Flor Ernestina Martinez-Espinosa

Chloroquine-Resistant Plasmodium vivax, Brazilian Amazon

To the Editor: Plasmodium vivax is the protozoan that causes the second most common form of malaria. Some resistant strains to chloroquine (CQ) occur in a few places in Asia and the Indo-Pacific Region (1–4). Although resistance of P. vivax to CQ has already been described in South America (5–7), there are limited data regarding this issue. CQ plus primaquine is the standard treatment for vivax malaria worldwide. Presently, this drug regimen exhibits satisfactory efficacy in the Brazilian Amazon. However, in recent years several treatment failures presumably related to CQ resistance, have been reported in the city of Manaus (Amazonas) where vivax malaria predominates (7). This observation warrants local attention despite these cases having no confirmation of CQ blood levels on the basis of the appearance of asexual parasites against CQ plus desethylchloroquine levels exceeding the minimally effective plasma concentration proposed for sensitive parasite strains (>10 ng/mL) (8), according to Pan American Health Organization recommendations (9). From September 2004 to February 2005, a 28-day in vivo test was conducted at the Foundation for Tropical Medicine of Amazonas (FMTAM) in Manaus, Brazil, to assess the efficacy of standard supervised CQ therapy. The test involved 166 volunteers with uncomplicated vivax malaria. Each volunteer was administered uncoated, scored, 150-mg CQ tablets (10 + 7.5 + 7.5 mg/kg at 24-hour intervals) (9). Primaquine was withheld until day 28 (dose regimen of 30 mg/day for 7 days). Among the 109 volunteers who completed the in vivo test, 19 had positive blood smears within the 28-day follow-up (1 on day 14, 3 on day 21, and 15 on day 28). All were required to undergo alternative therapy (mefloquine). Adequate CQ absorption was confirmed in these cases on day 2 with a mean ± SD CQ plasma concentration of 785.4 ± 800.1 ng/mL) (10) Suspected therapeutic failure (P. vivax CQ resistance) was confirmed in 11 (10.1%) of 109 persons with a mean isolated choloroquine plasma concentration >10 ng/mL (356.6 ± 296.1 ng/mL) (9). Desethylchloroquine levels in plasma were not measured. Previously, a CQ efficacy study demonstrated that 4.4% of those tested had CQ-resistant P. vivax (7). In comparison, the proportion of failures (10.1%) in the current study seems to be relevant; even though most of the P. vivax infections (98, 89.9%) were successfully evaluated and adequate clinical and parasitologic responses were obtained. Currently, the FMTAM Manaus Outpatient Clinic is detecting patients from different areas of the city who show parasitologic recurrences after correct treatment within 28 days of the routine clinical follow-up. This observation is an indirect indicator of the possible regional spread of P. vivax CQ-resistant strains (unpub. data). We believe our findings are important and merit the attention of local public health authorities. Considering the possibility of emerging underestimated P. vivax CQ resistance in Manaus, we feel it is essential to quickly clarify whether such documented resistance can copromote vivax malaria outbreaks in malaria-endemic areas within the Amazon.

Rosetting in Plasmodium vivax: A Cytoadhesion Phenotype Associated with Anaemia

Background Plasmodium vivax can potentially lead to life-threatening episodes but the mechanisms underlying severe disease remain poorly defined. Cytoadhesion of infected erythrocytes may contribute to P. vivax sequestration and organ injury although its physiological impact is still unknown. Here, we aimed to describe clinically-relevant cytoadhesive phenotypes of P. vivax isolates. Methodology/Principal findings Rosetting and adhesion to CSA, CD36, ICAM1, placental and brain cryosections were determined in P. vivax peripheral isolates from 12 pregnant women, 24 non-pregnant women and 23 men from Manaus (Brazil). P. falciparum co-infection was excluded by PCR and P. vivax isolates were genotyped by assessing the size polymorphism of microsatellites ms2, ms20 and msp1F3 through capillary electrophoresis of PCR products. P. vivax monoinfection was confirmed by PCR in 59 isolates, with 50 (85%) of them being single-clone infections. One P. vivax haplotype was more frequently found among pregnant women (33%) than in non-pregnant women (0%) and men (4%; p = 0.010). Rosetting was observed in 64% of the isolates, adhesion to CSA in 15%, to ICAM1 in 12% and to placental cryosections in 9%, being similar among pregnant and non-pregnant groups. Intensity of rosetting was higher among anaemic individuals compared to non-anaemic (p = 0.010) and decreased with increasing haematocrit (p = 0.033) and haemoglobin levels (p = 0.015). Conclusions/Significance P. vivax peripheral isolates from pregnant women do not exhibit a prominent adhesion to CSA, although other parasite phenotypes still unknown may increase the propagation of certain P. vivax clones observed among pregnant hosts. Rosetting is a frequent cytoadhesive phenotype in P. vivax infections that may contribute to the development of anaemia.

