Alex K. Owusu-Ofori

Bioavailability and Preliminary Clinical Efficacy of Intrarectal Artesunate in Ghanaian Children with Moderate Malaria

ABSTRACT We report the first detailed pharmacokinetic assessment of intrarectal (i.r.) artesunate (ARS) in African children. Artesunate was given intravenously (i.v.; 2.4 mg/kg of body weight) and i.r. (10 or 20 mg/kg formulated as 50- or 200-mg suppositories [Rectocaps]) in a crossover study design to 34 Ghanaian children with moderate falciparum malaria. The median relative bioavailability of dihydroartemisinin (DHA), the active antimalarial metabolite of ARS, was higher in the low-dose i.r. group (10 mg/kg) than in the high-dose i.r. group (20 mg/kg) (58 versus 23%; P = 0.018). There was wide interpatient variation in the area under the concentration-time curve after i.r. ARS administration (up to 9-fold in the high-dose group and 20-fold in the low-dose group). i.r. administered ARS was more rapidly absorbed in the low-dose group than the high-dose group (median [range] absorption half-lives, 0.7 h [0.3 to 1.24 h] versus 1.1 h [0.6 to 2.7 h] [P = 0.023]. i.r. administered ARS was eliminated with a median (range) half-life of 0.8 h (0.4 to 2.7 h) (low-dose group and 0.9 h (0.1 to 2.5 h) (high-dose group) (P = 1). The fractional clearances of DHA were 3.9, 2.6, and 1.5 liters/kg/h for the 20-mg/kg, 10-mg/kg and i.v. groups, respectively (P = 0.001 andP = 0.06 for the high-and low-dose i.r. groups compared with the i.v. groups, respectively). The median volumes of distribution for DHA were 1.5 liters kg (20 mg/kg, i.r. group), 1.8 liters/kg (10 mg/kg, i.r. group), and 0.6 liters/kg (i.v. group) (P< 0.05 for both i.r. groups compared with the i.v. group). Parasite clearance kinetics were comparable in all treatment groups. i.r. administered ARS may be a useful alternative to parenterally administered ARS in the management of moderate childhood malaria and should be studied further.

Transfusion-Transmitted Malaria in Countries Where Malaria Is Endemic: A Review of the Literature from Sub-Saharan Africa

Although international policies recommend that blood for transfusion should be screened for transfusion-transmitted infections, malaria screening is not performed in most malaria-endemic countries in sub-Saharan Africa. Our literature review identified 17 relevant studies from the period 1980-2009 and indicated that the median prevalence of malaria among 33,029 blood donors was 10.2% (range, 0.7% in Kenya to 55.0% in Nigeria). Malaria screening methods, including microscopy (used in 16 of 17 studies), are either insensitive or impractical for donor screening in resource-poor countries. Even if a suitable screening method were available, rejection of malaria-positive donors would jeopardize the blood supply. Only 1 study established the prevalence of parasitemia among transfusion recipients. This review highlights the need for more evidence about the clinical impact of transfusion-transmitted malaria to justify the policy of screening for blood for malaria in areas of endemicity and for a critical analysis of the feasibility of implementing such a policy and its effect on blood supply.

Population kinetics, efficacy, and safety of dichloroacetate for lactic acidosis due to severe malaria in children.

The authors conducted a randomized, double‐blind, placebo‐controlled trial of intravenous dichloroacetate (DCA) for the purpose of treating lactic acidosis in 124 West African children with severe Plasmodium falciparum malaria. Lactic acidosis independently predicts mortality in severe malaria, and DCA stimulates the oxidative removal of lactate in vivo. A single infusion of 50 mg/kg DCA was well tolerated. When administered at the same time as a dose of intravenous quinine, DCA significantly increased the initial rate and magnitude of fall in blood lactate levels and did not interfere with the plasma kinetics of quinine. The authors developed a novel population pharmacokinetic‐pharmacodynamic indirect‐response model for DCA that incorporated characteristics associated with disease reversal. The model describes the complex relationships among antimalarial treatment procedures, plasma DCA concentrations, and the drugs lactate‐lowering effect. DCA significantly reduces the concentration of blood lactate, an independent predictor of mortality in malaria. Its prospective evaluation in affecting mortality in this disorder appears warranted.

