Because of its close geographical proximity to mainland China, Hong Kong was one of the first regions outside of the Mainland to be affected by the severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19) epidemics.1 Since 2020, Hong Kong experienced an initial epidemic wave of imported COVID-19 cases and spillover effects, as well as subsequent epidemic waves of imported COVID-19 cases and associated local transmission.

The COVID-19 epidemic has resulted in millions of deaths worldwide. By late 2020, there had been multiple country-level analyses in other regions; however, there were limited data concerning outcomes among patients with severe or critical COVID-19 in Hong Kong.2 This study analysed 28-day mortality in these patients and explored risk factors for mortality among them during the first several months of the COVID-19 pandemic.

This retrospective multi-centre cohort study included all adult patients aged ≥18 years with severe or critical COVID-19 who were admitted to the medical wards or intensive care units (ICUs) of three public acute hospitals in Hong Kong from 22 January to 30 September 2020. The three hospitals were Pamela Youde Nethersole Eastern Hospital, Princess Margaret Hospital, and Ruttonjee and Tang Shiu Kin Hospitals.

Patients were diagnosed with COVID-19 if their respiratory samples contained severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA, according to reverse transcription polymerase chain reaction (RT-PCR) analysis. Respiratory samples included nasopharyngeal aspirate, nasopharyngeal swab, nasopharyngeal aspirate or swab paired with throat swab, or deep throat saliva. Coronavirus disease 2019 grade was considered mild, severe, or critical, in accordance with the guidelines of the Chinese Center for Disease Control and Prevention.3 Severe COVID-19 was characterised by dyspnoea, respiratory rate of ≥30 breaths/minute, blood oxygen saturation <94%, ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F ratio) <300, and/or a 50% increase in lung infiltrates within 2 days.3 Critical COVID-19 was characterised by respiratory failure, septic shock, and/or multiple organ dysfunction or failure.3

Hong Kong experienced three epidemic waves during the study period.4 The first epidemic wave, from mid-January to early March 2020, occurred after travellers from mainland China arrived in Hong Kong during the Chinese New Year. The second epidemic wave occurred when Hong Kong residents returned from overseas during the Easter Holiday, from mid-March to May 2020. The third epidemic wave extended from early July until late September 2020; disease transmission may have originated among commercial airline crews.4 Cases were classified as imported or local by the Centre for Health Protection within the Department of Health. Medical comorbidities were defined according to the International Classification of Diseases, Tenth Revision. Comorbidities were selected based on the STOP-COVID (Study of the Treatment and Outcomes in Critically Ill Patients With COVID-19) in the US, which analysed critical COVID-19 cases at 65 ICUs.5

All medical records and data from the Clinical Management System of Hospital Authority and Clinical Information System (IntelliVue Clinical Information Portfolio; Philips Medical, Amsterdam, Netherlands) used by the ICUs were retrospectively reviewed. Upper respiratory tract infection (URI)–related symptoms included cough, rhinorrhoea, and sore throat. For patients admitted to the ICU, disease grade on admission was determined using the APACHE IV (Acute Physiology and Chronic Health Evaluation IV) score and the SOFA (Sequential Organ Failure Assessment) score. For patients requiring mechanical ventilatory support, disease grade was determined by the P/F ratio on the day of intubation. Blood test parameters included minimum lymphocyte count, maximum C-reactive protein level, maximum lactate dehydrogenase (LDH) level, and maximum alanine aminotransferase level. Clinical outcome data included the use of oxygen supplementation, mechanical ventilation, vasopressor or inotrope, renal replacement therapy (RRT), extracorporeal membrane oxygenation, and cardiopulmonary resuscitation, as well as mortality and length of stay in the ICU and hospital. Patients were followed up until death or 31 March 2021, whichever occurred earlier.

