The outbreak of coronavirus disease 2019 (COVID-19) leads to a declaration of a serious level of response on 4 January 2020, which was escalated to the emergency level on 25 January 2020.1 2 Corresponding policies were imposed by the Hospital Authority at that time. Visiting periods were suspended, and mask wearing became mandatory in hospitals. In obstetrics, companionship during childbirth was stopped, as were visits to newborns staying with mothers in the postnatal ward. All prenatal exercise, antenatal talks, hospital tours, and postnatal classes were cancelled. The infection continued to spread worldwide, and a pandemic was declared by the World Health Organization on 11 March 2020. The first case of a COVID-19-infected pregnant mother was confirmed on 20 March 2020. The Hong Kong Government has further restricted travel and tightened social distancing and other measures to limit the spread of COVID-19.

Increased psychological stress and anxiety levels have been reported in countries with major outbreaks.3 4 As reflected by the Edinburgh Postnatal Depression Scale (EPDS), pregnant women assessed after the declaration of the COVID-19 epidemic had significantly higher rates of depressive symptoms than women assessed before the announcement in China.5 6 Behavioural changes have also been recognised among pregnant women.7 This evolving situation and its concomitant alterations in obstetric care can potentially pose extra psychological stress during the peripartum period.

In our university-affiliated tertiary hospital in Hong Kong, screening for women at risk of or having emotional problems is performed for all pregnancies antenatally during a booking visit. Counselling and support are provided by trained midwives and nurses from Comprehensive Child Development Service to those in need. Postpartum depression is routinely assessed after delivery using the validated EPDS.8 9 The aim of the present study was to examine the effect of COVID-19 and its concurrent service adjustments on couples’ obstetric planning and postpartum depression.

This was a retrospective study of the delivery data and EPDS scores of women who delivered at Queen Mary Hospital in Hong Kong from 1 January 2019 to 30 April 2020. Information related to the original number of bookings, actual deliveries, childbirth companionship, basic demographics, mode of delivery, epidural rate, and other methods of pain relief were retrieved from the Clinical Information System and Clinical Data Analysis and Reporting System of the Hospital Authority.

Screening for postpartum depression was performed routinely by asking all women to complete the EPDS questionnaire 1 day after delivery. This assessment was conducted again by phone within 1 week after delivery. The EPDS consists of 10 questions with a maximum score of 30 and has a validated Chinese version.9 10 A cut-off of ≥10 was adopted locally. Women with high scores were counselled by a dedicated team of midwives and psychiatric nurses.

Comparisons of delivery data and EPDS scores were performed between women who delivered during the pre-alert period (1 Jan 2019 to 4 Jan 2020) and the post-alert period (5 Jan 2020 to 30 Apr 2020). Analysis was performed using SPSS (Windows version 25; IBM Corp, Armonk [NY], United States). Student’s t tests and Chi squared tests were used as appropriate with P<0.05 considered as statistically significant.

There were 1997 pregnant women with expected delivery dates between January 2020 and April 2020 booked for delivery at Queen Mary Hospital, as compared with 1869 bookings for the corresponding 4-month period in 2019. However, there was a 13.1% reduction in the number of actual deliveries between 1 January and 30 April, from 1144 in 2019 to 994 in 2020. Fewer than half of the total number of women who originally booked for delivery in our hospital eventually delivered there, and the drop was more profound from February to April 2020. As a result, there were 3577 deliveries from 1 January 2019 to 4 January 2020 (ie, the pre-alert group) and 954 deliveries from 5 January 2020 to 30 April 2020 (ie, the post-alert group).

A significantly higher proportion of Chinese women (85.1% vs 81.5%; P<0.05) delivered during the post-alert period, while proportion of women with labour companionship was significantly reduced (21.8% vs 88.8%; P<0.05) compared with the pre-alert period. For pain relief during labour, more women received pethidine injections and fewer women used a birthing ball during the post-alert period. The other parameters were comparable between the two groups (Table 1).

Out of 4531 total deliveries, EPDS scores were available for 4357 (96.2%) 1 day after delivery and 3772 (83.2%) within 1 week after delivery. A significantly higher proportion of women had EPDS scores of ≥10 1 day after delivery in the post-alert group compared with the pre-alert group (14.4% vs 11.9%; P<0.05). This proportion was reduced to 2.9% on the second assessment within 1 week of delivery, at which point the scores became comparable with those of the pre-alert group (2.3%).

Compared with the first assessment 1 day after delivery, women in both groups demonstrated significantly lower mean EPDS scores on the second assessment within 1 week (pre-alert group: 4.71 vs 1.36; post-alert group: 4.93 vs 1.42; P<0.01). The mean EPDS scores obtained on both 1 day (4.93 vs 4.71) and within 1 week (1.42 vs 1.36) after delivery were higher following the declaration of alert response, although the difference was statistically insignificant. The monthly mean EPDS score 1 day after delivery was higher during the post-alert period (range, 4.87-4.99) than during the pre-alert period (4.71; 95% confidence interval=4.57-4.85; Table 2).

The present study is the first to report the impact of COVID-19 on obstetric care and postpartum depression in Hong Kong. The delivery rate in public hospitals has dropped dramatically in the post-alert period. This drop has been more profound since February 2020, especially among non-Chinese women. As of 30 April 2020, there had been three confirmed COVID-19 cases in pregnant women in Hong Kong. Although local changes in public health behaviour, social distancing, and isolation have largely contained the local outbreak of COVID-19,2 these policies could disrupt couples’ delivery plans. The reduced delivery rate could represent a shift of childbirth from public hospitals to private ones that did not manage suspected or confirmed COVID-19 patients. Non-Chinese women might have returned to their home countries out of fear of COVID-19. Women who deliver in public hospitals now increasingly have to face the challenge of childbirth without the companionship of family members and complete their hospital stay without visitors. All of these could account for the reduced delivery rate in the public sector.

Another important finding was the increased proportion of women with high EPDS scores in the post-alert period. We observed an increase in EPDS scores shortly after delivery during the post-alert period. This aligns with the findings of a multicentre study conducted in China following the announcement of human-to-human transmission.6 The COVID-19 pandemic could cause health anxiety and postpartum depression.7 11 Women of reproductive age in Hong Kong experienced the severe adult respiratory syndrome epidemic in 2002 to 2003. Thus, these women are potentially more stressed than those in other countries. An emergency response was raised in Hong Kong even before the declaration of a pandemic by the World Health Organization. The practice of mask wearing has been widely adopted previously, and supplies have been in huge demand in the past.1 The memories of severe acute respiratory syndrome coupled with the abrupt changes in social behaviour during the post-alert period might have triggered more stress in pregnant women and been reflected in their EPDS scores. Moreover, those who remained in the public system might not have had alternative delivery options elsewhere. Pregnant women are vulnerable to postpartum depression, and early identification and effective intervention from Comprehensive Child Development Service might help to relieve these women’s stress. These adverse effects could also potentially be ameliorated by the provision of online education materials, a lactation support hotline, early postnatal discharge, and family support.

Childbirth is a major life event for a family. Companions can provide information about childbirth, bridge communication gaps between healthcare workers and women, and facilitate non-pharmacological pain relief. They can also provide practical support, including encouraging women in labour to move around, providing massages, and holding their hands.12 The overall usage of non-pharmacological pain relief was similar between the pre- and post-alert periods. However, a significantly lower proportion of women used a birthing ball for pain relief during labour in the post-alert period, probably secondary to the suspension of childbirth companionship. Fewer women received childbirth massages, as they are usually provided by companions. Contrary to this, more women needed pethidine injections during labour. This indicates the contributory role of childbirth companionship to women’s overall birthing experience.

