Search

Background: Favipiravir, an anti-influenza drug, has in vitro antiviral activity against SARS-CoV-2. Clinical trial evidence to date is inconclusive. Favipiravir has been recommended for the treatment of COVID-19 in some countries. Methods: In a multicentre open-label, randomised, controlled, adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomised to one of ten treatment arms including high dose oral favipiravir (3.6g on day 0 followed by 1.6g daily to complete 7 days treatment) or no study drug. The primary outcome assessed in a modified intention-to-treat population (mITT) was the rate of viral clearance (derived under a linear mixed-effects model from the daily log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 8 days [18 swabs per patient]). The safety population included all patients who received at least one dose of the allocated intervention. This ongoing adaptive platform trial is registered at ClinicalTrials.gov (NCT05041907). Results: In the final analysis, the mITT population contained data from 114 patients randomised to favipiravir and 126 patients randomised concurrently to no study drug. Under the linear mixed-effects model fitted to all oropharyngeal viral density estimates in the first 8 days from randomisation (4,318 swabs), there was no difference in the rate of viral clearance between patients administered favipiravir and patients receiving no study drug -1% (95% CI: -14 to 14% change). High dose favipiravir was well tolerated. Interpretation: Favipiravir does not accelerate viral clearance in early symptomatic COVID-19.

BackgroundUncertainty over the therapeutic benefit provided by parenteral remdesivir in COVID-19 has resulted in varying treatment guidelines. Early in the pandemic the monoclonal antibody cocktail, casirivimab/imdevimab, proved highly effective in clinical trials but because of weak or absentin vitroactivity against the SARS-CoV-2 Omicron BA.1 subvariant, it is no longer recommended.MethodsIn a multicenter open label, randomized, controlled adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to one of eight treatment arms including intravenous remdesivir (200mg followed by 100mg daily for five days), casirivimab/imdevimab (600mg/600mg), and no study drug. The primary outcome was the viral clearance rate in the modified intention-to-treat population derived from daily log10viral densities (days 0-7) in standardized duplicate oropharyngeal swab eluates. This ongoing adaptive trial is registered atClinicalTrials.gov(NCT05041907).ResultsAcceleration in mean estimated SARS-CoV-2 viral clearance, compared with the contemporaneous no study drug arm (n=64), was 42% (95%CI 18 to 73%) for remdesivir (n=67). Acceleration with casirivimab/imdevimab was 58% (95%CI: 10 to 120) in Delta (n=13), and 20% (95%CI: 3 to 43) in Omicron variant (n=61) infections compared with contemporaneous no study drug arm (n=84). In apost hocsubgroup analysis viral clearance was accelerated by 8% in BA.1 (95%CI: −21 to 59) and 23% (95%CI: 3 to 49) in BA.2 and BA.5 Omicron subvariants.ConclusionsParenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Despite substantially reducedin vitroactivities, casirivimab/imdevimab retainsin vivoantiviral activity against COVID-19 infections caused by currently prevalent Omicron subvariants.Brief summaryIn early symptomatic COVID-19 remdesivir accelerated viral clearance by 42% while the monoclonal antibody cocktail casirivimab/imdevimab accelerated clearance by approximately 60% in SARS-CoV-2 Delta variant infections, and by approximately 25% in infections with Omicron subvariants BA.2 and BA.5.

Exuberant inflammation manifesting as a “cytokine storm” has been suggested as a central feature in the pathogenesis of severe coronavirus disease 2019 (COVID-19). This study investigated two prognostic biomarkers, the high mobility group box 1 (HMGB1) and interleukin-6 (IL-6), in patients with severe COVID-19 at the time of admission in the intensive care unit (ICU). Of 60 ICU patients with COVID-19 enrolled and analyzed in this prospective cohort study, 48 patients (80%) were alive at ICU discharge. HMGB1 and IL-6 plasma levels at ICU admission were elevated compared with a healthy control, both in ICU nonsurvivors and ICU survivors. HMGB1 and IL-6 plasma levels were higher in patients with a higher Sequential Organ Failure Assessment (SOFA) score (> 10), and the presence of septic shock or acute kidney injury. HMGB1 and IL-6 plasma levels were also higher in patients with a poor oxygenation status (PaO2/FiO2 < 150 mm Hg) and a longer duration of ventilation (> 7 days). Plasma HMGB1 and IL-6 levels at ICU admission also correlated with other prognostic markers, including the maximum neutrophil/lymphocyte ratio, D-dimer levels, and C-reactive protein levels. Plasma HMGB1 and IL-6 levels at ICU admission predicted ICU mortality with comparable accuracy to the SOFA score and the COVID-GRAM risk score. Higher HMGB1 and IL-6 were not independently associated with ICU mortality after adjustment for age, gender, and comorbidities in multivariate analysis models. In conclusion, plasma HMGB1 and IL6 at ICU admission may serve as prognostic biomarkers in critically ill COVID-19 patients.

