Host susceptibility genes of asymptomatic malaria from South Central Timor, Eastern Indonesia.

Host genetic factors, such as the genes for various cytokines and adhesion molecules, play a significant role in determining susceptibility to malaria infection. Polymorphisms in host genes have been correlated with malaria infection in both African and Asian regions. The purpose of this study was to investigate the association between both cytokine and adhesion molecule genotypes with susceptibility to malaria infection in humans. Ten cytokine polymorphism loci (IL4 + 33, IL4-590, IL6-174, IL10-1082, IL10-1035, IL12p40, TNF-238, TNF-308, TNF-1031, and TNF-ß) and three adhesion molecule polymorphism loci (CD36 exon 10, ICAM-1 Kilifi, and ICAM-1 exon 6) were genotyped using PCR-RFLP analysis. We conducted this study on 178 asymptomatic malaria subjects and 122 uninfected subjects. Results showed that certain CD36 exon 10 and IL10-3575 polymorphisms were associated with asymptomatic infection. The heterozygous (GT) and homozygous (GG) genotypes for CD36 exon 10 are associated with an increased risk of malaria infection. On the other hand, the homozygous genotype (AA) for IL10-3575 reduced the risk of asymptomatic malaria infection. No significant differences were found for the other polymorphisms studied. We also found that a polymorphism in CD36 exon 10 was strongly associated with asymptomatic malaria caused specifically by Plasmodium vivax. These findings suggest that the G allele of CD36 exon 10 is associated with an increased risk of asymptomatic malaria infection. On the other hand, the genotype AA for IL10-3575 was associated with a reduced risk of malaria infection.

The characteristics of bacteremia among patients with acute febrile illness requiring hospitalization in Indonesia.

Blood culturing remains the "gold standard" for bloodstream infection (BSI) diagnosis, but the method is inaccessible to many developing countries due to high costs and insufficient resources. To better understand the utility of blood cultures among patients in Indonesia, a country where blood cultures are not routinely performed, we evaluated data from a previous cohort study that included blood cultures for all participants. An acute febrile illness study was conducted from July 2013 to June 2016 at eight major hospitals in seven provincial capitals in Indonesia. All participants presented with a fever, and two-sided aerobic blood cultures were performed within 48 hours of hospital admission. Positive cultures were further assessed for antimicrobial resistance (AMR) patterns. Specimens from participants with negative culture results were screened by advanced molecular and serological methods for evidence of causal pathogens. Blood cultures were performed for 1,459 of 1,464 participants, and the 70.6% (1,030) participants that were negative by dengue NS1 antigen test were included in further analysis. Bacteremia was observed in 8.9% (92) participants, with the most frequent pathogens being Salmonella enterica serovar Typhi (41) and Paratyphi A (10), Escherichia coli (14), and Staphylococcus aureus (10). Two S. Paratyphi A cases had evidence of AMR, and several E. coli cases were multidrug resistant (42.9%, 6/14) or monoresistant (14.3%, 2/14). Culture contamination was observed in 3.6% (37) cases. Molecular and serological assays identified etiological agents in participants having negative cultures, with 23.1% to 90% of cases being missed by blood cultures. Blood cultures are a valuable diagnostic tool for hospitalized patients presenting with fever. In Indonesia, pre-screening patients for the most common viral infections, such as dengue, influenza, and chikungunya viruses, would maximize the benefit to the patient while also conserving resources. Blood cultures should also be supplemented with advanced laboratory tests when available.

Correction: An observational prospective cohort study of the epidemiology of hospitalized patients with acute febrile illness in Indonesia.

[This corrects the article DOI: 10.1371/journal.pntd.0007927.].

Prevalence of HIV Infection and Resistance Mutations in Patients Hospitalized for Febrile Illness in Indonesia.

HIV prevalence in Indonesia is increasing, and only 64% of infected individuals know their status. In a prospective cohort of 1,453 hospitalized patients with unexplained fever, 46 (3.2%) had HIV, including 15 (1.1%) patients without a prior HIV diagnosis. Among 31 subjects previously known to have HIV, 21 (68%) had been receiving combination antiretroviral therapy (cART) at the time of enrollment. Of 39 HIV cases with HIV RNA levels ≥ 100 copies/mL, sequencing for genotype analysis and resistance testing was successful in 30 (77%) subjects. The most common HIV subtypes were AE (90%) and B (10%). Five (16.7%) subjects had resistance mutations to nucleoside and non-nucleoside reverse transcriptase inhibitors, and all of them were on cART. No evidence of transmitted drug resistance was found in newly diagnosed individuals. Hospital-based screening may be an efficient method to expand HIV testing and identify a significant number of new cases. Access to care, close monitoring, expansion of anti-retroviral options, and ensuring availability of CD4 determinations, viral load testing, and genotyping are crucial to control of the epidemic in Indonesia.

