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1.
SSRN; 2022.
Preprint in English | SSRN | ID: ppcovidwho-331885

ABSTRACT

Background: Data on the impact of dysnatraemia and pre-existing hyponatraemia on clinical outcomes of COVID-19 remains elusive. Methods: We performed a territory-wide retrospective cohort study of COVID-19 patients between 23 January 2020 and 1 January 2021 in Hong Kong. The primary endpoint was all-cause mortality. The secondary endpoint was intensive care unit (ICU) admission and/or use of invasive mechanical ventilation (IMV). Mild hyponatraemia, moderate-to-severe hyponatraemia, normonatraemia, and hypernatraemia were defined as serum sodium of 130-<135, <130, 135-145, and >145 mmol/L , respectively. Background sodium level was measured at least one month before COVID-19 diagnosis. Findings: Of 8,407 patients, 738 (8·8%), 143 (1·7%), and 24 (0·3%) had mild hyponatraemia, moderate-to-severe hyponatraemia, and hypernatraemia at COVID-19 diagnosis, respectively. At a median follow-up of 12 days, 156 (1·9%) patients died;413 (4·9%) patients were admitted to ICU and/or required IMV use. Moderate-to-severe hyponatraemia (adjusted hazard ratio [aHR] 2·92, 95% CI 1·59–5·36, P<0·001) and hypernatraemia (aHR 7·60, 95% CI 5·16–11·20, P <0·001) were independently associated with an increased mortality rate . Mild (adjusted cause-specific HR [aCSHR] 1·94) and moderate-to-severe hyponatraemia (aCSHR 2·08) were independently associated with a higher rate of ICU admission/IMV use. Hypernatraemia was not associated with a higher rate of ICU admission/IMV use, yet was associated with a higher rate of competing death. Background hyponatraemia was associated with a higher rate of mortality. Interpretation: COVID-19 patients with dysnatraemia are associated with adverse clinical outcomes, in whom vigilant monitoring of serum sodium would be important.

2.
Microbiol Spectr ; 10(2): e0018222, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1752768

ABSTRACT

SARS-CoV-2 transcribes a set of subgenomic RNAs (sgRNAs) essential for the translation of structural and accessory proteins to sustain its life cycle. We applied RNA-seq on 375 respiratory samples from individual COVID-19 patients and revealed that the majority of the sgRNAs were canonical transcripts with N being the most abundant (36.2%), followed by S (11.6%), open reading frame 7a (ORF7a; 10.3%), M (8.4%), ORF3a (7.9%), ORF8 (6.0%), E (4.6%), ORF6 (2.5%), and ORF7b (0.3%); but ORF10 was not detected. The profile of most sgRNAs, except N, showed an independent association with viral load, time of specimen collection after onset, age of the patient, and S-614D/G variant with ORF7b and then ORF6 being the most sensitive to changes in these characteristics. Monitoring of 124 serial samples from 10 patients using sgRNA-specific real-time RT-PCR revealed a potential of adopting sgRNA as a marker of viral activity. Respiratory samples harboring a full set of canonical sgRNAs were mainly collected early within 1 to 2 weeks from onset, and most of the stool samples (90%) were negative for sgRNAs despite testing positive by diagnostic PCR targeting genomic RNA. ORF7b was the first to become undetectable and again being the most sensitive surrogate marker for a full set of canonical sgRNAs in clinical samples. The potential of using sgRNA to monitor viral activity and progression of SARS-CoV-2 infection, and hence as one of the objective indicators to triage patients for isolation and treatment should be considered. IMPORTANCE Attempts to use subgenomic RNAs (sgRNAs) of SARS-CoV-2 to identify active infection of COVID-19 have produced diverse results. In this work, we applied next-generation sequencing and RT-PCR to profile the full spectrum of SARS-CoV-2 sgRNAs in a large cohort of respiratory and stool samples collected throughout infection. Numerous known and novel discontinuous transcription events potentially encoding full-length, deleted and frameshift proteins were observed. In particular, the expression profile of canonical sgRNAs was associated with genomic RNA level and clinical characteristics. Our study found sgRNAs as potential biomarkers for monitoring infectivity and progression of SARS-CoV-2 infection, which provides an alternative target for the management and treatment of COVID-19 patients.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnosis , Humans , Open Reading Frames , RNA, Viral/genetics , SARS-CoV-2/genetics , Viral Load
3.
J Clin Virol Plus ; 2(1): 100062, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1616571