BackgroundThere is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infection. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has significant antiviral activity in vivo is uncertain.MethodsIn a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high dose ivermectin (600µg/kg daily for seven days), the monoclonal antibodies casirivimab and imdevimab (600mg/600mg), and no study drug. Viral clearance rates were derived from daily duplicate oropharyngeal quantitative PCR measurements. This ongoing trial is registered at ClinicalTrials.gov (NCT05041907).ResultsRandomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Compared with the no study drug arm, the mean estimated SARS-CoV-2 viral clearance following ivermectin was 9.1% slower [95%CI -27.2% to +11.8%; n=45 versus n=41], whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster [95%CI +7.0% to +115.1%; n=10 (Delta variant) versus n=41].ConclusionsHigh dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Measured in this way viral clearance rate is a valuable pharmacodynamic measure in assessing antiviral COVID-19 therapeutics in vivo.Funding“Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)” is funded by the Wellcome Therapeutics Accelerator (223195/Z/21/Z).ImpactRate of viral clearance determined from daily duplicate oropharyngeal swabs over one week is an efficient measure of antiviral efficacy in early COVID-19 infection.High dose ivermectin did not demonstrate measurable antiviral activity in early symptomatic COVID-19 infection.

Dengue is the most common mosquito-borne flaviviral infection in the world today. Several factors contribute and act synergistically to cause severe infection. One of these is dysregulated host immunological mediators that cause transient pathophysiology during infection. These mediators act on the endothelium to increase vascular permeability, which leads to plasma leakage compromising hemodynamics and coagulopathy. We conducted a prospective study to explore the expression of pro- and anti-inflammatory cytokines and how they relate to clinical dengue manifestations, by assessing their dynamics through acute dengue infection in adults admitted to the Hospital for Tropical Diseases, Bangkok, Thailand. We performed cytokine analysis at three phases of infection for 96 hospitalized adults together with serotyping of confirmed dengue infection during the outbreaks of 2015 and 2016. The serum concentrations of seven cytokines (interleukin [IL]-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha, and interferon gamma) were measured in duplicate using a commercial kit (Bio-Plex Human Cytokine Assay). In this study, the cytokine profile was suggestive of a T-helper 2 response. Most patients had secondary infection, and the levels of viremia were higher in patients with plasma leakage than those without plasma leakage. In addition, we observed that bleeding and hepatitis were associated with significantly higher levels of IL-8 during the early phases of infection. Furthermore, IL-6 levels in the early phase of infection were also elevated in bleeding patients with plasma leakage. These results suggest that IL-6 and IL-8 may act in synergy to cause bleeding in patients with plasma leakage.

The hallmark of severe dengue infection is the increased vascular permeability and hemodynamic alteration that might be associated with an intestinal permeability defect. However, the mechanisms underlying the gastrointestinal-related symptoms of dengue are not well characterized. A prospective observational study was conducted on patients with dengue who were categorized according to: (i) febrile versus critical phase and (ii) hospitalized patients with versus without the warning signs to evaluate the gut barrier using lactulose-to-mannitol excretion ratio (LEMR). Serum endotoxins, (1→3)-β-D-glucan (BG), and inflammatory parameters were measured. A total of 48 and 38 patients were enrolled in febrile illness and critical phase, respectively, while 22 and 64 patients presented with or without the warning signs, respectively. At enrollment, a positive LEMR test was found in 20 patients (91%) with warning signs, regardless of phase of infection. Likewise, serum endotoxins and BG, the indirect biomarkers for leaky gut, prominently increased in patients who developed severe dengue when compared with the non-severe dengue (endotoxins, 399.1 versus 143.4 pg/mL (p &lt, 0.0001), BG, 123 versus 73.8 pg/mL (p = 0.016)). Modest impaired intestinal permeability occurred in dengue patients, particularly those with warning signs, and were associated with endotoxemia and elevated BG. Thus, leaky gut syndrome might be associated with severity of dengue infection.

Introduction: Co-infection of influenza A and B has been reported, especially in outbreak situations, but epidemiological and clinical information is limited. We aimed to investigate an outbreak of influenza among health care workers in which the index case suffered from influenza A and B co-infection. Methodology: We investigated the outbreak setting through the utilization of structural questionnaires, molecular methods, and serological tests. Results: Among 13 persons, one index case and five confirmed secondary cases were confirmed. The overall influenza infection rate was 46.2% (6/13), with infection rates for influenza A and B at 38.5% (5/13) and 23.1% (3/13), respectively. Interestingly, one of the secondary cases had influenza A and B co-infection identical to the index case. There was no significant association between vaccination status and influenza infection. Conclusions: This study unveils the demonstration of human-to-human influenza A and B co-infection transmission for the first time. Surveillance systems, combined with epidemiological case investigation comprising molecular diagnosis, should be strengthened for future influenza outbreak preparedness.