Prevalence of Glucose 6-Phosphate Dehydrogenase Variants in Malaria-Endemic Areas of South Central Timor, Eastern Indonesia.

Primaquine is an effective anti-hypnozoite drug for Plasmodium vivax and Plasmodium ovale. However, it can trigger erythrocyte hemolysis in people with glucose 6-phosphate dehydrogenase (G6PD) deficiency. In a previous report from South Central Timor (SCT), Indonesia, we described the prevalence of Vanua Lava, Chatham, and Viangchan variants; in this study, other G6PD variants (Kaiping, Coimbra, Gaohe, Canton, and Mahidol) were subsequently analyzed. For clarity, all of these results are described together. The 381 DNA samples from the previous study during 2013-2014 were analyzed for G6PD variants by using PCR-restriction fragment length polymorphism (RFLP). The prevalence of G6PD deficiency in SCT was 6.3% (24/381 cases), including 4.2% (16/381 cases), 0.5% (2/381 cases), and 1.6% (6/381 cases) for Coimbra, Kaiping, and Vanua Lava variants, respectively. No other variants were found in this population. A significant association was found between ethnicity and the distribution of G6PD Kaiping in female subjects. A positive association was shown between G6PD activity and heterozygous females carrying Coimbra genotype, hemizygous males carrying Vanua Lava, Plasmodium falciparum infection in female subjects, and P. vivax infection in male subjects. Further molecular analysis of heterozygous females, particularly in malaria-endemic areas, is needed for mapping distribution of G6PD deficiency status in Indonesia.

Chikungunya in Indonesia: Epidemiology and diagnostic challenges.

BACKGROUND: Chikungunya virus (CHIKV) is often overlooked as an etiology of fever in tropical and sub-tropical regions. Lack of diagnostic testing capacity in these areas combined with co-circulation of clinically similar pathogens such as dengue virus (DENV), hinders CHIKV diagnosis. To better address CHIKV in Indonesia, an improved understanding of epidemiology, clinical presentation, and diagnostic approaches is needed. METHODOLOGY/PRINCIPAL FINDINGS: Acutely hospitalized febrile patients ≥1-year-old were enrolled in a multi-site observational cohort study conducted in Indonesia from 2013 to 2016. Demographic and clinical data were collected at enrollment; blood specimens were collected at enrollment, once during days 14 to 28, and three months after enrollment. Plasma samples negative for DENV by serology and/or molecular assays were screened for evidence of acute CHIKV infection (ACI) by serology and molecular assays. To address the co-infection of DENV and CHIKV, DENV cases were selected randomly to be screened for evidence of ACI. ACI was confirmed in 40/1,089 (3.7%) screened subjects, all of whom were DENV negative. All 40 cases initially received other diagnoses, most commonly dengue fever, typhoid fever, and leptospirosis. ACI was found at five of the seven study cities, though evidence of prior CHIKV exposure was observed in 25.2% to 45.9% of subjects across sites. All subjects were assessed during hospitalization as mildly or moderately ill, consistent with the Asian genotype of CHIKV. Subjects with ACI had clinical presentations that overlapped with other common syndromes, atypical manifestations of disease, or persistent or false-positive IgM against Salmonella Typhi. Two of the 40 cases were possibly secondary ACI. CONCLUSIONS/SIGNIFICANCE: CHIKV remains an underdiagnosed acute febrile illness in Indonesia. Public health measures should support development of CHIKV diagnostic capacity. Improved access to point-of-care diagnostic tests and clinical training on presentations of ACI will facilitate appropriate case management such as avoiding unneccessary treatments or antibiotics, early response to control mosquito population and eventually reducing disease transmission.

Leptospirosis in Indonesia: diagnostic challenges associated with atypical clinical manifestations and limited laboratory capacity.