ABSTRACT

Objectives: Little is known whether differences exist in virus shedding, immune and inflammatory response related to SARS-CoV-2 in people living with human immunodeficiency virus (PLWH). We assessed viral RNA and cytokine profiles of HIV and SARS-CoV-2 coinfection in Hong Kong. Methods: PLWH hospitalized with SARS-CoV-2 infection in Hong Kong were included, compared with age-matched and disease severity-matched SARS-CoV-2 infected controls (ratio of 1:5) from February 1st 2020 to July 31st 2020. SARS-CoV-2 infection was confirmed by public health laboratory and virus concentration was quantified by an in-house real-time reverse transcription-quantitative polymerase chain reaction. A panel of cytokines and chemokines were performed. Results: HIV patients had a similar respiratory shedding profile compared to controls. Duration of faecal shedding of patient A, B, C and D were at least 9, 10, 33, and 11 days, respectively. HIV patients had lower plasma levels of IL-10 and NT-pro-BNP. All 4 PLWH cases showed seroconversion to SARS-CoV-2 with anti-SARS-CoV-2 S antibodies detected in serum collected between day 18 and 30 after symptom onset. Conclusions: PLWH behaves similarly with HIV-negative controls in respiratory viral load, but with decrease in IL-10 and NT-proBNP. PLWH may have a lower risk of immunostimulatory effect due to lower IL-10.

4.
Cell Death Differ ; 29(6): 1240-1254, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1612182

ABSTRACT

A recent mutation analysis suggested that Non-Structural Protein 6 (NSP6) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a key determinant of the viral pathogenicity. Here, by transcriptome analysis, we demonstrated that the inflammasome-related NOD-like receptor signaling was activated in SARS-CoV-2-infected lung epithelial cells and Coronavirus Disease 2019 (COVID-19) patients' lung tissues. The induction of inflammasomes/pyroptosis in patients with severe COVID-19 was confirmed by serological markers. Overexpression of NSP6 triggered NLRP3/ASC-dependent caspase-1 activation, interleukin-1ß/18 maturation, and pyroptosis of lung epithelial cells. Upstream, NSP6 impaired lysosome acidification to inhibit autophagic flux, whose restoration by 1α,25-dihydroxyvitamin D3, metformin or polydatin abrogated NSP6-induced pyroptosis. NSP6 directly interacted with ATP6AP1, a vacuolar ATPase proton pump component, and inhibited its cleavage-mediated activation. L37F NSP6 variant, which was associated with asymptomatic COVID-19, exhibited reduced binding to ATP6AP1 and weakened ability to impair lysosome acidification to induce pyroptosis. Consistently, infection of cultured lung epithelial cells with live SARS-CoV-2 resulted in autophagic flux stagnation, inflammasome activation, and pyroptosis. Overall, this work supports that NSP6 of SARS-CoV-2 could induce inflammatory cell death in lung epithelial cells, through which pharmacological rectification of autophagic flux might be therapeutically exploited.


Subject(s)
COVID-19 , Coronavirus Nucleocapsid Proteins , NLR Family, Pyrin Domain-Containing 3 Protein , SARS-CoV-2 , Vacuolar Proton-Translocating ATPases , COVID-19/metabolism , COVID-19/virology , Coronavirus Nucleocapsid Proteins/genetics , Coronavirus Nucleocapsid Proteins/metabolism , Humans , Inflammasomes/metabolism , Interleukin-1beta/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pyroptosis , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Vacuolar Proton-Translocating ATPases/metabolism
5.
Clin Infect Dis ; 73(7): e1782-e1783, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1584993

Subject(s)
Wolves , Animals
6.
Brief Bioinform ; 22(2): 1466-1475, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1343667