SummaryBackgroundProduction of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It’s being developed in Thailand, Vietnam, and Brazil; herein are initial results from Thailand.MethodsThis phase 1 stage of a randomised, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial was conducted at the Vaccine Trial Centre, Mahidol University (Bangkok). Healthy adults aged 18-59 years, non-pregnant and negative for SARS-CoV-2 antibodies were eligible. Participants were block randomised to receive one of six treatments by intramuscular injection twice, 28 days apart: 1 µg±CpG1018 (a toll-like receptor 9 agonist), 3 µg±CpG1018, 10 µg, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited and spontaneously reported adverse events (AEs) during 7 and 28 days after each vaccination, respectively. Secondary outcomes were immunogenicity measures (anti-S IgG and pseudotyped virus neutralisation). An interim analysis assessed safety at day 57 in treatment-exposed individuals and immunogenicity through day 43 per protocol. ClinicalTrials.gov (NCT04764422).FindingsBetween March 20 and April 23, 2021, 377 individuals were screened and 210 were enrolled (35 per group); all received dose one; five missed dose two. The most common solicited AEs among vaccinees, all predominantly mild, were injection site pain (InterpretationNDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 µg and 3 µg+CpG1018 formulations advanced to phase 2.FundingNational Vaccine Institute (Thailand), National Research Council (Thailand), Bill & Melinda Gates Foundation, National Institutes of Health (USA)

Recurrent IgA nephropathy (IgAN) remains an important cause of allograft loss in renal transplantation. Due to the limited efficacy of corticosteroid in the treatment of recurrent glomerulonephritis, rituximab was used in kidney transplant (KT) recipients with severe recurrent IgAN. A retrospective cohort study was conducted between January 2015 and December 2020. Accordingly, there were 64 KT recipients with biopsy-proven recurrent IgAN with similar baseline characteristics that were treated with the conventional standard therapy alone (controls, n = 43) or together with rituximab (cases, n = 21). All of the recipients had glomerular endocapillary hypercellularity and proteinuria (&gt, 1 g/d) with creatinine clearance (CrCl) &gt, 30 mL/min/1.73 m2 and well-controlled blood pressure using renin–angiotensin–aldosterone blockers. The treatment outcomes were renal allograft survival rate, proteinuria, and post-treatment allograft pathology. During 3.8 years of follow-up, the rituximab-based regimen rapidly decreased proteinuria within 12 months after rituximab administration and maintained renal allograft function—the primary endpoint—for approximately 3 years. There were eight recipients in the case group (38%), and none in the control group reached a complete remission (proteinuria &lt, 250 mg/d) at 12 months after treatment. Notably, renal allograft histopathology from patients with rituximab-based regimen showed the less severe endocapillary hypercellularity despite the remaining strong IgA deposition. In conclusion, adjunctive treatment with rituximab potentially demonstrated favorable outcomes for treatment of recurrent severe IgAN post-KT as demonstrated by proteinuria reduction and renal allograft function in our cohort. Further in-depth mechanistic studies with the longer follow-up periods are recommended.

Background: The role of hepatitis B surface antigen (HBsAg) levels in predicting the risk of developing hepatocellular carcinoma (HCC) has remained unclear. The aim of this study was to obtain the most up-to-date estimated measure of the association between HBsAg levels and the development of HCC in patients. Methods: We performed a systematic review by searching for relevant studies on PubMed, Scopus, ProQuest and the Cochrane Central Register of Controlled Trials from January 2002 to November 2017. We presented the effects of HBsAg levels at each cut-off value as the odds ratios (ORs) at 95% confidence interval (CI). We also investigated HCC and its potential risk factors including HBeAg, and HBV DNA. We registered our protocol with the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42018081138. Results: We selected 10 studies representing 12 541 cases. At the 100 IU/ml cut-off, the OR for HCC at the high HBsAg level versus the low level was 4.99 (95% CI, 3.01–8.29) with high inconsistency (I2=79%). At the 1,000 IU/ml threshold, the pooled OR for HCC at the high HBsAg versus the low level was 2.46 (95% CI, 2.15–2.83) with low variance. We also found correlations between the risk of HCC and male gender (OR=2.12), hepatitis B e-antigen positivity (OR=2.99), or hepatitis B (HBV) viral load ≥ 2,000 IU/ml (OR=4.37). Conclusion: Our study revealed that HBsAg levels ≥ 100 IU/ml, and notably >1,000 IU/ ml, are associated with an increased risk of HCC development.

Dengue viral infections present with a wide clinical spectrum ranging from asymptomatic to severe manifestations with organ involvement. The term “expanded dengue syndrome” has been commonly used to illustrate the unusual or atypical manifestations; acute kidney injury (AKI) is one of the atypical manifestations of this syndrome. The use of heterogeneous criteria to determine the presence of AKI in dengue patients due to the vast diversity in populations led to difficulties in assessing the true incidence of dengue-associated AKI. This review presents a variable, but often high, frequency of dengue-associated AKI among vastly diverse populations with various disease severities. Dengue-associated AKI is not an uncommon complication, and its importance has often been neglected during the management of dengue patients. The risk factors and certain clinical and laboratory findings commonly reported among dengue patients with AKI should be considered to support a timely diagnosis and case management. This review highlights the need for clinicians to be aware of dengue-associated AKI to reduce the morbidity and mortality associated with this common and important tropical disease.

