AbstractMalaria remains a major public health problem in Eastern Indonesia. The problem is further complicated by the limitation of microscopy services, and emergence and spread of parasite resistance to the current existing antimalarial drugs. Rapid and effective disease management is an important part of strategies to control malaria. The overall aim of the thesis is therefore to improve the diagnosis and treatment of malaria in Eastern Indonesia.
The malariometric survey was performed in 13,079 children 0-9 years old in East and West Sumba, East Nusa Tenggara (NTT) province in 1997, and 2,217 children 0-9 years old in Genyem, lrian Jaya province in 1998. These two areas in Eastern Indonesia with different malaria endemicity were studied to determine local epidemiology, and to estimate the parasite density cutoff for a clinical malaria case definition at the population level in each area. The study of clinical predictors of malaria in both children and adults, with or without fever, who attended the health center in the study sites (2,169 in Radamata, West Sumba district in 1998, and 1,081 in Genyem, Jayapura district in 1999) was then performed to define the most suitable clinical predictors of uncomplicated malaria by developing and validating clinical malaria case definitions in these representative different malaria endemicity areas. The utility of dipstick rapid antigen detection test [ICT combined P. falciparum-P. vivax immunochromatographic test (ICT Malaria P.f/P.v)] as an alternative to microscopic diagnosis of malaria was evaluated using blinded microscopy as the "gold standard" in 560 patients with presumptive clinical diagnosis of malaria in Radamata. In parallel, evaluation of the therapeutic efficacy of the current antimalarial drugs [chloroquine (CQ) and sulfadoxine-pyrimethamine (SP)] in patients with uncomplicated falciparum and vivax malaria was undertaken in both study sites. A pilot study was then followed by a randomised controlled trial to quantify the benefit of adding artesunate (orally, 4 mg/kg bw/day, single daily dose for 3 days) to SP (orally, based on pyrimethamine dosage 1.25 mg/kg bw, single dose on day 0) in uncomplicated falciparum malaria. The therapeutic efficacy of combined artesunate and SP in vivax malaria was assessed in Genyem, and the utility of the ICT Malaria P.f/P.v in predicting chloroquine treatment outcome was assessed in Radamata.
Radamata was a hypo-mesoendemic malaria area, while Genyem was a meso-hyperendemic area, with respective prevalences of parasitemia of 5.1 % (197 of 3,861) and 38.8% (860 of 2,217) using parasite rate, and 17.1% and 51.0% using spleen rate. Children 1-9 years had a higher prevalence of parasitemia than infants. Although more than 50% of parasitemic children were afebrile, parasitemia was associated with fever and splenomegaly. There was a higher mean parasite density in parasitemic children with fever than without fever for each species in both Radamata and Genyem. Radamata had a lower calculated parasitemia fever threshold for a clinical case definition of malaria for any species of Plasmodium, P. falciparum, and any P. vivax (620/ul, 780/ul, and 240/ul respectively) than that in Genyem (1,260/ul, 1, 160/ul, and 660/ul respectively), with sensitivities and specificities of the thresholds of 88-99%. In Genyem, infants had a lower P. falciparum parasitemia fever threshold (480/ul) than children ~I year (1,320/ul). Parasitemia thresholds for P. vivax were less than for P. falciparum in both areas.
The most frequent clinical symptoms and signs in infants were generally similar to those found in children 1-4 years old in both Radamata and Genyem. The most frequent clinical symptoms and signs amongst children 5-12 years old were similar to those in adults in both Radamata and Genyem. There was no difference in reported severity of disease between children and adults in Radamata, and there was no severe disease found in Genyem. The clinical symptoms and signs differed little between P. falciparum and P. vivax. The significant clinical predictors for diagnosis of any parasitemia and also for parasitemia above the threshold levels were history of fever, rigors, headache, lack of runny nose, pallor, splenomegaly, hepatomegaly, and lack of crepitations in Radamata. In Genyem, the significant predictors were history of fever, rigors, anorexia, pallor, and splenomegaly. There were three diagnostic models developed at each site (Radamata 1-3, and Genyem 1-3) by combining history of fever with one or more other predictors with had areas under Receiver Operator Characteristic (AOC) curves for diagnosis of any parasitemia and parasitemia above the thresholds >0.78 and >0.81 in Radamata, and >0.75 and >0.80 in Genyem. The models gave moderate to high sensitivities for diagnosis based on microscopy as gold standard (65.8-96.2%), low to moderate specificities (37.7-64.0%), low to moderate Positive Predictive Values (PPVs) (7.2 65%), moderate to high Negative Predictive Values (NPVs) (72.1-99.6%), moderate Likelihood Ratio (LR) for positive tests (1.46-1.98), and low to moderate LR for negative tests (0.08-0.53). Of the six models, Genyem 2 was the best model for either diagnosis of any parasitemia or parasitemia above the threshold levels in all ages and for both P. falciparum and P. vivax, in both Radamata and Genyem. The Genyem 2 case definition, which is history of fever with one or more of (rigors, pallor, or splenomegaly) gave a high sensitivity (89.8-100%), very high NPV (95.0-100%} and low LR for negative tests (0.00-0.20) for diagnosis of parasitemia above the threshold in children <5 years and in those≥5 years old in both Radamata and Genyem. It was very close to history of fever alone for sensitivity, but had higher specificity, PPV, and LR for positive test.
