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Setting: A district level tuberculosis (TB) control programme in Papua Province, Indonesia., Objective: To determine the nature and extent of drug-resistant TB in newly diagnosed sputum smear-positive patients., Methods: Sputum was collected from previously untreated smear-positive pulmonary TB patients diagnosed in the district over a 10-month period. Sputum specimens were processed and inoculated into a BACTEC MGIT960 tube. Isolates were identified by Ziehl-Neelsen staining, hybridisation with nucleic acid probes and biochemical investigations. Susceptibility testing was performed using the radiometric proportion method. Pyrazinamide testing was performed using the Wayne indirect method., Results: One hundred and seven patients had sputum sent to a reference laboratory; 101 (94.4%) were culture-positive for Mycobacterium tuberculosis, with 87 (86.1%) fully sensitive to first-line anti-tuberculosis drugs. Two per cent were multidrug-resistant (MDR-TB) and 12 (11.9%) had other drug resistance. Each of the MDR-TB isolates was susceptible to amikacin, capreomycin, ciprofloxacin and para-aminosalicylic acid (PAS), but were resistant to rifabutin. One isolate was also resistant to ethionamide., Conclusions: MDR-TB is present in Indonesia but is not a major problem for TB control in this district. Generalisability to other districts in Indonesia, particularly large urban areas, needs to be confirmed by future studies.

Setting: A district level tuberculosis (TB) programme in Indonesia., Objective: To evaluate whether a single sputum specimen could be stored by refrigeration for an extended period of time, then transported to a reference laboratory and successfully cultured for Mycobacterium tuberculosis., Methods: Single sputum specimens were collected from newly diagnosed smear-positive pulmonary TB patients, refrigerated at the study site without addition of 1% cetylpyridinium chloride, batched and sent to the reference laboratory, where they were decontaminated and inoculated into BACTEC MGIT 960 liquid media., Results: One hundred and seven patients were enrolled. The median specimen storage time was 12 days (range 1-38) and median transportation time was 4 days (2-12). The median time from specimen collection until processing was 18 days (4-42). Only 4 (3.7%) specimens failed to grow Mycobacterium species and M. tuberculosis was isolated from 101 (94.4%) specimens. Six specimens with breakthrough contamination successfully grew M. tuberculosis after a second decontamination procedure., Conclusions: Single sputum specimens collected at a remote setting, refrigerated for relatively long periods without preservatives and transported without refrigeration to a reference laboratory can yield a high positive culture rate. These findings offer potential logistic simplification and cost savings for drug resistance surveys in low-resource countries.

Background: In patients with severe malaria, acute respiratory distress syndrome usually develops after the start of drug treatment and is a major cause of death. Its pathogenesis is not well understood., Methods: Respiratory symptom, spirometry, and gas transfer analyses were performed longitudinally in adults in Papua, Indonesia, with uncomplicated (n=50) and severe (n=30) falciparum malaria; normal values were derived from 109 control subjects. Gas transfer was partitioned into its alveolar-capillary membrane (D(M)) and pulmonary vascular (Vc) components, to characterize the site of impaired gas transfer., Results: Cough was frequent in both patients with uncomplicated malaria (50%) and those with severe malaria (30%) and resolved by day 14. Reduced midexpiratory flow indicated obstruction of the small airways. Gas transfer was significantly impaired in patients with severe malaria. D(M) was reduced in patients with severe malaria but not in those with uncomplicated malaria and only returned to normal levels after 2 weeks. In patients with uncomplicated malaria, Vc was reduced at presentation but improved thereafter. In patients with severe malaria, Vc decreased with treatment and was lowest at day 7., Conclusions: Our results suggest that pulmonary vascular occlusion occurs in both patients with uncomplicated malaria and those with severe malaria, likely from sequestration of both red blood cells (RBCs) and white blood cells. There was also impaired alveolar-capillary membrane function in patients with severe malaria but not in those with uncomplicated malaria. Persistent impairment long after clearance of parasitized RBCs suggests prolonged posttreatment inflammatory alveolar-capillary injury.