ABSTRACT

Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, causing significant mortality. There is a mechanistic relationship between intracellular coronavirus replication and deregulated autophagosome-lysosome system. We performed transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients and identified the aberrant upregulation of genes in the lysosome pathway. We further determined the capability of two circulating markers, namely microtubule-associated proteins 1A/1B light chain 3B (LC3B) and (p62/SQSTM1) p62, both of which depend on lysosome for degradation, in predicting the emergence of moderate-to-severe disease in COVID-19 patients requiring hospitalization for supplemental oxygen therapy. Logistic regression analyses showed that LC3B was associated with moderate-to-severe COVID-19, independent of age, sex and clinical risk score. A decrease in LC3B concentration <5.5 ng/ml increased the risk of oxygen and ventilatory requirement (adjusted odds ratio: 4.6; 95% CI: 1.1-22.0; P = 0.04). Serum concentrations of p62 in the moderate-to-severe group were significantly lower in patients aged 50 or below. In conclusion, lysosome function is deregulated in PBMCs isolated from COVID-19 patients, and the related biomarker LC3B may serve as a novel tool for stratifying patients with moderate-to-severe COVID-19 from those with asymptomatic or mild disease. COVID-19 patients with a decrease in LC3B concentration <5.5 ng/ml will require early hospital admission for supplemental oxygen therapy and other respiratory support.


Subject(s)
COVID-19/virology , Leukocytes, Mononuclear/metabolism , Lysosomes/metabolism , Microtubule-Associated Proteins/blood , SARS-CoV-2/metabolism , Adult , Autophagy , Biomarkers/blood , COVID-19/blood , Cell Cycle , Cholesterol/metabolism , Female , Humans , Male , Middle Aged , RNA-Binding Proteins/blood , Real-Time Polymerase Chain Reaction , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction
7.
Hepatology ; 74(4): 1750-1765, 2021 10.
Article in English | MEDLINE | ID: covidwho-1274697

ABSTRACT

BACKGROUND AND AIMS: We compared risk of acute liver injury and mortality in patients with COVID-19 and current, past, and no HBV infection. APPROACH AND RESULTS: This was a territory-wide retrospective cohort study in Hong Kong. Patients with COVID-19 between January 23, 2020, and January 1, 2021, were identified. Patients with hepatitis C or no HBsAg results were excluded. The primary outcome was mortality. Acute liver injury was defined as alanine aminotransferase or aspartate aminotransferase ≥2 × upper limit of normal (ULN; i.e., 80 U/L), with total bilirubin ≥2 × ULN (i.e., 2.2 mg/dL) and/or international normalized ratio ≥1.7. Of 5,639 patients included, 353 (6.3%) and 359 (6.4%) had current and past HBV infection, respectively. Compared to patients without known HBV exposure, current HBV-infected patients were older and more likely to have cirrhosis. Past HBV-infected patients were the oldest, and more had diabetes and cardiovascular disease. At a median follow-up of 14 (9-20) days, 138 (2.4%) patients died; acute liver injury occurred in 58 (1.2%), 8 (2.3%), and 11 (3.1%) patients with no, current, and past HBV infection, respectively. Acute liver injury (adjusted HR [aHR], 2.45; 95% CI, 1.52-3.96; P < 0.001), but not current (aHR, 1.29; 95% CI, 0.61-2.70; P = 0.507) or past (aHR, 0.90; 95% CI, 0.56-1.46; P = 0.681) HBV infection, was associated with mortality. Use of corticosteroid, antifungal, ribavirin, or lopinavir-ritonavir (adjusted OR [aOR], 2.55-5.63), but not current (aOR, 1.93; 95% CI, 0.88-4.24; P = 0.102) or past (aOR, 1.25; 95% CI, 0.62-2.55; P = 0.533) HBV infection, was associated with acute liver injury. CONCLUSION: Current or past HBV infections were not associated with more liver injury and mortality in COVID-19.


