use of CBRC. The questionnaire was evaluated and revised by specialists in Obstetrics and Gynaecology and subspecialists in Reproductive Medicine, all of whom worked in the Hospital Authority. It was then piloted by administration to five patients in the clinic with the aim of ensuring that patients could understand the questionnaire.

Women with infertility who attended infertility clinics in the Hospital Authority or FPA were invited to participate in the study. The questionnaire was distributed by clinic nurses to clinic attendees. Participation was voluntary and patients were invited to complete the questionnaire without assistance while awaiting medical consultation. The questionnaire required approximately 20 minutes to complete. Completed questionnaires were returned to the clinic nurse at the end of the consultation.

Calculations were performed using SPSS Statistics for Windows, version 25.0 (IBM Corp, Armonk [NY], US). Associations between attitudes towards CBRC and background variables (total monthly household income, education level, years of attempting conception, and age) were explored using the Chi squared test. P values <0.05 were considered to indicate statistical significance. Logistic regression was used to investigate whether respondent age, education level, years of attempting conception, and total monthly household income were associated with CBRC use.

In total, 1204 questionnaires were returned (Table 1): 175 (14.5%) from Pamela Youde Nethersole Eastern Hospital, 510 (42.4%) from Queen Mary Hospital, 293 (24.3%) from Kwong Wah Hospital, 146 (12.1%) from Prince of Wales Hospital, and 80 (6.6%) from the FPA. The mean age (±standard deviation) of the respondents was 34.7±6.8 years. Among the 1204 respondents, 913 women (76.6%) had primary infertility and 279 women (23.4%) had secondary infertility. Thirty one women had an existing child. All respondents indicated that they were married; the shortest duration was 0.2 years. This finding was presumably influenced by the marriage requirement for intrauterine insemination (IUI) and in vitro fertilisation (IVF) in Hong Kong. Concerning the duration of attempted conception, 863 women (72.0%) had been actively trying for fewer than 5 years, 311 women (26.0%) had been actively trying for 5 years to fewer than 10 years, 22 women (1.8%) had been actively trying for 10 years to fewer than 15 years, and two women (0.2%) had been actively trying for 15 years or more.

There were missing data in our study involving non-responses to some questionnaire components. The missing data exhibited a random pattern and did not cluster around a particular question. Because the number of missing values was small (<5%), these values were omitted from further analyses.

Overall, 1051 respondents (87.3%) reported unremarkable medical histories. The cause of infertility was unexplained in 516 respondents (43.0%, 516/1200), related to the male partner in 216 respondents (18.0%, 216/1200), caused by a tubal factor in 181 respondents (15.1%, 181/1200), and caused by anovulation in 103 respondents (8.6%, 103/1200). The remaining respondents noted that infertility was attributed to endometriosis, other factors, or unknown (ie, no previous consultation). Notably, 578 respondents (48.0%, 578/1204) or their partners were unwilling to accept adoption. When asked to rank the importance of having a child, 382 respondents (31.7%, 382/1204) reported a score of 10/10 (very important). Furthermore, 300 respondents (24.9%, 300/1204) reported that having a child was very important to their marital relationship (score of 10/10). Finally, 351 respondents (29.2%, 351/1204) felt that having a child was very important to their family members (score of 10/10).

In total, 178 women (14.8% of total respondents) had used CBRC (Table 2). Among respondents who had not used CBRC, 36.3% (372/1026) were planning or would consider it. The 550 respondents who had previously used CBRC, were planning for CBRC, or would consider CBRC were then asked to choose one reproductive technology that they preferred for use in CBRC; 54.4% selected non-donor IVF as their treatment of choice. In all, 40.6% of these respondents showed interest in IUI; only 0.6% showed interest in oocyte donation, 0.2% showed interest in sperm donation, and 0.4% showed interest in surrogacy for CBRC.

The two main factors positively influencing its use (ie, motivational factors) were long waiting times in the public sector and high treatment costs in the private sector, reported by 80.9% (445/550) and 12.0% (66/550), respectively, of the respondents who had used or would consider CBRC. Only 0.5% (3/550) of the respondents reported law evasion as a positive influence for the use of CBRC.

Most respondents indicated that Taiwan was their preferred destination (69.6%; 383/550); China was the second-most preferred destination (25.8%; 142/550).

Most respondents who had used or would consider CBRC (61.1%; 336/550) felt that it was difficult to allocate time for CBRC. In total, 14.5% of these respondents (80/550) had a suspicion of substandard medical technology in the destination countries. Some respondents were worried about a language barrier and the lack of communication between local doctors and doctors in the destination countries.

Respondents accessed information concerning CBRC through multiple channels (Table 2). Among the respondents who had used or would consider CBRC, more than half (57.1%; 314/550) accessed information from the internet; 32.7% (180/550) obtained relevant information from their friends. Notably, only 4.0% of these respondents (22/550) obtained information concerning CBRC from professional sources (eg, local fertility clinics).

Among respondents who had used or would consider CBRC (n=550), 340 (61.8%) indicated that they had received local counselling from their home country to assist in CBRC treatment. Among the 178 respondents who had previously used CBRC, 67 (37.6%) had some involvement from local doctors in their home country during CBRC treatment.

Among respondents who had engaged in CBRC and reached the point of embryo transfer (n=59), 40 (67.8%) had undergone transfer of two embryos. Surprisingly, 10 women (16.9%) had undergone transfer of three embryos and three women (5.1%) had undergone transfer of four embryos.

Among the 178 respondents who had used CBRC, three (1.7%) had ovarian hyperstimulation syndrome and three (1.7%) had other types of complications. Overall, 70.2% of the respondents believed that the authorities in Hong Kong should formulate some regulations or guidance regarding CBRC.

Associations between attitudes towards CBRC and background variables were also explored using the Chi squared test. Respondents who had a total monthly household income above >HK$100 000 were more likely to consider CBRC than those who had total monthly household income of ≤HK$100 000 (P<0.001). Respondents who had a university degree or above were also more likely to consider CBRC than those who had education below university level (P<0.001). Respondents who had been attempting conception for ≥5 years had a similar likelihood of CBRC use, compared with those who had been attempting conception for <5 years. Respondents aged ≥35 years had a similar likelihood of CBRC use, compared with those aged <35 years.

Logistic regression analysis of factors potentially associated with CBRC use revealed no relationships with respondent age, education, years of attempting conception, or total monthly household income.

To the best of our knowledge, this is the first study concerning the use of CBRC and factors affecting its use in Hong Kong. Nearly one in six women with infertility had used CBRC and approximately one-third of the respondents planned to use or would consider it. The main factors influencing the likelihood of CBRC use, instead of local reproductive care, included long waiting times in the public sector and high cost in the private sector. Over half of the respondents accessed information from the internet. More than two thirds of respondents believed that the authorities in Hong Kong should formulate some regulations or guidance regarding CBRC.

