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1.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-324729

ABSTRACT

Background: Host determinants of severe coronavirus disease 2019 include advanced age, comorbidities and male sex. Virologic factors may also be important in determining clinical outcome and transmission rates, but limited patient-level data is available. Methods: We conducted an observational cohort study at seven public hospitals in Singapore. Clinical and laboratory data were collected and compared between individuals infected with different SARS-CoV-2 clades. Firth’s logistic regression was used to examine the association between SARS-CoV-2 clade and development of hypoxia, and quasi-Poisson regression to compare transmission rates. Plasma samples were tested for immune mediator levels and the kinetics of viral replication in cell culture were compared. Findings: 319 patients with PCR-confirmed SARS-CoV-2 infection had clinical and virologic data available for analysis. 29 (9%) were infected with clade S, 90 (28%) with clade L/V, 96 (30%) with clade G (containing D614G variant), and 104 (33%) with other clades ‘O’ were assigned to lineage B.6. After adjusting for age and other covariates, infections with clade S (adjusted odds ratio (aOR) 0·030 (95% confidence intervals (CI): 0·0002-0·29)) or clade O (B·6) (aOR 0·26 (95% CI 0·064-0·93)) were associated with lower odds of developing hypoxia requiring supplemental oxygen compared with clade L/V. Patients infected with clade L/V had more pronounced systemic inflammation with higher concentrations of pro-inflammatory cytokines, chemokines and growth factors. No significant difference in the severity of clade G infections was observed (aOR 0·95 (95% CI: 0·35-2·52). Though viral loads were significantly higher, there was no evidence of increased transmissibility of clade G, and replicative fitness in cell culture was similar for all clades. Interpretation: Infection with clades L/V was associated with increased severity and more systemic release of pro-inflammatory cytokines. Infection with clade G was not associated with changes in severity, and despite higher viral loads there was no evidence of increased transmissibility.Funding Statement: This study was funded by grants from the Singapore National Medical Research Council (COVID19RF- 001, COVID19RF2-0001, COVID19RF-007, and COVID19RF-60) and Biomedical Research Council (project number H20/04/g1/006).Declaration of Interests: No conflicts of interest declared.Ethics Approval Statement: The epidemiological investigation was conducted under the Infectious Diseases Act (Singapore). Study protocols were approved by ethics committees of the National Healthcare Group and SingHealth. Written informed consent was obtained from participants for clinical data and biological sample collection as part of the PROTECT study (2012/00917;2018/3045). A waiver of informed consent for retrospective data collection only was granted for individuals admitted to the National Centre of Infectious Diseases (2020/01122). Healthy donor samples were collected under study numbers 2017/2806 and NUS IRB 04-140.

2.
Clin Infect Dis ; 73(9): e2932-e2942, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1500989

ABSTRACT

BACKGROUND: Key knowledge gaps remain in the understanding of viral dynamics and immune response of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. METHODS: We evaluated these characteristics and established their association with clinical severity in a prospective observational cohort study of 100 patients with PCR-confirmed SARS-CoV-2 infection (mean age, 46 years; 56% male; 38% with comorbidities). Respiratory samples (n = 74) were collected for viral culture, serum samples for measurement of IgM/IgG levels (n = 30), and plasma samples for levels of inflammatory cytokines and chemokines (n = 81). Disease severity was correlated with results from viral culture, serologic testing, and immune markers. RESULTS: Fifty-seven (57%) patients developed viral pneumonia, of whom 20 (20%) required supplemental oxygen, including 12 (12%) with invasive mechanical ventilation. Viral culture from respiratory samples was positive for 19 of 74 patients (26%). No virus was isolated when the PCR cycle threshold (Ct) value was >30 or >14 days after symptom onset. Seroconversion occurred at a median (IQR) of 12.5 (9-18) days for IgM and 15.0 (12-20) days for IgG; 54/62 patients (87.1%) sampled at day 14 or later seroconverted. Severe infections were associated with earlier seroconversion and higher peak IgM and IgG levels. Levels of IP-10, HGF, IL-6, MCP-1, MIP-1α, IL-12p70, IL-18, VEGF-A, PDGF-BB, and IL-1RA significantly correlated with disease severity. CONCLUSIONS: We found virus viability was associated with lower PCR Ct value in early illness. A stronger antibody response was associated with disease severity. The overactive proinflammatory immune signatures offer targets for host-directed immunotherapy, which should be evaluated in randomized controlled trials.