Subject(s)
Acute Lung Injury/epidemiology , COVID-19/mortality , Hepatitis B, Chronic/epidemiology , Acute Lung Injury/blood , Acute Lung Injury/diagnosis , Acute Lung Injury/virology , Adult , Age Factors , Aged , Alanine Transaminase , Aspartate Aminotransferases , COVID-19/complications , COVID-19/diagnosis , COVID-19/virology , Female , Hepatitis B Surface Antigens/isolation & purification , Hepatitis B virus/immunology , Hepatitis B virus/isolation & purification , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/diagnosis , Hepatitis B, Chronic/virology , Hong Kong/epidemiology , Humans , Male , Medical History Taking/statistics & numerical data , Middle Aged , Retrospective Studies , Risk Assessment/statistics & numerical data , Risk Factors
8.
Open Forum Infect Dis ; 8(6): ofab205, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1261053

ABSTRACT

BACKGROUND: Liver injury in patients with coronavirus disease 2019 (COVID-19) is common and prognostic. Direct viral tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for angiotensin-converting enzyme 2 receptors in hepatocytes may be one of the mechanisms of liver injury. We aimed to determine the role of viral persistence of SARS-CoV-2, based on cycle threshold (Ct) value, in liver injury in COVID-19. METHODS: This was a territory-wide retrospective cohort study of all public hospitals in Hong Kong. Laboratory-confirmed COVID-19 was identified. Serial liver biochemistries and Ct values of SARS-CoV-2 RNA were analyzed. RESULTS: We identified 7622 COVID-19 patients (mean age, 47 years; 48.2% male) diagnosed from March 24 to January 1, 2021, who had serial liver biochemistries and Ct values. A total of 1363 (17.9%) COVID-19 patients had alanine transferase (ALT)/aspartate aminotransferase (AST) elevations with 2 temporal patterns-early (within first 14 days of symptom onset) and late (>14 days from symptom onset). COVID-19 patients with ALT/AST elevations had a lower Ct value at admission (23 vs 25; P < .001), day 5 (24 vs 26; P < .001), and day 20 (31 vs 32; P < .001) after admission, compared with those without ALT/AST elevations. COVID-19 patients with ALT/AST elevations had a longer duration from first positive to first negative reverse transcription polymerase chain reaction test for SARS-CoV-2 (13 vs 9 days; P < .001). ALT/AST elevation and presence of diabetes were independent risk factors of viral persistence. CONCLUSIONS: Liver injury in COVID-19 is linked to a higher SARS-CoV-2 viral load during the early phase of infection, signifying a possible direct viral injury to the liver. Prolonged viral persistence of SARS-CoV-2 is associated with liver injury.

9.
J Am Soc Nephrol ; 2021 Jan 22.
Article in English | MEDLINE | ID: covidwho-1197445

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19) are closely related. The effect of AKI on the clinical outcomes of these two conditions is unclear. METHODS: This retrospective, territory-wide cohort study used an electronic public healthcare database in Hong Kong to identify patients with SARS or COVID-19 by diagnosis codes, virologic results, or both. The primary endpoint was a composite of intensive care unit admission, use of invasive mechanical ventilation, and/or death. RESULTS: We identified 1670 patients with SARS and 1040 patients with COVID-19 (median ages, 41 versus 35 years, respectively). Among patients with SARS, 26% met the primary endpoint versus 5.3% of those with COVID-19. Diabetes mellitus, abnormal liver function, and AKI were factors significantly associated with the primary endpoint among patients with either SARS or COVID-19. Among patients with SARS, 7.9%, 2.1%, and 3.7% developed stage 1, stage 2, and stage 3 AKI, respectively; among those with COVID-19, 6.6%, 0.4%, and 1.1% developed stage 1, stage 2, and stage 3 AKI, respectively. In both groups, factors significantly associated with AKI included diabetes mellitus and hypertension. Among patients with AKI, those with COVID-19 had a lower rate of major adverse clinical outcomes versus patients with SARS. Renal function recovery usually occurred within 30 days after an initial AKI event. CONCLUSIONS: AKI rates were higher among patients with SARS than those with COVID-19. AKI was associated with major adverse clinical outcomes for both diseases. Patients with diabetes mellitus and abnormal liver function were also at risk of developing severe consequences after SARS and COVID-19 infection.