Individuals living in regions of intense malaria transmission exhibit natural immunity that allows them to be without fever and other symptoms for most of the time despite frequent parasitization. Although this tolerance of parasitemia appears to be more effective in children than in adults (as evidenced by lower parasitemia fever thresholds with age), adults do exhibit a degree of tolerance but the mechanism(s) underlying this are unclear. Asymptomatic malaria-exposed children have higher levels of nitric oxide (NO) than children with severe disease, and NO has been proposed as a mediator of malarial tolerance. However, the ability of highly malaria-exposed asymptomatic adults to generate high-level basal NO is unknown, as is the relationship between NO and malaria tolerance in adults. The relationship between NO and malaria parasitemia was therefore determined in asymptomatic adults from Papua, Indonesia. Adults with Plasmodium falciparum parasitemia had markedly increased basal systemic NO production relative to aparasitemic Papuan controls, who in turn produced more NO than healthy controls from a region without malaria. Immunoglobulin E levels were universally elevated in malaria-exposed Papuan subjects, suggesting that the prevalence of intestinal parasitosis may be high and that nonmalarial infection may also contribute to high basal NO production. Basal peripheral blood mononuclear cell (PBMC) NO synthase activity was elevated in Papuans but poorly correlated with systemic NO production, suggesting that NO production in this setting arises not only from PBMCs but also from other tissue and cellular sources. NO production was associated with and may contribute to malaria tolerance in Papuan adults.

Drug tolerability affects compliance. We evaluated the tolerability levels of azithromycin (750-mg loading dose plus 250 mg/day; n = 148 subjects), doxycycline (100 mg/day; n = 75), and placebo (n = 77) as prophylaxis against malaria in Indonesian adults over 20 weeks. Self-reported and elicited symptoms, health perception, hearing, hematology, and biochemistry were assessed. The loading dose was well tolerated. The frequencies (number per person-years [p-yr]) of all daily reported symptoms were similar in the three arms of the study: 40.2/p-yr for azithromycin, 39.7/p-yr for doxycycline, and 38.2/p-yr for placebo. Relative to those who received placebo, azithromycin recipients complained more often of heartburn (rate ratio = 10.5 [95% confidence interval, 2.8 to 88.1]), paresthesia (2.03 [1.08 to 4.24]), and mild (1.55 [1.01 to 2.48]) and severe (11.2 [1.34 to infinity ]) itching but less often of fever (0.21 [0.09 to 0.49]) and tinnitus (0.09 [0.04 to 0.21]). Azithromycin recipients showed no evidence of clinical hearing loss or hematologic, hepatic, or renal toxicity. One azithromycin recipient developed an erythematous rash. Daily azithromycin was well tolerated by these Indonesian adults during 20 weeks of treatment.

Artemisinin-derivative combination therapies (ACT) are highly efficacious against multidrug-resistant Plasmodium falciparum malaria. Few efficacy data, however, are available for vivax malaria. With high rates of chloroquine (CQ) resistance in both vivax and falciparum malaria in Papua Province, Indonesia, new combination therapies are required for both species. We recently found artesunate plus sulfadoxine-pyrimethamine (ART-SP) to be highly effective (96%) in the treatment of falciparum malaria in Papua Province. Following a preliminary study of CQ plus sulfadoxine-pyrimethamine (CQ-SP) for the treatment of Plasmodium vivax infection, we used modified World Health Organization criteria to evaluate the efficacy of ART-SP for the treatment of vivax malaria in Papua. Nineteen of 22 patients treated with ART-SP could be evaluated on day 28, with no early treatment failures. Adequate clinical and parasitological responses were found by day 14 in all 20 (100%) of the patients able to be evaluated and by day 28 in 17 patients (89.5%). Fever and parasite clearance times were short, with hematological improvement observed in 70.6% of the patients. Double (at positions 58 and 117) and quadruple (at positions 57, 58, 61, and 117) mutations in the P. vivax dihydrofolate reductase (PvDHFR) were common in Papuan P. vivax isolates (46 and 18%, respectively). Treatment failure with SP-containing regimens was significantly higher with isolates with this PvDHFR quadruple mutation, which included a novel T-->M mutation at residue 61 linked to an S-->T (but not an S-->N) mutation at residue 117. ART-SP ACT resulted in a high cure rate for both major Plasmodium species in Papua, though progression of DHFR mutations in both species due to the continued use of SP monotherapy for clinically diagnosed malaria threatens the future utility of this combination.

