The American Journal of Tropical Medicine and Hygiene - Volume 77, Issue 6, December 2007

Plague and hantavirus pulmonary syndrome (HPS) are severe, often fatal diseases in humans that share a broad epidemiologic focus in the southwestern United States. Prevention of these diseases relies heavily on education and reducing rodent abundance in peridomestic environments. Resources for these activities are limited. Therefore, identifying areas sharing elevated risk for these two relatively rare but severe diseases could be useful for targeting limited public health resources. Using logistic regression and geographic information system–based modeling, we identified environmental predictors of elevated risk for plague (distance to piñon-juniper ecotones and amount of precipitation) and HPS (elevation and amount of precipitation) in northeastern Arizona and northwestern New Mexico. Our models accurately identified case locations as suitable (producer accuracies of 93% for plague and 96% for HPS) and indicated that approximately half of the coverage area was classified as suitable risk for either plague or HPS. The probability of a site being classified as suitable for plague was strongly correlated with its probability of being classified as suitable for HPS (ρs = 0.88). Increased risk for both diseases occurred for approximately 37% of the coverage area.

Over the years, multiple articles on Artemisinin-based Combination Therapies (ACTs) were published, highlighting the relative advantages or drawbacks of these combinations. Many studies were comparative. Because none of the studies compare all combinations and methodology varies between studies, there is no homogeneity. A multi-treatment Bayesian random-effects meta-analysis was designed to assess the relative effect of each combination therapy to artesunate + sulfadoxine-pyrimethamine (4 mg/kg/day for 3 days). By far the most attractive result for the variable adequate clinical and parasitological response at day 28 PCR corrected is given by the combination artemether-lumefantrine. Annual follow-up on the data published is intended to reveal the changes in the relative drug efficacy values of ACTs.

Three different drugs (mefloquine, atovaquone/proguanil, doxycycline) are recommended for malaria chemoprophylaxis, each with approximately the same efficacy but various adverse event profiles, regimens, and prices. We investigated which medication the travelers would have chosen on the basis of written evidence-based information and the impact that pretravel consultation had on their decision. A prospective study was performed in a travel clinic and private practice, and 1073 travelers were included; 45% chose mefloquine (Lariam or Mephaquine), 21% atovaquone/proguanil (Malarone), 18% doxycycline (Supracycline), 5% “no prophylaxis,” and 11% “do not know.” Lariam was principally chosen because of prior experience (38%), Mephaquine because of low price (34%), and doxycycline and Malarone because of the profile of adverse events (55% and 43%, respectively). Based on objective written information, travelers most frequently chose mefloquine for chemoprophylaxis. This suggests that evidence-based information weighs more heavily than negative publicity. Taking into account the perspective of the user should improve appropriateness of the pretravel advice.

There are rare comparative studies of the clinical and laboratory features of severe and moderate malaria, including predictors of poor outcome, in rural and urban areas for regions of high malaria transmission. We therefore studied 2,235 children hospitalized for malaria in a rural (Lambaréné) and an urban (Libreville) area in Gabon between January 2001 and December 2002. From children screened, 33% and 48% were hospitalized for malaria in Libreville and Lambaréné, respectively (P < 0.001). Two malaria clinical groups were identified according to the World Health Organization 2000 classification of severe malaria. In both areas, severe malaria was characterized by a high proportion of severe anemia. The case fatality rate was 5-fold lower in Lambaréné than in Libreville (1% versus 5%; P < 0.0001). In both sites, cerebral malaria associated with respiratory distress was the most important predictor of fatal malaria (odds ratio = 10.7, 95% confidence interval = 4.8–23.8 P < 0.0001).