10.
J Med Internet Res ; 23(4): e26645, 2021 04 16.
Article in English | MEDLINE | ID: covidwho-1192182

ABSTRACT

BACKGROUND: COVID-19 has plagued the globe, with multiple SARS-CoV-2 clusters hinting at its evolving epidemiology. Since the disease course is governed by important epidemiological parameters, including containment delays (time between symptom onset and mandatory isolation) and serial intervals (time between symptom onsets of infector-infectee pairs), understanding their temporal changes helps to guide interventions. OBJECTIVE: This study aims to characterize the epidemiology of the first two epidemic waves of COVID-19 in Hong Kong by doing the following: (1) estimating the containment delays, serial intervals, effective reproductive number (Rt), and proportion of asymptomatic cases; (2) identifying factors associated with the temporal changes of the containment delays and serial intervals; and (3) depicting COVID-19 transmission by age assortativity and types of social settings. METHODS: We retrieved the official case series and the Apple mobility data of Hong Kong from January-August 2020. The empirical containment delays and serial intervals were fitted to theoretical distributions, and factors associated with their temporal changes were quantified in terms of percentage contribution (the percentage change in the predicted outcome from multivariable regression models relative to a predefined comparator). Rt was estimated with the best fitted distribution for serial intervals. RESULTS: The two epidemic waves were characterized by imported cases and clusters of local cases, respectively. Rt peaked at 2.39 (wave 1) and 3.04 (wave 2). The proportion of asymptomatic cases decreased from 34.9% (0-9 years) to 12.9% (≥80 years). Log-normal distribution best fitted the 1574 containment delays (mean 5.18 [SD 3.04] days) and the 558 serial intervals (17 negative; mean 4.74 [SD 4.24] days). Containment delays decreased with involvement in a cluster (percentage contribution: 10.08%-20.73%) and case detection in the public health care sector (percentage contribution: 27.56%, 95% CI 22.52%-32.33%). Serial intervals decreased over time (6.70 days in wave 1 versus 4.35 days in wave 2) and with tertiary transmission or beyond (percentage contribution: -50.75% to -17.31%), but were lengthened by mobility (percentage contribution: 0.83%). Transmission within the same age band was high (18.1%). Households (69.9%) and social settings (20.3%) were where transmission commonly occurred. CONCLUSIONS: First, the factors associated with reduced containment delays suggested government-enacted interventions were useful for achieving outbreak control and should be further encouraged. Second, the shorter serial intervals associated with the composite mobility index calls for empirical surveys to disentangle the role of different contact dimensions in disease transmission. Third, the presymptomatic transmission and asymptomatic cases underscore the importance of remaining vigilant about COVID-19. Fourth, the time-varying epidemiological parameters suggest the need to incorporate their temporal variations when depicting the epidemic trajectory. Fifth, the high proportion of transmission events occurring within the same age group supports the ban on gatherings outside of households, and underscores the need for residence-centered preventive measures.


Subject(s)
COVID-19/epidemiology , Adult , Disease Progression , Female , Hong Kong/epidemiology , Humans , Male , Pandemics , Retrospective Studies , SARS-CoV-2/isolation & purification , Seasons
11.
Respirology ; 26(4): 322-333, 2021 04.
Article in English | MEDLINE | ID: covidwho-1124645

ABSTRACT

COVID-19 has hit the world by surprise, causing substantial mortality and morbidity since 2020. This narrative review aims to provide an overview of the epidemiology, induced impact, viral kinetics and clinical spectrum of COVID-19 in the Asia-Pacific Region, focusing on regions previously exposed to outbreaks of coronavirus. COVID-19 progressed differently by regions, with some (such as China and Taiwan) featured by one to two epidemic waves and some (such as Hong Kong and South Korea) featured by multiple waves. There has been no consensus on the estimates of important epidemiological time intervals or proportions, such that using them for making inferences should be done with caution. Viral loads of patients with COVID-19 peak in the first week of illness around days 2 to 4 and hence there is very high transmission potential causing community outbreaks. Various strategies such as government-guided and suppress-and-lift strategies, trigger-based/suppression approaches and alert systems have been employed to guide the adoption and easing of control measures. Asymptomatic and pre-symptomatic transmission is a hallmark of COVID-19. Identification and isolation of symptomatic patients alone is not effective in controlling the ongoing outbreaks. However, early, prompt and coordinated enactment predisposed regions to successful disease containment. Mass COVID-19 vaccinations are likely to be the light at the end of the tunnel. There is a need to review what we have learnt in this pandemic and examine how to transfer and improve existing knowledge for ongoing and future epidemics.