BACKGROUND: The burden of leptospirosis in Indonesia is poorly understood. Data from an observational study conducted from 2013 to 2016 in seven cities across Indonesia was used to estimate the incidence of leptospirosis and document its clinical manifestations in patients requiring hospitalization. METHODS: Specimens from patients hospitalized with acute fever were collected at enrollment, 14-28 days, and 3 months. Demographic and clinical information were collected during study visits and/or retrieved from medical records and double-entered into clinical report forms. After initially screening for dengue virus and other pathogens, specimens were tested at a central Reference Laboratory for anti-Leptospira IgM using commercial ELISA kits and for Leptospira DNA using an in-house quantitative real-time PCR assay. RESULTS: Of 1464 patients enrolled, 45 (3.1%) confirmed cases (by PCR and/or sero-coversion or four-fold increase of IgM) and 6 (0.4%) probable cases (by high titer IgM) of leptospirosis were identified by the Reference Laboratory. Disease incidence at sites ranged from 0 (0%) cases in Denpasar to 17 (8.9%) cases in Semarang. The median age of patients was 41.2 years (range of 5.3 to 85.0 years), and 67% of patients were male. Twenty-two patients (43.1%) were accurately diagnosed at sites, and 29 patients (56.9%) were clinically misdiagnosed as having another infection, most commonly dengue fever (11, 37.9%). Clinically, 20 patients (39.2%) did not present with hyperbilirubinemia or increased creatinine levels. Two patients (3.9%) died, both from respiratory failure. Fifteen patients (29.4%) clinically diagnosed with leptospirosis at sites were negative based on IgM ELISA and/or PCR at the Reference Laboratory. CONCLUSIONS: Leptospirosis remains an important cause of hospitalization in Indonesia. It can have diverse clinical presentations, making it difficult to differentiate from other common tropical infections. PCR combined with ELISA is a powerful alternative to the cumbersome gold-standard microscopic agglutination test, particularly in resource-limited settings.

An observational prospective cohort study of the epidemiology of hospitalized patients with acute febrile illness in Indonesia.

BACKGROUND: The epidemiology of acute febrile illness, a common cause of hospitalization in Indonesia, has not been systematically studied. METHODOLOGY/PRINCIPAL FINDINGS: This prospective observational study enrolled febrile patients (temperature ≥38°C) aged ≥1 year from July 2013 until June 2016 at eight government referral teaching hospitals in seven provincial capitals in Indonesia. Patients were managed according to the hospital standard-of-care (SOC), and blood samples were drawn for molecular and serological assays. Clinical data, laboratory results, and specimens for additional tests were collected at enrollment, days 14-28, and at three months. Regular follow-up visits were then scheduled for every three months either until symptoms resolved or until one year. In total, this study included 1,486 adult and pediatric patients presenting with multi-organ (768, 51.7%), gastrointestinal (497, 33.0%), respiratory (114, 7.7%), constitutional (62, 4.2%), skin and soft-tissue (24, 1.6%), central nervous system (17, 1.1%), or genitourinary (4, 0.3%) manifestations. Microbiological diagnoses were found in 1,003/1,486 (67.5%) participants, of which 351/1,003 (35.0%) were not diagnosed during hospitalization using SOC diagnostic tests. Missed diagnoses included all cases caused by Rickettsia spp., chikungunya, influenza, and Seoul virus. The most common etiologic agents identified were dengue virus (467, 46.6%), Salmonella spp. (103, 10.3%), and Rickettsia spp. (103, 10.3%). The overall mortality was 89 (5.9%). CONCLUSIONS/SIGNIFICANCE: Febrile illness in Indonesia has various microbiologic etiologies and substantial overall mortality. Diagnostic limitations and lack of epidemiologic data resulted in potentially treatable, and at times fatal, diseases being missed.

Treatment-seeking behaviour and associated costs for malaria in Papua, Indonesia.

