Iron Fortified Complementary Foods Containing a Mixture of Sodium Iron EDTA with Either Ferrous Fumarate or Ferric Pyrophosphate Reduce Iron Deficiency Anemia in 12- to 36-Month-Old Children in a Malaria Endemic Setting: A Secondary Analysis of a Cluster-Randomized Controlled Trial.

Iron deficiency anemia (IDA) is a major public health problem in sub-Saharan Africa. The efficacy of iron fortification against IDA is uncertain in malaria-endemic settings. The objective of this study was to evaluate the efficacy of a complementary food (CF) fortified with sodium iron EDTA (NaFeEDTA) plus either ferrous fumarate (FeFum) or ferric pyrophosphate (FePP) to combat IDA in preschool-age children in a highly malaria endemic region. This is a secondary analysis of a nine-month cluster-randomized controlled trial conducted in south-central Côte d'Ivoire. 378 children aged 12-36 months were randomly assigned to no food intervention (n = 125; control group), CF fortified with 2 mg NaFeEDTA plus 3.8 mg FeFum for six days/week (n = 126; FeFum group), and CF fortified with 2 mg NaFeEDTA and 3.8 mg FePP for six days/week (n = 127; FePP group). The outcome measures were hemoglobin (Hb), plasma ferritin (PF), iron deficiency (PF < 30 µg/L), and anemia (Hb < 11.0 g/dL). Data were analyzed with random-effect models and PF was adjusted for inflammation. The prevalence of Plasmodium falciparum infection and inflammation during the study were 44-66%, and 57-76%, respectively. There was a significant time by treatment interaction on IDA (p = 0.028) and a borderline significant time by treatment interaction on iron deficiency with or without anemia (p = 0.068). IDA prevalence sharply decreased in the FeFum (32.8% to 1.2%, p < 0.001) and FePP group (23.6% to 3.4%, p < 0.001). However, there was no significant time by treatment interaction on Hb or total anemia. These data indicate that, despite the high endemicity of malaria and elevated inflammation biomarkers (C-reactive protein or α-1-acid-glycoprotein), IDA was markedly reduced by provision of iron fortified CF to preschool-age children for 9 months, with no significant differences between a combination of NaFeEDTA with FeFum or NaFeEDTA with FePP. However, there was no overall effect on anemia, suggesting most of the anemia in this setting is not due to ID. This trial is registered at clinicaltrials.gov (NCT01634945).

Epidemiology of malaria in the Taabo health and demographic surveillance system, south-central Côte d'Ivoire.

BACKGROUND: A deep understanding of the local epidemiology of malaria is essential for the design and implementation of setting-specific control and elimination efforts. In Côte d'Ivoire, new initiatives are underway to reduce the burden of malaria, which requires high-quality longitudinal data. The epidemiology of malaria was studied in the Taabo health and demographic surveillance system (HDSS) in south-central Côte d'Ivoire and implications for control are discussed. METHODS: Two cross-sectional surveys were carried out in the rainy season of June/July in 2010 and 2011. Inhabitants of approximately 7% of randomly selected households in the Taabo HDSS were invited to participate. People were clinically examined, ear temperature was measured and spleen size determined. Finger-prick blood samples were collected and subjected to a rapid diagnostic test (RDT). Additionally, thick and thin blood films were prepared on microscope slides and diagnosed under a microscope for Plasmodium infection and parasitaemia. Haemoglobin (Hb) level was determined using a HemoCue device. RESULTS: A total of 1187 and 1264 people in 2010 and 2011, respectively, had complete data records. The prevalence of Plasmodium infection was 46.0% in 2010 and 56.6% in 2011, owing to a statistically significant difference (p < 0.05). Males showed a higher Plasmodium infection prevalence than females (49.6 and 62.8% versus 42.6 and 51.2%; respectively, in 2010 and 2011; both p < 0.05). The highest malaria prevalence was observed among infants and young children (aged ≤9 years). The risk of Plasmodium infection was significantly higher in villages compared to small hamlets and urban settings (p < 0.05). Fever, Hb level and splenomegaly were associated with parasitaemia. CONCLUSION: Malaria is highly endemic in the Taabo HDSS in south-central Côte d'Ivoire with considerable spatial heterogeneity of Plasmodium infection. There is a pressing need to scale-up control interventions against malaria.