The present study illustrates the impact of COVID-19 on pregnant women’s delivery plans and the need for attention to their emotional disturbance. This is important information for obstetricians to consider during the revision and adjustment of service provision. Remedial measures like teleconferencing and early postnatal discharge can facilitate speedy recovery from distress. Although we noted increased levels of postnatal depression in the post-alert period, this study was not designed to study the contributory effects of COVID-19, cessation of childbirth companionship, or elimination of visiting hours to postnatal depression. Another limitation is the lack of data on anxiety levels, which could provide a more comprehensive picture of the pregnant women’s emotional health. Moreover, this review is limited to the assessment of women who ultimately delivered in our hospital. Such women might be more adaptive and prepared for the altered environment than those who chose to give birth in the private sector or abroad. As the study was restricted to one public hospital, the findings might not be generalisable to hospitals in other catchment areas, which may have different population characteristics. The policies of restricted gathering and social distancing might affect the arrangements of family celebrations, baby showers, and the cultural practice of ‘doing the month’. It will be of interest to examine whether women’s stress and anxiety levels change during the later postnatal period. Further study is warranted to examine the social and psychological responses of pregnant women during the COVID-19 pandemic.

Measures to limit the spread of COVID-19 have resulted in fewer deliveries in our public hospital and more symptoms of postpartum depression. Obstetricians should be aware of these effects on the psychosocial well-being of pregnant women and offer timely intervention to provide stress relief.

Concept or design: All authors.
Acquisition of data: PW Hui, G Ma, MTY Seto.
Analysis or interpretation of data: PW Hui.
Drafting of the manuscript: PW Hui.
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 thank all midwives and nurses for their contributions to the assessment of postnatal depression in women who delivered at Queen Mary Hospital.

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

This research has been approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority West Cluster (HKU/HA HKW IRB; Ref UW 20-419).

1. Leung GM, Cowling BJ, Wu JT. From a sprint to a marathon in Hong Kong. N Engl J Med 2020;382:e45. Crossref

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

3. Moghanibashi-Mansourieh A. Assessing the anxiety level of Iranian general population during COVID-19 outbreak. Asian J Psychiatr 2020;51:102076. Crossref

4. Ozamiz-Etxebarria N, Dosil-Santamaria M, Picaza- Gorrochategui M, Idoiaga-Mondragon N. Stress, anxiety, and depression levels in the initial stage of the COVID-19 outbreak in a population sample in the Northern Spain [in English, Spanish]. Cad Saude Publica 2020;36:e00054020. Crossref

5. Wang C, Pan R, Wan X, et al. Immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (COVID-19) epidemic among the general population in China. Int J Environ Res Public Health 2020;17:1729. Crossref

6. Wu Y, Zhang C, Liu H, et al. Perinatal depressive and anxiety symptoms of pregnant women along with COVID-19 outbreak in China. Am J Obstet Gynecol 2020;223:240. e1-9. Crossref

7. Corbett GA, Milne SJ, Hehir MP, Lindow SW, O’Connell MP. Health anxiety and behavioural changes of pregnant women during the COVID-19 pandemic. Eur J Obstet Gynecol Reprod Biol 2020;249:96-7. Crossref

8. Leung WC, Kung F, Lam J, Leung TW, Ho PC. Domestic violence and postnatal depression in a Chinese community. Int J Gynaecol Obstet 2002;79:159-66. Crossref

9. Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry 1987;150:782-6. Crossref

10. Lee DT, Yip SK, Chiu HF, et al. Detecting postnatal depression in Chinese women. Validation of the Chinese version of the Edinburgh Postnatal Depression Scale. Br J Psychiatry 1998;172:433-7. Crossref

11. Rashidi Fakari F, Simbar M. Coronavirus pandemic and worries during pregnancy; a letter to editor. Arch Acad Emerg Med 2020;8:e21.

12. Bohren MA, Berger BO, Munthe-Kaas H, Tunçalp Ö. Perceptions and experiences of labour companionship: a qualitative evidence synthesis. Cochrane Database Syst Rev 2019;(3):CD012449. Crossref

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

Atopic dermatitis (AD) or eczema, asthma, and allergic rhinitis (AR) are associated diseases involved in the atopic march.1 2 3 Many children with AD develop asthma and/or AR when they reach adulthood. There are a number of clinical and laboratory tools to evaluate atopic status in patients with AD. The bronchial challenge test (BCT) is an important tool that evaluates airway hyperresponsiveness in patients with asthma. Responsive patients develop acute contraction of smooth muscles lining the bronchi, resulting in sudden narrowing and obstruction of the airway. The extent of airway narrowing can increase during periods of exacerbation and decrease during treatment with anti-inflammatory drugs.4 The inhalation of histamine or methacholine produces direct airway responses. Histamine maximises bronchial obstruction by directly activating H1 histamine receptors during inhalation challenge. It also stimulates nasal and mucus secretion, promotes vasodilation, and increases vascular permeability. Methacholine is a synthetic derivative of the acetylcholine neurotransmitter, which directly stimulates M3 muscarinic receptors on airway smooth muscles to induce bronchoconstriction.4 A low inhaled dose could trigger a high degree of airway hyperresponsiveness in patients with asthma.

In BCT, methacholine and histamine stimulate an increase in cyclic guanosine monophosphate level and a decrease in cyclic adenosine monophosphate level, thus contributing to smooth muscle contraction.5 Immediate bronchoconstriction reactions can begin immediately after challenge; the peak is within approximately 30 minutes. The effect is typically reversible within 1.5 to 2 hours with the aid of bronchodilators. This is regarded as a type 1 hypersensitivity reaction mediated by immunoglobulin E (IgE), which is present in patients with hypersensitivity pneumonitis, asthma, and other atopic diseases. Immunoglobulin E has a specific role in the induction of many allergic reactions as evidenced by its high serum level in patients with allergic diseases and those with atopic diseases.6 7

Distinct dosages are used for the inhalation of methacholine and histamine, but the inhalation challenge procedures are identical.8 During the test, a diluent is provided via nebulisation for five inhalations, followed by nebulisation of the test compound at low concentrations. A spirometry test is conducted after each dilution to assess the patient’s pulmonary function. A reduction in forced expiratory volume in 1 second (FEV₁) of ≥20% signifies a positive response and the end of the test. A bronchodilator is then provided to counteract the effects of the test compound. In subsequent tests, the dose that provokes the desirable ≥20% reduction of FEV₁ is employed.5

There are several contra-indications for the BCT. Patients with reduced lung function as evidenced by a low FEV₁ level in baseline spirometry may be predisposed to a greater risk of serious adverse events.9 A prior bronchodilator FEV₁ <60% predicted or FEV₁ <75% predicted during a single high stimulus (eg, exercise) are relative contra-indications.10 Airway obstruction in baseline spirometry supplemented with clinical features of asthma is sufficient for diagnosis and the BCT is unnecessary. Furthermore, an inability to follow the instructions of the spirometry test undermines the BCT quality.11 Individuals with a history of cardiovascular problems, increased intracranial pressure, or recent eye surgery may experience enhanced cardiovascular stress as a consequence of bronchoconstriction during the BCT and should not be subjected to this test.4 10 In general, patients with asthma respond to methacholine and histamine even at low concentrations, such that 84% and 73% react to the above compounds, respectively.12

This study aimed to investigate whether personal characteristics, history of allergen exposure, skin prick test results, clinical assessment scores, laboratory parameters, and personal or family histories of atopic diseases are associated with a positive BCT result in paediatric patients with AD. The result is useful in counselling parents and patients with AD and risks of asthma in the family.