BACKGROUND: Malaria remains a significant public health issue in Eastern Indonesia, where multidrug resistant Plasmodium falciparum and Plasmodium vivax are highly prevalent. The objective of this study was to describe treatment-seeking behaviour and household costs prior to a change to a unified treatment policy of dihydroartemisinin-piperaquine in Mimika district, Papua province in 2006. METHODS: In 2005 a randomized cross-sectional household survey was conducted to collect data on demographics, socio-economic status (SES), treatment-seeking, case management, and household costs. Information on the cost of illness was also collected from patients exiting health facilities, in order to compare the cost of episodes diagnosed as P. vivax compared with those diagnosed as P. falciparum. RESULTS: 825 households were included in the survey. Of the 764 individuals who sought treatment for fever outside the home in the last month, 46% (349/764) went to a public health facility. Of the 894 reported visits to healthcare providers, 48% (433) resulted in a blood test, of which 78% (337) were reportedly positive. Only 10% (17/177) of individuals who reported testing positive for P. falciparum or mixed infection received the first-line treatment of chloroquine with SP, and 38% (61/159) of those with a diagnosis of P. vivax reportedly received the first-line treatment of chloroquine and primaquine. Overall, public facilities were more likely to prescribe the correct prevailing first-line drug combinations than private providers (OR = 3.77 [95% CI 2.31-6.14], p < 0.001). The mean cost to the household of an episode of P. vivax was similar to the cost of P. falciparum [US$44.50 (SD: 46.23) vs US$48.58 (SD: 64.65)]. CONCLUSIONS: Private providers were a popular source of treatment for malaria, but adherence to the national guidelines was low and the economic burden of malaria for both P. falciparum and P. vivax infections was substantial. Engagement with the private sector is needed to ensure that patients have access to affordable good quality, effective diagnostics and anti-malarials for both P. falciparum and P. vivax.

Plasmodium vivax infection: a major determinant of severe anaemia in infancy.

BACKGROUND: Most malarious countries outside of Africa are co-endemic for Plasmodium falciparum and Plasmodium vivax. The comparative burden of anaemia in the community caused by these two species is incompletely characterized. METHODS: A three-stage, cross-sectional, community survey was used to determine the proportion of moderate or severe anaemia (haemoglobin <7 g/dL) attributable to patent P. vivax, P. falciparum and mixed parasitaemia in Papua, Indonesia. Adjusted population-attributable fractions were calculated from multivariable logistic regression models. Eight hundred and twenty-five households were surveyed with a total of 5255 occupants, 3890 (74 %) of whom were present and provided a blood sample. Plasmodium falciparum parasitaemia was present in 8.1 % (n = 315) of participants, P. vivax in 6.4 % (n = 250) and mixed infections in 1.9 % (n = 72). Overall, P. falciparum was associated with a mean reduction in haemoglobin of 1.16 g/dL compared to those without patent parasitaemia [95 % confidence interval (95 % CI) 0.91, 1.41 g/dL]. The corresponding values for P. vivax and mixed infections were 0.66 g/dL (95 % CI 0.35, 0.96) and 1.25 g/dL (0.71, 1.80), respectively. Overall, 16.7 % (95 % CI 8.52, 24.2 %) of haemoglobin concentrations <7 g/dL in the community were estimated to be attributable to patent parasitaemia. The fractions for infants and 1-5 years old were 34.4 % (95 % CI -3.30, 58.3 %) and 23.2 % (95 % CI 3.34, 39.0 %), respectively. Plasmodium vivax was associated with a greater than threefold higher attributable fraction of anaemia in infants compared with P. falciparum [27.6 % (95 % CI -3.20, 49.2 %) versus 7.94 % (-5.87, 20.0 %)]. CONCLUSION: Despite comparatively low-level endemicity, malaria is associated with a significant proportion of all cases of community anaemia in southern Papua. Contrary to its benign reputation, P. vivax is an important and preventable risk factor for anaemia during infancy-a probable consequence of relapsing disease prior to the development of immunity.

INA-RESPOND: a multi-centre clinical research network in Indonesia.

Nationally representative observational and translational research is needed to address the public health challenges in Indonesia due to the geographic disparity, recently decentralized health system, and diverse infectious disease priorities. To accomplish this, the Indonesian Ministry of Health in collaboration with the US National Institute of Health has established INA-RESPOND (Indonesia Research Partnership on Infectious Disease) - a clinical research network comprising 9 referral hospitals, 7 medical faculties, and 2 research centres across Indonesia. The network provides a forum to conduct research at a national scale and to address scientific questions that would be difficult to address in smaller research settings. Further, it is currently conducting multi-centre research on the etiologies of fever, sepsis, and tuberculosis. There are opportunities to leverage existing network resources for other public health research needs. INA-RESPOND is an Indonesian-led network in a country with diverse population groups and public health needs which is poised to collaborate with researchers, universities, donors, and industry worldwide. This paper describes the network and its goals and values, as well as the management structure, process for collaboration, and future vision.

