Etiologies, Risk Factors and Impact of Severe Diarrhea in the Under-Fives in Moramanga and Antananarivo, Madagascar.

BACKGROUND: Diarrheal disease remains a leading cause of death in children in low-income countries. We investigated the etiology, risk factors and effects on nutritional status of severe diarrhea in children from two districts in Madagascar. METHODS: We performed a matched case-control study in 2011 to 2014, on children under the age of five years from Moramanga and Antananarivo. The cases were children hospitalized for severe diarrhea and the controls were children without diarrhea selected at random from the community. Stool samples were collected from both groups. Anthropometric measurements were made during follow-up visits about one and two months after enrolment. RESULTS: We enrolled 199 cases and 199 controls. Rotavirus infection was the most frequently detected cause of diarrhea. It was strongly associated with severe diarrhea (OR: 58.3; 95% CI: 7.7-439.9), accounting for 42.4% (95% CI: 37.6-43.1) of severe diarrhea cases. At the household level, possession of cattle (OR = 0.3; 95% CI: 0.1-0.6) and living in a house with electricity (OR = 0.4; 95% CI: 0.2-0.8) were protective factors. The presence of garbage around the house was a risk factor for severe diarrhea (OR = 3.2; 95% CI: 1.9-5.4). We found no significant association between severe diarrhea and the nutritional status of the children at follow-up visits, but evident wasting at enrolment was associated with a higher risk of severe diarrhea (OR = 9; 95% CI: 4.5-17.9). CONCLUSIONS: Severe childhood diarrhea is mostly caused by rotavirus infection. An anti-rotavirus vaccine has already been introduced in Madagascar and should be promoted more widely. However, post-licensing surveillance is required. Interventions to improve the nutritional status of children, preventive measures focused on household and personal hygiene and nutritional rehabilitation during severe diarrheal disease should be reinforced.

Campylobacter infection in a cohort of rural children in Moramanga, Madagascar.

BACKGROUND: Campylobacter infection is the most common cause of bacterial gastroenteritis in developing countries, including Madagascar. Reports of pathogenicity have not been consistent and repeated exposures over time seem to lead to the development of protective immunity in developing areas. We conducted this study to support evidence for these hypotheses by exploring the association between infection and age, the reoccurrence of infection and the pathogenicity of Campylobacter. METHODS: We carried out a community-based longitudinal study of children under the age of 24 months in two rural villages in Moramanga, Madagascar. Children were visited twice a week and a stool specimen was collected in cases of diarrhoea. Stools specimens were collected bimonthly from all children enrolled, regardless of symptoms. Children were followed-up until the age of 36 months. RESULTS: Between January 2010 and May 31st 2012, 508 children were included in the cohort. We detected 319 episodes of Campylobacter infection in total, and 43.3% (n = 220) of the children had at least one episode of intestinal Campylobacter infection. The rate of Campylobacter isolation from stool specimens was 9.3%. The annual incidence rate for symptomatic Campylobacter infection was 0.05 episodes/child. The probability of Campylobacter infection was highest between the ages of six and 23 months. Taking children under six months of age as the reference group, the age-specific odds ratio for the association was 5.0 (95% CI: 2.9-8.6) for children aged six to 11 months, 5.7 (95% CI: 3.3-10.0) for children aged 12 to 17 months and 3.3 (95% CI: 1.8-5.8) for children aged 18 to 23 months. A second episode of infection occurred 63 days after the first episode in children with primary infections, and after 137 days in children with multiple infections (p < 0.01). First episodes of Campylobacter infection were associated with diarrhoea (odds ratio = 16.1; 95% CI: 1.8-140.8). CONCLUSION: Our findings suggest that protective immunity to Campylobacter may be acquired over time, following repeated exposures. However, Campylobacter infection prevention measures should be reinforced in the first year of life, as this age seems to be associated with the highest risk of diarrhoea during Campylobacter infection.

Case-control study of the etiology of infant diarrheal disease in 14 districts in Madagascar.

BACKGROUND: Acute diarrhea is a major cause of childhood morbidity and mortality worldwide. Its microbiological causes and clinico-epidemiological aspects were examined during the rainy seasons from 2008 to 2009 in 14 districts in Madagascar. METHODS: Stool specimens of 2196 children with acute diarrhea and 496 healthy children were collected in a community setting. Intestinal parasites were diagnosed by microscopy and bacteria by culturing methods. Rota-, astro and adenoviruses were identified using commercially available ELISA kits and rotaviruses were confirmed using reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Intestinal microorganisms were isolated from 54.6% of diarrheal patients and 45.9% of healthy subjects (p = <0.01). The most common pathogens in diarrheic patients were intestinal parasites (36.5%). Campylobacter spp. and Rotavirus were detected in 9.7% and 6.7% of diarrheic patients. The detection rates of Entamoeba histolytica, Trichomonas intestinalis and Giardia lamblia were much greater in diarrheal patients than in non diarrheal subjects (odds ratios of 5.1, 3.2, 1.7 respectively). The abundance of other enteropathogens among the non diarrheal group may indicate prolonged excretion or limited pathogenicity. CONCLUSION: In developing countries, where the lack of laboratory capacities is great, cross sectional studies of enteropathogens and their spatial distribution, including diarrheal and non diarrheal subjects, are interesting tools in order to advise regional policies on treatment and diarrheic patient management.

