ABSTRACT
Ninety-six million people are symptomatically infected with Dengue globally every year. Under the current standard-of-care, up to 20% of Dengue patients may be hospitalized, while only 500,000 develop Dengue Haemorrhagic Fever (DHF) and require hospitalization. This leads to unnecessary overwhelming of hospitals in tropical countries during large Dengue epidemics, especially when healthcare systems are grappling with large numbers of COVID-19 patients. Our research team set out to discover biomarkers to prognosticate Dengue patients, and augment the infectious disease clinician's decision-making process to hospitalize Dengue patients. Host biomarkers with concentrations significantly different between pooled serum samples of Dengue Fever (DF) patients and DHF patients were identified using protein array. The prognostication capabilities of selected biomarkers were then validated over 283 adult Dengue patients recruited from three Singapore tertiary hospitals, prior to the diagnosis of DHF. Three biomarkers (A2M, CMA1 and VEGFA) were identified that provide independent prognostication value from one another, and from clinical parameters commonly monitored in Dengue patients. The combination of all three biomarkers was able to identify from as early as Day 1 after the onset of fever, DF patients whose conditions will deteriorate into DHF. The biomarkers are robust and able to predict DHF well when trained on different AI/ML algorithms (logistic regression, support vector machine, decision tree, random forest, AdaBoost and gradient boosting). When stacked, prediction models based on the biomarkers were able to predict DHF with 97.3% sensitivity, 92.7% specificity, 66.7% PPV, 99.6% NPV and an AUC of 0.978. To the best of our knowledge, our panel of three biomarkers offers the highest accuracy in prognosticating Dengue to date. Further studies are required to validate the biomarkers in different geographical settings and pilot their implementation as part of the standard-of-care workflow for Dengue patients. [ FROM AUTHOR] Copyright of International Journal of Infectious Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)
ABSTRACT
Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 and was declared a global pandemic by the World Health Organization on 11 March 2020. A definitive diagnosis of COVID-19 is made after a positive result is obtained on reverse transcription-polymerase chain reaction assay. In Singapore, rigorous contact tracing was practised to contain the spread of the virus. Nasal swabs and chest radiographs (CXR) were also taken from individuals who were suspected to be infected by COVID-19 upon their arrival at a centralised screening centre. From our experience, about 40% of patients who tested positive for COVID-19 had initial CXR that appeared "normal". In this case series, we described the temporal evolution of COVID-19 in patients with an initial "normal" CXR. Since CXR has limited sensitivity and specificity in COVID-19, it is not suitable as a first-line diagnostic tool. However, when CXR changes become unequivocally abnormal, close monitoring is recommended to manage potentially severe COVID-19 pneumonia. Copyright © 2020 Annals, Academy of Medicine, Singapore.
ABSTRACT
Objective: To describe the neurological disorders associated with COVID-19 in Singapore. Background: Various neurological disorders have been reported in COVID-19 patients. Postulated mechanisms include hypercoagulopathy, dysimmunity, inflammation and direct viral invasion. The incidence and relationship to SARS-CoV-2, considering the confounding effect of a surge in COVID-19 cases on healthcare systems, are unclear. Design/Methods: This was a prospective, nation-wide, multi-centre, cohort study of patients with microbiologically-confirmed COVID-19 referred for any neurological complaints With in 3 months of infection. Neurological diagnoses and relationship to COVID-19 were made by consensus guided by contemporaneous published case definitions. Results: Between March-July 2020, 47,572 patients [median age 34 (1-102) years, 98% males] were diagnosed with COVID-19 in Singapore. Of 90 patients referred for neurological disorders, 39 [median age 41 (27-73) years, 97% males] were deemed related to COVID-19 and categorised as: i) Central nervous system syndromes - 3 encephalitis, 1 acute disseminated encephalomyelitis;ii) Cerebrovascular disorders - 19 acute ischemic stroke/transient ischemic attack (AIS/TIA), 4 cerebral venous thrombosis (CVT) and 2 intracerebral haemorrhage;iii) Peripheral nervous system - 7 mono/polyneuropathy;iv) Autonomic nervous system - 4 limited dysautonomia. Fifty-one other patients had pre/co-existent neurological conditions (headache, seizure, mononeuropathies and functional neurological disorders) unrelated to COVID-19. Encephalitis is delayed, occurring in critical COVID-19, while CVT and dysautonomia occurred relatively early and largely in mild infections. AIS/TIA was variable in onset;remarkably 63.2% had asymptomatic COVID-19. CVT was more frequent than expected and occurred in patients with mild/asymptomatic COVID-19. The pathophysiology of COVID-19 neurology appeared to be dysimmunity and/or prothrombotic tendency. There were no neurological complications in all 81 paediatric COVID-19 cases. Conclusions: COVID-19 neurology has a wide spectrum of dysimmune-thrombotic disorders. The relatively few cases recorded was probably because our outbreak affected mainly healthy young men with mild/asymptomatic COVID-19 and the pandemic did not unduly affect the Singapore healthcare system.
