Acute undifferentiated febrile illness (AUFI) is often undiagnosed in Thailand, resulting in delayed or ineffective treatment. We compared the demographic, exposure history, and clinical characteristics of AUFI patients with laboratory evidence of bacterial and nonbacterial pathogens. Patients aged 2-80 years presenting to 12 hospitals in Nakhon Phanom and Tak provinces were enrolled from April 2017 through May 2020. Interviews were conducted and blood, urine, and sputum were collected for culture as well as rapid diagnostic and molecular testing. A total of 1,263 patients tested positive for one or more bacterial, viral, or parasitic pathogens and were included in the analysis. Multivariable logistic regression was performed to compare factors associated with bacterial infections versus nonbacterial infections. Bacterial infections were more commonly identified in participants from Nakhon Phanom than Tak. Bacterial infections were independently associated with several factors including age ≥50 years (adjusted odds ratio [95% CI]): (4.18 [2.85-6.14]), contact with farm animals (1.82 [1.29-2.57]), antibiotic use within 72 hours of hospital presentation (2.37 [1.50-3.74]), jaundice (2.31 [1.15-4.63]), existing comorbidities (2.77 [1.93-3.96]), contact with febrile individuals (0.42 [0.31-0.57]), muscle pain (0.44 [0.31-0.64]), and rash (0.45 [0.29-0.70]). Bacterial infections were also associated with longer hospitalization (2.75 [2.08-3.64]) and lower odds of recovery at the time of discharge (0.14 [0.07-0.31]). Consideration of patient characteristics and signs/symptoms may help to inform targeted laboratory testing for suspected infectious etiologies. Understanding factors associated with bacterial and non-bacterial causes of AUFI may aid diagnosis and judicious use of antibiotics in resource-limited settings.

BACKGROUND: In response to the 2015-2016 Zika virus (ZIKV) outbreak and the causal relationship established between maternal ZIKV infection and adverse infant outcomes, we conducted a cohort study to estimate the incidence of ZIKV infection in pregnancy and assess its impacts in women and infants. METHODOLOGY/PRINCIPAL FINDINGS: From May 2018-January 2020, we prospectively followed pregnant women recruited from 134 participating hospitals in two non-adjacent provinces in northeastern Thailand. We collected demographic, clinical, and epidemiologic data and blood and urine at routine antenatal care visits until delivery. ZIKV infections were confirmed by real-time reverse transcriptase polymerase chain reaction (rRT-PCR). Specimens with confirmed ZIKV underwent whole genome sequencing. Among 3,312 women enrolled, 12 (0.36%) had ZIKV infections, of which two (17%) were detected at enrollment. Ten (83%, 3 in 2nd and 7 in 3rd trimester) ZIKV infections were detected during study follow-up, resulting in an infection rate of 0.15 per 1,000 person-weeks (95% CI: 0.07-0.28). The majority (11/12, 91.7%) of infections occurred in one province. Persistent ZIKV viremia (42 days) was found in only one woman. Six women with confirmed ZIKV infections were asymptomatic until delivery. Sequencing of 8 ZIKV isolates revealed all were of Asian lineage. All 12 ZIKV infected women gave birth to live, full-term infants; the only observed adverse birth outcome was low birth weight in one (8%) infant. Pregnancies in 3,300 ZIKV-rRT-PCR-negative women were complicated by 101 (3%) fetal deaths, of which 67 (66%) had miscarriages and 34 (34%) had stillbirths. There were no differences between adverse fetal or birth outcomes of live infants born to ZIKV-rRT-PCR-positive mothers compared to live infants born to ZIKV-rRT-PCR-negative mothers. CONCLUSIONS/SIGNIFICANCE: Confirmed ZIKV infections occurred infrequently in this large pregnancy cohort and observed adverse maternal and birth outcomes did not differ between mothers with and without confirmed infections.