It is difficult to compare the use of CBRC in Hong Kong with that in Europe (5%) and the US (4%); the methodologies have differed among studies and the extent of CBRC use in Hong Kong was not fully established in the present study. Where women in Europe frequently engage in CBRC for purposes of law evasion, women in Hong Kong appear to engage in CBRC primarily because of the long waiting lists for public fertility treatment. In a survey of European women, law evasion was a concern for 55% of women using CBRC (9% of patients in the UK, 65% in France, 71% in Italy, and 80% in Germany).12 Specific assisted reproduction treatment, such as surrogacy or oocyte donation, is prohibited in some countries (eg, Italy, Germany, and Japan), but legal in other countries (eg, Belgium, India, and the US). We found that only 0.5% of women in Hong Kong travelled for purposes of law evasion. This may be partly explained by the legal availability of gamete donation and surrogacy in Hong Kong (although no treatment centres in Hong Kong an appropriate licence to offer surrogacy). Because of differences in cultural backgrounds, compared with prior studies, women in Hong Kong may be less interested in gamete donation (eg, in relation to their traditional Chinese beliefs).

Surprisingly, many respondents in our study engaged in IUI during CBRC. Among respondents in this subgroup, the two main motivational factors were identical: long waiting times in the public sector and high treatment costs in the private sector. The waiting time for IUI in public hospitals within the Hospital Authority may be longer than many patients prefer; this includes the waiting time for the initial consultation, required examinations, and subsequent waiting list for IUI treatment. The treatment cost of IUI is much lower than that of IVF in the private sector, but may be prohibitive for many patients from lower and middle social classes. We also acknowledge possible misconceptions among our respondents, who may presume that IUI is always the first-line approach or must be performed prior to IVF.

Among women who had previously engaged in non-donor IVF during CBRC, 33.1% were aged <35 years. Among all the respondents who engaged in CBRC, 30% of the respondents were aged <35 years and had unexplained infertility. Given the large percentage of young women with unexplained infertility who actually engaged in IVF during CBRC, it is unclear whether there is an overtreatment problem or inappropriate use of IVF treatment during CBRC. However, the treatment of unexplained infertility is empirical. A recent Cochrane systemic review revealed insufficient evidence for differences in live birth between expectant management and the other four interventions (ovarian stimulation, IUI, stimulated IUI, and IVF).15 For most couples, the American Society of Reproductive Medicine recommends that the preferred initial therapy is three or four cycles of ovarian stimulation with oral medications and IUI, followed by IVF for those unsuccessful with stimulated IUI treatments.16 In contrast, the 2013 guidelines of the National Institute for Health and Care Excellence recommend IVF treatment for women with unexplained infertility who have not conceived after 2 years of regular unprotected sexual intercourse. Therefore, stimulated IUI and IVF are both appropriate treatment options for unexplained infertility as the first-line therapy after adequate counselling.17

Pre-implantation genetic testing is increasingly used to detect genetic abnormalities in embryos, thus allowing replacement with normal embryos. Pre-implantation genetic testing is useful when prospective parents either have or are carriers of a genetic disease that is potentially transmissible to their offspring. A small proportion of the patients in our study (1.5%) had engaged or were interested in CBRC for pre-implantation genetic testing. In Hong Kong, pre-implantation genetic testing is permitted for medical indications and is available in Queen Mary Hospital, Prince of Wales Hospital, and some private assisted reproduction centres. Because it is legal and available in Hong Kong, few of our respondents reported a desire to engage in CBRC for pre-implantation genetic testing. A small percentage of patients (0.4%) reported a desire to engage in CBRC for sex selection. Notably, sex selection of embryos for non-medical reasons is prohibited in Hong Kong and many Western countries; however, it is allowed in the US.

Our results found that the most popular CBRC destination for Hong Kong couples with infertility was Taiwan. This may be due to the presence of Taiwanese agencies established in Hong Kong who provide local couples with the option of going to Taiwan to undergo CBRC. It may also be associated with the close proximity, relatively lower costs, and potential family ties involving Taiwan.

Importantly, we found that the internet was the major source of information for women in Hong Kong seeking CBRC. Women who intended to go abroad sought information concerning CBRC primarily via the internet, rather than from their local doctors or fertility clinics. This phenomenon is consistent with the findings in another study, which reported that the internet was the main source of information for Swedish, German, and British women seeking CBRC.12

For respondents who had engaged in CBRC and reached the point of embryo transfer, the majority had undergone transfer of two embryos. An alarming result of our study was that one of the patients had undergone transfer of four embryos. High-order multiple pregnancies can potentially cause significant morbidity and mortality for the mother and the baby. To reduce the likelihood of multiple births, some countries/places (eg, the United Kingdom and Hong Kong) have placed restrictions on the number of embryos transferred during each cycle. A previous survey found that 14 countries had an upper limit of three embryos, 12 had a limit of four, and six had a limit of five.18 This indicates that CBRC may pose an increasing challenge for obstetricians and paediatricians due to the increasing likelihood of higher multiple pregnancies from CBRC, which indirectly leads to a burden on the local healthcare system. Clinicians should remind patients about the implications of the number of embryos transferred during CBRC and the potential risk of multiple pregnancy.

Potential advantages to CBRC include that it provides an equal opportunity for treatment, thus improving patient autonomy; however, that autonomy may come at a cost or involve law invasion. Cross-border reproductive care also illustrates the principle of freedom of patient movement, as set out in a 2008 Directive of the European Commission.19

The largest potential problem related to CBRC involves patient health and safety. In the context of assisted reproduction treatment, this could include multiple pregnancies, ovarian hyperstimulation syndrome, and infectious disease transmission. The lack of uniform clinical and safety regulations worldwide is further complicated by the lack of policies to govern CBRC. This could mean that patients are disadvantaged, such that they cannot receive information or services that are of a minimum quality standard. The lack of knowledge provided to patients could inhibit their ability to discover potential services. It is often difficult for a patient to assess the standard of quality of a fertility clinic in another country, in terms of infection screening measures, embryology laboratory quality, and risk management measures (eg, gamete and embryo handling). Therefore, patients assume greater risk when they engage in CBRC, compared with fertility treatment in their home country, because of the difference in accessible information. The safety of women in Hong Kong who travel abroad for fertility treatment is jeopardised by the current lack of uniform clinical and safety regulations in other parts of the world.

Strategies to minimise the negative impact of CBRC should focus on each of the relevant stakeholders: patients, clinicians, and local regulatory bodies. First, patients who are interested in CBRC should obtain more information prior to engaging in CBRC. They should be aware of the potential complications and the success rate in the destination country centre, then make informed choices for themselves when embarking on fertility treatment in another country. Second, clinicians must educate their patients about the potential risks of CBRC. Clinicians who are collaborating with doctors in other countries to facilitate in CBRC should formulate a clear plan concerning the role of patient management, ensuring that patients’ best interests are respected. Clinicians should also resume care of a patient who has returned after receiving CBRC treatment, especially if that patient has encountered complications from fertility treatment during CBRC. Third, in Europe, the European Society of Human Reproduction and Embryology has published a good practice guide for CBRC for centres and practitioners.2 Such guidelines can help regulators and policy makers create a framework to enable centres to abide by these rules. The Hong Kong SAR Government can also formulate guidance for clinicians and publish advice for patients who are considering CBRC, particularly highlighting the potential problems of CBRC. Over two thirds of respondents in the present study believed that authorities in Hong Kong should formulate some regulations or guidance regarding CBRC.