Dengue virus (DENV) causes dengue fever (DF) and dengue hemorrhagic fever in humans. Some DF patients suddenly develop severe symptoms around the defervescent period. Although the pathogenic mechanism of the severe symptoms has not been fully elucidated, the viremia level in the early phase has been shown to correlate with the disease severity. One of the hypotheses is that a phenomenon called antibody-dependent enhancement (ADE) of infection leads to high level of viremia. To examine the plausibility of this hypothesis, we examined the relationship between in vitro ADE activity and in vivo viral load quantity in six patients with dengue diseases. Blood samples were collected at multiple time points between the acute and defervescent phases, and the balance between neutralizing and enhancing activities against the autologous and prototype viruses was examined. As the antibody levels against DENV were rapidly increased, ADE activity was decreased over time or partially maintained against some viruses at low serum dilution. In addition, positive correlations were observed between ADE activity representing in vitro progeny virus production and viremia levels in patient plasma samples. The measurement of ADE activity in dengue-seropositive samples may help to predict the level of viral load in the subsequent DENV infection.

The chikungunya virus is an arthritogenic arbovirus that has re-emerged in many tropical and subtropical regions, causing explosive outbreaks. This re-emergence is due to a genomic polymorphism that has increased the vector susceptibility of the virus. The majority of those infected with chikungunya virus exhibit symptoms of fever, rash, and debilitating polyarthralgia or arthritis. Symptoms can persist for weeks, and patients can relapse months later. Fatalities are rare, but individuals of extreme age can develop severe infection. Here, we describe the 2019 outbreak, the second-largest since the virus re-emerged in the Maldives after the 2004 Indian Ocean epidemic, in which a total of 1,470 cases were reported to the Health Ministry. Sixty-seven patients presenting at the main referral tertiary care hospital in the Maldives capital with acute undifferentiated illness were recruited following a negative dengue serology. A novel point-of-care antigen kit was used to screen suspected cases, 50 of which were subsequently confirmed using real-time reverse transcription–polymerase chain reaction. We describe the genotype and polymorphism of Maldives chikungunya virus using phylogenetic analysis. All isolates were consistent with the East Central South African genotype of the Indian Ocean lineage, with a specific E1-K211E mutation. In addition, we explored the clinical and laboratory manifestations of acute chikungunya in children and adults, of which severe infection was found in some children, whereas arthritis primarily occurred in adults. Arthritides in adults occurred irrespective of underlying comorbidities and were associated with the degree of viremia.

BACKGROUND: Two main strategies to cope with the coronavirus disease 2019 (COVID-19) pandemic-lockdown (social restriction) and non-lockdown (herd immunity plan)-have been implemented in several countries. OBJECTIVE: This study aims to statistically compare the outcomes of the two strategies, represented by data from Thailand and Sweden, respectively. METHODS: Data for COVID-19 pandemic control from Thailand, representing social restriction, versus data from Sweden, representing the herd immunity plan, collected from January 13 to May 31, 2020, were analyzed by using the SIR (susceptible, infectious, recovered) model. RESULTS: The SIR model analysis demonstrated a beneficial effect of each model on the attenuation of the mortality rate, with lower mortality in social restriction and shorter overall pandemic duration in the herd immunity plan. However, the herd immunity plan demonstrated a higher mortality rate than social restriction (46.9% versus 1.9%) despite the later entry of the virus in Sweden. When the SIR model was used for predicting the COVID-19 status, Sweden was shown to likely end its COVID-19 epidemic earlier than Thailand (268 vs. 368 days). With the nonlinear estimation, at least one log difference between total confirmed cases versus active cases could be used as an indicator for relaxation of the lockdown policy in Thailand. CONCLUSIONS: Both the social restriction and herd immunity plans are beneficial for COVID-19 pandemic control in terms of the amelioration of pandemic mortality. The cumulative number of total recovered cases might be a potential parameter that could be used for determining the policy direction for COVID-19 control.

Chikungunya virus is an Alphavirus belonging to the family Togaviridae that is transmitted to humans by an infected Aedes mosquito. Patients develop fever, inflammatory arthritis, and rash during the acute stage of infection. Although the illness is self-limiting, atypical and severe cases are not uncommon, and 60% may develop chronic symptoms that persist for months or even for longer durations. Having a distinct periodical epidemiologic outbreak pattern, chikungunya virus reappeared in Thailand in December 2018. Here, we describe a cohort of acute chikungunya patients who had presented to the Bangkok Hospital for Tropical Diseases during October 2019. Infection was confirmed by real-time RT-PCR using serum collected at presentation to the Fever Clinic. Other possible acute febrile illnesses such as influenza, dengue, and malaria were excluded. We explored the sequence of clinical manifestations at presentation during the acute phase and associated the viral load with the clinical findings. Most of the patients were healthy individuals in their forties. Fever and arthralgia were the predominant clinical manifestations found in this patient cohort, with a small proportion of patients with systemic symptoms. Higher viral loads were associated with arthralgia, and arthralgia with the involvement of the large joints was more common in female patients