Public Health Emergency Operations Centers (PHEOCs) are the critical units to lead communications, information sharing, and resource mobilisation during national and international health emergencies, and are key components for maintaining global health security. This assessment sought to examine the coordination mechanisms between national and sub-national PHEOCs in Thailand, Cambodia, Lao People’s Democratic Republic, and Malaysia (TCLM countries) during the COVID-19 pandemic. Information was collected on PHEOC structures, functions, and cross-border communications in three stages: a literature review of national PHEOC and emergency preparedness capacities; questionnaire responses from stakeholders to describe PHEOC activity at the national level; and meetings with emergency response staff in five border provinces of Thailand to assess communications between sub-national PHEOCs across country borders. The findings showed that each of the countries has demonstrated a commitment to strengthening their national PHEOCs and improving cross-border communication in the face of the COVID-19 pandemic. Strong existing relationships between TCLM countries assisted in activating a coordinated pandemic response, but gaps remain in efficient data sharing, workforce capacity, and the utilisation of consistent communication platforms among countries. Lessons learned from the pandemic can be used to further strengthen countries’ preparedness for future health emergencies, in line with International Health Regulations (2005) and regional plans to build health security in the Southeast Asia region. This assessment provides TCLM countries with the opportunity to address weaknesses in national and international PHEOC capacities. It may be used alongside existing guidelines to prepare the region for a stronger response to future global and regional health emergencies. © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Among 11 patients in Thailand infected with severe acute respiratory syndrome coronavirus 2, we detected viral RNA in upper respiratory specimens a median of 14 days after illness onset and 9 days after fever resolution. We identified viral co-infections and an asymptomatic person with detectable virus RNA in serial tests. We describe implications for surveillance.

Melioidosis incidence and mortality have reportedly been increasing in endemic areas of Thailand, but little population-based data on culture-confirmed Burkholderia pseudomallei infections exist. We provide updated estimates of melioidosis bacteremia incidence and in-hospital mortality rate using integration of two population-based surveillance databases in Nakhon Phanom, Thailand, since automated blood culture became available in 2005. From 2009 to 2013, 564 hospitalized bacteremic melioidosis patients were identified. The annual incidence of bacteremic melioidosis ranged from 14 to 17 per 100,000 persons, and average population mortality rate was 2 per 100,000 persons per year. In-hospital mortality rate declined nonsignificantly from 15% (15/102) to 13% (15/118). Of 313 (56%) bacteremic melioidosis patients who met criteria for acute lower respiratory infection and were included in the hospital-based pneumonia surveillance system, 65% (202/313) had a chest radiograph performed within 48 hours of admission; 46% (92/202) showed radiographic evidence of pneumonia. Annual incidence of bacteremic melioidosis with pneumonia was 2.4 per 100,000 persons (95% confidence intervals; 1.9-2.9). In-hospital death was more likely among bacteremic melioidosis patients with pneumonia (34%; 20/59) compared with non-pneumonia patients (18%; 59/321) (P-value = 0.007). The overall mortality could have been as high as 46% (257/564) if patients with poor clinical condition at the time of discharge had died. The continued high incidence of bacteremic melioidosis, pneumonia, and deaths in an endemic area highlights the need for early diagnosis and treatment and additional interventions for the prevention and control for melioidosis.

BACKGROUND: Ranong Province in southern Thailand is one of the primary entry points for migrants entering Thailand from Myanmar, and borders Kawthaung Township in Myanmar where artemisinin resistance in malaria parasites has been detected. Areas of high population movement could increase the risk of spread of artemisinin resistance in this region and beyond. METHODS: A respondent-driven sampling (RDS) methodology was used to compare migrant populations coming from Myanmar in urban (Site 1) vs. rural (Site 2) settings in Ranong, Thailand. The RDS methodology collected information on knowledge, attitudes, and practices for malaria, travel and occupational histories, as well as social network size and structure. Individuals enrolled were screened for malaria by microscopy, Real Time-PCR, and serology. RESULTS: A total of 619 participants were recruited in Ranong City and 623 participants in Kraburi, a rural sub-district. By PCR, a total of 14 (1.1%) samples were positive (2 P. falciparum in Site 1; 10 P. vivax, 1 Pf, and 1 P. malariae in Site 2). PCR analysis demonstrated an overall weighted prevalence of 0.5% (95% CI, 0-1.3%) in the urban site and 1.0% (95% CI, 0.5-1.7%) in the rural site for all parasite species. PCR positivity did not correlate with serological positivity; however, as expected there was a strong association between antibody prevalence and both age and exposure. Access to long-lasting insecticidal treated nets remains low despite relatively high reported traditional net use among these populations. CONCLUSIONS: The low malaria prevalence, relatively smaller networks among migrants in rural settings, and limited frequency of travel to and from other areas of malaria transmission in Myanmar, suggest that the risk for the spread of artemisinin resistance from this area may be limited in these networks currently but may have implications for regional malaria elimination efforts.