Malaria’s relationship with socioeconomic status at the macroeconomic level has been established. This is the first study to explore this relationship at the microeconomic (household) level and estimate the direction of association. Malaria prevalence was measured by parasitemia, and household socioeconomic status was measured using an asset based index. Results from an instrumental variable probit model suggest that socioeconomic status is negatively associated with malaria parasitemia. Other variables that are significantly associated with parasitemia include age of the individual, use of a mosquito net on the night before interview, the number of people living in the household, whether the household was residing at their farm home at the time of interview, household wall construction, and the region of residence. Matching estimators indicate that malaria parasitemia is associated with reduced household socioeconomic status.

To explore the feasibility of field sites for malaria vaccine trials, we conducted a prospective study of clinical malaria incidence during two consecutive transmission seasons in children and young adults living in two areas of Mali with different entomologic inoculation rates (EIRs). Approximately 200 subjects (3 months to 2 years of age) were enrolled per site and followed weekly. Malaria smears were performed monthly in all participants and when symptoms or signs of malaria were present. In Sotuba (annual EIR < 15 infective bites per person), the incidence of clinical malaria was comparable across all age groups but varied significantly between the 2 years. In contrast, in Donéguébougou (annual EIR > 100 infective bites per person), incidence rates decreased significantly with increasing age but remained stable between years. Our results suggest that, although the age distribution of clinical malaria depends on transmission intensity, the total burden of disease may be similar or higher in settings of low transmission.

The potential role of polymorphisms in the pfcrt and pfmdr1 genes and in vitro susceptibility to amodiaquine and desethylamodiaquine were explored in 15 chloroquine-resistant Colombian Plasmodium falciparum isolates. Single nucleotide polymorphisms in the pfcrt gene, including a newly reported mutation (S334N), were seen in isolates with decreased susceptibility to amodiaquine and desethylamodiaquine. The lowest susceptibility found to amodiaquine was observed in an isolate carrying a pfcrt and pfmdr1 Dd2-like haplotype, whereas a pfcrt haplotype related to the 7G8 Brazilian strain was found in a Colombian isolate with the lowest susceptibility to desethylamodiaquine. This exploratory study suggests that polymorphisms in the pfcrt and pfmdr1 genes play a role in amodiaquine and desethylamodiaquine resistance and warrants further study.

We report the results of clinical studies carried out at six sites in Madagascar, between January and October 2006. The aims were (i) to update our knowledge of the burden of Plasmodium malariae infection and (ii) to assess the therapeutic efficacy of chloroquine for uncomplicated quartan malaria. Our findings confirm that P. malariae is the third leading cause of malaria, accounting for 1.1% of all malarial infections. They also demonstrate that chloroquine—currently recommended for the home management of presumed malaria in children under the age of five years and commonly used by adults—remains highly effective in patients with uncomplicated P. malariae infection.

The present study examined the genetic diversity and population structure of Plasmodium falciparum in western Kenya by analyzing the polymorphism of 12 microsatellite loci and two antigen loci. Malaria in highland areas is unstable and epidemic whereas malaria in lowland areas is endemic. Transmission intensity and malaria prevalence are substantially lower in the highlands than in the lowlands. Despite that the highland parasite populations exhibited reduced number of alleles, lower expected heterozygosity, and infection complexity in comparison to the surrounding lowland population, genetic diversity of the highland populations remained high in comparison to parasites from other meso-endemic regions. More than 70% of infections from western Kenya highland study sites were mixed genotype infections. Small but statistically significant genetic differentiation between highland and lowland populations was detected. These findings are discussed in the context of human travel and local transmission in the study area.

Many aspects of the human asymptomatic visceral leishmaniasis (VL) remain not elucidated, and moreover, almost all the data come from highly endemic areas. The recent appearance of American VL (AVL) in the northeastern region of the state of São Paulo, Brazil, offered a good opportunity for further understanding. We present the preliminary results from a seroprevalence study on AVL in humans in Araçatuba, São Paulo. This was a cross-sectional survey on a random sample of the population (one-stage simple random sampling) in two areas, using rK39 dipstick tests. The sex ratios and age distributions in the two areas were comparable. Detectable antibodies were found in 23 subjects (20%) in area A1 and in 6 subjects (4.8%) in area A2. There was no significant difference in age distribution of seropositivity between the areas. We observed a difference in asymptomatic infection rates between the two areas, possibly associated with socioeconomic levels and transmission intensity.