This study had a number of limitations. First, it included patients with infertility who were not pregnant at the time of consultation. Patients who had a successful pregnancy following CBRC would not attend infertility clinics; hence, they would not be included in our sample. This could have led to an underestimation of the use of CBRC. Second, this study only involved heterosexual couples who were legally married, which was a prerequisite for receiving assisted reproduction in Hong Kong. The study did not include single women, single men, or same-sex couples in Hong Kong who probably engaged in CBRC for gamete donation or surrogacy. Third, the infertility centres in this study cannot be considered representative of all infertility centres in Hong Kong. A relatively small number of patients were recruited. A territory-wide study should be performed to further evaluate the state of CBRC in Hong Kong.

Notably, the European Society of Human Reproduction and Embryology recognises that ideal reproductive care involves fair access to good quality treatment in a patient’s home country.2 To ensure fair access to infertility care in Hong Kong, the waiting lists in the public sector should be shortened. Based on the results of this questionnaire study, the current CBRC trend in Hong Kong will presumably continue until the local health authorities implement more effective measures to manage the long waiting lists in the public sector. Patient education on this topic should also be improved.

Nearly one in six women with infertility in Hong Kong had used CBRC. Among women who had not used CBRC, more than one third had planned to use or would consider it. The main factors influencing the likelihood of using CBRC instead of local reproductive care included long waiting times in the public sector and high cost in the private sector. These results will help clinicians to more effectively counsel patients considering CBRC and facilitate infertility services planning by authorities in Hong Kong.

Concept or design: DYT Ng, EHY Ng.
Acquisition of data: All authors.
Analysis or interpretation of data: DYT Ng, EHY Ng.
Drafting of the manuscript: DYT Ng, EHY Ng.
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.

We would like to express our gratitude to Ms Merie Yuen, project nurse of University of Hong Kong for data collection and entry.

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

The study was approved by the Institutional Review Boards of all participating centres, including the Hong Kong East Cluster Ethics Committee (HKECREC-2018-014); The University of Hong Kong Hong Kong West Cluster Clinical Research Ethics Committee (UW 18-266); Kowloon Central/Kowloon East Cluster Clinical Research Ethics Committee (KC/KE-18-0073/ER-4); North Territories East Cluster Clinical Research Ethics Committee (NTEC-2018-0384); and the Ethics Panel and the Health Services Subcommittee of the FPAHK (OA1-2).

All participants provided written informed consent to participate in the questionnaire study.

1. Inhorn MC, Patrizio P. The global landscape of cross-border reproductive care: twenty key findings for the new millennium. Curr Opin Obstet Gynecol 2012;24:158-63. Crossref

2. Shenfield F, Pennings G, de Mouzon J, Ferraretti AP, Goossens V, ESHRE Task Force ‘Cross Border Reproductive Care’ (CBRC). ESHRE’s good practice guide for cross-border reproductive care for centers and practitioners. Hum Reprod 2011;26:1625-7. Crossref

3. Inhorn MC, Patrizio P. Rethinking reproductive ‘‘tourism’’ as reproductive ‘‘exile’’. Fertil Steril 2009;92:904-6. Crossref

4. Mattorras R. Reproductive exile versus reproductive tourism. Hum Reprod 2005;20:3571. Crossref

5. Culley L, Hudson N, Rapport F, Blyth E, Norton W, Pacey AA. Crossing borders for fertility treatment: motivations, destinations and outcomes of UK fertility travellers. Hum Reprod 2011;26:2373-81. Crossref

6. Gomez VR, de La Rochebrochard E. Cross-border reproductive care among French patients: experiences in Greece, Spain and Belgium. Hum Reprod 2013;28:3103-10. Crossref

7. Gürtin ZB. Banning reproductive travel: Turkey’s ART legislation and third party assisted reproduction. Reprod Biomed Online 2011;23:555-64. Crossref

8. Bergmann S. Reproductive agency and projects: Germans searching for egg donation in Spain and the Czech Republic. Reprod Biomed Online 2011;23:600-8. Crossref

9. Hughes EG, Dejean D. Cross-border fertility services in North America: a survey of Canadian and American providers. Fertil Steril 2010;94:e16-9. Crossref

10. Inhorn MC, Shrivastav P, Patrizio P. Assisted reproductive technologies and fertility ‘‘tourism”: examples from global Dubai and the Ivy League. Med Anthropol 2012;31:249-65. Crossref

11. Yuri H, Yosuke S, Yasuhiro K, Yoshiaki H, Hiroyuki N. Attitudes towards cross-border reproductive care among infertile Japanese patients. Environ Health Prev Med 2013;18:477-84. Crossref

12. Shenfield F, de Mouson J, Pennings G, et al. Cross border reproductive care in six European countries. Hum Reprod 2010;25:1361-8. Crossref

13. Hudson N, Culley L, Blyth E, Norton W, Rapport F, Pacey A. Cross-border reproductive care: a review of the literature. Reprod Biomed Online 2011;22:673-85. Crossref

14. National Center for Chronic Disease Prevention and Health Promotion, Division of Reproductive Health, US Government. 2013 Assisted reproductive technology: national summary report 5 (2015). Available from: http://www.cdc.gov/art/pdf/2013-report/art_2013_national_summary_report.pdf. Accessed 4 Dec 2019.

15. Wang R, Danhof NA, Tjon-Kon-Fat RI, et al. Interventions for unexplained infertility: a systematic review and network meta-analysis. Cochrane Database Syst Rev 2019;(9):CD012692. Crossref

16. Practice Committee of the American Society for Reproductive Medicine. Evidence-based treatments for couples with unexplained infertility: a guideline. Fertil Steril 2020;113:305-22. Crossref

17. National Collaborating Centre for Women’s and Children’s Health (UK). Fertility: Assessment and Treatment for People with Fertility Problems. London: Royal College of Obstetricians and Gynaecologists; 2013.

18. International Federation of Fertility Societies. Global Reproductive Health: IFFS Surveillance 2016. September 2016. Available from: https://journals.lww.com/grh/Fulltext/2016/09000/IFFS_Surveillance_2016.1.aspx. Accessed 4 Dec 2019.

19. Commission of the European Communities. Proposal for a Directive of the European Parliament and of the Council on the application of patients’ rights in cross-border healthcare. 2008. Available from: http://ec.europa.eu/health/ph_overview/co_operation/healthcare/docs/COM_en.pdf. Accessed 4 Dec 2019.