Expansão urbana e distribuição espacial da malária no município de Manaus, Estado do Amazonas

In the municipality of Manaus, intensification of the migratory process, along with precarious epidemiological and entomological surveillance, resulted in reintroduction of malaria transmission on the urban perimeter (in the eastern zone), in July 1988, after 13 years without any records of autochthonous disease. This study reports on the epidemiological situation relating to malaria and to the areas that were subjected to human actions (deforestation, human settlement, fish-rearing activity, etc) in Manaus, between 1986 and 2005. In this municipality, the population increase from 1986 to 2005 was 105.2%. This resulted from occupation of space, in the form of invasions and housing projects. From 2003, the increase in relation to 1986 was more than 2,000%. In these areas, there were increases in disease incidence. The annual parasitic index in the municipality ranged from low to medium risk and, between urban zones, it ranged from no risk to high risk. In the eastern, western and northern zones, which still contain areas with agricultural characteristics, there was greater receptivity and vulnerability to transmission.

Factors associated with tuberculosis treatment default in an endemic area of the Brazilian Amazon: a case control-study.

Setting Treatment default is a serious problem in tuberculosis control because it implies persistence of infection source, increased mortality, increased relapse rates and facilitates the development of resistant strains. Objective This study analyzed tuberculosis treatment default determinants in the Amazonas State to contribute in planning appropriate control interventions. Design Observational study with a retrospective cohort using Brazilian Disease Notification System data from 2005 to 2010. A nested case control study design was used. Patients defaulting from treatment were considered as ‘cases’ and those completing treatment as ‘controls’. In the analysis, 11,312 tuberculosis patients were included, 1,584 cases and 9,728 controls. Results Treatment default was observed to be associated to previous default (aOR 3.20; p<0.001), HIV positivity (aOR 1.62; p<0.001), alcoholism (aOR 1.51; p<0.001), low education level (aOR 1.35; p<0.001) and other co-morbidities (aOR 1.31; p = 0.05). Older patients (aOR 0.98; p = 0.001) and DOT (aOR 0,72; p<0.01) were considered as protective factor for default. Conclusions Associated factors should be considered in addressing care and policy actions to tuberculosis control. Information on disease and treatment should be intensified and appropriate to the level of education of the population, in order to promote adherence to treatment and counter the spread of multidrug resistance to anti-TB drugs.

Malária durante a gravidez: efeito sobre o curso da gestação na região amazônica

OBJETIVO: Estimar o efeito da malaria sobre o curso da gestacao em mulheres na regiao amazonica e investigar possiveis fatores de risco nessa populacao. METODOS: Este estudo transversal e parte de um projeto maior para estudar malaria e gravidez na regiao amazonica. Foram incluidas gestantes com malaria atendidas na Fundacao de Medicina Tropical do Amazonas que responderam a entrevistas estruturadas. Dados socio-economicos, comportamentais e clinicos foram levantados na primeira consulta relacionada a cada novo episodio de malaria na gestante. Todas as gestantes foram acompanhadas ao longo de sua gestacao. Foram considerados os seguintes fatores de risco para alteracoes no curso da gestacao: idade materna menor do que 20 anos, primeira gestacao, primeira infeccao malarica e especie de plasmodio infectante. RESULTADOS: Foram avaliados 535 episodios de malaria em 417 gestantes, sendo 20,56 por cento causados pelo P. falciparum, 78,69 por cento pelo P. vivax e 0,75 por cento pela associacao dos dois parasitas. Alteracao no curso da gestacao foi um evento muito frequente (26,2 por cento). Ameaca de aborto ocorreu em 49 casos (25,5 por cento), aborto em dois (1,0 por cento), ameaca de parto prematuro em 74 (25,1 por cento) e parto prematuro em tres (1,0 por cento). Ser primigesta e adolescente apresentou associacao estatisticamente significativa com ameaca de parto prematuro e abortamento. CONCLUSAO: A alteracao no curso da gestacao foi um evento muito frequente durante o episodio agudo de malaria, embora a interrupcao da gestacao tenha tido baixa ocorrencia em nossa casuistica. Os resultados nao evidenciaram um fator de risco de destaque, sugerindo que qualquer gestante pode apresentar ameaca de interrupcao ou interrupcao da gestacao na vigencia de episodio agudo de malaria.(AU)