This retrospective case series included patients with AD who were treated at the paediatric dermatology clinic of a university hospital from January 2000 to November 2017; patients who had undergone the BCT were retrospectively selected for analysis. All selected patients were Chinese and aged >8 years (the minimum age at which patients can complete the BCT in our hospital pulmonology laboratory).4 11 13 Data concerning the following clinical and personal characteristics were obtained from the patients’ medical records: AD onset age, history of other atopy (ie, AR and atopic asthma), history of atopy (ie, AD, atopic asthma and AR) in parents and siblings, potential allergen exposure (ie, pet ownership and tobacco smoking), and AD treatment history (ie, allergen avoidance and use of traditional Chinese medicine). Clinical laboratory parameters obtained from the electronic patient record system included BCT results, highest serum IgE level, highest eosinophil counts (absolute and relative), and skin prick test results for allergic response to dust mite, cockroach, dogs, cats, and food allergens.

Atopic dermatitis severity was clinically scored by the SCORing Atopic Dermatitis (SCORAD), skin hydration, and transepidermal water loss (TEWL) during follow-up visits.14 The SCORAD is a mathematically derived score that considers the extent, severity, and subjective symptoms of AD.15 The skin hydration and TEWL were measured using Courage and Khazaka equipment, which indirectly measures the density gradient of water evaporation from the skin by two pairs of sensors that determine the temperature and relative humidity, respectively.16

The IBM SPSS Statistics (Windows version 20) was used to conduct all statistical analysis. Student’s t test was conducted to compare continuous variables between groups; these data were expressed as mean ± standard deviation. The Chi squared test (or Fisher’s exact test) was conducted to compare categorical variables between groups; these data were expressed as number (%). A P value of <0.05 was considered statistically significant. Backward binary logistic regression analysis was then used to analyse the data. The variable with the highest P value was removed at each step until the final equation included only variables with P<0.05.

The New Territories East Cluster and The Chinese University of Hong Kong ethics committee approved this retrospective study.

In total, 579 patients with AD were included in this study; 284 had confirmed BCT results. Patient follow-up data were censored as of November 2017 to February 2018. Of the 284 patients with BCT results, 106 had a positive result (BCT-positive group), while 178 had a negative result (BCT-negative group). There were significant differences in current age (P=0.039) and the age at BCT performance (P=0.004) between groups (Table 1).

A positive BCT result was associated with personal history of asthma (P<0.0005) and a sibling with asthma, compared with patients with a negative BCT result (28.6% vs 6.8%; P=0.048) [Table 1].

There were no significant associations between BCT results and personal AR, maternal atopy (specifically, asthma, AR, AD), paternal atopy (specifically asthma, AR, AD), siblings’ AR, and siblings’ AD. Moreover, BCT results were not associated with a history of skin prick response to allergens, including dust mites (Table 1).

There were no significant associations between BCT results and clinical measures of AD severity, in terms of objective SCORAD score, SH, or TEWL. Results of BCT were associated with markers of allergic reactions, including (highest) serum IgE (P=0.045), highest eosinophil count (P=0.017), and sensitisation to food allergens in skin prick test (P=0.027). However, they were not associated with other allergens tested in the skin prick panel, such as aeroallergens from dust mites, cockroaches, dogs, or cats (Table 1). Results of BCT had no significant association with previous exposure to potential environmental irritants, including smoking in the household, incense burning, cat ownership, or dog ownership. There were no significant associations between BCT results and history of AD treatment, including food avoidance and traditional Chinese medicine usage (Table 1).

Of the 284 patients with AD and confirmed BCT results, 142 patients had all relevant data available. Backward binary logistic regression (n=142) showed significant associations between a positive BCT result and a personal history of asthma (adjusted odds ratio [aOR]=4.05; 95% confidence interval [CI]=1.92-8.55; P<0.0005) and sibling atopy (aOR=2.25; 95% CI=1.03-4.92; P=0.042). However, it did not show associations with AD severity, young age at AD onset, personal history of AR, aeroallergen (including dust mite, cockroach, cat and dog hair) and food allergen sensitisation, parental history of atopy, or highest serum IgE level and blood eosinophil count (Table 2).

In our study, backward binary logistic regression analysis showed that a positive BCT result was independently and positively associated with a personal history of asthma in patients with AD. The Global Initiative for Asthma, a medical guidelines organisation, has established a standard for the diagnosis of asthma, which recommends the documentation of variable expiratory airflow limitation. Although asthma is principally a clinical diagnosis, the BCT can aid in this assessment.17 The sensitivity of the BCT in complementing asthma diagnosis is generally believed to approach 100% if a cut point is set at 8 mg/mL or 16 mg/mL, using a non-deep inhalation method.18 Cockcroft18 showed that when the PC20 (ie, histamine provocative concentration causing a 20% drop in FEV₁) cut-off was set at ≤8 mg/mL, all individuals with current symptomatic asthma could be identified in a random population with a sensitivity of nearly 100%.1

However, a recent study indicated that the prevalence of a positive BCT result in children with asthma is approximately 70%.19 This is attributed to the potential effects of several factors associated with a positive BCT result, especially using the methacholine challenge test; these factors include AR, respiratory infections, and chronic respiratory conditions (eg, bronchitis and chronic obstructive pulmonary disease).19 Despite its limitations, including that the test can only be used in older children, the BCT remains a useful tool for the diagnosis of asthma (Table 2). Clinical usage of the BCT in the diagnosis of asthma is based on its high sensitivity and negative predictive value, but a positive BCT result itself is not confirmatory for asthma.17 20

In this study of 284 patients with BCT results, the aOR of a positive BCT result for asthma in patients with AD was 4.05, implying that patients with AD who have a positive BCT result are fourfold more likely to have asthma. This is consistent with the findings of a 2015 meta-analysis that included 31 studies conducted in 102 countries; the risk ratio of AD to other two atopic disorders, including AR and asthma, was 4.24 (95% CI=3.75-4.79). The results demonstrated a clear relationship between the skin and the airways.21 Riiser et al22 followed 530 children who completed the BCT at the age of 10 years and underwent structured reviews and clinical examinations at the age of 16 years; they examined the predictability of BCT results for active asthma in adolescence. The investigators concluded that the presence of bronchial hyperreactivity (BHR), especially severe BHR, was a significant risk factor and that provocative dose 20 resulting in 20% decrease in FEV₁ in a positive test alone explained 10% of the variation in active asthma.22 Another study showed similar findings, in that airway hyperresponsiveness independently predicted asthma symptoms in childhood (aOR=2.6; 95% CI=1.8-3.7).23 Our results concurred with those of the above studies, indicating that BHR could develop before active asthma symptoms appear and that BCT might indeed predict asthma incidence in children with AD.

Atopy is known to have a strong hereditary component. A family study of 188 Caucasian patients and their family members demonstrated a twofold increase in risk of developing AD and atopy with each additional first-degree relative who exhibited atopy.24 Furthermore, a maternal history of atopic disease was associated with an elevated IgE level among infants. For maternal asthma, this association was only evident in infant girls.25 Hong Kong has a relatively high prevalence of single-child families; however, among patients with siblings, positive relationships with sibling atopy have been found.1 2 In our study, among 106 patients with a positive BCT result, rates of maternal, paternal, and sibling atopy were 40.0%, 53.7%, and 64.1%, respectively. A positive BCT result was independently and positively associated with sibling atopy (aOR=2.25; 95% CI=1.03-4.92; P=0.042), which includes asthma, AR, and/or AD. However, no associations with parental atopy were found. Patients with positive BCT results are presumably more likely to have siblings with atopy, in that 64.1% of patients with positive BCT results had siblings with atopy, compared with 52.7% of patients with negative BCT results. The most likely explanations of the association with siblings involve genetic heredity and similar epigenetic factors in childhood. Siblings of patients with atopy are predisposed to an inherited tendency to developing IgE antibodies to specific allergens, with subsequent hypersensitivity reactions. Several twin studies were conducted to demonstrate the roles of genetic and environmental factors on atopy. A multivariate genetic analysis with a total of 575 twin participants revealed that atopic conditions were associated with genetic and environmental factors; it also showed that different phenotypic conditions shared common genetic backgrounds.26 Family and twin studies have shown that genetic inheritance plays an important role in the development of atopy; they identified 79 genes associated with asthma or atopy in more than one population.27 Despite genetic involvement, atopic conditions are highly heterogeneous and involve complex epigenetic factors. The atopic state is presumably related to a pre-existing genotype that is activated by environmental factors.28 Both the factors themselves and duration of exposure are important. Several epigenetic factors with an impact on atopy have been established; these can be further subcategorised into prenatal, infancy, childhood, and adulthood types.29 Affected children and their siblings are exposed to common environmental factors in their childhood, such as tobacco smoke, allergic sensitisation, infections, and diet.