Chloroquine (CQ) treatment of CQ-resistant Plasmodium falciparum is associated with a significantly higher prevalence of post-treatment gametocytaemia which has been linked to the preferential transmission of CQ-resistant parasites. It is not known whether treatment failure (TF) with sulfadoxine-pyrimethamine (SP) is associated with the same higher prevalence of gametocytaemia as that seen with CQ TF. Using 1997 WHO in-vivo drug efficacy protocols for malaria, we therefore compared (in a study in 1999) the frequency of gametocytaemia in those with TF to the frequency seen in those with an adequate clinical and parasitological response (ACPR) following treatment with one of 3 regimens in Papua, Indonesia: SP monotherapy (n = 87; TF 20.7%), CQ monotherapy (n = 48; TF 83.3%), and the combination of CQ plus SP (n = 34; TF 38.2%). Following SP, day 7 prevalence was significantly higher in those with TF (67%) than with ACPR (38%, P = 0.03). Following combination treatment with CQ + SP, the day 14 gametocyte prevalence was significantly higher in those with TF (100% vs 38%, P = 0.016). The higher prevalence of SP TF-associated gametocytaemia may contribute to increased transmission of antifolate-resistant strains, and further cautions against the use of SP as monotherapy. Adding SP to CQ, after significant resistance has emerged to both drugs, may not prevent enhanced transmission of dual-resistant strains and progression of anti-folate resistance.

User-friendly, reliable, and inexpensive methods for diagnosing malaria are needed at the primary health care level. During a randomized treatment trial, the Parasight-F test was assessed on days 0, 3, 7, and 28 against standard light microscopy of Giemsa-stained thick blood smears for diagnosing Plasmodium falciparum parasitemia in patients with P. falciparum (n = 84) or P. vivax (n = 59) malaria. The median P. falciparum parasite count on day 0 was 2,373/microL (range = 20-74,432/microL). At the start of treatment, the Parasight-F test had a sensitivity of 95.2% (80 of 84; 95% confidence interval [CI] = 88.2-98.7), and a specificity of 94.9% (56 of 59; 95% CI = 85.8-98.9). On day 7, this test showed false-positive results in 17 (16.3%) of 104 patients (95% CI = 9.8-24.9). The Parasight-F test performed well when compared with light microscopy in detecting P. falciparum parasitemia in patients presenting with clinical malaria. However, the high false-positive rate on day 7 limits its use for patient follow-up.

A problem with rapid Plasmodium falciparum-specific antigen histidine-rich protein 2 (HRP2) detection tests for malaria is the persistence of antigen in blood after the disappearance of asexual-stage parasitemia and clinical symptoms, resulting in false-positive (FP) test results following treatment. The ICT P.f/P.v immunochromatographic test detects both HRP2 and a panmalarial antigen (PMA) found in both P. falciparum and Plasmodium vivax. To examine posttreatment antigen persistence with this test and whether persistent sexual-stage forms (gametocytes) are a cause of FP tests after treatment, we compared serial antigen test results with microscopy results from patients symptomatic with P. falciparum malaria in Indonesia for 28 days following treatment with chloroquine (CQ; n = 66), sulfadoxine-pyrimethamine (SP; n = 36), and artesunate plus sulfadoxine-pyrimethamine (ART + SP; n = 15). Persistent FP antigenemia following SP treatment occurred in 29% (HRP2) and 42% (PMA) of the patients on day 7 and in 10% (HRP2) and 23% (PMA) on day 14. The high rates of persistent HRP2 and PMA antigenemia following CQ and SP treatment were strongly associated with the presence of gametocytemia, with the proportion with gametocytes on day 7 posttreatment being significantly greater in those with FP results than in those with true-negative PMA and HRP2 results. Gametocyte frequency on day 14 post-SP treatment was also greater in those with FP PMA results. Following SP treatment, PMA persisted longer than HRP2, giving an FP diagnosis of P. vivax in up to 16% of patients on day 14, with all FP P. vivax diagnoses having gametocytemia. In contrast, PMA was rapidly cleared following ART + SP treatment in association with rapid clearance of gametocytemia. Gametocytes appear to be an important cause of persistent posttreatment panmalarial antigenemia in areas of endemicity and may also contribute in part to persistent HRP2 antigenemia following treatment.