Longitudinal survey of malaria morbidity over 10 years in Saharevo (Madagascar): further lessons for strengthening malaria control.

BACKGROUND: Madagascar has been known for having bio-geo-ecological diversity which is reflected by a complex malaria epidemiology ranging from hyperendemic to malaria-free areas. Malaria-related attacks and infection are frequently recorded both in children and adults living in areas of low malaria transmission. To integrate this variability in the national malaria control policy, extensive epidemiological studies are required to up-date previous records and adjust strategies. METHODS: A longitudinal malaria survey was conducted from July 1996 to June 2005 among an average cohort of 214 villagers in Saharevo, located at 900 m above the sea. Saharevo is a typical eastern foothill site at the junction between a costal wet tropical area (equatorial malaria pattern) and a drier high-altitude area (low malaria transmission). RESULTS: Passive and active malaria detection revealed that malaria transmission in Saharevo follows an abrupt seasonal variation. Interestingly, malaria was confirmed in 45% (1,271/2,794) of malaria-presumed fevers seen at the health centre. All four Plasmodia that infect humans were also found: Plasmodium falciparum; Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. Half of the malaria-presumed fevers could be confirmed over the season with the highest malaria transmission level, although less than a quarter in lower transmission time, highlighting the importance of diagnosis prior to treatment intake. P. falciparum malaria has been predominant (98%). The high prevalence of P. falciparum malaria affects more particularly under 10 years old children in both symptomatic and asymptomatic contexts. Children between two and four years of age experienced an average of 2.6 malaria attacks with P. falciparum per annum. Moreover, estimated incidence of P. falciparum malaria tends to show that half of the attacks (15 attacks) risk to occur during the first 10 years of life for a 60-year-old adult who would have experienced 32 malaria attacks. CONCLUSION: The incidence of malaria decreased slightly with age but remained important among children and adults in Saharevo. These results support that a premunition against malaria is slowly acquired until adolescence. However, this claims for a weak premunition among villagers in Saharevo and by extension in the whole eastern foothill area of Madagascar. While the Malagasy government turns towards malaria elimination plans nowadays, choices and expectations to up-date and adapt malaria control strategies in the foothill areas are discussed in this paper.

Spatial clustering of pulmonary tuberculosis and impact of the care factors in Antananarivo City.

OBJECTIVE: To analyse the spatial distribution of TB in Antananarivo and investigate risk factors. METHODS: Pulmonary TB data were collected through passive case detection in 16 Tuberculosis Diagnostic and Treatment Centers (DTC). New cases listed in the DTC registers from 2004 to 2006 and resident in Antananarivo were included in the study. Field workers of the national control program conducted household surveys of all cases to collect complementary information on socio-economic status. TB spatial organization and risk factors were analysed over two successive periods (August 2004-July 2005, August 2005-July 2006); analysis was done at the neighbourhood level, by searching for spatial clusters with the spatial scan test. RESULTS: 3075 pulmonary tuberculosis new cases were reported in Antananarivo from 2004 to 2006. The average incidence during the study period was 74/100,000 inhabitants (95% CI: 64.9-84.5). Spatial clusters occurred in three of the six arrondissements (districts) of the city (192 neighbourhoods). A decrease in clustering was observed with movement towards the southern neighbourhood. CONCLUSION: The change in risk of a TB cluster was linked to socio-economic (e.g. household amount of ownership of tap water) and patient care factors (e.g. patients lost to follow-up).

Lessons learnt from the six decades of chloroquine use (1945-2005) to control malaria in Madagascar.

On the island of Madagascar, malaria was nearly eradicated in the highland areas and malaria transmission was significantly decreased in the coastal areas between the 1940s and 1960s. The success of the control programme was primarily achieved by chloroquine (CQ) use at the community level. CQ was administered to children weekly on a routine basis for malaria prevention in the period 1949-1971. Then, the Malagasy Government was unable to financially support the malaria control programme. The malarial situation worsened in the 1980s, partly due to the shortage of CQ. A malaria epidemic occurred. To deal with this epidemic, massive CQ use was urgently adopted. CQ has remained the first-line drug since 1945, but the prevalence of Plasmodium falciparum carrying the pfcrt mutation associated with CQ resistance remains low (<3%). However, late CQ treatment failure has been reported and the prevalence may be as high as 35% during 14-day follow-up since 1982. In an effort to eliminate malaria as a public health problem, a shift from CQ to artemisinin-based combination therapy has been advocated by a new policy since December 2005. A change of this kind is complex and the lessons learnt from the six decades of CQ use are of the utmost importance to achieve malaria control.