ABSTRACT
Background: Remdesivir (RDV) has been shown to shorten recovery time and was well tolerated in patients with severe COVID-19. Hydroxychloroquine (HQN) is an experimental treatment for COVID-19. Effects of coadministration of HQN with RDV have not been studied and are relevant given the long half-life (∼22 days) of HQN. We report the impact of concomitant HQN and RDV use on clinical outcomes and safety in patients with moderate COVID-19. Methods: We enrolled hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation >94% on room air, and radiological evidence of pneumonia. Patients were randomized 1:1:1 to receive 5d or 10d of intravenous RDV once daily plus standard of care (SoC), or SoC only. We compared patients on concomitant HQN (HQNpos) vs not (HQNneg). Clinical recovery was evaluated using Cox proportional hazards. Covariate adjustment included age, sex, race, region, symptom duration, oxygen support status and obesity. Recovery and adverse events (AEs) were assessed through death, discharge, or d14. Results: Of 584 patients, 199 (34%) received HQN (5d RDV: n=57 [30%];10d RDV, n=49 [25%];SoC: n=93 [47%]). Through median follow-up of 13d (range 1-41d), HQNpos patients on 5d or 10d RDV had a lower recovery rate (adjusted HR [95% CI] 0.78 [0.59, 1.03], p=0.09) with longer median time to recovery (8 vs 6 days) compared to HQNneg. HQNpos compared to HQNneg patients in 5d RDV showed a trend of reduced recovery rate (HR: 0.69 [0.45,1.04], p=0.080);such an effect was not observed in 10d RDV or SoC (Table 1). More HQNpos than HQNneg patients had AEs in RDV (5/10d) or SoC arms evaluated separately, and all arms combined. This difference was significant for AEs and SAEs for all arms combined after covariate adjustment (Table 2). Conclusion: In moderate COVID-19 patients, concomitant HQN may delay recovery on RDV and showed no impact on recovery with SoC alone. The AE profile of HQNpos patients was worse than that observed for HQNneg patients, regardless of RDV treatment.
ABSTRACT
Background: Remdesivir (RDV) has been shown to shorten recovery time and was well tolerated in patients with severe COVID-19. Here we report baseline characteristics associated with clinical improvement at day (d) 14. Methods: We enrolled hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation >94% on room air, and radiological evidence of pneumonia. Patients were randomized 1:1:1 to receive 5d or 10d of intravenous RDV once daily plus standard of care (SoC), or SoC only. For this analysis, patients were followed through discharge, d14, or death. Baseline demographic and disease characteristics associated with clinical improvement in oxygen support (≥2-point improvement on a 7-category ordinal scale ranging from discharge to death) were evaluated using multivariable logistic regression methods. Results: 584 patients were randomized and treated (5/10d RDV, n=384;SoC: n=200). 159 (27%) were ≥65y, 227 (39%) female, 328 (61%) white, 102 (19%) Asian, and 99 (19%) Black. 252 participants (43%) were enrolled in Europe, 260 (45%) North America (NA), and 72 (12%) in Asia. Most patients (483 [83%]) were not on supplemental oxygen but required medical care at baseline. In a multivariable model, 5/10d RDV was significantly positively associated with clinical improvement (adjusted odds ratio [OR] 1.69, 95% CI: 1.08, 2.65;p=0.0226). Significant covariables positively associated with clinical improvement included age < 65y (p< 0.0001) and region of treatment (Europe and NA vs Asia, p< 0.0001 each;Table);other examined factors were not significantly associated with clinical improvement, including gender, race, ethnicity, baseline oxygen support, duration of symptoms and hospitalization, obesity, and baseline transaminase levels. Conclusion: In moderate COVID-19 patients, after adjusting for treatment arm, age < 65y and region (NA vs Asia;Europe vs Asia) were associated with higher rates of clinical improvement. These observations recapitulate younger age as positive prognostic factor, and highlight the differences in the impact of the pandemic globally.