The Indonesian Communicable Disease Control (CDC) national case definition showed low to moderate sensitivities (6.8-66.3%), moderate to high specificities (68.8-98.6%), low to moderate PPVs (5.5-85.7%), low to high NPVs (45.3-97.5%), low to high LR for positive tests (1.15-4.70), and moderate to high LR for negative tests (0.48-0.97) for diagnosis of any parasitemia for all ages and for both P. fa/ciparum and P. vivax. The health staff diagnosis showed moderate sensitivities (57.7- 74.5%), low to moderate specificities (47.8-65.9%), low to moderate PPVs (5.4-63.7%), low to high NPVs (54.1-96.7%), low to moderate LR for postive tests (1.12-1.78), and moderate to high LR for negative tests (0.47-0.87) for all ages and for both P. falciparum and P. vivax.
The ICT P.f/P.v immunochromatographic test was sensitive (95.5%) and specific (89.8%) for the diagnosis of falciparum malaria, with PPV and NPV of 88.1 % and 96.2%, respectively. The sensitivity for the diagnosis of P. vivax malaria was 96% with parasitemias of >500/ul but only 29% with parasitemias of <500/ul. False positive diagnoses of P. vivax were common, with overall specificity of 94.8% and PPV of only 50%. Therefore this ICT test was not acceptable for diagnosis of P. vivax malaria.
The high rates of persistent histidine rich protein 2 (HRP2) and pan-malarial antigen (PMA) antigenemia following CQ and SP treatment were strongly associated with presence of gametocytemia, with the proportion with gametocytes on day 7 post treatment being significantly greater in those with false positive (FP) relative to true negative PMA and HRP2 results. Following SP treatment, PMA persisted longer than HRP2, giving a FP diagnosis of P. vivax in up to 16% on day 14, with all FP vivax diagnoses having gametocytemia. In contrast, PMA was rapidly cleared following artesunate plus SP treatment, in association with rapid clearance of gametocytemia. Overall, the ICT test did not reliably confirm chloroquine treatment failure or adequate clinical response, with both false negative and false positive results.
Although CQ was well absorbed (only one of the 122 treated with CQ or CQ plus SP had blood samples which did not have detectable CQ plus desethylchloroquine >200ng/ml on day 2), CQ is no longer clinically effective for falciparum malaria in both Radamata [n=66, 65.2% treatment failure (TF): 9.1 % Early Treatment Failure (ETF) and 56.1 % Late Treatment Failure (L TF) and 35% Adequate Clinical Response (ACR), with 30.4% hematological recovery] and Genyem [n=48, 83.3% TF (6.2% ETF and 77.1% LTF), and 16.7% ACR, with 37.5% hematological recovery]. For vivax malaria, CQ is probably still effective in Radamata [n=9, 11.1 % TF (all L TF) and 88.9% ACR, with 50% haematological recovery] but not in Genyem [n=6, 5 TF(1 ETF and 4 L TF)] . SP alone is highly effective for the treatment of uncomplicated CO-resistant falciparum malaria in Radamata [n=32, 100% cure rate and 81.2% hematological recovery], and moderately effective in Genyem [n=41, 26.8% TF (2.4% ETF and 24.4% LTF) and 73.2% ACR, with 46.7% hematological recovery]. The combination of CQ with SP did not improve the efficacy of SP alone for the treatment of uncomplicated falciparum malaria in Genyem [n=34, 38.2% TF (2.9% ETF and 35.3% L TF), and 61.8% ACR, with 57.1 % hematological recovery].
The combination of 3 days artesunate plus SP single dose (ART3+SP1 )showed good clinical and parasitological response in uncomplicated falciparum malaria in a pilot study [n=20, no ETF, 100% ACR on day 14 and 93.3% on day 28, with 100% hematological recovery]. In the subsequent randomised comparative trial, TF rates on day 14 were 0% in the 47 patients treated with ART3+SP1 and 8.7% in the 46 patients treated with SP1 (p=0.12). TF rates on day 28 were 4.4% and 15.2% respectively (p=0.16). Relative risk of TF at 28 days was 0.3 (95% Cl: 0.1-1.3) with ART3+SP1. Mean fever clearance time (1.3 vs 1.7 days) and mean parasite clearance time (1.4 vs 2.0 days) were both faster with ART3+SP1 than with SP1 (p=0.08 and p<0.0001 respectively). Gametocyte carriage was lower following ART3+ SP1 than SP1 (RR=0.5, 95% Cl: 0.2-1.0 on day 7; and RR=0.5, 95% Cl: 0.2-1.1 on day 14). ART3+SP1 was also found to be effective in 22 patients with vivax malaria [no ETF, 100% and 89% ACRs by days 14 and 28].
Microscopy is still the gold standard for definitive diagnosis of malaria, although rapid diagnostics are likely to improve and become were affordable in the future. The Genyem 2 case definition for clinical diagnosis of uncomplicated malaria [history of fever with one or more of (rigors, pallor, or splenomegaly)] could be used to decide who will be treated for malaria, who will undergo microscopy (if microscopy is available) and to target the use of more expensive drug combinations. A combined regimen of chloroquine plus sulfadoxine-pyrimethamine (CQ3+SP1) could be a rational option to replace chloroquine (CQ3) for the presumptive treatment of uncomplicated clinical malaria, except for vulnerable groups (such as children <5 years old, pregnant women and transmigrants or non immune visitors), who should be treated with the most effective regimen of combined artesunate plus sulfadoxine-pyrimethamine (ART3+SP1). A recommended algorithm for case detection and treatment of malaria in both high and low malaria endemicity regions of Indonesia is presented together with recommendations for malaria research priorities for the country.
Note: Please note that images have been removed due to copyright.
|Date of Award||Jun 2001|
|Supervisor||Nicholas Anstey (Supervisor) & Bart Currie (Supervisor)|