Assessment of the efficacy of antimalarial drugs recommended by the National Malaria Control Programme in Madagascar: up-dated baseline data from randomized and multi-site clinical trials.

BACKGROUND: In order to improve the monitoring of the antimalarial drug resistance in Madagascar, a new national network based on eight sentinel sites was set up. In 2006/2007, a multi-site randomized clinical trial was designed to assess the therapeutic efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP), amodiaquine (AQ) and artesunate plus amodiaquine combination (ASAQ), the antimalarial therapies recommended by the National Malaria Control Programme (NMCP). METHODS: Children between six months and 15 years of age, with uncomplicated falciparum malaria, were enrolled. Primary endpoints were the day-14 and day-28 risks of parasitological failure, either unadjusted or adjusted by genotyping. Risks of clinical and parasitological treatment failure after adjustment by genotyping were estimated using Kaplan-Meier survival analysis. Secondary outcomes included fever clearance, parasite clearance, change in haemoglobin levels between Day 0 and the last day of follow-up, and the incidence of adverse events. RESULTS: A total of 1,347 of 1,434 patients (93.9%) completed treatment and follow-up to day 28. All treatment regimens, except for the chloroquine (CQ) treatment group, resulted in clinical cure rates above 97.6% by day-14 and 96.7% by day-28 (adjusted by genotyping). Parasite and fever clearance was more rapid with artesunate plus amodiaquine, but the extent of haematological recovery on day-28 did not differ significantly between the four groups. No severe side-effects were observed during the follow-up period. CONCLUSION: These findings (i) constitute an up-dated baseline data on the efficacy of antimalarial drugs recommended by the NMCP, (ii) show that antimalarial drug resistance remains low in Madagascar, except for CQ, compared to the bordering countries in the Indian Ocean region such as the Comoros Archipelago and (iii) support the current policy of ASAQ as the first-line treatment in uncomplicated falciparum malaria.

[Therapeutic efficacy of amodiaquine against uncomplicated malaria in Madagascar]. / Efficacité thérapeutique de l'amodiaquine dans le traitement du paludisme à Madagascar.

We report the results of a preliminary study carried out in 2004 to assess the therapeutic efficacy of amodiaquine in patients aged 5 years or older in Sainte Marie and Saharevo, in eastern Madagascar. Consenting patients with uncomplicated Plasmodium falciparum malaria were enrolled and followed up for 14 days: 46 were treated with chloroquine (25 mg/kg for 3 days) and 25 with amodiaquine (30 mg/kg for 3 days). No early treatment failure was observed with chloroquine but the overall late treatment failure rate was 17.4% (4.4% late clinical failures and 13% late parasitological failures). Amodiaquine was not associated with any cases of treatment failure through day 14. These preliminary results indicate that compared with chloroquine, amodiaquine is significantly more effective in treating uncomplicated malaria in our study sites. Amodiaquine is therefore recommended in combination with other antimalarial drugs. To generate useful data for decisions about drug use, further studies based on the WHO protocol should assess the clinical efficacy and also the safety of amodiaquine-containing antimalarial drugs in different regions in Madagascar, especially among children under 5 years.

[Rapid diagnostic test for malaria: preliminary study in Madagascar in 2003]. / Utilisation du test de diagnostic rapide du paludisme à Madagascar: étude préliminaire en 2003.

This study was conducted in 2003 as part of the training of laboratory technicians in the use of rapid diagnostic tests (RDTs) for malaria and to evaluate these tests in Madagascar in field conditions for the first time. Two types of RDT were used separately. The dipstick (Optimal-I) that detects circulating pLDH was tested in 168 patients with clinically suspected malaria (fever or recent history of fever) at primary health centers. Microscopy confirmed malaria in 93/168 (55.4%) cases. Monoparasitic P. falciparum infection was identified in 86/93, P. malariae in 3/93, P. vivax in 3/93 and P. ovale in 1/93. A positive Optimal-I test was a highly sensitive indicator of P. falciparum infection with parasitemia exceeding 500 trophozoites/mul (sensitivity of 97.2%; with a specificity of 100%); it also confirmed 6/7 cases of non-P. falciparum malaria. A community malaria survey used the Malaria Hexagon dipstick (detecting P. falciparum-specific HRP2) for 273 patients: 17 (6.2%) RDT tests were positive, and 16 (5.9%) microscopic tests. Although this dipstick did not detect the only case of infection with P. vivax, its specificity was 100% for detection of P. falciparum infection. Installing microscopes and qualified microscopists in the health centers of the one hundred and eleven districts in Madagascar would be extremely difficult, but our results show that RDT is an effective alternative diagnostic tool for daily use as well as for sporadic malaria epidemics. The revised antimalarial treatment policy, involving a drug ten to twenty times more expensive than chloroquine, demonstrates the need to improve malaria diagnosis: presumptive treatment has become prohibitively expensive. RDT can be used to improve malaria case management at the primary heath centers in Madagascar. We discuss the choice of RDTs.