Population Pharmacokinetics of Intramuscular Quinine in Children with Severe Malaria

ABSTRACT We present the first population pharmacokinetic analysis of quinine in patients with Plasmodium falciparum malaria. Ghanaian children (n = 120; aged 12 months to 10 years) with severe malaria received an intramuscular loading dose of quinine dihydrochloride (20 mg/kg of body weight). A two-compartment model with first-order absorption and elimination gave post hoc estimates for pharmacokinetic parameters that were consistent with those derived from non-population pharmacokinetic studies (clearance [CL] = 0.05 liter/h/kg of body weight; volume of distribution in the central compartment [V1] = 0.65 liter/kg; volume of distribution at steady state = 1.41 liter/kg; half-life at β phase = 19.9 h). There were no covariates (including age, gender, acidemia, anemia, coma, parasitemia, or anticonvulsant use) that explained interpatient variability in weight-normalized CL and V1. Intramuscular quinine was associated with minor, local toxicity in some patients (13 of 108; 12%), and 11 patients (10%) experienced one or more episodes of postadmission hypoglycemia. A loading dose of intramuscular quinine results in predictable population pharmacokinetic profiles in children with severe malaria and may be preferred to the intravenous route of administration in some circumstances.

Transfusion-Transmitted Malaria in Ghana

BACKGROUND In sub-Saharan Africa, the prevalence of malaria parasitemia in blood donors varies from 0.6% to 50%. Although the burden of TTM in malaria-endemic countries is unknown, it is recommended that all donated blood is screened for malaria parasites. This study aimed to establish the incidence of TTM and identify a suitable screening test. METHODS Pregnant women, children, and immunocompromised malaria-negative transfusion recipients in a teaching hospital in Ghana were recruited over the course of 1 year. Parasites detected in recipients within 14 days of the transfusion were genotyped and compared to parasites in the transfused blood. The presence of genotypically identical parasites in the recipient and the transfused blood confirmed transfusion-transmitted malaria. Four malaria screening tests were compared to assess their usefulness in the context of African blood banks. RESULTS Of the 50 patients who received transfusions that were positive for Plasmodium falciparum by polymerase chain reaction (PCR), 7 recipients developed PCR-detectable parasitemia. In only 1 of the 50 recipients (2%) was the parasite identical to that in the transfused blood. The prevalence of P. falciparum malaria in transfused blood was 4.7% (21/445) by microscopy, 13.7% (60/440) by rapid diagnostic test, 18% (78/436) by PCR, and 22.2% (98/442) by enzyme immunoassay. CONCLUSIONS Although malaria parasites are commonly detected in blood donors in malaria-endemic areas, transfusion-transmitted malaria occurs infrequently. Policies recommend screening blood donors for malaria, but none of the commonly used methods is sufficiently sensitive to be used by blood banks in malaria-endemic countries.

Treatment of Whole Blood With Riboflavin and UV Light: Impact on Malaria Parasite Viability and Whole Blood Storage

ABSTRACT Background: Sub-Saharan African countries utilize whole blood (WB) to treat severe anemia secondary to severe blood loss or malaria on an emergency basis. In many areas with high prevalence of transfusion-transmissible agents, blood safety measures are insufficient. Pathogen reduction technology applied to WB might considerably improve blood safety. Methods: Whole blood from 40 different donors were treated with riboflavin and UV light (pathogen reduction technology) in order to inactivate malaria parasite replication. The extent of parasite inactivation was determined using quantitative polymerase chain reaction methods and was correlated to studies evaluating the replication of malaria parasites in culture. Products were also stored for 21 days at +4°C and monitored for cell quality throughout storage. Results: Plasmodium amplicon was present in 21 samples (>100 copies/mL), doubtful in four (10–100 genome equivalents [gEq]/mL), and negative in 15 U. The majority of asymptomatic parasitemic donors carried low parasite levels, with only six donors above 5,000 copies/mL (15%). After treatment with riboflavin and UV light, these six samples demonstrated a 0.5 to 1.2 log reduction in quantitative polymerase chain reaction amplification. This correlated to equal to or greater than 6.4 log reductions in infectivity. In treated WB units, cell quality parameters remained stable; however, plasma hemoglobin increased to 0.15 g/dL. All markers behaved similarly to published data for stored, untreated WB. Conclusions: Pathogen reduction technology treatment can inactivate malaria parasites in WB while maintaining adequate blood quality during posttreatment cold storage for 21 days.