The primary outcome was 28-day mortality. Secondary outcomes included length of stay and mortality in the ICU and hospital, duration of oxygen supplementation and mechanical ventilatory support, and time to viral clearance or time to development of antibodies against SARS-CoV-2. Viral clearance was defined as the collection of two consecutive respiratory samples at least 24 hours apart that were both SARS-CoV-2–negative, according to RT-PCR analysis. Cycle threshold (Ct) value indicated the number of RT-PCR cycles required to amplify the viral RNA to a detectable level; this value was inversely related to viral load.6 Minimum Ct values were recorded to determine maximum viral load. Each patient’s blood was collected and qualitatively tested for antibodies against SARS-CoV-2 (ie, antibodies to SARS-CoV-2 nucleoprotein) using the Abbott SARS-CoV-2 Immunoglobulin G assay. Patients were generally released from isolation when they met the requirement for viral clearance or when they displayed serum antibodies, in accordance with recommendations from the Scientific Committee on Emerging and Zoonotic Diseases under the Centre for Health Protection within the Department of Health.7

The clinical characteristics and outcomes of patients with severe or critical COVID-19 were compared between 28-day survivors and non-survivors. Subgroup analysis was performed among patients who received ICU care between 28-day survivors and non-survivors; it was also performed among patients whose laboratory reports provided information regarding viral load (ie, Ct values) in respiratory samples. The frequencies of these characteristics and outcomes were expressed as medians ± interquartile ranges (IQRs) or as numbers of patients and corresponding percentages.

Based on the population of patients with COVID-19 (n=5080) in Hong Kong on 29 September 2020, where 351 patients had ever displayed serious or critical disease, the prevalence of outcome factors in this patient population was 6.9%. Using a confidence limit of 5% and a design effect of 2, the sample sizes required to achieve statistical powers of 80% and 90% were 84 patients and 138 patients, respectively.

For univariate analyses, the Pearson Chi squared test or Fisher’s exact test was used to compare categorical variables; the Mann-Whitney U test was used to compare continuous variables. Variables with a P value of <0.1 in univariate analyses were included in subsequent multivariable analyses. Independent predictors of 28-day mortality were assessed by logistic regression analysis using a forward stepwise approach. Considering the potential for unstable or extreme estimates because of the small sample sizes in subgroup analyses, logistic regression was not performed. All statistical analyses were performed using SPSS (Windows version 23.0; IBM Corp, Armonk [NY], US).

From 22 January to 30 September 2020, 1312 adult patients with COVID-19 were admitted to Princess Margaret Hospital, Pamela Youde Nethersole Eastern Hospital, and Ruttonjee and Tang Shiu Kin Hospitals. In total, 125 patients had severe or critical COVID-19.

The median age was 64 years (IQR=57-75); 69.6% of the patients were men and 93.6% were Chinese (Table 1). In total, 68.8% of the patients were admitted in the third epidemic wave and 86.4% acquired COVID-19 in Hong Kong. Almost half of the patients had hypertension or obesity (48.0% and 54.4%, respectively); 27.2% of patients had diabetes mellitus, and 21.6% had ever smoked. The median duration of symptoms before respiratory samples were confirmed SARS-CoV-2–positive was 3 days. The most common presenting symptom was fever (80.0%), followed by URI-related symptoms (64.8%). Overall, 5.6% of the patients were asymptomatic before their positive test result.

As shown in Table 1, 60% to 80% of patients received lopinavir-ritonavir, ribavirin, interferon beta-1b, or corticosteroids. Nearly half of the patients (48.8%) received anticoagulation treatment; <20% received remdesivir, tocilizumab, or convalescent plasma. More than 80% of the patients received antibiotics during hospitalisation. In total, 45.6% of the patients received ICU care. One patient received non-invasive ventilation, 41 patients (32.8%) received mechanical ventilation, and 11 patients (8.8%) received prone ventilation. Only one patient required extracorporeal membrane oxygenation. Approximately one-fourth of the patients required vasopressor support; 14 patients (11.2%) received acute RRT.

Fifteen patients (12%) died within 28 days (Table 1). Four additional patients died during hospitalisation; thus, the overall hospital mortality rate among patients with severe or critical COVID-19 was 15.2%. The median hospital length of stay was 21.8 days (IQR=15-31.8) and the median duration of oxygen supplementation was 7 days (IQR=4-12.5).