The transmission of parasites of the genus Leishmania involves a large diversity of mammalian reservoir hosts. However, many of these are yet to be identified, mainly in isolated biotopes such as the Amazonian rain forest. Furthermore, the trophic preferences of insect vectors have major epidemiologic implications. In this study, we developed a molecular tool for the identification of blood meals of phlebotomine sand flies. This assay is based on specific amplification and sequencing of the blood meal–derived single copy prepronociceptin (PNOC) gene, which is used as a target in phylogenetic studies of mammals. Sand flies were identified simultaneously with the blood-meal identification, using molecular analysis of a ribosomal locus. After a systematic assessment of the sensitivity and specificity of polymerase chain reaction amplification of the PNOC gene using human fed sand flies, the assay was tested on wild-caught sand flies. This work has important implications for the discovery of new Leishmania reservoir hosts and for a better understanding of complex parasite life cycles.

Leishmania major culture-derived, soluble, exogenous antigens have been shown to be a source of vaccine targets for the parasite. We have previously reported that L. major culture-derived, soluble, exogenous antigens can immunize BALB/c mice against challenge with L. major. However, the molecule(s) involved in this protection was not known. We describe the potential of one component of soluble exogenous antigens (recombinant nucleoside hydrolase) to vaccinate mice against challenge with L. major. We found that recombinant nucleoside hydrolase vaccinated BALB/c mice against a subsequent challenge with L. major. Protection was manifested by a significant decrease in lesion size (as much as a 30-fold reduction) and parasite burden (as much as a 71-fold reduction). Protection was achieved whether recombinant nucleoside hydrolase was administered to mice in the presence or absence of adjuvant (interleukin-12). Finally, protection was accompanied by an increase in interferon-γ production but a decrease in interleukin-10 production by vaccinated animals in response to challenge with L. major.

Assessment of resistance to DDT and permethrin insecticides and molecular detection of knockdown resistance (kdr) alleles were conducted in three populations of Anopheles arabiensis from eastern Sudan. Bioassay mortalities ranged from 96.9% to 99.6% for 4% DDT and from 98.4% to 100% for 1% permethrin. The L1014F and L1014S alleles were detected in 25 of 498 mosquitoes. The overall kdr frequencies ranged from 7.0% in the area where insecticide-treated nets were used to 3.0% in the area with agricultural insecticide use. The presence of the kdr alleles in An. arabiensis in Sudan emphasizes the need to develop appropriate resistance monitoring and management strategies for An. arabiensis.

We studied effects of compliance on the impact of mass drug administration (MDA) with diethylcarbamazine and albendazole for lymphatic filariasis (LF) in an Egyptian village. Baseline microfilaremia (mf) and filarial antigenemia rates were 11.5% and 19.0%, respectively. The MDA compliance rates were excellent (> 85%). However, individual compliance was highly variable; 7.4% of those surveyed after five rounds of MDA denied having ever taken the medications and 52.4% reported that they had taken all five doses. The mf and antigenemia rates were 0.2% and 2.7% in those who reported five doses of MDA and 8.3% and 13.8% in those who reported zero doses. There was no significant difference in residual infection rates among those who had taken two or more doses. These results underscore the importance of compliance for LF elimination programs based on MDA and suggest that two ingested doses of MDA are as effective as five doses for reducing filariasis infection rates.