Plasma glutamine levels and falciparum malaria

Glutamine deficiency is associated with increased rates of sepsis and mortality, which can be prevented by glutamine supplementation. Changes in glutamine concentration were examined in Ghanaian children with acute falciparum malaria and control cases. The mean (SD) plasma glutamine concentration was lower in patients with acute malaria (401 (82) mumol/L, n = 50) than in control patients (623 (67) mumol/L, n = 7; P < 0.001). Plasma glutamine concentrations all rose in convalescence. The mean (SD) increase in plasma glutamine was 202 (123) mumol/L (n = 18; P < 0.001) compared with acute infection. We conclude that acute falciparum malaria is associated with large decreases in plasma glutamine and these falls may increase susceptibility to sepsis and dyserythropoeisis.

Transfusion-transmitted syphilis in teaching hospital, Ghana.

To the Editor: Transfusion-transmitted syphilis, which is caused by Treponema pallidum subspecies pallidum, is one of the oldest recognized infectious risks of blood transfusion (1). Routine screening of blood donors and refrigeration of donated blood before its use has resulted in only 3 reported cases of transfusion-transmitted syphilis over the past 4 decades (2–6). The World Health Organization recommends screening all donated blood for syphilis (7), but doing so is challenging for many developing countries. Many blood banks in low-income countries, including Komfo Anokye Teaching Hospital in Kumasi, Ghana, do not screen donated blood for syphilis. This study was conducted at Komfo Anokye Teaching Hospital. The purpose of this study was to determine the prevalence of syphilis among blood donors and whether seroconversion occurred in transfusion recipients. The study was approved by the ethics committees in Kumasi, Ghana, and Liverpool, UK. Pretransfusion plasma samples from 200 conscious transfusion recipients in adult, pediatric, and obstetric inpatient departments and samples of their transfused blood were tested for syphilis. A positive initial result by enzyme immunoassay (EIA) (Bioelisa Syphilis 3.0; Biokit, Barcelona, Spain) was confirmed by using a T. pallidum hemagglutination assay (TPHA) (Syphagen; Biokit). A rapid plasma reagin (RPR) assay (RPR Reditest; Biokit) was used to determine whether seropositivity was caused by recent infection. Seronegative recipients who had received seropositive blood were retested 30 days posttransfusion to identify seroconversions. All donors and recipients with recent infections were offered counseling and treatment in accordance with national guidelines. A total of 145 (73%) blood donors were male, and 109 (57%) units of blood had been stored for <4 days. Sixteen units (8%, 95% confidence interval [CI] 4.3%–11.7%) were seropositive for syphilis by EIA and TPHA. Of these units, 7 (44%) were RPR reactive, which indicated a prevalence of recent infections of 3.5% (95% CI 1.0%–6.0%) (Table). Twenty-six transfusion recipients (13%; 95% CI 8.3%–17.7%) were seropositive by EIA and TPHA. Of these recipients, blood samples from 9 (35%) were RPR reactive, indicating a prevalence of recent infection of 4.5%. Table Characteristics of 16 recipients of syphilis-positive blood transfusions, Kumasi, Ghana* One recipient, an 8-year-old girl with severe malarial anemia (recipient 10), showed seroconversion after receiving an RPR-reactive unit of blood that had been refrigerated for only 1 day before being issued for use. Posttransfusion fever developed in this recipient, who responded to treatment with cefuroxime and gentamicin, although results of blood culture for bacteremia and peripheral blood film for malaria parasites were negative. She had no relevant sexual history, had been febrile after the transfusion, and showed no evidence of mucocutaneous lesions or lymphadenopathy at her follow-up visit 1 month after the transfusion. She was referred to pediatricians for treatment of syphilis. This recipient who showed seroconversion most likely had a case of transfusion-transmitted syphilis. Other treponemal infections such as yaws cannot be differentiated serologically from syphilis, and a diagnosis of yaws is based on clinico-epidemiologic features (8); however, yaws is not endemic to Kumasi, and because this child had no clinical evidence of yaws, this disease is unlikely to be the cause of the seroconversion. Refrigeration of units of blood for ≥5 days kills T. pallidum, but 57% of the donated blood in this study was stored for <4 days before use. This situation prevails across many blood banks in sub-Saharan Africa where, because of inadequate supply and high demand, blood is used as soon as it becomes available. Such short periods of blood storage do not provide an adequate margin of safety against transfusion-transmitted syphilis. Findings from this study have been discussed with the hospital transfusion committee, and new syphilis screening guidelines and testing algorithms are being developed. The high prevalence of syphilis seropositivity in blood donors and seroconversion of a transfusion recipient shows that in centers where screening is not conducted, recipients of blood transfusions are at risk for contracting transfusion-transmitted syphilis. This finding is likely in blood banks that have a high demand for blood and where blood is stored only for a few days. This study highlights transfusion-transmitted syphilis as a serious public health issue in developing countries and demonstrates that screening of donor blood for syphilis should be conducted.