Twenty-eight–day non-survivors were older than 28-day survivors (84 years [IQR=71-86] vs 62 years [IQR=56-71.3]; P<0.001) and more frequently had a history of ischaemic heart disease (26.7% vs 5.5%; P=0.019) or stroke (26.7% vs 4.5%; P=0.012). Moreover, non-survivors had a shorter duration of symptoms before RT-PCR confirmation of SARS-CoV-2 positivity in respiratory samples (1 day [IQR=1-2] vs 3 days [IQR=1-6]; P=0.014); fewer non-survivors displayed URI-related symptoms (33.3% vs 69.1%; P=0.010). Non-survivors had a higher maximum C-reactive protein level (209 mg/L [IQR=82-248] vs 103 mg/L [IQR=63.6-153.5]; P=0.031); they more frequently received mechanical ventilation (66.7% vs 28.2%; P=0.006), acute RRT (40.0% vs 7.3%; P=0.002), and vasopressor support (66.7% vs 19.1%; P<0.001). Finally, non-survivors received a shorter duration of lopinavir-ritonavir treatment (1 day [IQR=0-2] vs 6 days [IQR=0.75-11]; P=0.007) [Table 1].

Logistic regression analysis revealed that age (odds ratio [OR] per 1-year increase in age=1.12, 95% confidence interval [CI]=1.04-1.21; P=0.002), history of stroke (OR=15.96, 95% CI=1.65-154.66; P=0.017), use of acute RRT (OR=15.32, 95% CI=2.67-87.83; P=0.002), and lopinavir-ritonavir duration (OR per 1-day increase=0.82, 95% CI=0.68-0.98; P=0.034) were independent predictors of 28-day mortality (Table 2).

Among the 57 patients admitted to the ICU, nine died; the ICU mortality rate was 15.8% (Table 3). The median ICU length of stay was 9.6 days (IQR=4.6-14.9). Univariate analysis demonstrated that 28-day non-survivors were older; more frequently had a history of ischaemic heart disease or stroke; had a shorter duration of symptoms; less frequently presented with URI-related symptoms; more frequently received mechanical ventilation, acute RRT, and vasopressor support; and received a shorter course of lopinavir-ritonavir treatment. Other significant differences between non-survivors and survivors were the minimum lymphocyte count (0.32 × 10⁹/L [IQR=0.17-0.4] vs 0.4 × 10⁹/L [IQR=0.3-0.6]; P=0.042), maximum LDH level (706 U/L [IQR=492.2-5255.5] vs 474.5 U/L [IQR=406.3-616]; P=0.043), anticoagulation duration (8 days [IQR=3- 10] vs 12.5 days [IQR=7.5-26.8]; P=0.045), APACHE IV score upon ICU admission (83 [IQR=64.5-98] vs 54.5 [IQR=46-61.8]; P<0.001), and SOFA score upon ICU admission (10 [IQR=5.5-13] vs 4 [IQR=3-5.8]; P=0.001).

The median P/F ratio on the day of intubation was 94.1 (IQR=81.9-117.7) for patients with COVID-19 requiring mechanical ventilation, and the median duration of ventilation for all ICU patients with COVID-19 was 8.5 days (IQR=5-18); these values were similar between survivors and non-survivors (Table 3).

As shown in Table 4, 28-day non-survivors were older and more frequently had a history of ischaemic heart disease or stroke; fewer of them had URI-related symptoms (36.4% vs 68.8%; P=0.010). Non-survivors more frequently received mechanical ventilation (81.8% vs 29.9%; P=0.001), acute RRT (45.5% vs 7.8%; P=0.004), and vasopressor support (81.8% vs 23.4%; P<0.001); they received a shorter course of lopinavir-ritonavir treatment (1 day [IQR=0-2] vs 6 days [IQR=0.75-11]; P=0.010). Additionally, non-survivors had a lower minimum lymphocyte count (0.37 × 10⁹/L [IQR=0.16-0.4] vs 0.49 × 10⁹/L [IQR=0.3-0.7], P=0.041) and lower minimum Ct value (15.1 [IQR=12.6-18.5] vs 19 [IQR=16.4-22.9]; P=0.004).