Timely reperfusion for ischaemic stroke with intravenous thrombolysis (IVT) or mechanical thrombectomy can substantially improve patient outcomes.1 Hence, all possible efforts should be made to shorten the stroke onset-to-treatment time. The major benchmark for measurement of acute stroke treatment speed is the door-to-needle time, that is, the duration between Accident and Emergency Department (AED) arrival and administration of IVT. Other benchmarks include duration between AED arrival and brain computed tomography (door-to-CT time) and duration between AED arrival and groin puncture for mechanical thrombectomy (door-to–groin puncture time). The recommended intervals are within 60 minutes for door-to-needle time, 25 minutes for door-to-CT time, and 120 minutes for door-to–groin puncture time.

The American Heart Association/American Stroke Association Target Stroke initiative supports implementation of strategies to shorten the door-to-needle time. These include advance hospital notification by emergency medical service (EMS) personnel, rapid triage protocol in the AED, rapid acquisition of brain imaging data, and a team-based approach. These strategies were consolidated in the recent recommendation for establishing a system of care for patients with stroke.2 3

Before 2018, there was no pre-hospital stroke notification system in Hong Kong.4 Patients with ischaemic stroke, including those who are within the therapeutic window for reperfusion therapy, are transferred to the nearest AED under the regular triage system, which may delay reperfusion treatment. Herein, we investigate the effects of a team-based pre-hospital stroke notification system designed to improve the delivery of acute stroke care.

Our pre-hospital stroke notification system was established in collaboration between the AED, stroke neurologists, neurosurgeons, and the ambulance service. This included an advance hospital notification by EMS personnel, rapid triage protocol, advance stroke team notification, and image acquisition via CT. The EMS personnel screened patients with suspected stroke using a locally formulated pre-hospital stroke assessment scale to identify reperfusion-eligible patients with stroke. For patients who met all criteria, advance hospital notification was activated by calling a designated number in the AED; this call served to alert the stroke team, triage station, and on-duty AED medical officer. A CT scan was then arranged by the AED medical officer in the next available urgent slot.

Our simple pre-hospital stroke assessment in Chinese was formulated on the basis of the Los Angeles Pre-hospital Stroke Screen and the Face drooping, Arm weakness, Speech difficulty, Time to call 911 (FAST) screening criteria.5 6 In contrast to the Los Angeles Pre-hospital Stroke Screen and FAST criteria, we aimed to identify only patients eligible for reperfusion therapy, in whom earlier treatment would provide the greatest benefit. The inclusion criteria were as follows: (1) ≤4 hours since onset of symptoms, (2) sudden limb weakness or speech impairment, (3) age >18 years, (4) stroke unrelated to recent trauma, (5) Glasgow Coma Scale score ≥8, (6) systolic blood pressure of >100 mm Hg, (7) no history of seizures/epilepsy, and (8) absence of previous wheelchair-bound or bed-ridden status. Patients who satisfied all eight inclusion criteria underwent a point-based Chinese FAST screening (speech disturbance = 2 points; unilateral facial drooping = 1 point; and unilateral limb weakness = 2 points). Advance hospital notification was activated for eligible patients with ≥2 points in the FAST screening.

All EMS personnel within our hospital’s catchment area attended a 2-hour stroke training session delivered by a team of stroke neurologists, neurosurgeons, and emergency physicians. This included didactic instruction concerning stroke subtypes, symptoms, reperfusion therapy pre-hospital management, and hands-on training for utilisation of the ambulance stroke assessment scale.

The pre-hospital stroke screening and notification system was implemented on 1 July 2018. All patients with acute stroke admitted via ambulance transfer from July 2018 to October 2019 were prospectively included in this study. Data were collected concerning patient characteristics, stroke severity, and temporal trends of stroke treatment. Patients admitted via the AED whose admission had included acute stroke diagnosis, during the period from January 2018 to June 2018 (6 months before implementation of the pre-hospital stroke screening and notification system), were retrospectively identified as historical controls.

Categorical variables were compared using Chi squared analysis, while continuous variables were compared using independent t tests and one-way analysis of variance. Univariate analysis was initially used on all variables; the results were recorded as odds ratios with 95% confidence intervals. Kaplan–Meier curve and log rank test analyses of door-to-needle time with and without notification were performed. Statistical significance was set at P<0.05. All analyses were performed using SPSS Statistics for Windows, version 25.0 (IBM Corp, Armonk [NY], United States).

During the study period, 298 patients with suspected stroke were screened by the ambulance staff. Of these 298 patients, 213 fulfilled the screening criteria for pre-hospital notification; the AED was notified for 211 (99.1%), in accordance with study protocol. Among patients for whom the AED was notified, 166 (78.7%) were eventually diagnosed with acute stroke. The final diagnoses of patients without stroke included vasovagal syncope, fever/sepsis, and acute coronary syndrome (Fig 1).

Among the 211 patients for whom pre-arrival notification was performed, 32 (15.2%) received reperfusion therapy (IVT and/or intra-arterial endovascular thrombectomy [IAT]). Reperfusion therapy was not administered to the remaining 134 patients for reasons such as intracranial haemorrhage, resolution of symptoms after arrival, and mild neurological deficits. Among the 85 patients who did not fulfil the screening criteria, one eventually received thrombectomy. Stroke notification was not performed for this patient due to uncertain time of symptom onset.

We compared the temporal trends in provision of acute stroke care after the implementation of ambulance stroke screening with a historical cohort from the period prior to implementation (Table 1). The door-to-CT time (25.6 min vs 32.0 min, P=0.021), door-to-needle time (49.2 min vs 70.1 min, P=0.003) [Fig 2], and door-to–groin puncture time for IAT (126.7 min vs 168.6 min, P=0.04) were significantly shortened after implementation of the pre-hospital stroke screening and notification system, compared with the historical control cohort. The proportions of patients who underwent CT within 25 minutes (68.6% vs 51.6%, P=0.001) and groin puncture within 120 minutes were also increased (72.3% vs 18.2%, P=0.008). Notably, the onset-to-door time was shortened by more than 1.5 hours (100.6 min vs 197.6 min, P<0.001) after implementation of our system.

Furthermore, we compared the temporal trends in patients who received reperfusion therapy (ie, IVT and IAT) during the study period between patients who underwent pre-notification screening and those who did not (Table 2). The door-to-needle time was significantly reduced with pre-notification screening (49.2 min vs 75.2 min, P=0.005). The door-to-CT time and door-to–groin puncture time also tended to be shorter with pre-notification, although these differences were not statistically significant.

The typical patient with stroke loses 1.9 million neurons per minute while the stroke remains untreated.7 Each minute saved between onset of stroke and treatment grants 1.8 days of extra healthy life.1 Timely reperfusion therapy with thrombolysis or thrombectomy has been demonstrated to reduce long-term disability when administered early to eligible patients. Earlier thrombolysis also lowers the risks of complications such as haemorrhagic transformation.8 9 Our study demonstrated that the implementation of a simple yet effective pre-hospital screening notification system significantly shortened time to diagnosis of acute stroke and subsequent intervention. This confirms the importance of pre-hospital notification in facilitating downstream management of patients with acute stroke by allowing the AED and stroke team to prepare for the patient’s arrival in advance.