In areas such as eastern Indonesia where both Plasmodium falciparum and Plasmodium vivax occur, rapid antigen detection tests for malaria need to be able to detect both species. We evaluated the new combined P. falciparum-P. vivax immunochromatographic test (ICT Malaria P.f/P.v.) in Radamata Primary Health Centre, Sumba, Indonesia, from February to May 1998 with 560 symptomatic adults and children with a presumptive clinical diagnosis of malaria. Blinded microscopy was used as the "gold standard," with all discordant and 20% of concordant results cross-checked blindly. Only 50% of those with a presumptive clinical diagnosis of malaria were parasitemic. The ICT Malaria P.f/P.v immunochromatographic test was sensitive (95. 5%) and specific (89.8%) for the diagnosis of falciparum malaria, with a positive predictive value (PPV) and a negative predictive value (NPV) of 88.1 and 96.2%, respectively. HRP2 and panmalarial antigen line intensities were associated with parasitemia density for both species. Although the specificity and NPV for the diagnosis of vivax malaria were 94.8 and 98.2%, respectively, the overall sensitivity (75%) and PPV (50%) for the diagnosis of vivax malaria were less than the desirable levels. The sensitivity for the diagnosis of P. vivax malaria was 96% with parasitemias of >500/microl but only 29% with parasitemias of <500/microl. Nevertheless, compared with the test with HRP2 alone, use of the combined antigen detection test would reduce the rate of undertreatment from 14.7 to 3.6% for microscopy-positive patients, and this would be at the expense of only a modest increase in the rate of overtreatment of microscopy-negative patients from 7.1 to 15. 4%. Cost remains a major obstacle to widespread use in areas of endemicity.

There is renewed interest in the rich nickel and cobalt deposits of Pulau Gag, an isolated but malarious island off the northwest coast of Irian Jaya. In preparation for an expanded workforce, an environmental assessment of malaria risk was made, focusing upon malaria prevalence in the small indigenous population, and the in vivo sensitivity of Plasmodium falciparum and P. vivax to chloroquine (CQ) and sulfadoxine/pyrimethamine (S/P), the respective first- and second-line drugs for uncomplicated malaria in Indonesia. During April-June 1997, mildly symptomatic or asymptomatic malaria infections were found in 24% of 456 native residents. Infections by P. falciparum accounted for 60% of the cases. Respective day 28 cure rates for CQ (10 mg base/kg on days 0 and 1; 5 mg/kg on day 2) in children and adults were 14% and 55% (P < 0.005). Type RII and RIII resistance characterized only 5% of the CQ failures. Re-treatment of 36 P. falciparum CQ treatment failures with S/P (25 mg/kg and 1.25 mg/kg, respectively) demonstrated rapid clearance and complete sensitivity during the 28-day follow-up period. More than 97% of the P. vivax malaria cases treated with CQ cleared parasitemia within 48 hr. Three cases of P. vivax malaria recurred between days 21 and 28, but against low drug levels in the blood. The low frequency of RII and RIII P. falciparum resistance to CQ, the complete sensitivity of this species to S/P, and the absence of CQ resistance by P. vivax are in contrast to in vivo and in vitro test results from sites on mainland Irian Jaya.

New drugs are needed for preventing drug-resistant Plasmodium falciparum malaria. The prophylactic efficacy of azithromycin against P. falciparum in malaria-immune Kenyans was 83%. We conducted a double-blind, placebo-controlled trial to determine the prophylactic efficacy of azithromycin against multidrug-resistant P. falciparum malaria and chloroquine-resistant Plasmodium vivax malaria in Indonesian adults with limited immunity. After radical cure therapy, 300 randomized subjects received azithromycin (148 subjects, 750-mg loading dose followed by 250 mg/d), placebo (77), or doxycycline (75, 100 mg/d). The end point was slide-proven parasitemia. There were 58 P. falciparum and 29 P. vivax prophylaxis failures over 20 weeks. Using incidence rates, the protective efficacy of azithromycin relative to placebo was 71.6% (95% confidence interval [CI], 50.3-83.8) against P. falciparum malaria and 98.9% (95% CI, 93.1-99.9) against P. vivax malaria. Corresponding figures for doxycycline were 96.3% (95% CI, 85.4-99.6) and 98% (95% CI, 88.0-99.9), respectively. Daily azithromycin offered excellent protection against P. vivax malaria but modest protection against P. falciparum malaria.

Immune suppression, a potential side effect of long-term chemoprophylaxis, was evaluated as part of a randomized, placebo-controlled trial that compared daily primaquine against weekly chloroquine for malaria prevention. In the last month of the year-long trial, baseline in vitro lymphoproliferative responses to tetanus toxoid were measured, and a tetanus-diphtheria (Td) immunization was administered. Proliferative responses to tetanus toxoid in each Td-immunized group increased significantly over pre-Td baselines and those of the unvaccinated control. Highest initial responses were measured in the primaquine group. The proportion of responders and the magnitude of proliferation was consistently low in the chloroquine group, and end point responses in this group were significantly below those of the placebo. These results suggest that the development and duration of the cellular response to tetanus immunization was impaired by long-term weekly chloroquine prophylaxis, while daily primaquine prophylaxis over the same time period had no inhibitory effect.