Among the 125 patients with severe or critical COVID-19, 38 underwent regular monitoring of viral load via RT-PCR analysis of respiratory samples for SARS-CoV-2 RNA; viral clearance was achieved within a median of 26 days (IQR=19-35). Among the 79 patients with access to antibody testing, a median of 14 days (IQR=10-18) was elapsed between the first positive RT-PCR result and the emergence of antibodies against SARS-CoV-2.

In this cohort of Hong Kong patients with severe or critical COVID-19, the 28-day mortality rate was 12.0%; it was 15.8% among such patients who were admitted to the ICU. In 2020, higher mortality rates were observed among cohorts in the US (35.4% in the STOP-COVID cohort5), Italy (ICU and hospital mortality rates of 48.8% and 53.4%, respectively8), and China (28-day mortality of 38.7% among severely and critically ill patients9). Patient baseline characteristics were similar across the cohorts—the median age was 60 to 70 years and the most common comorbidity was hypertension (40%-50%).5 8 9 The proportion of patients requiring mechanical ventilation varied across cohorts, ranging from 67% to 87% in the US5 and Italian8 cohorts, whereas it was 30% in the Chinese cohort.9 Overall, 70.2% of patients in our ICU subgroup received mechanical ventilation, which is comparable with the percentages in the US5 and Italy.8 The P/F ratio in our cohort was similar to the ratio in the STOP-COVID (median, 94.1 vs 124),5 reflecting moderate to severe hypoxaemia. Extracorporeal membrane oxygenation was required by <3% of patients in our cohort and the three comparison cohorts. In addition to patient factors, non-patient factors (eg, ICU bed availability and patient-to–hospital staff ratio) may affect quality of care and patient outcomes. Among hospitals of the Department of Veterans Affairs in the US, COVID-19 mortality was significantly greater when ICU demand exceeded 75%.10 Hospitals in the US with fewer ICU beds and nurses per COVID-19 case also had greater mortality.11 The relatively low prevalence, limited local transmission, and better ICU availability in Hong Kong may have contributed to the lower mortality rate observed in this study.

In our cohort, older age, history of stroke, use of acute RRT, and shorter duration of lopinavir-ritonavir treatment were independent predictors of 28-day mortality. Across studies in 2020, older age was commonly identified as a risk factor for COVID-19 mortality.5 8 9 A history of stroke was also identified as a significant risk factor for COVID-19 mortality in a large cohort study in China; higher neutrophil and interleukin-6 levels were observed in patients with a history of stroke, possibly because of a stronger inflammatory response to COVID-19.12 In an American cohort, the hospital mortality rate was 50% among patients who developed acute kidney injury, and the highest mortality risk was present in patients requiring dialysis.13 In 2020, the mechanism of acute kidney injury was speculated to involve direct viral invasion of renal tissue, considering post-mortem findings in China.14 Such injury was closely related to respiratory failure; in another American cohort, the median time from mechanical ventilation to the initiation of acute RRT was 0.3 hour.15

A shorter duration of lopinavir-ritonavir was identified as a risk factor in our cohort. Lopinavir-ritonavir was originally a protease inhibitor for the treatment of human immunodeficiency virus infection.16 In 2020, this repurposed drug was included in treatment recommendations in Hong Kong, where it effectively reduced viral load when used in combination with ribavirin and/or interferon beta-1b16; however, there was no difference in mortality between treatment and control groups as no patient died during the study.16 Two Chinese cohorts did not show significant outcome differences when using lopinavir-ritonavir,17 consistent with interim results from the World Health Organization Solidarity trial.18 Lopinavir-ritonavir treatment has been associated with gastrointestinal upset and liver dysfunction. Our findings may differ from the results of other cohort studies because, in the present study, lopinavir-ritonavir treatment was not administered to patients with severe liver dysfunction or to those who were presumably unable to tolerate side-effects because of their illness. In contrast, up to 80% of the ICU patients in an American cohort received hydroxychloroquine and/or azithromycin,5 despite doubtful efficacy and significant arrhythmia risk with QT prolongation.19 The selection of antiviral treatment may partly explain the differences in mortality among cohorts.