Treatment policy change to dihydroartemisinin-piperaquine contributes to the reduction of adverse maternal and pregnancy outcomes.

BACKGROUND: In Papua, Indonesia, maternal malaria is prevalent, multidrug resistant and associated with adverse outcomes for mother and baby. In March 2006, anti-malarial policy was revised for the second and third trimester of pregnancy to dihydroartemisinin-piperaquine (DHP) for all species of malaria. This study presents the temporal analysis of adverse outcomes in pregnancy and early life following this policy change. METHODS: From April 2004 to May 2010, a standardized questionnaire was used to collect information from all pregnant women admitted to the maternity ward. A physical examination was performed on all live birth newborns. The relative risks (RR) and the associated population attributable risks (PAR) of adverse outcomes in women with a history of malaria treatment to the risk in those without a history of malaria during the current pregnancy were examined to evaluate the temporal trends before and after DHP deployment. RESULTS: Of 6,556 women enrolled with known pregnancy outcome, 1,018 (16%) reported prior anti-malarial treatment during their pregnancy. The proportion of women with malaria reporting treatment with DHP rose from 0% in 2004 to 64% (121/189) in 2010. In those with history of malaria during pregnancy, the increasing use of DHP was associated with a 54% fall in the proportion of maternal malaria at delivery and a 98% decrease in congenital malaria (from 7.1% prior to 0.1% after policy change). Overall policy change to more effective treatment was associated with an absolute 2% reduction of maternal severe anaemia and absolute 4.5% decrease in low birth weight babies. CONCLUSIONS: Introduction of highly effective treatment in pregnancy was associated with a reduction of maternal malaria at delivery and improved neonatal outcomes. Ensuring universal access to arteminisin combination therapy (ACT) in pregnancy in an area of multidrug resistance has potential to impact significantly on maternal and infant health.

Impaired systemic tetrahydrobiopterin bioavailability and increased dihydrobiopterin in adult falciparum malaria: association with disease severity, impaired microvascular function and increased endothelial activation.

Tetrahydrobiopterin (BH4) is a co-factor required for catalytic activity of nitric oxide synthase (NOS) and amino acid-monooxygenases, including phenylalanine hydroxylase. BH4 is unstable: during oxidative stress it is non-enzymatically oxidized to dihydrobiopterin (BH2), which inhibits NOS. Depending on BH4 availability, NOS oscillates between NO synthase and NADPH oxidase: as the BH4/BH2 ratio decreases, NO production falls and is replaced by superoxide. In African children and Asian adults with severe malaria, NO bioavailability decreases and plasma phenylalanine increases, together suggesting possible BH4 deficiency. The primary three biopterin metabolites (BH4, BH2 and B0 [biopterin]) and their association with disease severity have not been assessed in falciparum malaria. We measured pterin metabolites in urine of adults with severe falciparum malaria (SM; n=12), moderately-severe malaria (MSM, n=17), severe sepsis (SS; n=5) and healthy subjects (HC; n=20) as controls. In SM, urinary BH4 was decreased (median 0.16 »mol/mmol creatinine) compared to MSM (median 0.27), SS (median 0.54), and HC (median 0.34)]; p<0.001. Conversely, BH2 was increased in SM (median 0.91 »mol/mmol creatinine), compared to MSM (median 0.67), SS (median 0.39), and HC (median 0.52); p<0.001, suggesting increased oxidative stress and insufficient recycling of BH2 back to BH4 in severe malaria. Overall, the median BH4/BH2 ratio was lowest in SM [0.18 (IQR: 0.04-0.32)] compared to MSM (0.45, IQR 0.27-61), SS (1.03; IQR 0.54-2.38) and controls (0.66; IQR 0.43-1.07); p<0.001. In malaria, a lower BH4/BH2 ratio correlated with decreased microvascular reactivity (r=0.41; p=0.03) and increased ICAM-1 (r=-0.52; p=0.005). Decreased BH4 and increased BH2 in severe malaria (but not in severe sepsis) uncouples NOS, leading to impaired NO bioavailability and potentially increased oxidative stress. Adjunctive therapy to regenerate BH4 may have a role in improving NO bioavailability and microvascular perfusion in severe falciparum malaria.