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Background: Remdesivir (RDV), a RNA polymerase inhibitor with potent in vitro activity against SARS-CoV-2, is the only treatment with demonstrated efficacy in shortening the duration of COVID-19. Here we report regional differences in clinical outcomes of severe COVID-19 patients treated with RDV, as part of an open-label, randomized phase-3 trial establishing RDV treatment duration. Methods: Hospitalized patients with oxygen saturation ≤94%, a positive SARS-CoV-2 PCR in the past 4 days and radiographic evidence of pneumonia were randomized 1:1 to receive 5d or 10d of intravenous RDV. We compared d14 clinical outcomes of patients from different geographical areas, as measured by mortality rates, change in clinical status from baseline (BL) on a 7-point ordinal scale and change in O2 requirements from BL. Based on previous analyses in compassionate use data showing region as an important predictor of outcome, Italy was examined separately from other regions. Results: 397 patients were treated with RDV, of which 229 (58%) were in the US, 77 (19%) Italy, 61 (15% in Spain), 12 (3%) Republic of Korea, 9 (2%) Singapore, 4 (1%) Germany, 4 (1%) Hong Kong and 1 (< 1%) Taiwan. BL clinical status was worse in Italy compared to other regions (72% vs 17% requiring high-flow oxygen delivery or higher), and Italian patients were more likely to be male than patients from other regions (69% vs 63%). Overall results showed 5d RDV was as effective as 10d. Mortality at d14 was higher in Italy (18%) compared to all other countries except Italy (7%). Similarly, clinical improvement at d14, measured as ≥2-point increase in the ordinal scale, was lower in Italian patients (39%) compared to all other countries combined (64%). (Fig.1). Conclusion: Overall, our results demonstrate significant geographical differences in the clinical course of severe COVID-19 patients treated with RDV. We observed worse outcomes, such as increased mortality and lower rate of clinical improvement, in patients from Italy compared to other regions. (Table Presented).
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Background: Remdesivir (RDV), a nucleotide analogue prodrug that inhibits viral RNA polymerases, has demonstrated potent in vitro and in vivo activity against SAR-CoV-2 and favorable clinical efficacy and tolerability in patients with moderate and severe COVID-19 Elevated transaminase levels are commonly seen in patients with severe COVID-19 prior to treatment Here we report safety and clinical outcomes after RDV treatment in patients with normal versus elevated baseline alanine aminotransferase (ALT) levels Methods: We conducted a randomized, open-label, phase 3 trial, involving hospitalized patients with confirmed COVID-19 pneumonia with Sat<94% Patients with screening ALT or AST> 5x the upper limit of normal (ULN) were excluded from the study Patients were randomized 1:1 to receive either 5 or 10 days of intravenous RDV once daily We compared patients with baseline ALT below and above the ULN based on AASLD criteria (ALT 35 U/L for males and 25 U/L for females) Covariates for adjustment included age, sex, race and baseline oxygen support Clinical recovery and all-cause mortality were evaluated using logistic regression Clinical outcomes and adverse events (AEs) were assessed through day 28 Results: Of 397 patients treated with RDV, 215 (54%) had elevated baseline ALT Median ALT was 53 U/L (IQR: 40 - 78 U/L) in the high ALT group Patients with high ALT at time of RDV initiation were younger (median 58 vs 65 years, p<0 001), required less oxygen (p=0 02), and had longer symptom duration (median 10 vs 8 days, p<0.001) prior to first dose of RDV. Incidence of serious AEs, grade ≥3 AEs, and AE leading to discontinuation were similar between groups (Table1). Grade ≥3 hepatobiliary adverse events, particularly transaminase elevations, were not common but numerically higher in the high ALT group (8 8% vs 3 3%, p=0 068) Time to clinical recovery, 2-point clinical improvement, 1-point clinical improvement, room air, and death were similar between groups Conclusion: In severe COVID-19 patients, adverse events and clinical outcomes after RDV initiation were similar among patients with baseline normal ALT and those with elevated ALT (1-5x ULN)(Table Presented).
ABSTRACT
As of 27 October 2020, there have been 57,980 confirmed cases of COVID-19 in Singapore, with 28 fatalities. To summarise the Singapore experience in managing and containing COVID-19 based on available published data and from relevant sources, a review of literature using research databases such as PubMed and OVID Medline, along with non-peer-reviewed articles and other sources, was conducted with the search terms 'COVID-19' and 'Singapore'. Research conducted in Singapore has provided insight into the clinical manifestations and period of infectivity of COVID-19, demonstrated evidence of pre-symptomatic transmission, linked infection clusters using serological tools, and highlighted aspects of hospital-based environmental contamination. It has also provided guidance for diagnostic testing and has described immune and virologic correlates with disease severity. Evidence of effectiveness of containment measures such as early border control, rigorous contact training, and calibrated social distancing measures have also been demonstrated. Singapore's multipronged strategy has been largely successful at containing COVID-19 and minimising fatalities, but the risk of re-emergence is high.