Background Dengue virus infection (DVI) is a major health problem in many parts of the world. Its manifestations range from asymptomatic infections to severe disease. Although cardiac involvement has been reported in DVI, its incidence has not yet been well established. Methods From July 2016 to January 2018, patients hospitalized at the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Thailand, with dengue virus infection confirmed by positive NS1 or positive dengue immunoglobulin M findings, participated in the study. We characterized the incidence and change in cardiac function by serial echocardiography and levels of troponin-T and creatine kinase-myocardial band (CK-MB) on the day of admission, the day of defervescence, the first day of hypotension (if any), and at 2 week follow-up. Results Of the 81 patients evaluated, 6 (7.41%) exhibited elevated biomarker levels. There was no difference in clinical presentation amongst dengue fever, dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS), except for the amount of bleeding. Cardiac involvement was found in 22.2% of patients: 3 (3.70%) had left ventricular systolic dysfunction, 3 (3.70%) had transient diastolic dysfunction, 6 (7.41%) had increased levels of at least one cardiac biomarker (troponin-T or CK-MB), and 6 (7.41%) had small pericardial effusion. Myocarditis was suspected in only two patients (with DHF); thus, myocarditis was uncommon in patients with dengue virus infection. Three patients developed DSS during admission and were transferred to the intensive care unit. Conclusion Cardiac involvement in adults with dengue infection was common, ranging from elevated cardiac biomarker to myocarditis. Abnormalities in cardiac function had resolved spontaneously by the day of follow-up, without specific treatment. We found that DHF was a significant risk factor for cardiac involvement. Echocardiography is the investigation of choice for evaluating the haemodynamic status of patients with DVI, especially in severe dengue.

Background The global incidence of dengue has increased with the ageing population. We examined the prevalence, clinical manifestations and risk factors associated with dengue severity among older patients. Methods A retrospective cohort study was conducted at a hospital in Thailand from 2013 to 2018. Data were collected from patient records. Older patients were those aged ≥60 y, whereas adult patients were aged at least 18 y but younger than 60 y. Results In total, 1822 patients were included in the study. The prevalence of older dengue was 7.96%. Older dengue patients were at a higher risk of developing dengue haemorrhagic fever (DHF) than adult dengue patients (40.69% vs 30.71%). Haematuria was significantly more frequent in older patients (24.82% vs 3.58%), whereas other clinical manifestations had similar frequencies between the groups. Multivariate logistic regression indicated that hypertension (adjusted OR [aOR]=3.549, 95% CI 1.498 to 8.407) and abdominal pain (aOR=10.904, 95% CI 1.037 to 114.710) were significantly associated with DHF among older patients. Conclusions Dengue is common in older adults, who also have a higher incidence of developing DHF. Older patients with dengue and comorbid hypertension and abdominal pain should be monitored for their increasing risk of DHF.

Travelers’ diarrhea (TD) is common among foreign travelers to Thailand. We performed a prospective cohort study to determine the TD incidence among foreign adult travelers to Thailand. We retrieved baseline demographic data, travel plans, and health history on enrolling individuals and collected follow-up questionnaires on days 7, 14, and 28 from the day of arrival. We analyzed data from 349 eligible participants. The mean participants’ age was 32.3 years; 55.4% were men. Most of the participants had visited a travel clinic for vaccinations and counseling after arrival in Thailand. The cumulative incidences of the participants developing TD were 14.0% (49/349), 23.5% (82/349), and 33.0% (115/349) at 7, 14, and 28 days, respectively. The median time to develop TD was 9 days (interquartile range 5–18 days) post-arrival. Of 115 participants with TD, 64.3% (74/115) consulted a physician, 1.7% (2/115) were hospitalized, and 11.3% (13/115) had to change their travel plans. We identified young age, eating street food, and not routinely washing hands after using a toilet as risk factors significantly associated with the incidence of TD using the log-rank test in our survival analysis. Up to one-third of foreign travelers developed diarrhea during the first month, and some cases were severe. Although no highly effective TD prevention method exists, the practice of good personal hygiene and avoidance of food and drinks derived from unsanitary sources are still recommended to reduce the risk of travelers’ TD.

Plasmodium falciparum infection causes febrile illness and severe disease with multiple organ failure and death when treatment is delayed. Antipyretic treatment is standard, and inducing hypothermia has been proposed to protect the brain in cerebral malaria. Here, we investigated the temperature dependence of asexual-stage parasite development and parasite multiplication in vitro. Plasmodium falciparum laboratory strain TM267 was incubated for 2 hours (short exposure) or 48 hours (continuous exposure) at different temperatures (32°C, 34°C, 35°C, 38°C, 39°C, and 40°C). The starting parasite developmental stage (ring, trophozoite, or schizont) varied between experiments. The parasite multiplication rate (PMR) was reduced under both hyper- and hypothermic conditions; after continuous exposure, the mean PMR ± SD was 9.1 ± 1.2 at 37°C compared with 2.4 ± 1.8 at 32°C, 2.3 ± 0.4 at 34°C, and 0.4 ± 0.1 at 40°C (P < 0.01). Changes in PMR were not significant after 2-hour exposure at temperatures ranging from 32°C to 40°C. Morphological changes in parasite cytoplasm and nucleus could be observed after long exposure to low or high temperature. After 48-hour incubation, rosette formation (≥ 2 uninfected red blood cells bound to infected red blood cells) was decreased at 34°C or 39°C compared with that at 37°C. In conclusion, both hyper- and hypothermia reduce PMR and delay erythrocytic stage development of P. falciparum, subsequently reducing rosette formation.