Decreased endothelial nitric oxide bioavailability, impaired microvascular function, and increased tissue oxygen consumption in children with falciparum malaria.

Endothelial nitric oxide (NO) bioavailability, microvascular function, and host oxygen consumption have not been assessed in pediatric malaria. We measured NO-dependent endothelial function by using peripheral artery tonometry to determine the reactive hyperemia index (RHI), and microvascular function and oxygen consumption (VO2) using near infrared resonance spectroscopy in 13 Indonesian children with severe falciparum malaria and 15 with moderately severe falciparum malaria. Compared with 19 controls, children with severe malaria and those with moderately severe malaria had lower RHIs (P = .03); 12% and 8% lower microvascular function, respectively (P = .03); and 29% and 25% higher VO2, respectively. RHIs correlated with microvascular function in all children with malaria (P < .001) and all with severe malaria (P < .001). Children with malaria have decreased endothelial and microvascular function and increased oxygen consumption, likely contributing to the pathogenesis of the disease.

Rapid clinical assessment to facilitate the triage of adults with falciparum malaria, a retrospective analysis.

BACKGROUND: Most adults dying from falciparum malaria will die within 48 hours of their hospitalisation. An essential component of early supportive care is the rapid identification of patients at greatest risk. In resource-poor settings, where most patients with falciparum malaria are managed, decisions regarding patient care must frequently be made using clinical evaluation alone. METHODS: We retrospectively analysed 4 studies of 1801 adults with severe falciparum malaria to determine whether the presence of simple clinical findings might assist patient triage. RESULTS: If present on admission, shock, oligo-anuria, hypo- or hyperglycaemia, an increased respiratory rate, a decreased Glasgow Coma Score and an absence of fever were independently predictive of death. The variables were used to construct a simple clinical algorithm. When applied to the 1801 patients, this algorithm's positive predictive value for survival to 48 hours was 99.4 (95% confidence interval (CI) 97.8-99.9) and for survival to discharge 96.9% (95% CI 94.3-98.5). In the 712 patients receiving artesunate, the algorithm's positive predictive value for survival to 48 hours was 100% (95% CI 97.3-100) and to discharge was 98.5% (95% CI 94.8-99.8). CONCLUSIONS: Simple clinical findings are closely linked to the pathophysiology of severe falciparum malaria in adults. A basic algorithm employing these indices can facilitate the triage of patients in settings where intensive care services are limited. Patients classified as low-risk by this algorithm can be safely managed initially on a general ward whilst awaiting senior clinical review and laboratory data.

Dihydroartemisinin-piperaquine treatment of multidrug resistant falciparum and vivax malaria in pregnancy.

BACKGROUND: Artemisinin combination therapy (ACT) is recommended for the treatment of multidrug resistant malaria in the second and third trimesters of pregnancy, but the experience with ACTs is limited. We review the exposure of pregnant women to the combination dihydroartemisinin-piperaquine over a 6 year period. METHODS: From April 2004-June 2009, a prospective hospital-based surveillance screened all pregnant women for malaria and documented maternal and neonatal outcomes. RESULTS: Data were available on 6519 pregnant women admitted to hospital; 332 (5.1%) women presented in the first trimester, 324 (5.0%) in the second, 5843 (89.6%) in the third, and in 20 women the trimester was undocumented. Peripheral parasitaemia was confirmed in 1682 women, of whom 106 (6.3%) had severe malaria. Of the 1217 women admitted with malaria in the second and third trimesters without an impending adverse outcome, those treated with DHP were more likely to be discharged with an ongoing pregnancy compared to those treated with a non-ACT regimen (Odds Ratio OR = 2.48 [1.26-4.86]); p = 0.006. However in the first trimester 63% (5/8) of women treated with oral DHP miscarried compared to 2.6% (1/38) of those receiving oral quinine; p<0.001. Of the 847 women admitted for delivery those reporting a history of malaria during their pregnancy who had been treated with quinine-based regimens rather than DHP had a higher risk of malaria at delivery (adjusted OR = 1.56 (95%CI 0.97-2.5), p = 0.068) and perinatal mortality (adjusted OR = 3.17 [95%CI: 1.17-8.60]; p = 0.023). CONCLUSIONS: In the second and third trimesters of pregnancy, a three day course of DHP simplified antimalarial treatment and had significant benefits over quinine-based regimens in reducing recurrent malaria and poor fetal outcome. These data provide reassuring evidence for the rational design of prospective randomized clinical trials and pharmacokinetic studies.