The efficiency of the acute stroke treatment pathway was improved by the notification system for the following reasons. First, early notification by the ambulance team allowed the AED and stroke physicians to assess the patient’s medical history, including their eligibility and contra-indications for emergency reperfusion therapy, before patient arrival at the hospital. Second, the triage process at the AED was streamlined and patients with suspected stroke could be prioritised and immediately attended by the medical team. Moreover, the CT-suite staff were alerted to ensure the availability of a CT scan slot upon patient arrival. Third, the acute stroke nurse was consulted early to standby for patient arrival at the AED. Finally, the stroke alert created a sense of urgency among all medical and allied health professionals involved in stroke care, thereby enhancing the speed of the entire care pathway. Our experience is consistent with the reports from other medical systems that have implemented stroke alert systems to reduce door-to-needle time.10 11 12

Notably, the present study demonstrated that the door-to–groin puncture time for thrombectomy candidates was also markedly reduced by pre-arrival notification, enabling the majority of patients to undergo groin puncture within 120 minutes. This is likely due to the longer time required to coordinate the neurointerventionist, interventional suite, and anaesthesiology care team; this process was initiated early with pre-arrival stroke notification. Consistent with our findings, pre-arrival notification is now recommended for all patients with suspected stroke, according to the 2019 guidelines of the American Stroke Association.3 Future efforts should focus on pre-hospital screening of thrombectomy-eligible patients with large vessel occlusion and establishment of a diversion system to ensure patients are transported to thrombectomy-capable hospitals.10

One concern related to pre-hospital stroke screening was the potential for over-calling and thus overloading the acute stroke treatment pathway, thereby negatively affecting the AED service for patients with non-stroke emergencies. To maximise cost-effectiveness, the screening criteria were tailored to reduce notification for patients with stroke mimics and to exclude patients who were unlikely to benefit from acute reperfusion therapy. The addition of criteria such as the time of onset and pre-morbid functional status enabled efficient detection of reperfusion-eligible patients without excessively overloading the acute stroke treatment pathway. These approaches are known to prioritise patients with salvageable stroke for timely reperfusion therapy and are especially relevant in resource-limited public healthcare systems with restricted capacity to expeditiously manage all patients with stroke.13 As capacity improves, the criteria can be modified to include patients with delayed presentation after stroke onset.

Our study also validated the use of a Chinese version of the FAST criteria for screening of patients with suspected acute stroke. An important criticism of the FAST criteria is that they are not universally applicable in Chinese-speaking populations because there is no direct translation of “Face Arm Speech Time” to a memorable phase.14 15 In Hong Kong, the FAST mnemonic has been modified to “談笑用兵”, which is a well-recognised Chinese idiom where the characters represent Speech, Smile (Face), Mobilise (Arm), and Troop (Time to call for help). This version has been promoted widely by local healthcare professionals and stroke awareness organisations in the past decade. This concise screening algorithm is easily learned and rapidly performed, as reflected by the high accuracy in stroke detection by our ambulance staff after a 2-hour education session. To the best of our knowledge, this is the first study concerning the clinical utility of this modified screening algorithm. Recently, Chinese versions of similar scales, such as “Stroke 1-2-0” (China) and “Stroke 112” (Taiwan), have been proposed in other Chinese-speaking countries; each has achieved satisfactory acceptance among healthcare professionals.14 15 However, these scales have not achieved widespread recognition by the general populations of those countries. Improved versions that aim to stratify large vessel occlusion strokes (ie, BE-FAST) or a new score developed specifically for use by ambulance staff may be introduced in the future. Comparative studies of these different scales and their applicability among Chinese-speaking countries will provide useful information to unify stroke awareness efforts across these populations. Further cost-effectiveness studies to evaluate the impact and sustainability of the system on a territory-wide scale will be beneficial for long-term infrastructure development in acute stroke care.

This study had some limitations. First, because of logistical considerations, symptom onset time of ≤4 hours was used as a screening criterion. This was established on the basis of the practical expected times required to institute thrombolysis (30 min) or coordinate thrombectomy (120 min) at the time of study initiation. Because the time window for thrombectomy has been expanded from 6 to 24 hours in patients with favourable penumbra demonstrated with CT perfusion imaging, the cut-off time of symptom onset can be extended accordingly. Second, EMS personnel may serve multiple catchment areas. Hence, patients with stroke may be transported by ambulances with EMS personnel who did not undergo the additional training; these patients may not be screened and hospitals may not be notified before patient arrival. Third, clinical outcome data were not consistently available for the historical cohort, precluding analysis of clinical benefits due to improved stroke treatment times. This issue might be resolved through territory-wide adoption of a stroke screening protocol.

Implementation of pre-hospital stroke screening using criteria based on a modified version of the FAST test, together with pre-arrival notification, significantly shortened the door-to-reperfusion therapy time for patients with acute ischaemic stroke. Pre-hospital stroke screening during ambulance transport by EMS personnel who complete a 2-hour focused training session is effective for identifying reperfusion-eligible patients with stroke.

Concept or design: KC Teo, MMY Tse, WM Lui, TC Tsang, ACO Tsang.
Acquisition of data: WCY Leung, WM Kwok, LHC Lam, OMY Choi, ACO Tsang.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: WCY Leung, KC Teo, OMY Choi, ACO Tsang.
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 no conflicts of interest to disclose.

We would like to acknowledge the ambulance staff of the Ambulance Command (Hong Kong Division), Fire Services Department for the support in this project and in improving stroke patient care in Hong Kong.

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

The study was approved by The University of Hong Kong/Hospital Authority Hong Kong West Cluster Research Ethics Committee (Ref UW20-442). The patients provided written informed consent for all treatments and procedures.

1. Meretoja A, Keshtkaran M, Saver JL, et al. Stroke thrombolysis: save a minute, save a day. Stroke 2014;45:1053-8. Crossref

2. Adeoye O, Nyström KV, Yavagal DR, et al. Recommendations for the establishment of stroke systems of care: a 2019 update. Stroke 2019;50:e187-210. Crossref

3. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019;50:e344-418. Crossref

4. Tsang AC, Yeung RW, Tse MM, Lee R, Lui WM. Emergency thrombectomy for acute ischaemic stroke: current evidence, international guidelines, and local clinical practice. Hong Kong Med J 2018;24:73-80. Crossref

5. Kidwell CS, Starkman S, Eckstein M, Weems K, Saver JL. Identifying stroke in the field. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). Stroke 2000;31:71-6. Crossref

6. Harbison J, Hossain O, Jenkinson D, Davis J, Louw SJ, Ford GA. Diagnostic accuracy of stroke referrals from primary care, emergency room physicians, and ambulance staff using the face arm speech test. Stroke 2003;34:71-6. Crossref

7. Saver JL. Time is brain—quantified. Stroke 2006;37:263-6. Crossref

8. Saver JL, Fonarow GC, Smith EE, et al. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke. JAMA 2013;309:2480-8. Crossref

9. Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010;375:1695-703. Crossref

