N. J. White

Malaria during pregnancy in an area of unstable endemicity

A prospective study of malaria during pregnancy was conducted between September 1986 and December 1989 in an area of unstable (mesoendemic) malaria transmission on the Thai-Burmese border. Antenatal clinics were set up in camps for displaced persons of the Karen ethnic minority and 1358 pregnant women were enrolled at a mean estimated gestational age of 23 weeks (standard deviation 5.7 weeks) and were followed weekly until delivery. Malaria developed in 505 women (37.2%); 80.2% of infections were Plasmodium falciparum, 17.1% were P. vivax, and 2.7% were mixed. Primigravidae were infected more commonly than multigravidae: 153/322 (47.5%) compared with 318/953 (33.3%) (P less than 0.001). The incidence of malaria declined from the 20th week of gestation (12%) towards term (4.4%). Most infections were detected before symptoms developed, and there were no deaths associated with malaria. Despite this, malaria was associated with an overall 123 g reduction in birthweight (95% confidence interval [CI] 34-212 g). This reduction was largely accounted for by lower birthweights of babies born to infected primigravidae (mean reduction 151 g, 95% CI 21-282 g) and women in their 2nd and 3rd pregnancies (mean reduction 185 g, 95% CI 84-286 g). The incidence of anaemia requiring treatment was higher in women who developed malaria, 149/420 (35.4%) compared with 191/670 (28.5%), and was proportional to the number of parasitaemic episodes. Thus, despite regular antenatal clinic attendance with prompt detection and treatment of malaria (the currently employed antimalarial strategy in areas with multidrug-resistant P. falciparum), malaria still had a significant adverse effect on pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Fluid Replacement in Dengue Shock Syndrome: A Randomized, Double-Blind Comparison of Four Intravenous-Fluid Regimens

Dengue hemorrhagic fever and dengue shock syndrome (DSS) are major causes of childhood morbidity and mortality in many tropical countries. Increased intravascular permeability leading to shock is the cardinal feature of DSS. Fluid resuscitation to counteract massive plasma leakage is the mainstay of treatment. A double-blind, randomized trial comparing four intravenous-fluid regimens for acute resuscitation of 50 children with DSS was conducted. Colloids (dextran 70 or the protein digest gelafundin 35,000) restored cardiac index and blood pressure and normalized hematocrit more rapidly than crystalloids (Ringers lactate or 0.9%-weight/volume saline). Dextran 70 provided the most rapid normalization of the hematocrit and restoration of the cardiac index, without adverse effects, and may be the preferred solution for acute resuscitation in DSS. Further large-scale double-blind trials are required to provide an evidence-based approach to the management of DSS.

Identification of Pseudomonas pseudomallei in clinical practice: use of simple screening tests and API 20NE.

The API 20NE kit and a simple screening system involving Grams stain, the oxidase reaction, colistin and gentamicin resistance, and colonial characteristics on a differential agar medium, were used to test 400 strains of Pseudomonas pseudomallei. The API kit identified 390 (97.5%) strains correctly on first testing and all but one of the remainder on second testing. Only one strain was initially misidentified (as Ps cepacia). The screening system was 100% accurate in identifying Ps pseudomallei. In non-endemic areas the API 20NE kit may be used to identify sporadic imported strains of Ps pseudomallei. Such kits may also help to delineate the geographical distribution of melioidosis. In endemic areas the screening tests described offer a cheap, simple, and accurate means of presumptively identifying Ps pseudomallei from clinical specimens.

Biochemical characteristics of clinical and environmental isolates of Burkholderia pseudomallei

The biochemical characteristics of 213 isolates of Burkholderia pseudomallei from patients with melioidosis and 140 isolates from the soil in central and northeastern Thailand were compared. Whereas the biochemical profiles of all the clinical isolates were similar, all soil isolates from the central area and 25% of isolates from northeastern Thailand comprised a different phenotype. This was characterised by the ability to assimilate L-arabinose (100%), adonitol (100%), 5-keto-gluconate (90%) and D-xylose (84%), but failure to assimilate dulcitol (0%), erythritol (0%) and trehalose (10%). Compared with clinical isolates, these organisms had similar antibiotic susceptibility profiles and were also recognised by a specific polyclonal antibody against B. pseudomallei. As melioidosis is rare in central Thailand, but common in the northeast, this raises the possibility that this biochemical phenotype may be less virulent, or may even represent a different species.

Relation of the stage of parasite development in the peripheral blood to prognosis in severe falciparum malaria

Admission blood films from 72 patients who died of severe falciparum malaria (50 Thai adults, 22 Gambian children) were matched retrospectively for parasitaemia with equal numbers of survivors. The peripheral blood parasites from fatal cases were more mature than those from survivors. Tiny rings (TR) comprised > 50% of parasites in 47/72 (65%) survivors but only 12/72 (17%) of fatal cases (P < 0.001). Parasites containing visible pigment (MTS: mature trophozoites and schizonts) comprised < 20% of the total parasite count in 10/72 (14%) survivors compared with 31/72 (43%) fatal cases (P < 0.001). Of the 39 patients with > 10(4) MTS/microL, 30 (81%) died. These findings were confirmed in a prospective study of 279 adult Thai patients admitted sequentially with acute falciparum malaria. Only 4 of the 19 fatal cases (21%) had > 50% TR, compared with 130 of 260 (50%) survivors, whereas > 20% MTS were found in 10/19 (53%) fatal cases, compared with 28/108 (27%) severe malaria survivors, and 26/155 (17%) patients with moderately severe malaria (P = 0.001). As a predictor of fatal outcome, the finding of either > 10(4) MTS/microL or > 5 x 10(5) parasites/microL in severe malaria had a sensitivity of 90% (95% confidence interval [CI] = 75-97%) and a specificity of 72% (95% CI = 59-86%). These observations are consistent with the hypothesis that a predominance of mature parasites in the peripheral blood reflects a greater sequestered biomass, and thus more severe disease. Simple microscopical assessment of parasite maturity on an admission blood slide provides important pathophysiological and prognostic information in severe falciparum malaria.