Subject(s)
COVID-19 , Communicable Disease Control , SARS-CoV-2 , Asia/epidemiology , Australasia/epidemiology , COVID-19/epidemiology , COVID-19/physiopathology , COVID-19/prevention & control , COVID-19/virology , Civil Defense/organization & administration , Communicable Disease Control/legislation & jurisprudence , Communicable Disease Control/methods , Communicable Disease Control/organization & administration , Communicable Disease Control/statistics & numerical data , Government Regulation , Humans , International Cooperation , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology
12.
Brief Bioinform ; 22(2): 1466-1475, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1096499

ABSTRACT

Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, causing significant mortality. There is a mechanistic relationship between intracellular coronavirus replication and deregulated autophagosome-lysosome system. We performed transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients and identified the aberrant upregulation of genes in the lysosome pathway. We further determined the capability of two circulating markers, namely microtubule-associated proteins 1A/1B light chain 3B (LC3B) and (p62/SQSTM1) p62, both of which depend on lysosome for degradation, in predicting the emergence of moderate-to-severe disease in COVID-19 patients requiring hospitalization for supplemental oxygen therapy. Logistic regression analyses showed that LC3B was associated with moderate-to-severe COVID-19, independent of age, sex and clinical risk score. A decrease in LC3B concentration <5.5 ng/ml increased the risk of oxygen and ventilatory requirement (adjusted odds ratio: 4.6; 95% CI: 1.1-22.0; P = 0.04). Serum concentrations of p62 in the moderate-to-severe group were significantly lower in patients aged 50 or below. In conclusion, lysosome function is deregulated in PBMCs isolated from COVID-19 patients, and the related biomarker LC3B may serve as a novel tool for stratifying patients with moderate-to-severe COVID-19 from those with asymptomatic or mild disease. COVID-19 patients with a decrease in LC3B concentration <5.5 ng/ml will require early hospital admission for supplemental oxygen therapy and other respiratory support.


Subject(s)
COVID-19/virology , Leukocytes, Mononuclear/metabolism , Lysosomes/metabolism , Microtubule-Associated Proteins/blood , SARS-CoV-2/metabolism , Adult , Autophagy , Biomarkers/blood , COVID-19/blood , Cell Cycle , Cholesterol/metabolism , Female , Humans , Male , Middle Aged , RNA-Binding Proteins/blood , Real-Time Polymerase Chain Reaction , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction
13.
Gut ; 70(4): 698-706, 2021 04.
Article in English | MEDLINE | ID: covidwho-1024254

ABSTRACT

OBJECTIVE: Although COVID-19 is primarily a respiratory illness, there is mounting evidence suggesting that the GI tract is involved in this disease. We investigated whether the gut microbiome is linked to disease severity in patients with COVID-19, and whether perturbations in microbiome composition, if any, resolve with clearance of the SARS-CoV-2 virus. METHODS: In this two-hospital cohort study, we obtained blood, stool and patient records from 100 patients with laboratory-confirmed SARS-CoV-2 infection. Serial stool samples were collected from 27 of the 100 patients up to 30 days after clearance of SARS-CoV-2. Gut microbiome compositions were characterised by shotgun sequencing total DNA extracted from stools. Concentrations of inflammatory cytokines and blood markers were measured from plasma. RESULTS: Gut microbiome composition was significantly altered in patients with COVID-19 compared with non-COVID-19 individuals irrespective of whether patients had received medication (p<0.01). Several gut commensals with known immunomodulatory potential such as Faecalibacterium prausnitzii, Eubacterium rectale and bifidobacteria were underrepresented in patients and remained low in samples collected up to 30 days after disease resolution. Moreover, this perturbed composition exhibited stratification with disease severity concordant with elevated concentrations of inflammatory cytokines and blood markers such as C reactive protein, lactate dehydrogenase, aspartate aminotransferase and gamma-glutamyl transferase. CONCLUSION: Associations between gut microbiota composition, levels of cytokines and inflammatory markers in patients with COVID-19 suggest that the gut microbiome is involved in the magnitude of COVID-19 severity possibly via modulating host immune responses. Furthermore, the gut microbiota dysbiosis after disease resolution could contribute to persistent symptoms, highlighting a need to understand how gut microorganisms are involved in inflammation and COVID-19.