Background There are few studies of the incidence of health problems among travelers to Southeast Asia. The current study sought to determine the incidence of self-reported health problems among travelers visiting the region. Methods A prospective questionnaire-based study was conducted among travelers from high-income countries who visited Southeast Asia. Participants were enrolled at time of their pre-travel visit at Mahidol University, Bangkok, Thailand. Travelers were prospectively followed by self-administered questionnaires 2 weeks after arrival, upon return to their home country and 2 weeks after return. Results During January 2018–February 2019, 359 travelers were enrolled in Bangkok, Thailand, and the first questionnaire was administered. Follow-up questionnaires were returned by 191, 96 and 64 participants 2 weeks later, at the end of the trip and 2 weeks after return, respectively. A total of 6094 travel days were included in the final analysis. The incidence of acute diarrhea per month per 1000 travelers was 217 [95% confidence interval (CI), 189–248] episodes; skin problems, 197 (95% CI, 170–227); respiratory symptoms, 133 (95% CI, 111–158); fever, 49 (95% CI, 36–65); and potential rabies exposure, 34 (95% CI, 24–48). The incidence of acute diarrhea episodes per month per 1000 travelers was significantly higher during the first 2 weeks of travel compared with subsequent weeks of travel: 325 (95% CI, 291–362) vs 132 (95% CI, 110–1157) (P Conclusions In this prospective cohort study we observed substantial burden of acute diarrhea and skin and respiratory symptoms among travelers to Southeast Asia. The higher incidence of diarrhea in the first 2 weeks of travel should be further investigated.

Dengue infection (DI) is a major vector-borne disease in southeast Asia and an important cause of morbidity. The complications such as hepatic impairment are common, and because the physiology of the liver differs between children and adults, the DI-associated liver impairments might be expected to differ as well. This study aims to compare the differences in liver impairment between adults and children with DI. We retrospectively studied 158 adults and 79 children with serologically confirmed DI admitted to the Bangkok Hospital for Tropical Diseases from 2008 to 2012. In total, 93% of adults and 87% of children exhibited abnormal liver enzyme levels during hospitalization. Overall, 76 (42.4%) adults and 16 (20.3%) children had dengue hemorrhagic fever (DHF). Compared with children, adults with dengue fever (DF) presented a significantly higher incidence of liver function impairment (alanine transaminase [ALT] > 2 × upper limit of normal [ULN]) (47.1% versus 25.5%), hepatitis (ALT > 4 × ULN) (29.4% versus 12.8%), and severe hepatitis (aspartate transaminase [AST]/ALT > 10 × ULN) (16.5% versus 4.3%). Children with DHF showed a significantly higher incidence of liver function impairment due to AST derangement than did adults (100% versus 73%). There were no differences in the total bilirubin, albumin, or total protein levels between adults and children. Liver enzymes normalized significantly more slowly in adults, and AST recovery was faster than ALT. In conclusion, liver function impairment was more common among adults than children with DF. As the severity progressed to DHF, liver injury became more common in children.

In recent decades, chikungunya virus (CHIKV) has become geographically widespread. In 2004, the CHIKV East/Central/South African (ECSA) genotype moved from Africa to Indian ocean islands and India followed by a large epidemic in Southeast Asia. In 2013, the CHIKV Asian genotype drove an outbreak in the Americas. Since 2016, CHIKV has re-emerged in the Indian subcontinent and Southeast Asia. In the present study, CHIKVs were obtained from Bangladesh in 2017 and Thailand in 2019, and their nearly full genomes were sequenced. Phylogenetic analysis revealed that the recent CHIKVs were of Indian Ocean Lineage (IOL) of genotype ECSA, similar to the previous outbreak. However, these CHIKVs were all clustered into a new distinct sub-lineage apart from the past IOL CHIKVs, and they lacked an alanine-to-valine substitution at position 226 of the E1 envelope glycoprotein, which enhances CHIKV replication in Aedes albopictus. Instead, all the re-emerged CHIKVs possessed mutations of lysine-to-glutamic acid at position 211 of E1 and valine-to-alanine at position 264 of E2. Molecular clock analysis suggested that the new sub-lineage CHIKV was introduced to Bangladesh around late 2015 and Thailand in early 2017. These results suggest that re-emerged CHIKVs have acquired different adaptations than the previous CHIKVs.

There is no proven preventative therapy or vaccine against COVID-19. Theinfection has spread rapidly and there has already been a substantial adverse impact on the global economy. Healthcare workers have been affected disproportionately in the continuing pandemic. Significant infection rates in this critical group have resulted in a breakdown of health services in some countries. Chloroquine, and the closely related hydroxychloroquine, are safe and well tolerated medications which can be given for years without adverse effects. Chloroquine and hydroxychloroquine have significant antiviral activity against SARS-CoV-2, and despite the lack of benefit of hydroxychloroquine treatment in patients hospitalised with severe COVID-19, these drugs could still work in prevention. The emerging infection paradigm of an early viral peak, and late inflammation where there is benefit from corticosteroids. If these direct actiing antivirals are to work, they have the best chance given either early in infection and before infection occurs. We describe the study protocol for a multi-centre, multi-country randomised, double blind, placebo controlled trial to answer the question- can chloroquine/ hydroxychloroquine prevent COVID-19. 40,000 participants working in healthcare facilities or involved in the management of COVID-19 will be randomised 1:1 to receive chloroquine/ hydroxychloroquine or matched placebo as daily prophylaxis for three months. The primary objective is the prevention of symptomatic, virological or serologically proven coronavirus disease (COVID-19). The study could detect a 23% reduction from an incidence of 3% in the placebo group for either drug with 80% power. Secondary objectives are to determine if chloroquine/hydroxychloroquine prophylaxis attenuates severity, prevents asymptomaticCOVID-19 and symptomatic acute respiratory infections of another aetiology (non-SARS-CoV-2).