High morbidity during treatment and residual pulmonary disability in pulmonary tuberculosis: under-recognised phenomena.

BACKGROUND: In pulmonary tuberculosis (PTB), morbidity during treatment and residual pulmonary disability can be under-estimated. METHODS: Among adults with smear-positive PTB at an outpatient clinic in Papua, Indonesia, we assessed morbidity at baseline and during treatment, and 6-month residual disability, by measuring functional capacity (six-minute walk test [6MWT] and pulmonary function), quality of life (St George's Respiratory Questionnaire [SGRQ]) and Adverse Events ([AE]: new symptoms not present at outset). Results were compared with findings in locally-recruited volunteers. RESULTS: 200 PTB patients and 40 volunteers were enrolled. 6WMT was 497m (interquartile range 460-529) in controls versus 408m (IQR 346-450) in PTB patients at baseline (p<0.0001) and 470m (IQR 418-515) in PTB patients after 6 months (p=0.02 versus controls). SGRQ total score was 0 units (IQR 0-2.9) in controls, versus 36.9 (27.4-52.8) in PTB patients at baseline (p<0.0001) and 4.3 (1.7-8.8) by 6 months (p<0.0001). Mean percentage of predicted FEV1 was 92% (standard deviation 19.9) in controls, versus 63% (19.4) in PTB patients at baseline (p<0.0001) and 71% (17.5) by 6 months (p<0.0001). After 6 months, 27% of TB patients still had at least moderate-severe pulmonary function impairment, and 57% still had respiratory symptoms, despite most achieving 'successful' treatment outcomes, and reporting good quality of life. More-advanced disease at baseline (longer illness duration, worse baseline X-ray) and HIV positivity predicted residual disability. AE at any time during treatment were common: itch 59%, arthralgia 58%, headache 40%, nausea 33%, vomiting 16%. CONCLUSION: We found high 6-month residual pulmonary disability and high AE rates. Although PTB treatment is highly successful, the extent of morbidity during treatment and residual impairment could be overlooked if not specifically sought. Calculations of PTB-related burden of disease should acknowledge that TB-related morbidity does not stop at 6 months. Early case detection and treatment are key in minimising residual impairment.

Tuberculosis outcomes in Papua, Indonesia: the relationship with different body mass index characteristics between papuan and non-Papuan ethnic groups.

Weight gain achieved during pulmonary tuberculosis (PTB) treatment is associated with the likelihood of bacteriological treatment success. It is recognised that weight and body mass index (BMI) characteristics differ between ethnic groups in health and illness states. However there has been no prior investigation of how ethnic differences in BMI might influence tuberculosis treatment outcome. Our aim was to investigate predictors of microbiological response to PTB treatment at the Tuberculosis Clinic in Timika, Papua Province, Indonesia and specifically, to determine the contribution of ethnicity. The population comprises two distinct ethnic groups - Asian (Non-Papuan) and Melanesian (Papuan). We conducted a prospective study of adults with smear-positive PTB. Treatment outcomes were 1- and 2-month sputum culture and time to microscopy conversion. Clinical measures included weight, BMI, chest radiograph, pulmonary function including forced expiratory volume in 1 second (FEV1) and haemoglobin. One hundred eighty six participants (83 Papuan, 103 non-Papuan Indonesians) were enrolled. At baseline, Papuans had higher mean weight and BMI than non-Papuans (50.0 kg versus 46.9 kg, p = 0.006 and 20.0 kg/m2 versus 18.7 kg/m2, p = 0.001 respectively). This was despite having lower mean haemoglobin (11.3 vs 13.1 g/dL, p<0.0001), higher smoking and HIV rates (37% vs 21%, p = 0.02 and 20% vs 5%, p = 0.01 respectively) and longer median illness duration (3 vs 2 months, p = 0.04), but similar radiological severity (proportion with cavities 55% vs 57%, p = 0.7), sputum smear grade (p = 0.3) and mean % predicted FEV1 (63% vs 64%, p = 0.7). By 2 months, Papuans had gained still more weight (mean 5.9 vs 4.2 kg, p = 0.02), and were more likely to have negative sputum culture (49/56 vs 45/67, p = 0.02), in univariable and multivariable analyses controlling for other likely determinants of culture conversion. In conclusion, Papuans had better early microbiological outcome from PTB treatment, which may relate to better preservation of weight and greater early weight gain.