There was minimal information concerning birth order and family size in the present study, although these factors may have substantial impacts on allergic disease susceptibility. Asthma prevalence is reportedly inversely related to family size in families with ≥4 children.30 An inverse relationship between birth order and asthma risk has also been suggested. Compared with younger siblings, stronger associations with older siblings with asthma have been demonstrated.30 However, family size was not specified in those studies; thus, there is a need to determine whether family size or birth order exerts a greater impact upon the risk of atopy. The mechanism by which younger children are protected against atopy is unknown. One possible explanation is the hygiene hypothesis, which suggests that children with less exposure to pathogens and other microorganisms in early childhood are more susceptible to allergic diseases. An implication is that the attempt to create dust-free and pathogen-free clean environment leads to increased atopy prevalence. The presence of older siblings and larger family size is presumed to protect children from atopy through greater exposure in early childhood, thus modulating their immune systems.

Univariate analysis showed that food sensitisation, but not aeroallergen sensitisation, was significantly associated with a positive BCT result in patients with AD (P=0.027). The association was not statistically significant following regression analysis. It has been reported that 40% of patients with food allergy, but no diagnosis of asthma, have a substantial degree of bronchial hyperactivity (measured by the BCT).31 Another small study (n=22 patients with allergic asthma) showed no relationship between skin prick test sensitisation and inhaled reactivity (measured by the methacholine BCT).32 Skin allergen sensitisation does not accurately predict airway allergen response.32 33 This result was confirmed by several other studies,34 35 which showed no relationship between methacholine responsiveness and the presence or degree of atopy. Hence, food and aeroallergen sensitisation are generally not associated with BCT results.

Univariate analysis showed significant associations of serum IgE level (P=0.045) and blood eosinophil count (P=0.017) with a positive BCT result. These findings were consistent with the results published by Liu et al36 concerning significant relationships of BHR to methacholine and increased total serum IgE to a positive BCT result (P=0.001). Sears et al37 showed that BHR was related to serum IgE level in children not diagnosed with asthma; this relationship persisted despite the exclusion of children with a history of AR or AD. Hence, BHR is dependent on serum IgE level and is unrelated to the presence of AD. Nevertheless, IgE can be measured in young children when BHR is difficult to demonstrate; notably, IgE is a simple blood marker of AD severity and asthma risk.7 38

The “one airway” hypothesis (ie, “united airway disease”) is based on the bidirectional interaction between asthma and rhinitis, with the implication that both upper and lower airways should be treated for optimal symptomatic control.39 40 However, our study showed no association between the presence of AR and a positive BCT result in children with AD (P=0.079). Although several studies have shown an association between AR and BHR, they did not equate a positive BCT result with the diagnosis of AR.20 41 42

In our study, there was no association between AD severity (based on objective SCORAD score, SH, and TEWL) and a positive BCT result. Liu et al36 found that BHR to methacholine was related to atopy (P=0.0063), while the degree of BHR was not significantly associated with the severity of any atopic disease.

The strengths of this study included collection and review of the data over 10 years, which enabled the addition of follow-up assessments for many of the patients. The Prince of Wales Hospital is a public hospital; the family cost of healthcare service is relatively low, which supports a low dropout rate and consistent long-term follow-up. Our relatively large sample size enabled examination of various atopic phenotypes. Patients with AD who exhibited both skin and airway manifestations confirm the presumed atopic march with progression from AD to AR and asthma, or co-expression of asthma and AD phenotypes (ie, skin sensitivity plus wheeze).

The primary limitation of the present study was that data were missing for some factors, notably family atopic conditions and laboratory tests. Regarding the family history, many parents did not provide clear information concerning their own atopic conditions. Those with mild symptoms may fail to seek medical advice, although they reported self-diagnosed atopic conditions. Although only physician-diagnosed conditions were included in the data analysis, there was difficulty confirming the validity of those family histories. A substantial number of patients were only children in their families and had no siblings. Additionally, the BCT is a medical test that provokes airway narrowing. It is physically demanding and can cause severe discomfort (eg, violent coughing) which makes the measurement difficult. The irritating nature of the BCT makes it suitable solely for older children and causes high failure rates; thus, the number of patients with a positive BCT result was relatively low. Our observations concerning the usefulness of the BCT should be confirmed in a prospective study.

In patients with paediatric AD, a positive BCT result was independently and positively associated with personal history of asthma and sibling history of atopy, but not with any other clinical parameters.

Concept or design: KL Hon, AHY Ng, CCC Chan, PXY Ho, EPM Tsoi, TF Leung.
Acquisition of data: AHY Ng, CCC Chan, PXY Ho, EPM Tsoi.
Analysis or interpretation of data: KL Hon, AHY Ng, CCC Chan, PXY Ho, EPM Tsoi, KYC Tsang.
Drafting of the manuscript: KL Hon, AHY Ng, CCC Chan, PXY Ho, EPM Tsoi, FW Ko.
Critical revision of the manuscript for important intellectual content: KL Hon, FW Ko, TF Leung.

As the editor of the journal, KL Hon was not involved in the peer review process. Other 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.

This study was approved by The Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (The Joint CUHK-NTEC CREC).

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16. Hon KL, Wong KY, Leung TF, Chow CM, Ng PC. Comparison of skin hydration evaluation sites and correlations among skin hydration, transepidermal water loss, SCORAD index, Nottingham eczema severity score, and quality of life in patients with atopic dermatitis. Am J Clin Dermatol 2008;9:45-50. Crossref

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Pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as coronavirus disease 2019 (COVID-19), has become a pandemic.1 2 3 By 1 March 2020, a total of 87 137 cases were confirmed globally, including 79 968 in China and 7169 distributed across 58 countries outside China. On 23 January 2020, the Chinese Central Government imposed a lockdown in Wuhan and other cities in Hubei Province to isolate the epicentre of the outbreak; to the best of our knowledge, the ‘Wuhan lockdown’ represents the first lockdown of a major city in modern history.4 Subsequently, compulsory policies have been established, such as suspension of public gatherings and the requirement to wear masks.5 In addition to non-medical interventions, the scientific community is responding to this challenge by working to understand and control the disease.6 7 8 9 10 11 However, there have been limited studies regarding the clinical and radiological features of patients with COVID-19, based on multicentre, multiprovincial cohorts at the peak of the epidemic.

In this context, we retrospectively analysed 189 patients with laboratory-confirmed COVID-19, using data collected from seven hospitals in four provinces from 18 January 2020 to 3 February 2020. We compared clinical features, laboratory tests, and chest computed tomography (CT) image findings of these patients with respect to time (ie, before and after Wuhan lockdown) and space (ie, in and outside of Wuhan epidemic area); we investigated potential associations between CT findings and laboratory data. Our findings may help further understand the epidemiological characteristics of COVID-19 and improve the public health response to the epidemic; they can be used as a reference for implementing control measures in other regions or countries with increasing numbers of patients with COVID-19.

