Ronald Bertus Geskus

Early identification of individuals at risk of complications is important to improve dengue case-management and promote appropriate use of limited resources in high burden settings. In this prospective observational cohort, 7428 febrile outpatients were enrolled across 8 countries in Asia and Latin America and followed daily; 2230 individuals with confirmed dengue were included in the analysis, among whom 304 (14%) progressed to moderate/severe dengue and 38 (2%) to severe dengue during follow-up. We demonstrate evolving relationships between common clinical features, WHO clinical warning signs, and simple haematological parameters, with progression. Key predictors of moderate/severe dengue include low lymphocyte percentage, low total white blood cell count, low platelet count, and persistent vomiting and significant abdominal pain/tenderness. Multivariable models incorporating these variables predict the risk of moderate/severe dengue, initially with modest performance (AUC ~ 0.68), but improving subsequently as new daily data is included into the predictions (AUC ~ 0.73-0.85). We also demonstrate that using these models in combination with clinical decision-making pathways could facilitate earlier admission of high-risk patients without markedly increasing admissions of uncomplicated cases. These results should prove instrumental for updating guidelines on dengue triage and management, potentially providing major public health benefits in resource poor settings.

Adjunctive corticosteroids such as dexamethasone are recommended in tuberculous meningitis treatment, despite modest and heterogeneous survival benefit. Leukotriene A4 hydrolase ( LTA4H ) genotypes associate with distinct intracerebral inflammatory phenotypes and may determine corticosteroid response in tuberculous meningitis, with benefit observed in hyperinflammatory TT genotype but uncertain benefit in lower inflammation CC and CT genotypes. Here, in a phase 3, placebo-controlled trial of human immunodeficiency virus-negative Vietnamese adults with tuberculous meningitis, we randomized 613 LTA4H CC- and CT-genotype participants to 6–8 weeks of dexamethasone or placebo, aiming to show noninferiority of placebo (hazard ratio margin of 0.75) or its superiority. Given the significant survival benefit of dexamethasone previously seen in LTA4H TT-genotype individuals, TT-genotype participants all received open-label dexamethasone and were not randomized. A total of 89 TT-genotype participants received open-label dexamethasone. In CC- and CT-genotype participants, the primary endpoint of all-cause death or new neurological event over 12 months from randomization occurred in 108/305 (35.4%) given dexamethasone and 110/308 (35.7%) given placebo (hazard ratio of 0.99, 96% confidence interval (adjusted for multiple testing) 0.748–1.31). The number of observed primary endpoints ( n = 218) exceeded the prespecified number ( n = 184) used to calculate the trial’s sample size and power. Placebo noninferiority was not established in the CC and CT population or in individual genotype subpopulations. Benefit or heterogeneity of effect was not observed by any prespecified subgroup. In TT-genotype participants, the primary endpoint occurred in 28/89 (31.5%) participants, similar to CC and CT participants. Outcomes were not significantly better in TT-genotype participants versus CC- or CT-genotype participants. In CC- and CT-genotype participants, serious adverse events occurred in 161/305 (52.8%) dexamethasone-treated participants and 160/308 (51.9%) placebo-treated participants. In conclusion, neither noninferiority nor superiority of placebo was established in human immunodeficiency virus-negative LTA4H CC- and CT-genotype adults with tuberculous meningitis, and dexamethasone was safe. The modest and heterogeneous benefit of dexamethasone indicates that greater understanding of tuberculous meningitis pathophysiology is needed, alongside better targeted, more effective anti-inflammatory agents than corticosteroids (ClinicalTrials.gov NCT03100786 ).

Background: The latency time (from infection to infectiousness) guides the choice of measures required to control an infectious disease. Estimates of the SARS-CoV- 2 latency time are sparse due to lack of appropriate and representative data. Infection time is rarely known exactly and exposure information may be subject to several biases. Information on the endpoint requires repeated testing. Moreover, estimation is challenging because both the starting point and endpoint are typically interval censored and data may be subject to length-biased sampling (truncation). Methods: We collected detailed information on exposure from public health reports produced during an outbreak with the SARS-CoV- 2 Delta variant in Ho Chi Minh City, Vietnam, in May-July 2021. Using a custom digital form and application facilitated reliable choices on exposure window. This comprehensive data set on exposure and test results from 1951 individuals, collected in the absence of large-scale vaccination or earlier infection, is the first of its kind outside of China. We accounted for the doubly interval censored nature of the observations and went beyond the standard assumption of a constant infection risk over calendar time (exponential growth) and allowed for flexibility regarding the latency time (generalized gamma distribution). We addressed right truncation due to a cutoff in data collection and a finite quarantine length. Employing a Bayesian approach, using the program , made the analyses relatively straightforward. Results: Assuming exponential growth, our estimate of SARS-CoV- 2 Delta variant’s mean latency time was 3.22 (95% Credible Interval 2.89 - 3.55) days; the median was 1.81 (95% CrI 1.44- 2.16) days; the 95 th percentile was 10.98 (95% CrI 9.91 - 12.41) days. These values were much larger if a uniform infection risk was assumed. Conclusions: Using a Bayesian approach with the program, we were able to estimate the SARS-CoV- 2 latency time distribution of the Delta variant in infection-naive and vaccine-naive individuals. Estimates were sensitive to the assumptions made regarding the risk of infection within the exposure window. Compared to earlier studies, the median latency time was shorter, while the 95 th percentile was larger. Our results stress the importance of thoughtful data collection and analysis for evidence-based control of an infectious disease.

Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Corticosteroids are currently recommended as an adjunctive therapy in HIV-negative adults with TBM. However, benefit from corticosteroids in TBM may depend upon host leukotriene A4 hydrolase (LTA4H) genotype and the corresponding inflammatory phenotypes. This article describes the planned analyses for the primary publication of the results of the LAST ACT clinical trial (NCT03100786): ‘Leukotriene A4 hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-negative adults with Tuberculous meningitis’. The primary hypothesis addressed by the trial is that LTA4H genotype, in particular CC or CT genotype, determines whether adjunctive dexamethasone benefits or harms adults with TBM. The trial was an LTA4H genotype stratified, parallel group, randomised, double blind, placebo-controlled multi-centre Phase III trial of dexamethasone given for 6–8 weeks in addition to standard anti-tuberculosis drugs. LTA4H genotype (CC, CT, TT) was determined in all participants prior to randomisation; only those with CC or CT genotype were randomised to dexamethasone or placebo. All TT genotype participants received dexamethasone because prior data indicated survival was increased by dexamethasone in this genotype. The primary endpoint was all-cause death or new neurological event over the first 12 months after randomisation. We took a hybrid trial-design approach which aims to prove non-inferiority of placebo first but also allows claiming superiority of placebo in case dexamethasone causes substantial harm. This statistical analysis plan expands upon and updates the analysis plan outlined in the published study protocol.

Background Awake prone positioning (APP) may be beneficial in patients with respiratory failure who are not receiving mechanical ventilation. Randomized controlled trials of APP have been performed during peak COVID-19 periods in unvaccinated populations, with limited data on compliance or patient acceptability. We aimed to evaluate the efficacy and acceptability of APP in a lower-middle income country in an open-label randomized controlled trial using a dedicated APP implementation team and wearable continuous-monitoring devices. Methods The trial was performed at a tertiary level hospital in Ho Chi Minh City, Vietnam, recruiting adults (≥18 years) hospitalized with moderate or severe COVID-19 and receiving supplemental oxygen therapy via nasal/facemask systems or high-flow nasal cannula (HFNC). Patients were allocated by a computer-generated random number sequence in a 1:1 ratio to standard care or APP, where a dedicated team provided bedside support. Wearable devices continuously recorded pulse oximetry and body position continuously. Our primary outcome was escalation of respiratory support within 28 days of randomization. Results Ninety-three patients were enrolled in this study between March 2022 and March 2023. Eighty (86%) patients had received ≥2 doses of SARS-CoV2 vaccine. The study was terminated early because of a reduction in the number of eligible patients. Data from 46 patients allocated to APP and 47 to standard care were available for analysis. At baseline, 19/47 (40%) patients allocated to the standard care group and 14/46 (30%) patients allocated to the APP group received HFNC. Continuous monitoring data were available for all patients monitored with wearable devices. Significantly greater mean daily APP times were achieved in those allocated to APP, however, most achieved less than the target 8 h/day. We did not detect clear differences in the primary outcome (relative risk,RR, 0.85, 95% CI 0.40-1.78, p=0.67) or secondary outcomes, including intubation rate and 28-day mortality. Patients reported prone positioning was comfortable, although almost all patients preferred supine positioning. No adverse events associated with the intervention were observed. Conclusions APP was not associated with benefit, but there was no sign of harm. Continuous monitoring with wearable devices is both feasible and acceptable for patients. In our population, achieving prolonged APP time was challenging despite a dedicated support team, and patients preferred supine positioning. Clinical Trials Registration NCT05083130.

Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Corticosteroids are currently recommended as an adjunctive therapy in HIV-negative adults with TBM. However, benefit from corticosteroids in TBM may depend upon host leukotriene A4 hydrolase (LTA4H) genotype and the corresponding inflammatory phenotypes. This article describes the planned analyses for the primary publication of the results of the LAST ACT clinical trial (NCT03100786): ‘Leukotriene A4 hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-negative adults with Tuberculous meningitis’. The primary hypothesis addressed by the trial is that LTA4H genotype, in particular CC or CT genotype, determines whether adjunctive dexamethasone benefits or harms adults with TBM. The trial was an LTA4H genotype stratified, parallel group, randomised, double blind, placebo-controlled multi-centre Phase III trial of dexamethasone given for 6–8 weeks in addition to standard anti-tuberculosis drugs. LTA4H genotype (CC, CT, TT) was determined in all participants prior to randomisation; only those with CC or CT genotype were randomised to dexamethasone or placebo. All TT genotype participants received dexamethasone because prior data indicated survival was increased by dexamethasone in this genotype. The primary endpoint was all-cause death or new neurological event over the first 12 months after randomisation. We took a hybrid trial-design approach which aims to prove non-inferiority of placebo first but also allows claiming superiority of placebo in case dexamethasone causes substantial harm. This statistical analysis plan expands upon and updates the analysis plan outlined in the published study protocol.

Background Novel host-directed therapies are urgently needed for patients with dengue, particularly those at high risk of developing severe disease. Broad immunosuppression using corticosteroids in unselected patients with dengue has so far been unsuccessful. Patients with hyperinflammation (raised CRP and/or ferritin levels) are at highest risk of poor outcomes in dengue. Anakinra is a licensed, bio-engineered form of the naturally occurring IL-1R antagonist which has shown efficacy in other acute viral-associated hyperinflammatory syndromes. Methods This is a randomized placebo-controlled phase II trial of anakinra in 160 patients ≥ 12 years old, diagnosed as having dengue with warning signs or severe dengue and the hyperinflammatory syndrome (plasma ferritin >2000 ng/ml). Participants will receive a 4-day course of either anakinra or placebo. The primary endpoint is the efficacy of anakinra measured by the delta mSOFA score* (change in mSOFA score over 4 days after randomization). The accompanying immunological and transcriptomic analyses aim to identify novel mechanisms and pathways that may represent future biomarkers and therapeutic targets. Discussion The observed immunomodulatory benefit of anakinra in acute viral-associated hyperinflammatory syndromes including COVID-19 and auto-immune diseases makes this medication a promising potential treatment for dengue patients with hyperinflammation. This trial will assess the safety and efficacy of anakinra in patients with severe dengue or at high risk of developing life-threatening dengue disease. Registration ClinicalTrials.gov (NCT05611710).

Background Awake prone positioning (APP) may be beneficial in patients with respiratory failure who are not receiving mechanical ventilation. Randomized controlled trials of APP have been performed during peak COVID-19 periods in unvaccinated populations, with limited data on compliance or patient acceptability. We aimed to evaluate the efficacy and acceptability of APP in a lower-middle income country in an open-label randomized controlled trial using a dedicated APP implementation team and wearable continuous-monitoring devices. Methods The trial was performed at a tertiary level hospital in Ho Chi Minh City, Vietnam, recruiting adults (≥18 years) hospitalized with moderate or severe COVID-19 and receiving supplemental oxygen therapy via nasal/facemask systems or high-flow nasal cannula (HFNC). Patients were allocated by a computer-generated random number sequence in a 1:1 ratio to standard care or APP, where a dedicated team provided bedside support. Wearable devices continuously recorded pulse oximetry and body position continuously. Our primary outcome was escalation of respiratory support within 28 days of randomization. Results Ninety-three patients were enrolled in this study between March 2022 and March 2023. Eighty (86%) patients had received ≥2 doses of SARS-CoV2 vaccine. The study was terminated early because of a reduction in the number of eligible patients. Data from 46 patients allocated to APP and 47 to standard care were available for analysis. At baseline, 19/47 (40%) patients allocated to the standard care group and 14/46 (30%) patients allocated to the APP group received HFNC. Continuous monitoring data were available for all patients monitored with wearable devices. Significantly greater mean daily APP times were achieved in those allocated to APP, however, most achieved less than the target 8 h/day. We did not detect clear differences in the primary outcome (relative risk,RR, 0.85, 95% CI 0.40-1.78, p=0.67) or secondary outcomes, including intubation rate and 28-day mortality. Patients reported prone positioning was comfortable, although almost all patients preferred supine positioning. No adverse events associated with the intervention were observed. Conclusions APP was not associated with benefit, but there was no sign of harm. Continuous monitoring with wearable devices is both feasible and acceptable for patients. In our population, achieving prolonged APP time was challenging despite a dedicated support team, and patients preferred supine positioning. Clinical Trials Registration NCT05083130.