Subject(s)
Bacteria , COVID-19 , Dysbiosis , Gastrointestinal Microbiome/immunology , Gastrointestinal Tract , Immunity , SARS-CoV-2 , Adult , Bacteria/genetics , Bacteria/immunology , Bacteria/isolation & purification , C-Reactive Protein/analysis , COVID-19/blood , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/immunology , Cytokines/analysis , DNA, Bacterial/isolation & purification , Dysbiosis/epidemiology , Dysbiosis/etiology , Dysbiosis/immunology , Dysbiosis/virology , Female , Gastrointestinal Tract/immunology , Gastrointestinal Tract/microbiology , Gastrointestinal Tract/virology , Hong Kong , Humans , Male , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Severity of Illness Index , Transferases/analysis
14.
Cell Death Dis ; 12(1): 53, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1015001

ABSTRACT

Interleukin-38 has recently been shown to have anti-inflammatory properties in lung inflammatory diseases. However, the effects of IL-38 in viral pneumonia remains unknown. In the present study, we demonstrate that circulating IL-38 concentrations together with IL-36α increased significantly in influenza and COVID-19 patients, and the level of IL-38 and IL-36α correlated negatively and positively with disease severity and inflammation, respectively. In the co-cultured human respiratory epithelial cells with macrophages to mimic lung microenvironment in vitro, IL-38 was able to alleviate inflammatory responses by inhibiting poly(I:C)-induced overproduction of pro-inflammatory cytokines and chemokines through intracellular STAT1, STAT3, p38 MAPK, ERK1/2, MEK, and NF-κB signaling pathways. Intriguingly, transcriptomic profiling revealed that IL-38 targeted genes were associated with the host innate immune response to virus. We also found that IL-38 counteracts the biological processes induced by IL-36α in the co-culture. Furthermore, the administration of recombinant IL-38 could mitigate poly I:C-induced lung injury, with reduced early accumulation of neutrophils and macrophages in bronchoalveolar lavage fluid, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines and permeability of the alveolar-epithelial barrier. Taken together, our study indicates that IL-38 plays a crucial role in protection from exaggerated pulmonary inflammation during poly(I:C)-induced pneumonia, thereby providing the basis of a novel therapeutic target for respiratory viral infections.


Subject(s)
COVID-19/metabolism , Immunity, Innate/drug effects , Influenza, Human/metabolism , Interleukins/pharmacology , Pneumonia/prevention & control , Poly I-C/toxicity , Respiratory System/immunology , Animals , COVID-19/immunology , COVID-19/virology , Cytokines/metabolism , Epithelial Cells/immunology , Epithelial Cells/metabolism , Epithelial Cells/pathology , Humans , Influenza A virus/isolation & purification , Influenza, Human/immunology , Influenza, Human/virology , Interleukin-1/blood , Interleukins/blood , Male , Mice , Mice, Inbred C57BL , Pneumonia/chemically induced , Pneumonia/immunology , Pneumonia/pathology , Respiratory System/metabolism , Respiratory System/pathology , SARS-CoV-2/isolation & purification
17.
Clin Infect Dis ; 72(10): e466-e475, 2021 05 18.
Article in English | MEDLINE | ID: covidwho-811336