L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Vitamin D (vitD) and L-arginine have important antimycobacterial effects in humans. Adjunctive therapy with these agents has the potential to improve outcomes in active tuberculosis (TB). METHODS: In a 4-arm randomised, double-blind, placebo-controlled factorial trial in adults with smear-positive pulmonary tuberculosis (PTB) in Timika, Indonesia, we tested the effect of oral adjunctive vitD 50,000 IU 4-weekly or matching placebo, and L-arginine 6.0 g daily or matching placebo, for 8 weeks, on proportions of participants with negative 4-week sputum culture, and on an 8-week clinical score (weight, FEV1, cough, sputum, haemoptysis). All participants with available endpoints were included in analyses according to the study arm to which they were originally assigned. Adults with new smear-positive PTB were eligible. The trial was registered at ClinicalTrials.gov NCT00677339. RESULTS: 200 participants were enrolled, less than the intended sample size: 50 received L-arginine + active vitD, 49 received L-arginine + placebo vit D, 51 received placebo L-arginine + active vitD and 50 received placebo L-arginine + placebo vitD. According to the factorial model, 99 people received arginine, 101 placebo arginine, 101 vitamin D, 99 placebo vitamin D. Results for the primary endpoints were available in 155 (4-week culture) and 167 (clinical score) participants. Sputum culture conversion was achieved by week 4 in 48/76 (63%) participants in the active L-arginine versus 48/79 (61%) in placebo L-arginine arms (risk difference -3%, 95% CI -19 to 13%), and in 44/75 (59%) in the active vitD versus 52/80 (65%) in the placebo vitD arms (risk difference 7%, 95% CI -9 to 22%). The mean clinical outcome score also did not differ between study arms. There were no effects of the interventions on adverse event rates including hypercalcaemia, or other secondary outcomes. CONCLUSION: Neither vitD nor L-arginine supplementation, at the doses administered and with the power attained, affected TB outcomes. REGISTRY: ClinicalTrials.gov. Registry number: NCT00677339.

A randomized pilot study of L-arginine infusion in severe falciparum malaria: preliminary safety, efficacy and pharmacokinetics.

BACKGROUND: Decreased nitric oxide (NO) and hypoargininemia are associated with severe falciparum malaria and may contribute to severe disease. Intravenous L-arginine increases endothelial NO in moderately-severe malaria (MSM) without adverse effects. The safety, efficacy and pharmacokinetics of L-arginine or other agents to improve NO bioavailability in severe malaria have not been assessed. METHODS: In an open-label pilot study of L-arginine in adults with severe malaria (ARGISM-1 Study), patients were randomized to 12 g L-arginine hydrochloride or saline over 8 hours together with intravenous artesunate. Vital signs, selected biochemical measures (including blood lactate and L-arginine) and endothelial NO bioavailability (using reactive hyperemia peripheral arterial tonometry [RH-PAT]) were assessed serially. Pharmacokinetic analyses of L-arginine concentrations were performed using NONMEM. RESULTS: Six patients received L-arginine and two saline infusions. There were no deaths in either group. There were no changes in mean systolic (SBP) and diastolic blood pressure (DBP) or other vital signs with L-arginine, although a transient but clinically unimportant mean maximal decrease in SBP of 14 mmHg was noted. No significant changes in mean potassium, glucose, bicarbonate, or pH were seen, with transient mean maximal increases in plasma potassium of 0.3 mmol/L, and mean maximal decreases in blood glucose of 0.8 mmol/L and bicarbonate of 2.3 mEq/L following L-arginine administration. There was no effect on lactate clearance or RH-PAT index. Pharmacokinetic modelling (n = 4) showed L-arginine concentrations 40% lower than predicted from models developed in MSM. CONCLUSION: In the first clinical trial of an adjunctive treatment aimed at increasing NO bioavailability in severe malaria, L-arginine infused at 12 g over 8 hours was safe, but did not improve lactate clearance or endothelial NO bioavailability. Future studies may require increased doses of L-arginine. TRIAL REGISTRATION: ClinicalTrials.gov NCT00616304.