Data regarding 189 patients were obtained from the following seven hospitals: Taihe Hospital (n=59), Xiangya Hospital of Central South University (n=21), The Second Xiangya Hospital of Central South University (n=9), Wenzhou Hospital (n=76), Jinling Hospital (n=1), Nanjing Drum Tower Hospital (n=12), and Wuhan Hospital (n=11). Wenzhou is the prefecture-level city with the most confirmed cases outside Hubei Province. Symptom onset time was recorded from 31 December 2019 to 2 February 2020; patients were hospitalised from 18 January 2020 to 3 February 2020, with final follow-up for this report on 4 February 2020. Patients with suspected COVID-19 were admitted and quarantined, then diagnosed with COVID-19 in accordance with the ‘Novel Coronavirus Pneumonia Prevention and Control Program’ (sixth edition)—a patient was confirmed to have COVID-19 based on high throughput sequencing or real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assays of nasal and pharyngeal swab specimens.12 Two target genes—open reading frame 1ab (ORF1ab) and nucleocapsid protein (N)—were simultaneously amplified and tested in real-time RT-PCR assays. Target 1 (ORF1ab) comprised forward primer 5’-CCCTGTGGGTTTTACACTTAA-3’, reverse primer 5’-ACGATTGTGCATCAGCTGA-3’, and the probe 5’-VIC-CCGTCTGCGGTATGTGGAAAGGTTATGG-BHQ1-3’. Target 2 (N) comprised forward primer 5’-GGGGAACTTCTCCTGCTAGAAT-3’, reverse primer 5’-CAGACATTTTGCTCTCAAGCTG-3’, and the probe 5’-FAMTTGCTGCTGCTTGACAGATT-TAMRA-3’. Real-time RT-PCR assays were conducted using a SARS-CoV-2 nucleic acid detection kit, in accordance with the manufacturer’s protocol (Shanghai BioGerm Medical Technology Company, Shanghai, China).

Epidemiological, clinical, laboratory, and radiological characteristics were obtained from electronic medical records by using data collection forms. Date of disease onset was defined as the day when symptoms were noticed. The number of days between symptom onset and date of the first positive test was recorded. Fever was defined as an axillary temperature of ≥37.5°C. Hypoxaemia was defined as 94% oxygen saturation, in accordance with respiratory department criteria. Major CT features were described using standard international nomenclature, defined by the Fleischner Society glossary and peer-reviewed literature regarding viral pneumonia. Degree of COVID-19 severity at the time of admission was defined as mild, moderate, severe, or critical, using preliminary diagnostic guidance from the National Health Commission of the People’s Republic of China. Disease was further separated into non-severe (ie, mild and moderate) and severe (ie, severe and critical) classifications for simplicity. Direct exposure history was defined as patient confirmation of a direct visit to Wuhan, China, during a particular period; close exposure history was defined as close patient contact with an individual who had confirmed or suspected COVID-19. To analyse spatiotemporal differences, patients were divided into different categories according to the start date for the Wuhan lockdown (ie, 23 January 2020) for temporal analysis or heavy epidemic province classification (eg, Hubei and Zhejiang provinces13) for spatial analysis.

Continuous variables were described as the mean (±standard deviation); categorical variables were expressed as frequency (%). All statistical analyses were conducted with R (version 3.6.2; https://www.r-project.org/), using Fisher’s exact test for categorical data and a two-sample Mann-Whitney test or Student’s t test for continuous data (as appropriate). Correlations were measured by Pearson’s correlation coefficient (ρ). Co-morbidities, signs, and symptoms that appeared in more than 10% of the patients were regarded as common co-existing medical conditions. For unadjusted comparisons, two-sided P values <0.05 were considered statistically significant. The analyses were not adjusted for multiple comparisons; thus, given the potential for type I error, the findings should be interpreted as exploratory and descriptive.

The present study included 189 patients with confirmed COVID-19 from four provinces in China, including 70 (37.0%) from Hubei (11 [5.8%] from Wuhan), 30 (15.9%) from Hunan, 76 (40.2%) from Zhejiang, and 13 (6.9%) from Jiangsu. Dates of confirmed infection by RT-PCR ranged from 18 January 2020 to 3 February 2020. The mean date of disease onset was 21 January 2020; the mean date of confirmed infection by RT-PCR was 28 January 2020. The mean duration between symptomology onset and first positive test was 6±5 days. Patients in severely affected areas (eg, Hubei and Zhejiang provinces) showed symptoms earlier than patients in other areas (Fig 1).

The overall characteristics of included patients are summarised in Table 1. The mean age was 44±14 years (range, 17-92 years); 100 patients (52.9%) were men. Of the 189 patients, 181 (95.8%) exhibited positive findings for COVID-19 in the initial RT-PCR assay; 186 patients (98.4%) had ≥1 co-existing medical condition. Fever (161 [86.1%]; two missing records), cough (113 [59.8%]), fatigue (68 [36.0%]), myalgia (35 [18.5%]), diarrhoea (25 [13.2%]), and headache (19 [10.1%]) were the most common symptoms at onset; hypertension (34 [18.0%]) was the most common co-morbidity. Less common co-morbidities included chronic obstructive pulmonary disease, chronic kidney disease, and malignancy (one patient each). Most patients (180 [95.2%]) had non-severe disease; patients with severe disease tended to be older (P=0.067) and had significantly greater breathing frequency (P=0.009) than patients with non-severe disease (online supplementary Appendix 1). Notably, fever was the primary symptom indicative of COVID-19 in patients with suspected disease during the epidemic; however, in our cohort, fever was independent of other imaging findings (data not shown).

On admission, 10 patients (5.3%) presented with hypoxaemia at the time of initial diagnosis; leukopenia was present in 31.2% of the patients, lymphocytopenia was present in 20.6%, and neutropenia was present in 13.2%. Patients with critical disease had more laboratory abnormalities than those with severe disease, including lymphocytopenia (44.4% vs 19.6%; P=0.09) and hypoxaemia (55.6% vs 2.8%; P<0.001). Approximately 91.0% of lesions exhibited subpleural distribution; 17.5% of lesions were diffusely distributed. The most common patterns on chest CT were mixed ground-glass opacity with consolidation (mGGO-C, 84.7%); 59.8% of patients had grid-like shadows and 27.5% of patients exhibited radiological manifestations of typical paving stones (Fig 2). Patients with severe disease showed more frequent involvement of multiple lobes (all P<0.05) and more frequent diffuse distribution (P=0.008), compared with patients who exhibited non-severe disease (online supplementary Appendix 1).

To evaluate the severity of respiratory damage caused by COVID-19, 26 patients (13.8%) who presented with subjective dyspnoea or objective hypoxia were selected for detailed analysis (Table 2). These 26 patients were generally older (50±16 years; P=0.013) and showed more diverse clinical symptoms (eg, cough [80.8%; P=0.033], fatigue [53.8%; P=0.068], nausea [30.8%; P<0.001], diarrhoea [34.6%; P=0.002], and abdominal pain [11.5%; P=0.017]), co-morbidities (eg, hypertension [38.5%; P=0.008]), and haematological abnormalities (eg, lymphocytopenia [38.5%; P=0.051]), compared with patients who did not exhibit dyspnoea or hypoxia. The radiological manifestations in these patients were not optimistic because all patients demonstrated multiple lesions (100%; P=0.123) and mGGO-C (100%; P=0.361); many patients had diffusely distributed lesions (42.3%; P=0.001) and grid-like shadows (80.8%; P=0.033) [Table 3]. Among nine patients with severe disease, seven (77.8%) had varying degrees of hypoxia and dyspnoea. Additionally, patients with haematological abnormalities (especially leukopenia or lymphocytopenia) showed more severe lobe involvement and tended to show diffusely distributed pulmonary lesions (online supplementary Appendix 2). Specifically, the white blood cell count was significantly negatively correlated with the numbers of lesions in left upper (ρ=-0.18, P=0.012), left lower (ρ=-0.23, P=0.002), and right lower lobes (ρ=-0.19, P=0.009).