Results from regular drug efficacy monitoring should always be interpreted in the context of the many limitations inherent to attributing apparent treatment failures to antimalarial resistance, as concisely summarized by Hamed and Kuhen (1). Notably, in study settings where direct supervision of the evening doses of artemether-lumefantrine (AL) is operationally infeasible or culturally unacceptable, low efficacy can also potentially be attributed to inaccurate dosing or underdosing. Details of how we strived to guarantee participant compliance with evening doses in lieu of direct supervision are found in our original report (2). Importantly, procedures were identical in both provinces, and we have no indication that participant adherence to the evening doses or food consumption guidelines was different in Zaire Province, where we found lower efficacy of AL. While lack of direct observation of doses and nonadherence to guidelines regarding food consumption with drug administration have been shown to be associated with lower blood lumefantrine levels, they have not been directly associated with decreased efficacy of AL (3, 4). | | While in vitro susceptibility testing requires infrastructure rarely found at drug efficacy monitoring sites, there is a long history of complementing clinical outcome data with testing for known molecular markers of resistance (5). Samples from treatment failures with mutations associated with resistance provide more evidence of resistance than clinical outcome data alone. In our study, the detection of pfmdr1 haplotypes previously associated with decreased sensitivity to lumefantrine (6) and the absence of mutations associated with artemisinin resistance in AL treatment failures support the hypothesis of lumefantrine resistance. | | Notably, the NFD and NYD pfmdr1 haplotypes predominated not only in recrudescent infections but also in reinfections in the AL arms. Contrary to Hamed and Kuhen's assertion, reinfections observed during follow-up do provide important data on efficacy. For the calculation of uncorrected efficacy, an important outcome for therapeutic efficacy studies, both reinfections and recrudescences are considered treatment failures. The reporting and interpretation of uncorrected efficacy results are standard components of drug efficacy monitoring for two primary reasons (7,–9). First, uncorrected efficacy estimates are not subject to the limitations and potential biases of using genotyping data to differentiate reinfection from recrudescence. Second, uncorrected efficacy results provide data concerning the posttreatment prophylactic effect of the partner drug in artemisinin-based combination therapies and thus the proportion of clients that will require retreatment, data of increasing interest to malaria control programs. The reinfection rates in the AL arms in Zaire and Uíge Provinces provide a good example of the potential utility of reinfection rates. The reinfection rate in Zaire (13%) was measured as more than twice the rate in Uíge (5.1%). This was despite our screening data, where 67% of the children screened tested positive for malaria in Uíge, compared to 53% in Zaire, indicating that transmission was almost certainly higher in Uíge at the time of our study. This unexpectedly high rate of reinfection in Zaire could therefore point to a parasite population that is less sensitive to lumefantrine and that consequently has a higher likelihood of successfully invading patients with subtherapeutic doses of lumefantrine following AL treatment (10). | | Finally, we would like to reaffirm that while certain screened children had parasitemia levels above 100,000 parasites/μl, only children with parasitemia levels between 2,000 and 100,000 parasites/μl were enrolled in the study, as described in Materials and Methods. Given that no children with parasitemia levels above 100,000 parasites/μl were enrolled in any of the study arms at either site, differences in hyperparasitemia rates between the Uíge and Zaire AL arms cannot explain the difference in efficacy as Hamed and Kuhen suggest.

The development of resistance to antimalarials is a major challenge for global malaria control. Artemisinin-based combination therapies, the newest class of antimalarials, are used worldwide but there have been reports of artemisinin resistance in Southeast Asia. In February-May 2013, we conducted open-label, nonrandomized therapeutic efficacy studies of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) in Zaire and Uige Provinces in northern Angola. The parasitological and clinical responses to treatment in children with uncomplicated P. falciparum monoinfection were measured over 28 days and the main outcome was PCR-corrected adequate clinical and parasitological response (ACPR) proportion on day 28. Parasites from treatment failures were analyzed for the presence of putative molecular markers of resistance to lumefantrine and artemisinins, including the recently identified mutations in the K13-propeller gene. In the 320 children finishing the study, 25 treatment failures were observed, 24 in the AL arms and one in the DP arm. The PCR-corrected ACPR proportion on day 28 for AL was 88% (95% CI: 78-95) in Zaire and 97% (91-100) in Uige. For DP, it was 100% (95-100) in Zaire, and 100% (96-100) in Uige. None of the treatment failures had molecular evidence of artemisinin resistance. In contrast, 91% of AL treatment failures had markers associated with lumefantrine resistance on day of failure. The absence of molecular markers for artemisinin resistance and the observed efficacies of both drug combinations suggest no evidence of artemisinin resistance in northern Angola. There is evidence of increased lumefantrine resistance in Zaire, which should continue to be monitored.