10. Chiu YC, Tang SC, Sun JT, et al. Using G-FAST to recognize emergent large vessel occlusion: a training program for a prehospital bypass strategy. J Neurointerv Surg 2020;12:104-8. Crossref

11. Tan BY, Ngiam NJ, Sunny S, et al. Improvement in door-to-needle time in patients with acute ischemic stroke via a simple stroke activation protocol. J Stroke Cerebrovasc Dis 2018;27:1539-45. Crossref

12. Zhang S, Zhang J, Zhang M, et al. Prehospital notification procedure improves stroke outcome by shortening onset to needle time in Chinese urban area. Aging Dis 2018;9:426-34. Crossref

13. Tsang AC, Yang IH, Orru E, et al. Overview of endovascular thrombectomy accessibility gap for acute ischemic stroke in Asia: a multi-national survey. Int J Stroke 2020;15:516-20. Crossref

14. Zhao J, Eckenhoff MF, Sun WZ, Liu R. Stroke 112: a universal stroke awareness program to reduce language and response barriers. Stroke 2018;49:1766-9. Crossref

15. Zhao J, Liu R. Stroke 1-2-0: a rapid response programme for stroke in China. Lancet Neurol 2017;16:27-8. Crossref

The rapid spread of coronavirus disease 2019 (COVID-19) has become a focus of public health concern since November 2019. According to the World Health Organization report with data updated on 6 November 2020, the COVID-19 pandemic has caused over 48.5 million confirmed cases and over 1.23 million deaths worldwide.1 The 2019 novel coronavirus has been designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the Coronavirus Study Group of the International Committee on Taxonomy of Viruses. The Law on Prevention and Control of Infectious Diseases, China categorises COVID-19 as a Category B infectious disease, but it is supervised as Category A in China.

During the early stage of the COVID-19 outbreak, especially before the lockdowns of Wuhan City and then Hubei Province, some people who had been infected by the virus travelled back to Hangzhou from Wuhan. Then the disease was disseminated by person-to-person transmission within the Hangzhou community. A familial cluster of the disease occurred during the self-isolation and home quarantine period because of intrafamilial transmission. The XiXi Hospital of Hangzhou was immediately designated by the government as the only municipal hospital for diagnosis and therapy of patients with COVID-19 in Hangzhou City. We reviewed and analysed the hospital’s medical records to determine the epidemiological and clinical characteristics of these cases.

This retrospective observational study was performed on the records of patients who were treated from 15 January 2020 to 30 March 2020 at the XiXi Hospital of Hangzhou. The study adhered to the ethical principles of medical research involving human subjects of the World Medical Association Declaration of Helsinki and was approved by the Ethics Committee of the XiXi Hospital of Hangzhou. Informed consent was waived because of the retrospective nature of this study.

The following instruments and materials were used in the study: a blood gas analyser (Radiometer ABL90, Denmark), an automatic haematology analyser (SYSMEX XE-5000, Japan), an automatic coagulation analyser (SYSMEX CS5100, Japan), an automatic biochemistry analyser (Beckman Coulter AU5831, US), and a vacuum blood collection tube (BD Vacutainer containing lithium heparin anticoagulant, US). Body surface temperature was detected by a non-contact infrared thermometer (JXB-178, Berrcom, Guangzhou). A fever was defined as a body temperature >37.0°C. Chest computed tomography (CT) scans (GE Revolution EVO, US) were conducted on every patient. Standard nucleic acid detection for SARS-CoV-2 was conducted at the Hangzhou Municipal Center for Disease Control and Prevention by the way of qualitative polymerase chain reaction (PCR). The diagnostic criteria were based on the recommendation of the National Institute for Viral Disease Control and Prevention, China (http://ivdc.chinacdc.cn/kyjz/202001/ t20200121_211337.html).

Epidemiological and demographic information about patients with COVID-19 was collected and reviewed, including age, gender, height, weight, co-morbidities like hypertension and type 2 diabetes mellitus, history of smoking, drinking and surgery, and recent travel and residence history. The clinical features and symptoms were recorded and reviewed during hospital visits. The results of the first laboratory tests performed on hospital admission were analysed. During hospitalisation, clinical and laboratory characteristics including SARS-CoV-2 nucleic acid test results were evaluated. Radiological manifestations on chest CT scan were examined. The outcomes of treatment were checked, and the patients received follow-up.

Two attending doctors were responsible for the diagnosis and treatment of all patients with COVID-19 according to the clinical diagnosis guideline and treatment protocol for COVID-19 released by the National Health Commission & National Administration of Traditional Chinese Medicine, China and the Zhongnan Hospital of Wuhan University Novel Coronavirus Management and Research Team.2 3 The radiological diagnosis of chest CT scans was decided by two attending radiologists and another two attending clinical doctors independently.

The laboratory-confirmed cases were classified according to severity as mild (ie, mild symptoms without pneumonia), moderate (ie, respiratory symptoms and fever with pneumonia), severe (ie, respiratory distress, respiratory frequency ≥30/min, blood oxygen saturation ≤93%, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen <300 mm Hg, and/or lung infiltration >50% within 24-48 hours), and critical (ie, respiratory failure, shock, and/or multiple organ dysfunction or failure).

The discharge criteria were normalisation of body temperature for more than 3 days, obvious improvement of respiratory symptoms, pulmonary imaging showing distinct inflammation absorption, and two consecutive negative nucleic acid tests on respiratory tract samples such as sputum or nasopharyngeal swab (with a sampling interval of at least 24 hours). Patients with COVID-19 who met the above criteria could be discharged.

We used SPSS (Windows version 19.0; IBM Corp, Armonk [NY], US) for all statistical analyses. One-way analysis of variance was performed to compare continuous, normally distributed numeric variables, which were presented as means and 95% confidence intervals. The Mann-Whitney U non-parametric test was used to compare continuous numeric variables with skewed distributions, which were shown as medians and 95% confidence intervals. The Pearson χ² test was employed to compare categorical variables, which were presented as frequencies and proportions (percentages). A stratified analysis by age was also conducted. Comparative analysis between early and late discharge was implemented to explore potentially associated factors. A P value of <0.05 was considered to be statistically significant.

Among these 96 patients with COVID-19, six were aged 0 to 18 years and 14 were aged >60 years (Table 1). Most (79.2%) patients were aged between 19 and 60 years. No significant sex difference was discovered. All patients had basically normal body mass index values. Half of patients aged >60 years had a history of hypertension. Eight adult patients had a surgical history involving pituitary tumour, pulmonary abscess, coronary artery bypass grafting because of coronary heart disease, gallbladder stone, ovarian cyst, Caesarean section, or splenectomy because of trauma. Other co-morbidities were exclusively observed in patients aged >40 years, including type 2 diabetes mellitus, fatty liver, hepatitis B, liver cirrhosis, and bronchiectasis. A history of smoking or drinking was reported by nine (9.4%) and 10 (10.4%) patients, respectively.