Prevalence of infection for HIV, HTLV, HBV and of syphilis and chlamydia in pregnant women in a tertiary health unit in the western Brazilian Amazon region

PURPOSE to estimate the prevalence infection of human immunodeficiency virus (HIV), human T-cell lymphotropic vírus (HTLV), hepatitis B virus (HBV), Chlamydia trachomatis (C. trachomatis) and syphilis in pregnant women, as well as risk factors associated with these infections, in Fundação de Medicina Tropical do Amazonas (FMTAM). METHODS a cross-sectional study was carried including 674 pregnant women consecutively attended of the spontaneous demand of FMTAM between March and September 2008. Demographic, epidemiologic, socioeconomic, clinical and obstetric information have been collected through specific questionnaires. Patients had blood sample collected by peripheral venous for accomplishment of serological tests of HIV, HTLV, HBV and syphilis. Cervical secretion sample has been collected for C. trachomatis antigens detection test. The Odds Ratio has been used to evaluate risk factors associated to infections. Statistical analysis has been done with the t-Student, chi2 and Fishers exact tests. RESULTS the average age was 23.9 years old (SD 6.3). The observed prevalence was 0.6% to infection by HIV; 0.7% by HBsAg; 1.0% of syphilis and 2.7% by C. trachomatis. All the samples went negatives to HTLV. There were no variables associated with infection by HIV, HBV and syphilis. Significative statistically association was observed between pregnant woman with age under 20 years and of first pregnancy with C. trachomatis infection. CONCLUSIONS the study evidenced that the prevalence infection by HIV in pregnant women assisted in FMTAM is similar to the values described in the Brazilian literature, while the prevalence by HTLV, HBV, syphilis and C. trachomatis in the studied population are below found by other authors. The main risk factor for the infection by C. trachomatis was being under 20 years old.

Malária em mulheres de idade de 10 a 49 anos, segundo o SIVEP- Malária, Manaus, Amazonas, 2003-2006

INTRODUCTION The SIVEP-Malaria Epidemiological Surveillance Information System has been in use for notification of malaria cases diagnosed in Brazil since 2003. This study analyzed malaria cases notified among women aged 10 to 49 years between 2003 and 2006, according to the presence or absence of pregnancy. METHODS Authorization to evaluate the data was requested from the Health Surveillance Foundation (FVS). RESULTS Over this period, 13,308 malaria cases were notified, of which 815 (6.1%) were among pregnant women. There was a gradual decrease in the absolute numbers of cases among pregnant and non-pregnant women. Regarding species, 14.3% of the notified cases were caused by Plasmodium falciparum; 85% by Plasmodium vivax and 0.6 % by both of them. The frequency of Plasmodium falciparum infection was greater among pregnant women than among non-pregnant women (p > 0.05). Although most of the cases lived in the eastern zone of the city, the western zone appeared to be the likely location of infection in 39% of the cases. Endemic peaks of malaria in July and August were observed among the non-pregnant women in all four years analyzed. CONCLUSIONS The data showed that SIVEP-Malaria was an important tool for determining the distribution of malaria cases and that it should be used for controlling the endemic disease. However, the data from its first four years of operation showed that the quality was compromised by data entry failures, using the field of notification of pregnancy as an example.

Effects of Vivax Malaria Acquired Before 20 Weeks of Pregnancy on Subsequent Changes in Fetal Growth

The resistance index (RI), pulsatility index (PI), fetal biometry, fetal heart rate (FHR), placental thickness, and hemoglobin levels were compared in 30 Plasmodium vivax-infected women between 14 and 20 weeks of pregnancy and a control group. Evaluations were performed at the moment of the malaria diagnosis and 26 weeks of pregnancy. The malaria group had lower levels of hemoglobin and greater placental thickness in both assessments, higher FHR in the first evaluation, and lower values on fetal biometry in the second assessment. There were no differences when comparing RI and PI on umbilical arteries between the two groups. Birth weight and height were lower in newborns in the malaria group than the control group. The results suggest that P. vivax infections at an earlier gestational age do not affect umbilical arteries blood flow but do affect fetal biometry in the second trimester of pregnancy and at birth.