Artemisinin-based combinations are currently the most effective anti-malarials and, in addition to vector control, have led to significant declines in malaria morbidity and mortality. However, foci of artemisinin drug resistance have been identified in the Greater Mekong subregion (GMS) of the Asia Pacific, threatening the major gains made in malaria control and potentially creating a parasite pool that is more difficult to treat and eliminate. Efforts are underway to halt the spread of artemisinin resistance, including coordination of activities and funding, and identification of areas of suspected artemisinin resistance, now using a newly identified molecular marker. However, targeting resources to the containment of resistant parasites is likely inefficient and monitoring impact is challenging. A more sustainable solution is the rapid elimination of all Plasmodium falciparum parasites from the GMS. This strategy is more efficient for several reasons. First, a subregional strategy is in line with current commitment to elimination and will build upon the existing national political support for elimination as well as enhancing collaboration among countries. Second, the challenge of human mobility in the GMS is subregional in scope and requires a harmonized elimination strategy. Third, countries will need to improve and intensify malaria operations to reach elimination, and this will be a singular goal across the subregion. Rallying around the goal of P. falciparum elimination will not only utilize existing regional bodies to catalyze political and funding support, but will also leverage the funding already in place to achieve this subregional goal.

BACKGROUND: Anti-malarial regimens containing sulphonamide or artemisinin ingredients are widely used in malaria-endemic countries. However, evidence of the incidence of adverse drug reactions (ADR) to these drugs is limited, especially in Africa, and there is a complete absence of information on the economic burden such ADR place on patients. This study aimed to document ADR incidence and associated household costs in three high malaria transmission districts in rural Tanzania covered by demographic surveillance systems. METHODS: Active and passive surveillance methods were used to identify ADR from sulphadoxine-pyrimethamine (SP) and artemisinin (AS) use. ADR were identified by trained clinicians at health facilities (passive surveillance) and through cross-sectional household surveys (active surveillance). Potential cases were followed up at home, where a complete history and physical examination was undertaken, and household cost data collected. Patients were classified as having 'possible' or 'probable' ADR by a physician. RESULTS: A total of 95 suspected ADR were identified during a two-year period, of which 79 were traced, and 67 reported use of SP and/or AS prior to ADR onset. Thirty-four cases were classified as 'probable' and 33 as 'possible' ADRs. Most (53) cases were associated with SP monotherapy, 13 with the AS/SP combination (available in one of the two areas only), and one with AS monotherapy. Annual ADR incidence per 100,000 exposures was estimated based on 'probable' ADR only at 5.6 for AS/SP in combination, and 25.0 and 11.6 for SP monotherapy. Median ADR treatment costs per episode ranged from US$2.23 for those making a single provider visit to US$146.93 for patients with four visits. Seventy-three per cent of patients used out-of-pocket funds or sold part of their farm harvests to pay for treatment, and 19% borrowed money. CONCLUSION: Both passive and active surveillance methods proved feasible methods for anti-malarial ADR surveillance, with active surveillance being an important complement to facility-based surveillance, given the widespread practice of self-medication. Household costs associated with ADR treatment were high and potentially catastrophic. Efforts should be made to both improve pharmacovigilance across Africa and to identify strategies to reduce the economic burden endured by households suffering from ADR.