Among 96 patients with confirmed infection, 28 (29.2%) had travelled from Wuhan City, and 51 cases were acquired via close contact. However, a few patients had no definitive contact history, even after rigorous tracing. Familial clusters of the disease accounted for 48 of this study’s cases, and 11 patients who had travelled from Wuhan City presented in familial clusters. In most familial clusters, two members were attacked, however, six family members were also found to be infected in two separate familial clusters.

The mean time from symptom onset to the first visit was 3.7 days, and the time to hospital admission was 4.5 days. The period from symptom onset to definitive diagnosis based on positive viral nucleic acid test was 5.2 days. The mean incubation time was 7.0 days. The mean time with fever before admission was 3.3 days, and the maximum body temperature before admission was 37.9°C.

The laboratory-confirmed patients’ main symptoms were fever, cough, fatigue, sore throat, chills, expectoration, shortness of breath, headache, dizziness, decreased appetite, diarrhoea, nausea, and vomiting (Table 2). These symptoms essentially involved the respiratory system, in addition to the alimentary and central nervous systems. The symptoms were basically similar across different age-groups, except that shortness of breath occurred more commonly among patients aged >60 years.

As presented in Table 3, the mean white blood cell count was not elevated. Besides white blood cells, the levels of haemoglobin, eosinophil, and platelets were basically within normal ranges. Lymphocytopenia was observed predominantly in patients aged >60 years. The concentrations of blood electrolytes, glucose, lactate, triglycerides, and free fatty acids were largely normal. Injury to the liver, kidney, heart, and coagulation systems were not observed. Further, hypoxaemia was not found in most cases on hospital admission, except for several patients aged >60 years. The overall ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen was about 340 mm Hg. Inflammatory biomarkers are an acute-phase response to the virus insult and are therefore involved in the development of the disease. Generally, the level of blood C-reactive protein was slightly elevated on admission (16.2 mg/L), and that of patients aged >60 years was relatively higher (31.6 mg/L). Serum amyloid A concentration increased in almost all cases (61.7 mg/L), especially for patients aged >60 years (88.1 mg/L). The procalcitonin level did not increase across all cases on admission.

During hospitalisation, eight patients with COVID-19 were transferred to a designated provincial hospital in Hangzhou to enact an optimal allocation policy. Therefore, we analysed the clinical and laboratory features of 88 cases during hospitalisation (Table 4). The severity of disease was mild or moderate in 83 patients (around 94%). Among 12 patients aged >60 years, three (25%) had severe disease. The mean length of stay across all cases was 15.6 days. The mean time with fever during hospitalisation was 4.4 days. The mean maximum body temperature was 37.8°C. Hypokalaemia, hyponatraemia, and hypoalbuminaemia were more likely to develop in patients aged >60 years. The time from symptom onset to secondary negative result of a viral nucleic acid test was about 17 days, and the mean time to patient discharge was about 20 days.

Most cases (59.1%) were supported through nasal catheter or mask oxygen. No one was assisted by non-invasive or invasive mechanical ventilation. All patients were treated with one or two kinds of antivirals, ie, α-interferon, lopinavir/ritonavir, or abidor. Antibiotics like levofloxacin and moxifloxacin were prescribed when bacterial infection was suspected. Adjuvant therapy with glucocorticoids (methylprednisolone, 40-80 mg/d) or γ-globulin was implemented only in a small percentage of cases (around 10%) and exclusively in adult patients. All patients successfully recovered and were discharged. No one progressed to the critically ill state, and the absence of recurrence in all cases was confirmed by follow-up until 20 June 2020.

Radiological pulmonary imaging was evaluated during hospitalisation of the patients with moderate and severe disease (74 cases) [Table 5 and Fig]. A total of 19 (25.7%) and 55 (74.3%) patients presented with unilateral and bilateral pulmonary lesions, respectively. Ground-glass opacities in the lungs were discovered on chest CT scan in approximately 50% of cases. Radiological pulmonary changes were mostly distributed in the subpleural area (around 80%), and pleural effusion rarely occurred in any age-stratified group. The mean time from symptom onset to the worst CT imaging finding was 9 days, and the mean time to the start of pulmonary infiltration absorption on CT imaging was about 12 days.

We explored the factors that could potentially be associated with early discharge of patients with COVID-19 (Table 6). Early discharge was defined as a hospital length of stay (LOS) of ≤10 days. A comparison was conducted between early (LOS ≤10 days) and late (LOS >10 days) discharge of patients with COVID-19. Of the investigated patients, 20 cases were discharged early, whereas 68 cases underwent late discharge. We compared 13 factors between the two groups. Two factors were significantly associated with early discharge: more patients in the early discharge group compared with the late discharge group had travelled from Wuhan City (50.0% vs 22.1%). Further, the time from symptom onset to secondary negative result of a viral nucleic acid test was shorter in the early discharge group than the late discharge group (11.8 days vs 18.7 days).

The emergence and spread of COVID-19 has caused a new public health crisis to threaten the world. Patient zero of the disease is still unknown, although many of the initial cases in Wuhan City had exposure to the Huanan Seafood Wholesale Market in common.4 5 A probable bat origin of SARS-CoV-2 has been considered.6 Angiotensin-converting enzyme II has been reported to be the entry receptor on epithelial and endothelial cells within the lung, heart, kidney, and intestine.6 7 As a highly contagious disease, COVID-19 is transmitted by inhalation or contact with infected droplets. On 23 January 2020, Wuhan City, as the epicentre of COVID-19 in China, was locked down to prevent the disease’s spread. Before the lockdown, some infected people left Wuhan City for other cities outside Hubei Province. Then, extensive person-to-person transmission occurred.8 9 Thanks to healthcare service providers, all hospitalised patients with COVID-19 in our research survived, recovered successfully, and then were eventually discharged. The findings of our observational study can provide help with decision making about public health policy involving COVID-19 prevention and therapy.

This retrospective study reports the epidemiological, demographic, clinical, laboratory, and radiological findings of patients with COVID-19 who were treated at a designated hospital in Hangzhou City. A comparative analysis according to age stratification was implemented. Deterioration was more probable in patients aged over 60 years with underlying co-morbidities. The finding is consistent with those of another previous report.10 Deterioration could be associated with the ageing and dysfunction of organs, especially reduced immune function as lymphocytopenia. Severe acute respiratory syndrome coronavirus 2 can consume lymphocytes, which is probably an important cause of the proliferation and spread of the virus. Although we did not detect the plasma levels of pro-inflammatory mediators like tumour necrosis factor and interleukin, the cytokine storm has been previously reported to be associated with COVID-19 severity.11

Respiratory symptoms like fever, cough, sore throat, and shortness of breath were commonly the first presentations during hospital visits among the patients in the present study. The disease should be differentiated from influenza and common cold-causing rhinovirus or parainfluenza virus infections. In the early stage of the pandemic, a policy of selfisolation and home quarantine was implemented. However, because of the high contagiousness of SARS-CoV-2, 50% (48 of 96) of the cases in our study appeared as familial clusters. Prior studies also reported the discoveries of case clusters within familial households.12 13 14 The basic reproductive number (R0) has been revealed to be as high as 2.2 or even 5.7.15 16 Therefore, strict control measures should be implemented to avoid intrafamilial dissemination during self-isolation and home quarantine.