Impact of inconsistent policies for transfusion-transmitted malaria on clinical practice in Ghana.

Background Policies concerning the prevention of transfusion transmitted malaria (TTM) are the responsibility of blood transfusion services and malaria control programmes. To prevent spreading drug resistance due to over-use of malaria drugs, recent malaria treatment guidelines recommend prompt parasitological confirmation before treatment is started. In contrast, blood safety policies from the World Health Organisation (WHO) recommend presumptive malaria treatment for recipients of blood in endemic countries but evidence supporting this approach is lacking. Our study documented how these conflicting policies relating to malaria transmission through blood transfusion impact on clinical practice in a teaching hospital in West Africa. Methods/Principal Findings We randomly selected and reviewed case notes of 151 patients within 24 hours of their receiving a blood transfusion. Transfusion practices including the confirmation of diagnosis and anti-malarial treatment given were compared across three departments; Obstetrics and Gynaecology (O&G), Paediatrics and Medicine. Overall, 66 (44%) of patients received malaria treatment within 24 hrs of their blood transfusion; of which only 2 (3%) received anti-malarials based on a laboratory confirmation of malaria. Paediatric patients (87%) received the most anti-malarials and only 7% and 24% of recipients in medicine and O&G respectively received anti malarials. In 51 patients (78%), the anti-malarials were prescribed at the same time as the blood transfusion and anti-malarials prescriptions exceeded the number of patients with a presumptive diagnosis of malaria. Conclusions It is common practice in paediatrics to prescribe anti-malarials routinely with blood transfusions. This contravenes the malaria treatment guidelines of laboratory confirmation before treatment but is in accordance with the less-well evidenced blood safety guidelines. There is an urgent need for more evidence about the clinical impact of transfusion transmitted malaria to enable malaria and blood transfusion programmes to harmonize their policies and give clear guidance to clinicians who prescribe blood transfusions in malaria-endemic areas

Role of Diagnostic Testing in Schistosomiasis Control Programs in Rural Ghana

Background: Schistosomiasis affects an estimated 200-300 million people worldwide. Construction of dams has contributed to the high prevalence of urinary schistosomiasis in Ghana. To assist rural villages downstream from the Barekese dam in schistosomiasis control programs, this study evaluated possible detection methods of schistosomiasis. Methods: A cross-sectional survey of volunteers was conducted in a rural setting of Ghana. Five hundred and thirty four (534) volunteers provided symptom information and urine samples for urinalysis. Microscopic egg count of 341 random samples was used to determine prevalence of disease and to analyze effectiveness of urinalysis and symptom information for diagnosing schistosomiasis. Results: Schistosomiasis prevalence was 41.1 % for the village. The highest prevalence was in the 10-14 age groups (71.1 %). Sensitivity and specificity for hematuria was 76.1 and 77.7 % respectively, and proteinuria was 58.2 & 68.7 % respectively. The positive predictive value was highest for hematuria (71.1 %). The highest negative predictive value was among positive proteinuria or hematuria (84.0 %). From urinary symptom information, reporting pain and dark urine yielded the highest positive predictive value (72.0 %). Reporting pain, difficulty, or dark urine yielded the highest negative predictive value (75.8 %). Discussion: The positive and negative predictive values of urine analysis and symptom information may be an inexpensive tool for diagnosing schistosomiasis in areas of high prevalence.