Regarding viral load, univariate analysis in our cohort showed that lower minimum Ct values were associated with greater 28-day mortality. In a study at Cornell in the US,6 the SARS-CoV-2 viral load on admission independently predicted the risks of intubation and mortality. In a Brazilian cohort, Ct values of <25 were associated with greater mortality.21 The implications of Ct values may become clearer if patients with mild disease are analysed together.

Lymphopenia on admission has been associated with worse outcomes in terms of ICU care requirement and mortality,22 presumably because of the cytokine storm phenomenon and the infection of T cells by SARS-CoV-2,19 which infection of T cells by SARS-CoV-2 was confirmed both in vitro and by flow cytometry and immunofluorescence studies.20 In the present study, the minimum lymphocyte count was significantly lower among 28-day non-survivors in both subgroups. Multi-centre COVID-19 studies have shown that an elevated LDH level is associated with a six-fold increase in the likelihood of severe disease and a 16-fold increase in the likelihood of mortality.24 In the present study, although univariate analysis showed that the maximum LDH level was associated with greater 28-day mortality in the overall cohort, it was not an independent predictor in logistic regression; this finding may have been influenced by the sample size.

To our knowledge, this large study was the first investigation in Hong Kong concerning the clinical characteristics and outcomes of patients with severe or critical COVID-19; it included three public acute hospitals and covered three waves of the COVID-19 pandemic in Hong Kong. This study also explored the impacts of viral parameters and treatment modalities on 28-day mortality.

First, this retrospective study in Hong Kong may have been subject to confounding factors and selection bias. The results may not be generalisable to patients with COVID-19 worldwide. Second, this study lacked information concerning viral parameters (eg, specific SARS-CoV-2 strains or mutations). Third, although some studies showed that inborn errors in type 1 interferon immunity and autoantibodies to type 1 interferons were associated with critical COVID-19,25 26 this study did not explore such factors because patient immunity data were unavailable. Fourth, the use of remdesivir was limited; most treatment courses were solely available to patients enrolled in studies by the pharmaceutical company concerned. Finally, other novel treatment options, including antivirals such as nirmatrelvir/ritonavir and molnupiravir, anti-inflammatory agents such as baricitinib and tocilizumab, and neutralising monoclonal antibodies against SARS-CoV-2, were not available or introduced during the study period. Fifth, the sample size of this study did not reach the statistical powers of 90% and may then not be of high enough power.

In this Hong Kong cohort, the 28-day mortality among patients with severe or critical COVID-19 was 12.0%. Age, history of stroke, use of RRT, and shorter course of lopinavir-ritonavir treatment were associated with greater 28-day mortality. In the future, larger studies with a focus on viral and host factors (eg, mutations in SARS-CoV-2 spike genes and interferon-1 immunity status) could improve prognosis prediction.

All authors contributed to the concept or design of the study, acquisition of data, analysis or interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

The authors thank the guidance and support of the following seniors and colleagues: Dr KK Chan from the Department of Medicine of Pamela Youde Nethersole Eastern Hospital, Dr Jenny YY Leung and Dr Alwin WT Yeung from the Department of Medicine and Geriatrics of Ruttonjee and Tang Shiu Kin Hospitals, and Dr Dominic HK So from Intensive Care of Princess Margaret Hospital.

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

The study protocol was approved by the Hong Kong East Cluster Research Ethics Committee (Ref No.: HKECREC—2020-115) and the Kowloon West Cluster Research Ethics Committee (Ref No.: KW/EX-21-005 [155-05]). The requirement for written informed patient consent was waived by both Committees due to the retrospective nature of the research.

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