The disease has very strong infectivity by human-to-human transmission, even during the incubation period. Based on the gradually increasing understanding of the disease’s characteristics, the policy for personnel travelling from the epidemic area to Hangzhou City was changed from self-isolation and home quarantine to centralised compulsory isolation on 21 March 2020. Consequently, person-to-person transmission was effectively controlled. Therefore, strict quarantine has been confirmed to be the only effective intervention to decrease the contagion rate.

Early negative turning of the viral nucleic acid test was associated with early discharge of patients with COVID-19 in this study. This may imply early recovery of injured organs. A relatively high proportion of patients who travelled from Wuhan City were discharged early. Thus, SARS-CoV-2 could have mutated and evolved. More research is needed to clarify that whether its virulence has increased or decreased after its propagation through generations.

In this study, five (5.7%) patients had the severe disease type, but no patients died. In a summary report from Chinese Center for Disease Control and Prevention with data updated through 11 February 2020, 14% of 44 415 confirmed cases were classified as severe, and 5% were critical.13 The overall case-fatality rate was 2.3% (1023 of 44 672 confirmed cases). In Italy, the corresponding rate was reported to be 7.2% (1625 deaths of 22 512 cases) based on data through 17 March 2020.17 The case-fatality rate of COVID-19 is much lower than those of the prior SARS and Middle East Respiratory Syndrome, which were 9.6% and 34.4%, respectively.13 However, because of the shortage of PCR test kits and the existence of false-negative PCR results, the actual number of cases in the population is unknown. Serological tests, when available, could be adopted widely in the future for COVID-19 diagnosis. Although the quantity of cases in this study is limited, overall recovery from the disease will proceed well when diagnosis and treatment are conducted early and properly, if overcrowding of medical resources is avoided.

Bilateral distribution of patchy shadows and ground-glass opacities in the subpleural area were the most frequently discovered radiological findings in the present study, and these are typical hallmarks of radiological pulmonary imaging in COVID-19.18 Although multiple organs (eg, those of the respiratory, alimentary, genitourinary, and central nervous systems) can interact with SARS-CoV-2 owing to viraemia and the cytokine storm, the lungs are still the principal target of the virus. Generally, the pulmonary presentation is consistent with the clinical severity of COVID-19. Because there were no critical cases in our study, more severe chest imaging findings were not present (eg, entire lungs involved in exudation and consolidation). Certain critical patients in intensive care units with severe acute respiratory distress syndrome even need extracorporeal membrane oxygenation support.19 In epidemic areas, chest CT could also be adopted as an early supplementary diagnostic tool.20

So far, there is no specifically proven antiviral treatment for COVID-19. The mainstay of therapy is optimised supportive care, including proper oxygen supply. The efficacy of antiviral drugs, including lopinavir/ritonavir, is still unknown.21 The pharmacotherapies used in the present study, including antiviral and immunomodulating treatments, are only empirical and palliative. Further randomised clinical trials are urgently needed to determine the most effective evidence-based treatments.

The current study has several limitations. First, this is a retrospective study with data from a single centre. The number of included cases is relatively small. However, it is meaningful for the evaluation of characteristics of early cases outside of Wuhan City, especially for policy makers. Second, no potentially effective antiviral drugs can be proposed by the present study. Further basic and clinical research is required to elucidate effective and safe pharmacotherapies, as to date, no proven antiviral drugs are available. Third, asymptomatic infection of COVID-19 is currently an important issue. We do not have enough data to provide associated information. More studies are needed to provide diagnosis and differentiation of asymptomatic cases, particularly involving the serological and nucleic acid tests that have recently become available to the general population.

During the early stage of the COVID-19 outbreak, half of the patients from a designated hospital in Hangzhou City were discovered as familial clusters. Therefore, strict prevention and control measures should be implemented during self-isolation. Patients aged >60 years with underlying co-morbidities were prone to lymphocytopenia and severe infection.

Concept or design: J Gao, S Zhang.
Acquisition of data: K Zhou, X Zhao, J Liu.
Analysis or interpretation of data: J Gao, Z Pu.
Drafting of the manuscript: J Gao, Z Pu.
Critical revision of the manuscript for important intellectual content: S Zhang, K Zhou, X Zhao, J Liu.

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.

All authors thank all of the patients with COVID-19 and healthcare service providers at XiXi Hospital of Hangzhou, China.

This research was supported by the Innovative Talents Supportive Project from Medical Health Science and Technology Programme of Zhejiang Provincial Health Commission, China (Ref 2020RC072). The funder had no role in study design, data collection/analysis/interpretation, or manuscript preparation.

The study was approved by the Ethics Committee of the XiXi Hospital of Hangzhou, China (Ref 2020-31). The requirement for informed consent was waived because of the retrospective nature of this study.

1. World Health Organization. Coronavirus disease (COVID-2019) situation report. 6 Nov 2020. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/. Accessed 8 Nov 2020.

2. Zhao JY, Yan JY, Qu JM. Interpretations of “diagnosis and treatment protocol for novel coronavirus pneumonia (Trial Version 7)”. Chin Med J (Engl) 2020;133:1347-9. Crossref

3. Jin YH, Cai L, Cheng ZS, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res 2020;7:4. Crossref

4. Forster P, Forster L, Renfrew C, Forster M. Phylogenetic network analysis of SARS-CoV-2 genomes. Proc Natl Acad Sci USA 2020;117:9241-3. Crossref

5. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727-33. Crossref

6. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-3. Crossref

7. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020;367:1444-8. Crossref

8. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708-20. Crossref

9. Li X, Zai J, Wang X, Li Y. Potential of large “first generation” human-to-human transmission of 2019-nCoV. J Med Virol 2020;92:448-54. Crossref

10. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507-13. Crossref

11. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. Crossref

12. Chan JF, Yuan S, Kok KH, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2020;395:514-23. Crossref

13. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020;323:1239-42. Crossref

14. Yu P, Zhu J, Zhang Z, Han Y. A familial cluster of infection associated with the 2019 novel coronavirus indicating possible person-to-person transmission during the incubation period. J Infect Dis 2020;221:1757-61. Crossref

15. Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 2020;382:1199-207. Crossref

16. Sanche S, Lin YT, Xu C, Romero-Severson E, Hengartner N, Ke R. High contagiousness and rapid spread of severe acute respiratory syndrome coronavirus 2. Emerg Infect Dis 2020;26:1470-7. Crossref

17. Onder G, Rezzz G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA 2020;323:1775-6. Crossref

18. Cao Y, Liu X, Xiong L, Cai K. Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2: a systematic review and meta-analysis. J Med Virol 2020 Apr 3. Epub ahead of print. Crossref

19. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061-9. Crossref

20. Ai T, Yang Z, Hou H, et al. Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases. Radiology 2020;296:E32- 40. Crossref

21. Cao B, Wang Y, Wen D, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe COVID-19. N Engl J Med 2020;382:1787-99. Crossref