Although there is no evidence that patients with hypertension are more susceptible to COVID-19, 18.0% of patients with confirmed disease exhibited hypertension, which was the most common clinical co-morbidity in our cohort. These patients were likely to exhibit hypoxaemia (14.7%; P=0.022); furthermore, their lung lobes were severely involved (all P<0.05) and lesions were significantly diffusely distributed (35.3%; P=0.006). Therefore, these patients require close clinical monitoring (Table 4).

In this cohort, all patients with severe disease showed mGGO-C. Paving stones, a sign of the inflammatory absorption period, and grid-like shadows, a sign of interstitial lung lesions, were significantly associated with the presence of mGGO-C (both P<0.05); thus, these radiological findings might serve as comprehensive indicators of disease severity in patients with COVID-19 (online supplementary Appendix 3). Additionally, these patients also showed unfavourable imaging findings, including multiple lesions and severe lung lobe involvement (all P≤0.001).

To further investigate the spatiotemporal differences among patients with COVID-19, we compared clinical, laboratory, and radiological characteristics of patients with respect to the start date of the Wuhan lockdown, as well as heavy epidemic province classification status (online supplementary Appendices 4 and 5). We found that patients in severely affected areas (eg, Hubei and Zhejiang provinces) demonstrated slightly higher body temperature (mean: 37.9℃ vs 37.6℃; P=0.070), more frequent fatigue (39.7% vs 23.3%, P=0.072), and more frequent dyspnoea (11.6% vs 0, P=0.041), compared with patients in other areas. Imaging findings showed more manifestations of multiple lesions (92.9% vs 78.0%, P=0.031), more severe lobe involvement, and more frequent radiological manifestations of mGGO-C (87.7% vs 74.4%, P=0.060). Additionally, after implementation of the ‘Wuhan lockdown’ policy, the symptoms of cough (51.0% vs 70.1%, P=0.012), nausea (3.9% vs 16.1%, P=0.010), and dyspnoea (2.0% vs 17.2%, P=0.001) were significantly alleviated in patients with newly confirmed COVID-19; lung lobe involvement was also dramatically improved, compared with patients who had been diagnosed prior to the start date of the lockdown.

This study assessed the epidemiological, clinical, laboratory, and imaging characteristics of 189 patients with confirmed COVID-19 from multiple hospitals and provinces; it also included spatiotemporal analysis of disease in these patients. As expected, there were more male patients than female patients in our cohort; fever, cough, and dyspnoea were the main symptoms at the time of initial diagnosis, accompanied by lymphocytopenia, hypoxaemia, and other haematological abnormalities. Furthermore, patients with severe disease showed significantly more severe lobe involvement and diffuse distribution of pulmonary lesions, consistent with the findings in previous studies.6 11 12 13 14 Reductions in the numbers of white blood cells or lymphocytes are closely associated with lobe involvement and diffuse distribution, such that a large number of inflammatory cells is consumed at pulmonary lesions in a short period; this finding is consistent with past pathological findings in patients with COVID-1915—interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, have been observed in both lungs; multinucleated syncytial cells with atypical enlarged pneumocytes (characterised by large nuclei, amphophilic granular cytoplasm, and prominent nucleoli) were identified in intra-alveolar spaces, which constituted a viral cytopathy-like change. Additionally, lymphopenia is a common laboratory finding in patients with COVID-19. A serological study16 and a pathological result15 demonstrated that patients’ interleukin-6 levels increased during the course of the disease, whereas the levels of CD4+ T cells, CD8+ T cells, and natural killer cells decreased. These findings imply that, as the disease progresses, patients begin to develop immunosuppression; lymphopenia may therefore be a key factor related to disease severity and mortality in patients with COVID-19.

Another important finding in this study was that patients with hypertension were likely to exhibit hypoxaemia, accompanied by unfavourable radiological manifestations; this was presumably because the patients included in this study were mostly middle-aged or elderly people. The reported prevalence of hypertension in China was 23.2% in adults,17 which was slightly higher than the prevalence in our cohort. In general, older people are more susceptible to COVID-19 and more likely to experience severe disease, compared with people younger than 50 years of age, because older people exhibit greater numbers of health conditions and co-morbidities. Notably, the zinc metallopeptidase angiotensin-converting enzyme 2 (ACE2)18 19—a negative regulator of the angiotensin system which affects heart function, hypertension, and diabetes—has been identified as a key receptor for SARS-CoV-2 in humans. Angiotensin-converting enzyme 2 protects against acute lung injury in several animal models of acute respiratory distress syndrome, which indicates that the renin-angiotensin system may play a critical role in the pathogenesis of acute lung injury. Thus, enhancement of ACE2 activity might be a novel approach for the treatment of acute lung failure in several diseases. Angiotensin-converting enzyme 2 receptors are widely expressed in nasal mucosa, bronchus, lung, heart, oesophagus, kidney, stomach, bladder, and ileum; importantly, the entrance of SARS-CoV-2 into cells mainly occurs through binding to ACE2. Thus, unlike other β-coronaviruses, SARS-CoV-2 replication is not limited to the upper respiratory mucosa epithelium (eg, nasal cavity and pharynx); it also occurs in the digestive tract and other organs, which partially explains the non-respiratory symptoms (eg, diarrhoea, liver damage, and kidney damage).20 Multiple affected organs cause diverse clinical manifestations and large individual differences, which lead to complex conditions. Accordingly, patients with a history of hypertension should receive closer monitoring.

Respiratory system infections end in respiratory failure or multiple organ failure.21 Similar to previous reports of patients with severe acute respiratory syndrome (SARS), some patients in the present study experienced dyspnoea and hypoxaemia during the course of COVID-19 (online supplementary Appendix 6). Notably, our patients showed greater numbers of clinical symptoms and unfavourable imaging findings. Pathologically, SARS mainly causes the formation of hyaline membranes, which result in large numbers of inflammatory exudates into the alveolar cavity, as well as patchy haemorrhage and focal necrosis; these changes lead to respiratory failure and extremely high mortality. In contrast, our patients with COVID-19 generally exhibited mGGO-C as the main imaging feature, which causes airway obstruction without obvious hyaline membrane formation; thus, ventilator support can be used to improve patient prognosis. We presume that the presence of early imaging findings indicates that proactive interventions (eg, positive pressure ventilation) are needed to enhance blood oxygen concentration.

Fever, the most common symptom at the first visit and the most commonly used indicator for COVID-19, showed no significant relationship with radiological findings in the present study, which implies that patients may show no abnormalities (eg, changes in body temperature) when obvious lesions form in the lungs. Furthermore, a recent study22 demonstrated that the sensitivity of RT-PCR for confirmation of COVID-19 is lower than the sensitivity of chest imaging scans, which also suggests that radiological examinations should be used as the primary screening method in this epidemic because of their efficiency, instead of the current approach of body temperature checks and RT-PCR assays.

Overall, the spatial distribution of the epidemic demonstrated here is consistent with the official statistics.23 The distribution of disease incidence had a clear relationship with population mobility. In particular, cities surrounding Wuhan (throughout Hubei Province) reported the vast majority of cases, followed by Wenzhou (Zhejiang Province), which has a large floating population from Wuhan. Wan et al24 and Wrapp et al25 showed that SARS-CoV-2 is more infectious than SARS-CoV. Imported cases were most common in the early period of the epidemic; symptoms then began to appear among individuals who had been in contact with the first group of infected individuals, which contributed to a rapid increase in the number of infections. The symptoms of fatigue and dyspnoea were alleviated outside severely affected areas, which implied reduction of virus potency during intergenerational transmission and early admission to hospitals. In the present study, we used the date of disease onset for analysis of affected patients. Patients in Hubei and Zhejiang provinces showed symptoms earlier and were confirmed to have COVID-19 an average of 6 days later, compared with patients in other areas; these findings coincide with the reported 14-day incubation period.26 Gradually, clinical symptoms and chest CT findings were alleviated in patients with newly confirmed COVID-19 after the beginning of the Wuhan lockdown; these changes also implied reduction of virus potency during intergenerational transmission.