Subject(s)
COVID-19 , Pneumonia, Viral , Antibodies, Viral , Female , Humans , Immunoglobulin M , Male , Middle Aged , Prospective Studies , SARS-CoV-2 , Seroconversion
3.
EBioMedicine ; 66: 103319, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1174196

ABSTRACT

BACKGROUND: Host determinants of severe coronavirus disease 2019 include advanced age, comorbidities and male sex. Virologic factors may also be important in determining clinical outcome and transmission rates, but limited patient-level data is available. METHODS: We conducted an observational cohort study at seven public hospitals in Singapore. Clinical and laboratory data were collected and compared between individuals infected with different SARS-CoV-2 clades. Firth's logistic regression was used to examine the association between SARS-CoV-2 clade and development of hypoxia, and quasi-Poisson regression to compare transmission rates. Plasma samples were tested for immune mediator levels and the kinetics of viral replication in cell culture were compared. FINDINGS: 319 patients with PCR-confirmed SARS-CoV-2 infection had clinical and virologic data available for analysis. 29 (9%) were infected with clade S, 90 (28%) with clade L/V, 96 (30%) with clade G (containing D614G variant), and 104 (33%) with other clades 'O' were assigned to lineage B.6. After adjusting for age and other covariates, infections with clade S (adjusted odds ratio (aOR) 0·030 (95% confidence intervals (CI): 0·0002-0·29)) or clade O (B·6) (aOR 0·26 (95% CI 0·064-0·93)) were associated with lower odds of developing hypoxia requiring supplemental oxygen compared with clade L/V. Patients infected with clade L/V had more pronounced systemic inflammation with higher concentrations of pro-inflammatory cytokines, chemokines and growth factors. No significant difference in the severity of clade G infections was observed (aOR 0·95 (95% CI: 0·35-2·52). Though viral loads were significantly higher, there was no evidence of increased transmissibility of clade G, and replicative fitness in cell culture was similar for all clades. INTERPRETATION: Infection with clades L/V was associated with increased severity and more systemic release of pro-inflammatory cytokines. Infection with clade G was not associated with changes in severity, and despite higher viral loads there was no evidence of increased transmissibility.


Subject(s)
COVID-19/etiology , COVID-19/transmission , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Adult , Age Factors , Aged , COVID-19/epidemiology , COVID-19/immunology , Comorbidity , Female , Humans , Hypoxia/therapy , Hypoxia/virology , Male , Middle Aged , Singapore/epidemiology , Viral Load
4.
Sci Rep ; 11(1): 7477, 2021 04 05.
Article in English | MEDLINE | ID: covidwho-1169408

ABSTRACT

We aim to describe a case series of critically and non-critically ill COVID-19 patients in Singapore. This was a multicentered prospective study with clinical and laboratory details. Details for fifty uncomplicated COVID-19 patients and ten who required mechanical ventilation were collected. We compared clinical features between the groups, assessed predictors of intubation, and described ventilatory management in ICU patients. Ventilated patients were significantly older, reported more dyspnea, had elevated C-reactive protein and lactate dehydrogenase. A multivariable logistic regression model identified respiratory rate (aOR 2.83, 95% CI 1.24-6.47) and neutrophil count (aOR 2.39, 95% CI 1.34-4.26) on admission as independent predictors of intubation with area under receiver operating characteristic curve of 0.928 (95% CI 0.828-0.979). Median APACHE II score was 19 (IQR 17-22) and PaO2/FiO2 ratio before intubation was 104 (IQR 89-129). Median peak FiO2 was 0.75 (IQR 0.6-1.0), positive end-expiratory pressure 12 (IQR 10-14) and plateau pressure 22 (IQR 18-26) in the first 24 h of ventilation. Median duration of ventilation was 6.5 days (IQR 5.5-13). There were no fatalities. Most COVID-19 patients in Singapore who required mechanical ventilation because of ARDS were extubated with no mortality.