IMPORTANCE: Intermittent preventive therapy with sulfadoxine-pyrimethamine to control malaria during pregnancy is used in 37 countries in sub-Saharan Africa, and 31 of those countries use the standard 2-dose regimen. However, 2 doses may not provide protection during the last 4 to 10 weeks of pregnancy, a pivotal period for fetal weight gain. OBJECTIVE: To perform a systematic review and meta-analysis of trials to determine whether regimens containing 3 or more doses of sulfadoxine-pyrimethamine for intermittent preventive therapy during pregnancy are associated with a higher birth weight or lower risk of low birth weight (LBW) (<2500 g) than standard 2-dose regimens. DATA SOURCES AND STUDY SELECTION: ISI Web of Knowledge, EMBASE, SCOPUS, PubMed, LILACS, the Malaria in Pregnancy Library, Cochrane CENTRAL, and trial registries from their inception to December 2012, without language restriction. Eligible studies included randomized and quasi-randomized trials of intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine monotherapy. DATA EXTRACTION: Data were independently abstracted by 2 investigators. Relative risk (RR), mean differences, and 95% CIs were calculated with random-effects models. RESULTS: Of 241 screened studies, 7 trials of 6281 pregnancies were included. The median birth weight in the 2-dose group was 2870 g (range, 2722-3239 g) and on average 56 g higher (95% CI, 29-83 g; I2 = 0%) in the ≥3-dose group. Three or more doses were associated with fewer LBW births (RR, 0.80; 95% CI, 0.69-0.94; I 2 = 0%), with a median LBW risk per 1000 women in the 2-dose group (assumed control group risk) of 167 per 1000 vs 134 per 1000 in the ≥3-dose group (absolute risk reduction, 33 per 1000 [95% CI, 10-52]; number needed to treat = 31). The association was consistent across a wide range of sulfadoxine-pyrimethamine resistance (0% to 96% dihydropteroate-synthase K540E mutations). There was no evidence of small-study bias. The ≥3-dose group had less placental malaria (RR, 0.51; 95% CI, 0.38-0.68; I 2 = 0%, in 6 trials, 63 vs 32 per 1000; absolute risk reduction, 31 per 1000 [95% CI, 20-39]). In primigravid plus secundigravid women, the risk of moderate to severe maternal anemia was lower in the ≥3-dose group (RR, 0.60; 95% CI, 0.36-0.99; I2 = 20%; in 6 trials, 36 vs 22 per 1000; absolute risk reduction, 14 per 1000 [95% CI, 0.4-23]). There were no differences in rates of serious adverse events. CONCLUSIONS AND RELEVANCE: Among pregnant women in sub-Saharan Africa, intermittent preventive therapy with 3 or more doses of sulfadoxine-pyrimethamine was associated with a higher birth weight and lower risk of LBW than the standard 2-dose regimens. These data provide support for the new WHO recommendations to provide at least 3 doses of intermittent preventive therapy during pregnancy at each scheduled antenatal care visit in the second and third trimester.

In the 1970s, Chinese government scientists working on a secret “Project 523” developed a new class of potent antimalarial drugs, the artemisinins or qinghaosu derivatives. In mostly unpublished work that has just been recognized by a 2011 Lasker Award to Tu Youyou, researchers in China isolated the active compounds from the plant Artemisia annua, tested them in mice, analyzed the chemical structure of the artemisinins, and demonstrated their high potency and rapid efficacy in human trials. Although they were widely used in China during the 1980s, only in the 1990s did the artemisinins come to wider global attention in the form of artemisinin-based combination therapies. Over the past decade, these highly efficacious treatments, along with other malaria-control measures, have contributed to significant reductions of the malaria burden in many areas of the world, including parts of Africa. | Together, these successes and increased funding have revived the bold aspiration to eradicate malaria. About one quarter of malaria-afflicted countries are already shifting their focus from malaria control to elimination. Past successful malaria-elimination schemes have all depended on reliable curative drugs, used in conjunction with vector-control methods. Similarly, current elimination plans rely on the long-term availability of effective antimalarial drugs — a requirement that is pivotally dependent on the efficacy of artemisinins. The artemisinin derivative artesunate has also proven to be the best drug against severe falciparum malaria. Losing the artemisinins to resistance would be a disaster for the control and treatment of malaria and would bring eradication efforts to a standstill.

Drug resistance in malaria and in tuberculosis (TB) are major global health problems. Although the terms multidrug-resistant TB and extensively drug-resistant TB are precisely defined, the term multidrug resistance is often loosely used when discussing malaria. Recent declines in the clinical effectiveness of antimalarial drugs, including artemisinin-based combination therapy, have prompted the need to revise the definitions of and/or to recategorize antimalarial drug resistance to include extensively drug-resistant malaria. Applying precise case definitions to different levels of drug resistance in malaria and TB is useful for individual patient care and for public health.