The pathologic manifestations of Onchocerca volvulus infection depend on the interplay between the host and the parasite. A genetic single nucleotide polymorphism in the FcγRIIa gene, resulting in arginine (R) or histidine (H) at position 131, affects the binding to the different IgG subclasses and may influence the clinical variations seen in onchocerciasis. This study investigated the relationship between this polymorphism and disease outcome. FcγRIIa genotyping was performed on clinically characterized onchocerciasis patients (N = 100) and healthy controls (N = 74). FcγRIIa genotype R/R131 frequencies were significantly higher among patients with severe dermatopathology (P < 0.001). Increased risk of developing this form was mostly associated with one tribe (Masalit) (OR = 3.2, 95% CI 1–9.9, P = 0.042). The H131 allele was found to be significantly associated with a reduced risk of having the severe form of the disease (adjusted OR = 0.26, 95% CI = 0.13–0.46, P < 0.001). Our findings suggest that the polymorphism influences the clinical outcome of onchocerciasis.

To elucidate determinants of morbidity in schistosomiasis mansoni, a community-based study was undertaken involving 2,451 subjects (mean age, 18.8 ± 15.3 [SD] years) from four endemic sites in Ethiopia. Overall prevalence of infection was 65.9%, reported blood in stools was 35.8%, and schistosomal periportal thickening/fibrosis (PPT/F) was 4.6%. Similarly, 43.2% were positive for at least one marker of hepatitis B virus (HBV), 5.3% were HBsAg positive, and 1.3% were anti-hepatitis C virus (HCV) positive. Prevalence of PPT/F increased significantly with increasing community prevalence and intensity of S. mansoni infection. In a multiple logistic regression analysis, intensity of egg excretion, markers of HBV infection, age, and male sex were significantly associated with PPT/F, whereas co-infection with other intestinal helminths was associated with lower odds for PPT/F. HCV was not associated with S. mansoni infection or with schistosomal PPT/F. In conclusion, integrated helminth control targeting school-aged children, who have the highest burden infection, should be used to substantially reduce the risk of periportal fibrosis.

An agar plate (AP) method has been developed for culturing infectious larvae of the hookworm Ancylostoma ceylanicum. The third-stage larvae reared using the AP method displayed similar morphology to those cultured using Baermann or Harada-Mori coproculture techniques. The yield of viable larvae from the AP method (50%) was comparable to that of the Baermann (47%), and both were superior to Harada-Mori (2.1%). Third-stage larvae cultured by the AP method established patent infection in naturally permissive laboratory hosts, although the yield of adult worms was reduced compared with animals infected with L3 obtained by Baermann culture. The AP method is useful for defining growth requirements for hookworm development, as well as characterizing the effects of bacterially expressed compounds on hookworm larvae in vivo.

A controlled randomized trial of anti-helminthic treatment was undertaken in 1996–1997 in a rural area of Madagascar where populations were simultaneously infected with Ascaris lumbricoides, Plasmodium falciparum, and Schistosoma mansoni. Levamisole was administered bimonthly to 107 subjects, whereas 105 were controls. Levamisole was highly effective in reducing Ascaris egg loads in the treated group (P < 10−3 at all visits), whereas it had no effect on schistosomiasis. Subjects 5–14 years of age, treated with levamisole, had a significant increase of their P. falciparum densities compared with controls (P = 0.003). There was no effect of the treatment on children 6 months to 4 years of age, nor on adults > 15 years of age. This study confirms the results of a randomized trial, which showed a negative interaction in those > 5 years of age between Ascaris and malaria parasite density in another Malagasy population, submitted to a higher malaria transmission.

This report describes a 32-year-old male AIDS patient. He presented with a clinical picture characterized by severe headache, blurred vision, and fever that had lasted for 10 days. At admission, no remarkable neurologic abnormalities were observed. Cranial tomography showed a ring-enhanced lesion with edema and a mass effect in the right occipital lobe. The initial diagnosis was toxoplasmosis, and treatment of this was administered. However, 5 days later, the patient’s clinical status worsened and he died. The necropsy showed necrotizing and hemorrhagic encephalitis, with trophozoites similar to an amoeba species. Furthermore, the kidneys, adrenal glands, thyroid gland, and liver were also involved. The amoeba Balamuthia mandrillaris was identified by an immunofluorescence test.