Burden and impact of Plasmodium vivax in pregnancy: A multi-centre prospective observational study

Background Despite that over 90 million pregnancies are at risk of Plasmodium vivax infection annually, little is known about the epidemiology and impact of the infection in pregnancy. Methodology and principal findings We undertook a health facility-based prospective observational study in pregnant women from Guatemala (GT), Colombia (CO), Brazil (BR), India (IN) and Papua New Guinea PNG). Malaria and anemia were determined during pregnancy and fetal outcomes assessed at delivery. A total of 9388 women were enrolled at antennal care (ANC), of whom 53% (4957) were followed until delivery. Prevalence of P. vivax monoinfection in maternal blood at delivery was 0.4% (20/4461) by microscopy [GT 0.1%, CO 0.5%, BR 0.1%, IN 0.2%, PNG 1.2%] and 7% (104/1488) by PCR. P. falciparum monoinfection was found in 0.5% (22/4463) of women by microscopy [GT 0%, CO 0.5%, BR 0%, IN 0%, PNG 2%]. P. vivax infection was observed in 0.4% (14/3725) of placentas examined by microscopy and in 3.7% (19/508) by PCR. P. vivax in newborn blood was detected in 0.02% (1/4302) of samples examined by microscopy [in cord blood; 0.05% (2/4040) by microscopy, and 2.6% (13/497) by PCR]. Clinical P. vivax infection was associated with increased risk of maternal anemia (Odds Ratio-OR, 5.48, [95% CI 1.83–16.41]; p = 0.009), while submicroscopic vivax infection was not associated with increased risk of moderate-severe anemia (Hb<8g/dL) (OR, 1.16, [95% CI 0.52–2.59]; p = 0.717), or low birth weight (<2500g) (OR, 0.52, [95% CI, 0.23–1.16]; p = 0.110). Conclusions In this multicenter study, the prevalence of P. vivax infection in pregnancy by microscopy was overall low across all endemic study sites; however, molecular methods revealed a significant number of submicroscopic infections. Clinical vivax infection in pregnancy was associated with maternal anemia, which may be deleterious for infant’s health. These results may help to guide maternal health programs in settings where vivax malaria is endemic; they also highlight the need of addressing a vulnerable population such as pregnant women while embracing malaria elimination in endemic countries.

Evaluation of new strategies for the diagnosis of tuberculosis among pediatric contacts of tuberculosis patients.

Background: In young children, underdiagnosis and diagnostic delay have an adverse effect on morbidity and mortality of tuberculosis (TB). This study evaluated new strategies for early TB diagnosis using an outpatient protocol in children between 0 and 5 years of age, with a recent household TB contact. Methods: Case recruitment was performed in Manaus, Amazonas, Brazil, from 2008 to 2009. Epidemiologic and clinical data, tuberculin test, chest radiograph and 2 induced sputum respiratory samples from each participant were obtained. Laboratory diagnosis was based on Lowenstein-Jensen (LJ) culture, mycobacteria growth indicator tube (MGIT) and polymerase chain reaction. We conducted a study of comparison of diagnostic tests and a study of cases and controls to identify the clinical characteristics of the population with positive culture and polymerase chain reaction results. Results: A total of 102 children were evaluated. Thirty-two fulfilled criteria of suspicion of TB. MGIT was more sensitive (P = 0.035) and faster (P < 0.001) than LJ. Clinical score, MGIT, LJ and polymerase chain reaction presented no concordance or slight concordance. A positive MGIT culture was only associated with a strong tuberculin test reaction (P = 0.026). The combination of MGIT with the clinical score allowed the diagnosis of 33% more cases with little or no symptomatology compared with the exclusive use of the clinical classification. Conclusions: The sensitivity and speed of MGIT demonstrate the utility of liquid cultures for the diagnosis in children. Furthermore, these results suggest that the use of MGIT in children presenting recent household TB contact and a strong tuberculin test reaction may be a strategy to improve early TB diagnosis.