ABSTRACT

BACKGROUND: The case-fatality ratios (CFR) of coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) appeared to differ substantially. We aimed to compare the CFR and its predictors of COVID-19 and SARS patients using a territory-wide cohort in Hong Kong. METHODS: This was a territory-wide retrospective cohort study using data captured from all public hospitals in Hong Kong. Laboratory-confirmed COVID-19 and SARS patients were identified. The primary endpoint was a composite endpoint of intensive care unit admission, use of mechanical ventilation, and/or death. RESULTS: We identified 1013 COVID-19 patients (mean age, 38.4 years; 53.9% male) diagnosed from 23 January to 14 April 2020 and 1670 SARS patients (mean age, 44.4 years; 44.0% male) from March to June 2003. Fifty-five (5.4%) COVID-19 patients and 432 (25.9%) SARS patients had reached the primary endpoint in 30 days. By 30 June 2003, 286 SARS patients had died (CFR, 17.1%). By 7 June 2020, 4 COVID-19 patients had died (CFR, 0.4%). After adjusting for demographic and clinical parameters, COVID-19 was associated with a 71% lower risk of primary endpoint compared with SARS (adjusted hazard ratio, 0.29; 95% confidence interval, .21-.40; P < .0001). Age, diabetes mellitus, and laboratory parameters (high lactate dehydrogenase, high C-reactive protein, and low platelet count) were independent predictors of the primary endpoint in COVID-19 patients, whereas use of antiviral treatments was not associated with primary endpoint. CONCLUSIONS: The CFR of COVID-19 was 0.4%. Age and diabetes were associated with worse outcomes, whereas antiviral treatments were not.


Subject(s)
COVID-19 , Severe Acute Respiratory Syndrome , Adult , Cohort Studies , Female , Hong Kong/epidemiology , Hospitalization , Humans , Male , Retrospective Studies , SARS-CoV-2 , Severe Acute Respiratory Syndrome/epidemiology
18.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-876

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) are two infectious diseases caused by coronaviruses - SARS-CoV-2 an

19.
Gut ; 70(4): 733-742, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-638266

ABSTRACT

OBJECTIVE: Data on serial liver biochemistries of patients infected by different human coronaviruses (HCoVs) are lacking. The impact of liver injury on adverse clinical outcomes in coronavirus disease 2019 (COVID-19) patients remains unclear. DESIGN: This was a retrospective cohort study using data from a territory-wide database in Hong Kong. COVID-19, severe acute respiratory syndrome (SARS) and other HCoV patients were identified by diagnosis codes and/or virological results. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation was defined as ALT/AST ≥2 × upper limit of normal (ie, 80 U/L). The primary end point was a composite of intensive care unit (ICU) admission, use of invasive mechanical ventilation and/or death. RESULTS: We identified 1040 COVID-19 patients (mean age 38 years, 54% men), 1670 SARS patients (mean age 44 years, 44% men) and 675 other HCoV patients (mean age 20 years, 57% men). ALT/AST elevation occurred in 50.3% SARS patients, 22.5% COVID-19 patients and 36.0% other HCoV patients. For COVID-19 patients, 53 (5.1%) were admitted to ICU, 22 (2.1%) received invasive mechanical ventilation and 4 (0.4%) died. ALT/AST elevation was independently associated with primary end point (adjusted OR (aOR) 7.92, 95% CI 4.14 to 15.14, p<0.001) after adjusted for albumin, diabetes and hypertension. Use of lopinavir-ritonavir ±ribavirin + interferon beta (aOR 1.94, 95% CI 1.20 to 3.13, p=0.006) and corticosteroids (aOR 3.92, 95% CI 2.14 to 7.16, p<0.001) was independently associated with ALT/AST elevation. CONCLUSION: ALT/AST elevation was common and independently associated with adverse clinical outcomes in COVID-19 patients. Use of lopinavir-ritonavir, with or without ribavirin, interferon beta and/or corticosteroids was independently associated with ALT/AST elevation.


Subject(s)
Alanine Transaminase/blood , Antiviral Agents , Aspartate Aminotransferases/blood , COVID-19 , Liver , Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/adverse effects , Adult , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , COVID-19/blood , COVID-19/complications , COVID-19/diagnosis , COVID-19/drug therapy , Drug Combinations , Female , Hong Kong/epidemiology , Hospitalization/statistics & numerical data , Humans , Liver/drug effects , Liver/virology , Liver Function Tests/methods , Liver Function Tests/statistics & numerical data , Lopinavir/administration & dosage , Lopinavir/adverse effects , Male , Retrospective Studies , Ribavirin/administration & dosage , Ribavirin/adverse effects , Ritonavir/administration & dosage , Ritonavir/adverse effects , SARS-CoV-2/isolation & purification , Severity of Illness Index
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