Development and validation of a liquid chromatographic-tandem mass spectrometric method for determination of piperaquine in plasma Stable isotope labeled internal standard does not always compensate for matrix effects

A bioanalytical method for the analysis of piperaquine in human plasma using off-line solid-phase extraction and liquid chromatography coupled to positive tandem mass spectroscopy has been developed and validated. It was found that a mobile phase with high pH (i.e. 10) led to better sensitivity than mobile phase combinations with low pH (i.e. 2.5-4.5) despite the use of positive electrospray and a basic analyte. The method was validated according to published FDA guidelines and showed excellent performance. The within-day and between-day precisions expressed as R.S.D., were lower than 7% at all tested concentrations (4.5, 20, 400 and 500ng/mL) and below 10% at the lower limit of quantification (LLOQ) (1.5ng/mL). The calibration range was 1.5-500ng/mL with a limit of detection (LOD) at 0.38ng/mL. Validation of over-curve samples ensured that it would be possible with dilution if samples went outside the calibration range. Matrix effects were thoroughly evaluated both graphically and quantitatively. Matrix effects originating from the sample clean-up (i.e. solid-phase extraction) procedure rather than the plasma background were responsible for the ion suppression seen in this study. Salts remaining from the buffers used in the solid-phase extraction suppressed the signals for both piperaquine and its deuterated internal standard. This had no effect on the quantification of piperaquine. Triethylamine residues remaining after evaporation of the solid-phase extraction eluate were found to suppress the signals for piperaquine and its deuterated internal standard differently. It was found that this could lead to an underestimation of the true concentration with 50% despite the use of a deuterated internal standard.

High rate of Plasmodium vivax relapse following treatment of falciparum malaria in Thailand.

Within two months of treatment for falciparum malaria, Plasmodium vivax infections developed in 58 (33%) of 174 patients who had received a quinine or quinidine regimen and in 46 (32%) of 145 patients who had received mefloquine with inpatient follow-up of more than six weeks. The time to vivax relapse was significantly longer after mefloquine treatment (median 47 days, range 30-65) than after quinine or quinidine treatment (21 days, 15-36; p less than 0.0001). All patients remained outside areas of malaria transmission. These findings suggest a very high rate of double infection in Thailand with acute suppression of vivax by falciparum malaria, and warrant evaluation of radical therapy with primaquine in certain patients with acute falciparum malaria.

PATHOPHYSIOLOGICAL AND PROGNOSTIC SIGNIFICANCE OF CEREBROSPINAL-FLUID LACTATE IN CEREBRAL MALARIA

Cerebrospinal-fluid (CSF) lactate concentrations were elevated in all but 1 of 45 patients with cerebral malaria. They were significantly higher in patients who died (9.0 +/- 5.3 mmol/l, mean +/- SD) than in survivors (3.4 +/- 1.1 mmol/l, p = 0.0002) and had returned to normal values in each of 9 patients studied after recovery of consciousness. There was a significant negative correlation between CSF lactate and CSF glucose. All 11 patients with CSF lactate concentrations above 6 mmol/l died. CSF lactate is thus an important prognostic indicator in cerebral malaria and these findings suggest that hypoxia contributes to the pathogenesis of this disorder.

Population Pharmacokinetics of Piperaquine after Two Different Treatment Regimens with Dihydroartemisinin-Piperaquine in Patients with Plasmodium falciparum Malaria in Thailand

ABSTRACT The population pharmacokinetics of piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria treated with two different dosage regimens of dihydroartemisinin-piperaquine were characterized. Piperaquine pharmacokinetics in 98 Burmese and Karen patients aged 3 to 55 years were described by a two-compartment disposition model with first-order absorption and interindividual random variability on all parameters and were similar with the three- and four-dose regimens. Children had a lower body weight-normalized oral clearance than adults, resulting in longer terminal elimination half-lives and higher total exposure to piperaquine (area under the concentration-time curve from 0 to 63 days [AUCday 0-63]). However, children had lower plasma concentrations in the therapeutically relevant posttreatment prophylactic period (AUCday 3-20) because of smaller body weight-normalized central volumes of distribution and shorter distribution half-lives. Our data lend further support to a simplified once-daily treatment regimen to improve treatment adherence and efficacy and indicate that weight-adjusted piperaquine doses in children may need to be higher than in adults.

Do patients with cerebral malaria have cerebral oedema? A computed tomography study.

Computed tomography of the brain in 10 patients with severe cerebral malaria, 5 of whom died, showed evidence of cerebral oedema in only 2 fatal cases. Small areas of altered density were seen in 4 cases; these were not associated with focal neurological signs and were still visible in convalescent scans in 2 survivors. 4 patients, including 1 of the fatalities, had completely normal scans. Cerebral oedema may occur in severe cerebral malaria but is not a consistent feature of living patients and cannot, therefore, always be the cause of their coma.