Background: Mefloquine and doxycycline are the two drugs recommended for prophylaxis of malaria for visitors to areas where Plasmodium falciparum is resistant to chloroquine., Objective: To compare the efficacy and tolerability of mefloquine with those of doxycycline as prophylaxis for malaria., Design: Randomized, double-blind, placebo-controlled field trial of chemoprophylaxis of malaria., Setting: Northeastern Irian Jaya, Indonesia., Participants: 204 Indonesian soldiers., Intervention: After radical curative treatment, participants were randomly assigned to receive 100 mg of doxycycline per day and mefloquine placebo; 250 mg of mefloquine per week (preceded by a loading dose of 250 mg/d for 3 days) and doxycycline placebo; or placebos for both drugs. Prophylaxis lasted approximately 13 weeks., Measurements: The primary end point for efficacy was the first occurrence of malaria, as documented by a positive malaria smear. Malaria smears were obtained weekly and when patients had symptoms suggesting malaria. Reported symptoms were recorded daily, and an exit study questionnaire was conducted., Results: In the placebo group, 53 of 69 soldiers developed malaria (9.1 person-years), resulting in an attack rate of 5.8 cases per person-year (95% CI, 4.3 to 7.7 cases per person-year). Plasmodium falciparum accounted for 57% of cases, and P. vivax accounted for 43% of cases. No malaria occurred in the 68 soldiers (16.9 person-years) in the mefloquine group; thus, the protective efficacy of mefloquine was 100% (CI, 96% to 100%). In the doxycycline group, P. falciparum malaria occurred in 1 of 67 soldiers (16.0 person-years), yielding a protective efficacy of 99% (CI, 94% to 100%). Both drugs were very well tolerated., Conclusions: Mefloquine and doxycycline were both highly efficacious and well tolerated as prophylaxis of malaria in Indonesian soldiers.

Extended chemoprophylaxis against endemic malaria raises concern with regard to susceptibility after ceasing use of the drug. In this study, we measured attack rates of malaria among adult men for 28 weeks after they ended one year of prophylaxis using either weekly chloroquine (5 mg base/kg, n = 20), daily primaquine (0.5 mg base/kg, n = 30), or a placebo of primaquine (n = 41). The 28-week incidence densities, times to parasitemia, parasite densities, and symptoms of primary post-prophylaxis infections were not significantly different among the former primaquine, chloroquine, and placebo groups. However, the incidence of Plasmodium falciparum infection in the post-chloroquine group was significantly greater than in the post-primaquine group during the first (P = 0.03) and second (P = 0.02) months post-prophylaxis. Six of 10 primary P. falciparum and three of 10 P. vivax infections occurred in the former chloroquine group within one month after ending prophylaxis and the mean time to infection was 30-35 days. In contrast, only one P. falciparum and no P. vivax infections occurred during the first month after ending primaquine prophylaxis. The mean time to first parasitemia by either species of malaria parasite in this group was 72-77 days. There was no indication that daily use of primaquine for one year placed subjects at greater risk of malaria infection or to more severe clinical symptoms of malaria than subjects who had taken placebo or chloroquine, despite the potential for some degree of immunity to have been acquired in these latter two groups during the year-long prophylaxis period. The results do suggest that chloroquine suppressed P.falciparum infections until drug levels decreased, and that primaquine had effectively prevented the establishment of liver-stage parasites.

This report describes one of the few remaining foci of endemic malaria on the island of Java, the Kokap subdistrict, near the Southcentral coast. Kokap was hypoendemic in June 1994 with prevalence of parasitemia at 0.98% (n = 10,606 of 40,246 residents). Plasmodium vivax comprised 63% of infections and P. falciparum all others. The incidence of indigenous infection during 1993 was 48 cases/1,000 person-years (p-yr), and it was relatively uniform among age groups (38 to 53/1,000 p-yr). Nine deaths due to malaria had been recorded in the past three years (8.3 deaths per 100,000 p-yr); the case fatality rate was 0.17%. Subdistricts adjoining Kokap to the north, east, and south reported incidence rates of < 2 cases/1,000 p-yr. To the west, Purworejo District had a high case incidence (11 cases/1,000 p-yr) but other districts to the west did not (< 1.2 cases/1,000 p-yr). The highest case incidence village area within Kokap (169 cases/1,000 p-yr) bordered the district of Purworejo to the west. Endemic malaria in Kokap and Purworejo coincided with where steep hills and narrow valleys dominated the terrain.