Severe dengue cases have been increasingly reported in Thailand, and the under-reporting of acute kidney injury (AKI) in cases of dengue viral infection has become an obstacle in obtaining an accurate description of the true nature and epidemiology of AKI. Because AKI may lead to patient morbidity and mortality, an early diagnosis is important in preventing its onset in dengue patients. This study aimed to determine the prevalence, clinical and laboratory characteristics, and associated factors of AKI among adult dengue patients. This retrospective study reviewed admission data from the medical records of adult dengue patients admitted to the Bangkok Hospital for Tropical Diseases between January 2012 and November 2017 and stratified these patients into AKI and non-AKI groups using the Kidney Disease Improving Global Outcomes criteria (KDIGO). A total of 1,484 patients were included in the study, with 71 categorized into the AKI group. The prevalence of AKI was 4.8%. In the AKI group, the predominant age range was 18–40 years (71.8%), with a female to male ratio of 1:2.7. These patients showed significantly (P < 0.05) higher proportions of altered consciousness, dyspnea, low mean arterial blood pressure, high-grade fever, major bleeding, severe thrombocytopenia, hypoalbuminemia, severe transaminitis, coagulopathy, metabolic acidosis, rhabdomyolysis, proteinuria, hematuria, and pyuria. Our study established that older age, male sex, diabetes mellitus, obesity, severe dengue, and coexisting bacterial infection were significant associated factors for AKI in dengue by multivariate analysis. A total of 10 (14.1%) patients with AKI received dialysis, among which 9 (12.7%) patients from the AKI group died. Our findings suggest that an awareness of AKI, its early diagnosis, and evaluation of clinical and laboratory characteristics of dengue patients will help clinicians to initiate appropriate therapy for dengue-associated AKI.

We report a case ofPlasmodium vivaxand murine typhus coinfection in a 30-year-old woman who presented with intermittent, high-grade fever. Her peripheral blood smear showed ring-form trophozoites ofP. vivax, with an initial murine typhus serological test being negative. Althoughthe P. vivaxinfection was successfully treated, she still had intermittent, high-grade fever, developed dyspnoea and bilateral interstitial pneumonitis shown in the chest X-ray. Thus, coinfection was suspected, and empirical antibiotics were given. The second serological test confirmed the concomitant murine typhus infection, and antibiotics treatment were successful with the complete recovery. This case emphasises that an initial negative murine typhus serological test does not necessarily rule out the presence of the disease. A follow-up murine typhus serological or molecular test within 1–2 weeks is therefore recommended.

Serological testing of paired (i.e. admission and convalescent) sera from 103 fever patients in Kathmandu, Nepal, was performed to estimate the prevalence rates of scrub typhus, murine typhus, Leptospira and dengue virus antibodies and to determine their role in the cause of active infections. Blood cultures from 15 patients grew Salmonella enterica serovar Typhi, 8 grew S. Paratyphi A and 6 grew other bacteria. Diagnostic antibody levels were detected against murine typhus (27/103; 26%), scrub typhus (23/103; 22%), Leptospira (10/103; 10%) and dengue virus (8/103; 8%). Nineteen patients (18%) had diagnostically raised antibodies to more than one infectious agent. Seven S. Typhi (7/15; 47%) and two S. Paratyphi A (2/8; 25%) patients had significant scrub typhus, murine typhus, Leptospira or dengue virus IgM antibody titres. This study confirms the presence of leptospiral, rickettsial and dengue infections in Kathmandu as well as evidence for mixed infections with S. Typhi and Orientia tsutsugamushi or Rickettsia typhi. These infections should be kept in mind when considering the differential diagnoses of fever and empirical treatment options in Nepal. Many patients demonstrated static IgM antibody results between paired serum collections, suggesting recent rather than acutely active infections.

The global spread of the four dengue virus serotypes (DENV-1 to -4) has made this virus a major and growing public health concern. Generally, pre-existing neutralizing antibodies derived from primary infection play a significant role in protecting against subsequent infection with the same serotype. By contrast, these pre-existing antibodies are believed to mediate a non-protective response to subsequent heterotypic DENV infections, leading to the onset of dengue illness. In this study, we prepared hybridomas producing human monoclonal antibodies (HuMAbs) against DENV using peripheral blood mononuclear cells (PBMCs) from patients in the acute phase (around 1 week after the onset of illness) or the convalescent phase (around 2 weeks after the onset of illness) of secondary infection. Interestingly, a larger number of hybridoma clones was obtained from patients in the acute phase than from those in the convalescent phase. Most HuMAbs from acute-phase infections were cross-reactive with all four DENV serotypes and showed significant neutralization activity to all four DENV serotypes. Thus, secondary DENV infection plays a significant role in stimulating memory cells to transiently increase the number of antibody-secreting plasma cells in patients in the early phase after the secondary infection. These HuMAbs will enable us to better understand the protective and pathogenic effects of DENV infection, which could vary greatly among secondarily-infected individuals.