In general, the radiological manifestations of COVID-19 are similar to those of SARS and Middle East respiratory syndrome (MERS), but pleural effusion is rare in patients with COVID-19 (online supplementary Appendix 6). In two previous studies,27 28 the proportions of patients with SARS and MERS who had pleural effusions were 25% (4/16) and 14.5% (8/55), whereas only one patient with COVID-19 (0.5%) had pleural effusions in our cohort. Current studies indicate that the binding forces between the SARS-CoV-2 S protein and human ACE2 are similar to (or stronger than) those between the SARS-CoV S protein and its receptor.25 Given the state of the epidemic, SARS-CoV-2 is highly infectious; its basic reproduction number (R0) is considerably greater than that of either SARS or MERS.29 The World Health Organization reported that the R0 of SARS-CoV-2 ranged from 1.4 to 2.5, whereas a study in China indicated an R0 of 3.3 to 5.530 and a study in the United States estimated an R0 of 3.77 (95% confidence interval, 3.51-4.05).31 The findings of our multicentre retrospective study demonstrate that current measures have affected the early epidemiological pattern (ie, rapid increase) because R0 is decreasing each day in China; however, considering the complexity of influencing factors, further evaluations and predictions are needed. The majority of patients with COVID-19 exhibit non-severe disease, which is an essential source of infection and a ‘blind spot’ for public health efforts; therefore, CT findings such as infiltration, nodules, and consolidation should be identified during early diagnosis. Notably, flu season is approaching rapidly; there is a need for attention to epidemiological history and condition monitoring, as well as efforts to block routes of transmission as quickly as possible.

We acknowledge some limitations in this study. First, the cohort size was relatively small, and data were not collected equally from each included province, which may have led to bias in the conclusions. Second, documentation was incomplete for some patients, given the variations in electronic database structures among participating sites and the urgent timeline for data extraction. Missing data included contact history, heart rate, respiratory rate, and body temperature. Because of the small numbers of patients for whom these data were missing, the main conclusions of this study were presumably unaffected. Third, the sizes and densities of mGGO-C were not compared among patients; thus, analysis of relationships between these characteristics and COVID-19 progression warrants investigation.

Clinical and imaging features were compared among patients with COVID-19 at the peak of epidemic in China. The findings suggest that mGGO-C, paving stones, and grid-like shadows might serve as comprehensive indicators of disease severity in these patients. Furthermore, radiological examinations may be useful as the primary screening method in this epidemic because of their efficiency, in contrast to the current approach of body temperature checks and RT-PCR assays.

Overall spatiotemporal trends were also evaluated retrospectively in this study. Patients in severely affected areas demonstrated slightly higher body temperature, more frequent fatigue, and more frequent dyspnoea. After implementation of the ‘Wuhan lockdown’ policy, cough, nausea, and dyspnoea were significantly alleviated in patients with newly confirmed COVID-19. These data indicate that the preventive measures adopted by China’s Central Government may be appropriate for planning efforts in other regions or countries with increasing numbers of infected patients.

Concept or design: Y Wang, F Yan, B Zhang, DY Zhang, and ZY Sun.
Acquisition of data: ZQ Wen, W Chen, W Chen, WH Liao, J Liu, Y Yang, JC Shi, SD Liu, F Xia, and ZH Yan.
Analysis or interpretation of data: X Lu, T Chen, and Y Wang.
Drafting of the manuscript: Y Wang, S Luo, CS Zhou, X Lu, and T Chen.
Critical revision of the manuscript for important intellectual content: Y Wang, B Zhang, DY Zhang, and Z Sun.

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.

The authors declare no competing interests.

We thank Prof Guangming Lu (Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China) for his coordination during the cross-centre data collection process. We also thank all hospital staff for their efforts in collecting the information used in this study; all patients who consented to inclusion of their data in the analysis; and all medical staff involved in patient care.

This work was supported by the National Natural Science Foundation of China (81720108022, 91649116, 81571040, 81973145), the Social Development Project of Science and Technology in Jiangsu Province (BE2016605, BE201707), the National Key R&D Program of China (2017YFC0112801), the Key Medical Talents of Jiangsu Province, the ‘13th Five-Year’ Health Promotion Project of Jiangsu Province (B.Z.2016-2020), the Jiangsu Provincial Key Medical Discipline (Laboratory) (ZDXKA2016020), the Project of the Sixth Peak of Talented People (WSN-138, BZ), the China Postdoctoral Science Foundation (2019M651805), the “Double First-Class” University project (CPU2018GY09), and Nanjing Health and Family Planning Commission (YKK17089). The funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

This study adhered to the tenets of the Declaration of Helsinki and was approved by the ethics committees of the seven hospitals (Taihe Hospital, Xiangya Hospital of Central South University, The Second Xiangya Hospital of Central South University, Wenzhou Hospital, Jinling Hospital, Nanjing Drum Tower Hospital, and Wuhan Hospital) with a unified approval number [M202003050028] led by Nanjing Drum Tower Hospital; a waiver of informed consent was granted because the study involved patients with emerging infectious diseases.

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Ductal carcinoma in situ (DCIS) is a premalignant disease in the breast cancer spectrum, in which cancer cells are confined within the basement membrane of the breast ductal system.1 Because of the enhanced availability of breast imaging and breast cancer awareness, the incidence of DCIS has increased over the past two decades.2 Although the incidence of invasive breast cancer has declined over the past decade, diagnoses of DCIS have continued to rise.3

Although DCIS is the earliest recognised form of breast cancer, its natural history remains largely unknown.4 5 Long-term survival studies have found that mortality of DCIS could be as low as 3% over 10 years of follow-up.6 The current gold standard treatment for DCIS is surgery, with or without radiotherapy, according to the type of surgery performed on a particular patient. To the best of our knowledge, there has been no randomised controlled trial comparing mastectomy and breast-conserving surgery in the context of DCIS treatment; however, a meta-analysis suggested that local recurrence rates were substantially lower among women treated with mastectomy.7

In recent decades, the incidence of DCIS has increased due to the widespread use of breast imaging screenings, on the basis of enhanced breast cancer awareness. As in other screening-detected disorders, there is widespread debate regarding whether DCIS is overdiagnosed and overtreated. Some clinicians have advocated a watchful-waiting strategy for DCIS, with the presumption that not all DCIS will progress to invasive cancer.8

In contrast to many developed countries, a population-based breast cancer screening programme is not available in Hong Kong. A recent study showed that DCIS is more frequently detected and treated in the private sector in Hong Kong, compared with the public health care system. Notably, DCIS is reportedly detected more frequently among patients in higher social classes due to self-initiated breast screening; more than half of these patients undergo successful treatment with breast-conserving surgery.9 Here, we present the results of long-term survival analyses based on a territory-wide breast cancer registry.

This was a retrospective analysis of a territory-wide, prospectively maintained database from the Hong Kong Cancer Registry, concerning patients diagnosed during the period from 1997 to 2006; data were censored in December 2015 for retrieval of long-term survival outcomes. The Hong Kong Cancer Registry is a population-based cancer registry managed by the Hong Kong Hospital Authority; this registry has been responsible for collecting basic demographic data, cancer site information, and cancer histology results for all patients diagnosed with cancer in all public and private medical institutions in Hong Kong since 1963. All raw data were validated by various crosschecking procedures involving the locally designed Cancer Case Audit System; they were scrutinised by multiple quality control processes, commensurate with the recommendations by the International Agency for Research on Cancer, a component of the World Health Organization. Queries and “unusual cases” were referred to a clinical oncologist for re-validation.