Randomized clinical trial of artemisinin versus non-artemisinin combination therapy for uncomplicated falciparum malaria in Madagascar.

BACKGROUND: Data concerning antimalarial combination treatment for uncomplicated malaria in Madagascar are largely lacking. Randomized clinical trial was designed to assess therapeutic efficacies of chloroquine (CQ), amodiaquine (AQ), sulphadoxine-pyrimethamine (SP), amodiaquine plus sulphadoxine-pyrimethamine combination (AQ+SP) and artesunate plus amodiaquine combination (AQ+AS). METHODS: 287 children between 6 months and 15 years of age, with uncomplicated falciparum malaria, were enrolled in the study. Primary endpoints were the day-14 and day-28 risks of parasitological failure, either unadjusted or adjusted by genotyping. RESULTS: All treatment regimens, except for CQ treatment, gave clinical cure rates above 97% by day-14 and 92% by day-28 (PCR-corrected). AQ+SP was as effective as AQ+AS. The risk of new infection within the month after therapy was generally higher for AQ+AS than AQ+SP. CONCLUSION: These findings show that the inexpensive and widely available combination AQ+SP may be valuable in for the treatment of uncomplicated malaria in Madagascar and could have an important role in this country, where much of the drugs administered go to patients who do not have malaria.

Which malaria rapid test for Madagascar? Field and laboratory evaluation of three tests and expert microscopy of samples from suspected malaria patients in Madagascar.

Field and laboratory studies were carried out in October and November 2005 to provide a comparative evaluation of the performance of three rapid malaria detection tests, two of which were recently introduced (the CareStart Malaria test and the SD Malaria Antigen Bioline test) and the well-known OptiMAL-IT test. Compared with microscopy, the sensitivity of the three tests to detect Plasmodium falciparum malaria was 97% for the CareStart Malaria test, 89.4% for the SD Malaria Antigen Bioline test, and 92.6% for the OptiMAL-IT test. The three tests were less sensitive in detecting non-P. falciparum infections, and the sensitivity decreased at levels of parasitemiaor=100 parasites/microL.

Susceptibility of Plasmodium falciparum to the drugs used to treat severe malaria (quinine) and to prevent malaria (mefloquine, cycloguanil) in Comoros Union and Madagascar.

OBJECTIVES: To monitor the sensitivity of Plasmodium falciparum to the drugs used to treat severe malaria and to prevent malaria in Comoros and Madagascar. DESIGN: We used the in vitro isotopic method to test the sensitivity of P. falciparum to quinine, mefloquine and cycloguanil. RESULTS: We tested fresh isolates of P. falciparum, collected from patients living in urban, suburban and rural areas and suffering from uncomplicated malaria in 2001, against at least one of the antimalarials cited above. In both countries all of the successfully tested isolates were sensitive to quinine (N = 243) and to cycloguanil (N = 67). The mean IC50 ranged from 85.7 to 133.7 nM for quinine. For cycloguanil, the mean IC50 ranged from 1.4 to 20.2 nM and the highest IC50 value (102.5 nM) was recorded in Comoros. Only 0.9% (1/110) of the informative isolates from Madagascar were mefloquine-resistant (0/18 in Comoros). The mefloquine mean IC50s were 8.2 nM, 14.1 nM and 11.6 nM respectively in the rural, suburban and urban areas of Madagascar, and 5.9 nM in Comoros. A positive correlation was found between quinine and mefloquine IC50s (N = 127, r = 0.48, p < 10(-6)), but in vitro mefloquine was 6-16 times more potent than quinine. No correlation was noticed between the activities of quinine and cycloguanil or between the activities of mefloquine and cycloguanil. CONCLUSION: We therefore advocate the use of a full-course regimen of quinine, as recommended by the World Health Organisation (WHO), to treat above all severe malaria in Madagascar and Comoros. Our results also demonstrate that the use of mefloquine- and cycloguanil-based antimalarials is still justified to prevent malaria in both countries, mainly in the case of travellers.