Background There is increasing concern about the potential for nephrotoxicity in patients with chronic hepatitis B (CHB) treated long-term with nucleotide analogs. Methods We examined renal dysfunction and its associated risk factors in patients with CHB treated with antiviral regimens containing either nucleosides or nucleotide analogs. We undertook a retrospective cohort study from 2006 to 2014 at the Hospital for Tropical Diseases, Bangkok, Thailand, and analyzed the data of 102 patients with a median follow-up time of 44.5 months (range 4–101 months). Results Seventy-three patients were treated with an antiviral regime containing a nucleoside analog, and 29 with a regime containing a nucleotide analog. Abnormally elevated serum creatinine concentration was observed in 12 patients (11.8 %) after 8 years of treatment. Thirty one percent of patients treated with nucleotide analogs had elevated serum creatinine levels and three of these patients (10.3 %) developed nephrotoxicity. In contrast, serum creatinine concentrations were elevated in three of the 73 patients treated with a nucleoside analog (4.1 %), and none developed nephrotoxicity. The incidence of renal dysfunction by the nucleotide analog regimen was cumulative, with 11.1, 21.0, 26.5 and 47.6 % of patients affected after 2, 4, 6 and 8 years, respectively. Univariate and multivariate analysis indicated that a nucleotide analog-based regimen significantly predicted renal dysfunction (odds ratio 10.5, 95 % confidence intervals 2.6–42.4, P

A new fixed-dose artesunate (AS)-mefloquine (MQ) was assessed in adults hospitalized for 28 days with uncomplicated drug-resistant falciparum malaria. The patients ( n = 25/arm) were treated with (i) two fixed-dose tablets (AS-MQ arm; 100 mg AS-200 mg MQ/tablet) daily for 3 days (days 0, 1, and 2) or (ii) nonfixed AS (AS-plus-MQ arm; 4 mg/kg of body weight/day for 3 days) plus MQ (15 mg/kg on day 1 and 10 mg/kg on day 2), dosed by weight. Clinical laboratory electrocardiogram (ECG), adverse events (AEs), efficacy, and pharmacokinetic parameters were assessed over 28 days. Both regimens were well tolerated. No AEs were drug related. Two serious AEs of malaria-induced hypotension occurring in the AS-MQ arm necessitated rescue treatment. There were no significant changes in hematology, biochemistry, or PR and QRS intervals. For all patients, mean Fridericia-corrected QT intervals were significantly ( P ≤ 0.0027) prolonged on day 3 (407 ms) and day 7 (399 ms) versus day 0 (389 ms), in parallel with significant ( P ≤ 0.0003) falls in heart rates (67 [day 3], 73 [day 7], and 83 [day 0] beats/minute). Fixed-nonfixed formulations were bioequivalent for MQ, but not for AS and dihydroartemisinin (DHA). One AS-MQ patient developed a new infection on day 28; his day 28 plasma MQ concentration was 503.8 ng/ml. Fixed-dose AS-MQ was well tolerated, had pharmacokinetic (PK) profiles broadly similar to those of nonfixed AS plus MQ, and is a suitable replacement.

Rabies remains a problem in Southeast Asia where large numbers of backpackers visit each year. During May-June 2008, a survey study was conducted of foreign backpackers in Bangkok, Thailand to assess their risk of rabies exposure. Eight hundred seventy (870) questionnaires were collected and analyzed. The median age of the backpackers was 25.5 years. Most of them were European (68.4%), followed by North American (13.2%). Although 80.7% had sought health information before traveling, only 55.6% had received information about rabies. Only 18.1% had completed pre-exposure rabies vaccination (3 shots) before travel, whereas 70.9% had not been vaccinated for rabies at all. In this study, the incidence of being licked was 3.56%, and of being bitten 0.69%, on average stays of 30.06 days in Southeast Asia. More than a half (54%) of exposures occurred in the first 10 days after arrival in Southeast Asia.

SUMMARY: Background: Patients on dialysis are at high risk of acquiring viral hepatitis infections. However, there were only few data from Thailand. The aim of the present study was to assess the prevalence, incidence and associated risk factors of viral hepatitis infections among dialysis patients. Methods: A retrospective study was conducted to evaluate 5179 medical records of dialysis patients from the Thailand Renal Replacement Therapy Registry. Results: In 2002, the seroprevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections were 6.3% (n = 2454) and 4.8% (n = 2167), respectively. HBV and HCV seroprevalence became 6.5% (n = 2585) and 4.3% (n = 2399) in 2003. The incidence of HBV and HCV infections were 1.5 and 2.4 cases per 1000 patient-years, respectively. Logistic regression analysis showed that age and gender were significant risk factors for HBV infection, but not for HCV infection. Conclusion: In Thailand, it was not uncommon for dialysis patients to acquire viral hepatitis infections. However, our prevalence is similar to reports from some other South-East Asian countries.