Institutional review board approval was not needed for this retrospective review of a breast cancer registry database. This study included all patients with DCIS who were diagnosed from 1997 to 2006. Exclusion criteria were age <30 years or ≥70 years, lobular carcinoma in situ, Paget’s disease, and co-existing invasive carcinoma (ie, diagnosed within 6 months of DCIS onset). Patients were stratified into those diagnosed from 1997 to 2001 and those diagnosed from 2002 to 2006. Five- and 10-year breast cancer–specific survival rates were evaluated; standardised mortality ratios were calculated (with reference to the general population of women in Hong Kong).

From 1997 to 2006, 1391 patients were diagnosed with DCIS and included in the Hong Kong Cancer Registry breast cancer database. In total, 449 patients were diagnosed from 1997 to 2001, while 942 patients were diagnosed from 2002 to 2006. The mean age at diagnosis was 49.2±9.2 years. Most patients (43.5%) were aged 40 to 49 years (Table 1). More than half of the patients (n=712, 51.2%) underwent mastectomy, while 399 (28.7%) underwent breast-conserving surgery. Overall, 410 patients (29.5%) received adjuvant radiotherapy. In addition, 221 patients (15.9%) received risk-reducing hormonal therapy with tamoxifen (Table 1).

The median follow-up interval was 11.6 years; overall breast cancer–specific mortality rates were 0.3% and 0.9% after 5 and 10 years of follow-up, respectively (Table 2). In total, 109 patients (7.8%) developed invasive breast cancer after a considerable delay. Invasive breast cancer rates were comparable between patients diagnosed from 1997 to 2001 and those diagnosed from 2002 to 2006: 37 (8.2%) and 72 (7.6%), respectively (Table 1).

Subgroup analysis revealed higher breast cancer–specific mortality in patients with human epidermal growth factor receptor 2 (HER2)–positive DCIS after 10 years of follow-up, compared with patients who exhibited HER2-negative DCIS (2.9% vs 0%; P=0.0181, Fisher’s exact test). In contrast, 10-year breast cancer–specific mortality rates were comparable between patients with low-/intermediate-grade DCIS and those with high-grade DCIS (0.5% vs 0.8%; P=0.6776).

The breast cancer–specific mortality rate (per 100 000) was 2.2 among patients aged 30 to 34 years; this rate slowly increased and peaked at 34.8 among patients aged 60 to 64 years (Table 3). Patients with DCIS were more likely to die of breast cancer, compared with the general population of women in Hong Kong (standardised mortality ratio=5.7; 95% confidence interval=3.1-8.3).

Breast cancer is the most common cancer among women in Hong Kong, such that it constituted 26.1% of all newly diagnosed cancers among women in Hong Kong in 2015.10 Notably, a population-wide breast cancer screening programme is not available in Hong Kong. However, because of improved patient-level and population-level education regarding breast cancer awareness, rates of self-initiated breast cancer screening by ultrasonography and mammography have increased over the past decade.9 This might well explain the doubling of DCIS incidence from 449 patients (1997-2001) to 942 patients (2002-2006).

The mortality rate of patients with DCIS has substantially declined over the past few decades in the United States: the 10-year breast cancer mortality rate was 3.4% for women who received a diagnosis from 1978 to 1983, then decreased to 1.9% for women who received a diagnosis from 1984 to 198911 and 1.1% for women who received a diagnosis from 1988 to 2011.2 The mortality rate of patients with DCIS in Hong Kong has remained stable during this same period, despite improved detection through selfinitiated breast screening. Nevertheless, the 10-year breast cancer–specific mortality rate of 0.9% in the current study is comparable with the findings from Western nations; in particular, the 10-year breast cancer–specific mortality rate was reportedly 1.8% in a randomised trial of 1046 Swedish patients with DCIS, who were diagnosed from 1987 to 1999.12 The underlying reason for such an improvement in survival is beyond the scope of this study, but we presume that it is multifactorial (eg, earlier detection and improved surgical oncologic treatment for DCIS).13 However, reports on the improved survival of patients with DCIS (including the current cohort) should be interpreted with care, because this improvement may be the result of overdiagnosis of DCIS.

Overdiagnosis and overtreatment for DCIS have been a major focus of debate over the past decade.12 Several randomised controlled trials, such as the COMET (NCT02926911) and LORIS trials, are currently investigating the feasibility and non-inferiority of active surveillance with or without endocrine therapy for management of low-risk DCIS.

Biological markers such as HER2 receptor and oestrogen receptor statuses have been used for assessment of prognosis and tumour behaviour in patients with invasive breast cancers,14 but their roles in the context of DCIS may have been previously underestimated. Human epidermal growth factor receptor 2–positive DCIS is considered the most unstable precursor among all molecular subtypes, because of its high invasion rate and frequent association with a discordant phenotype.15 Our results may provide clinical validation of this postulation, because they demonstrated that the 10-year breast cancer–specific mortality is significantly worse in patients with HER2-positive disease. However, because of the relatively small number of events included in the subgroup analysis, it may be premature to conclude that positive HER2 findings are associated with adverse survival outcome. Oestrogen receptor–positive DCIS was associated with slightly lower 10-year breast cancer–specific mortality (Table 2). Indeed, the use of systemic hormonal therapy with tamoxifen in patients with oestrogen receptor–positive DCIS has been shown to reduce the risk of future invasive cancer.16

We acknowledge that this study was limited by its retrospective in nature, because all pathological diagnoses were supplied by the breast cancer database from The Hong Kong Cancer Registry. A formal pathology review might have identified patients whose diagnoses were modified from DCIS (in core biopsy) to invasive cancers (in final pathology); other diagnoses might have been modified from invasive cancers to DCIS. While some researchers reported a 17% exclusion rate after a central pathology review,17 others reported a much lower exclusion rate of 2% after secondary pathological review of patients with DCIS.18 19 20 Nevertheless, our analysis was based on a large territory-wide cancer registry. All data were maintained and validated in a consistent manner. In addition, the extended follow-up period enabled detailed long-term survival analysis for patients with DCIS.

Data from the Hong Kong Cancer Registry revealed that the incidence of DCIS doubled from the late 1990s to the early 2000s. The estimated standardised mortality ratio of patients with DCIS in Hong Kong was 5.7, compared with the general population of women in Hong Kong. Our cohort represents one of the largest DCIS cohorts in the published literature. For locations where population-wide breast cancer screening is not available, as in Hong Kong, we believe that the results of our study support further investigation of the cost-effectiveness of population-wide breast cancer screening implementation.

Concept or design: M Co, A Kwong.
Acquisition of data: A Kwong, OWK Mang, RKC Ngan, AHP Tam, KH Wong.
Analysis or interpretation of data: M Co, A Kwong, OWK Mang, AHP Tam.
Drafting of the manuscript: M Co, A Kwong.
Critical revision of the manuscript for important intellectual content: A Kwong, RKC Ngan, KH Wong.

The authors have no conflicts of interest to disclose.

We thank the Dr Ellen Li Charitable Foundation and the Kuok Foundation for their continual support in providing the staff for collection of the data to make this possible. We also thank members of the Hong Kong Breast Cancer Research group for their advice on the research during the period of data collection.

This research was funded by the Dr Ellen Li Charitable Foundation and the Kuok Foundation. The funders had no role in the design of this study, the analysis and interpretation of the data, or the decision to submit the results for publication.

This study was approved by the Hong Kong Hospital Authority West Cluster Research Ethics Committee (Ref UW 09-045). Patient consent was obtained for data collection and analysis.

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