Subject(s)
COVID-19/pathology , Adult , Area Under Curve , C-Reactive Protein/metabolism , COVID-19/virology , Dyspnea/etiology , Female , Humans , Intensive Care Units , L-Lactate Dehydrogenase/metabolism , Logistic Models , Male , Middle Aged , Neutrophils/cytology , Prospective Studies , ROC Curve , Respiration, Artificial , Respiratory Rate , SARS-CoV-2/isolation & purification , Severity of Illness Index , Singapore
5.
Open Forum Infect Dis ; 7(11): ofaa486, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-944366

ABSTRACT

This is a retrospective cohort study of hospitalized adults with coronavirus disease 2019 (COVID-19). Fifty-seven patients received treatment alone, and 35 patients received treatment with adjunctive prednisolone. A combination of corticosteroids and antivirals was associated with lower risk of clinical progression and invasive mechanical ventilation or death in early COVID-19 pneumonia.

6.
Lancet ; 396(10251): 603-611, 2020 08 29.
Article in English | MEDLINE | ID: covidwho-719049

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with a 382-nucleotide deletion (∆382) in the open reading frame 8 (ORF8) region of the genome have been detected in Singapore and other countries. We investigated the effect of this deletion on the clinical features of infection. METHODS: We retrospectively identified patients who had been screened for the ∆382 variant and recruited to the PROTECT study-a prospective observational cohort study conducted at seven public hospitals in Singapore. We collected clinical, laboratory, and radiological data from patients' electronic medical records and serial blood and respiratory samples taken during hospitalisation and after discharge. Individuals infected with the ∆382 variant were compared with those infected with wild-type SARS-CoV-2. Exact logistic regression was used to examine the association between the infection groups and the development of hypoxia requiring supplemental oxygen (an indicator of severe COVID-19, the primary endpoint). Follow-up for the study's primary endpoint is completed. FINDINGS: Between Jan 22 and March 21, 2020, 278 patients with PCR-confirmed SARS-CoV-2 infection were screened for the ∆382 deletion and 131 were enrolled onto the study, of whom 92 (70%) were infected with the wild-type virus, ten (8%) had a mix of wild-type and ∆382-variant viruses, and 29 (22%) had only the ∆382 variant. Development of hypoxia requiring supplemental oxygen was less frequent in the ∆382 variant group (0 [0%] of 29 patients) than in the wild-type only group (26 [28%] of 92; absolute difference 28% [95% CI 14-28]). After adjusting for age and presence of comorbidities, infection with the ∆382 variant only was associated with lower odds of developing hypoxia requiring supplemental oxygen (adjusted odds ratio 0·07 [95% CI 0·00-0·48]) compared with infection with wild-type virus only. INTERPRETATION: The ∆382 variant of SARS-CoV-2 seems to be associated with a milder infection. The observed clinical effects of deletions in ORF8 could have implications for the development of treatments and vaccines. FUNDING: National Medical Research Council Singapore.


Subject(s)
Coronavirus Infections/virology , Gene Deletion , Genome, Viral/genetics , Pneumonia, Viral/virology , Adult , Aged , Betacoronavirus , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Humans , Hypoxia/etiology , Hypoxia/therapy , Middle Aged , Open Reading Frames , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Prospective Studies , Respiratory Therapy , SARS-CoV-2 , Severity of Illness Index , Singapore/epidemiology , Virus Replication
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