The effect of iron-fortified complementary food and intermittent preventive treatment of malaria on anaemia in 12- to 36-month-old children: a cluster-randomised controlled trial.

BACKGROUND: Iron deficiency (ID) and malaria co-exist in tropical regions and both contribute to high rates of anaemia in young children. It is unclear whether iron fortification combined with intermittent preventive treatment (IPT) of malaria would be an efficacious strategy for reducing anaemia in young children. METHODS: A 9-month cluster-randomised, single-blinded, placebo-controlled intervention trial was carried out in children aged 12-36 months in south-central Côte d'Ivoire, an area of intense and perennial malaria transmission. The study groups were: group 1: normal diet and IPT-placebo (n = 125); group 2: consumption of porridge, an iron-fortified complementary food (CF) with optimised composition providing 2 mg iron as NaFeEDTA and 3.8 mg iron as ferrous fumarate 6 days per week (CF-FeFum) and IPT-placebo (n = 126); group 3: IPT of malaria at 3-month intervals, using sulfadoxine-pyrimethamine and amodiaquine and no dietary intervention (n = 127); group 4: both CF-FeFum and IPT (n = 124); and group 5: consumption of porridge, an iron-fortified CF with the composition currently on the Ivorian market providing 2 mg iron as NaFeEDTA and 3.8 mg iron as ferric pyrophosphate 6 days per week (CF-FePP) and IPT-placebo (n = 127). The primary outcome was haemoglobin (Hb) concentration. Linear and logistic regression mixed-effect models were used for the comparison of the five study groups, and a 2 × 2 factorial analysis was used to assess treatment interactions of CF-FeFum and IPT (study groups 1-4). RESULTS: After 9 months, the Hb concentration increased in all groups to a similar extent with no statistically significant difference between groups. In the 2 × 2 factorial analysis after 9 months, no treatment interaction was found on Hb (P = 0.89). The adjusted differences in Hb were 0.24 g/dl (95 % CI -0.10 to 0.59; P = 0.16) in children receiving IPT and -0.08 g/dl (95 % CI -0.42 to 0.26; P = 0.65) in children receiving CF-FeFum. At baseline, anaemia (Hb <11.0 g/dl) was 82.1 %. After 9 months, IPT decreased the odds of anaemia (odds ratio [OR], 0.46 [95 % CI 0.23-0.91]; P = 0.023), whereas iron-fortified CF did not (OR, 0.85 [95 % CI 0.43-1.68]; P = 0.68), although ID (plasma ferritin <30 µg/l) was decreased markedly in children receiving iron fortified CF (OR, 0.19 [95 % CI 0.09-0.40]; P < 0.001). CONCLUSIONS: IPT alone only modestly decreased anaemia, but neither IPT nor iron fortified CF significantly improved Hb concentration after 9 months. Additionally, IPT did not augment the effect of the iron fortified CF. CF fortified with highly bioavailable iron improved iron status but not Hb concentration, despite three-monthly IPT of malaria. Thus, further research is necessary to develop effective combination strategies to prevent and treat anaemia in malaria endemic regions. TRIAL REGISTRATION: http://www.clinicaltrials.gov ; identifier NCT01634945; registered on July 3, 2012.

Causes of death in the Taabo health and demographic surveillance system, Côte d'Ivoire, from 2009 to 2011.

BACKGROUND: Current vital statistics from governmental institutions in Côte d'Ivoire are incomplete. This problem is particularly notable for remote rural areas that have limited access to the health system. OBJECTIVE: To record all deaths from 2009 to 2011 and to identify the leading causes of death in the Taabo health and demographic surveillance system (HDSS) in south-central Côte d'Ivoire. DESIGN: Deaths recorded in the first 3 years of operation of the Taabo HDSS were investigated by verbal autopsy (VA), using the InterVA-4 model. InterVA-4 is based on the World Health Organization 2012 VA tool in terms of input indicators and categories of causes of death. RESULTS: Overall, 948 deaths were recorded, of which 236 (24.9%) had incomplete VA data. Among the 712 deaths analyzed, communicable diseases represented the leading causes (58.9%), with most deaths attributed to malaria (n=129), acute respiratory tract infections (n=110), HIV/AIDS (n=80), and pulmonary tuberculosis (n=46). Non-communicable diseases accounted for 18.9% of the deaths and included mainly acute abdomen (n=38), unspecified cardiac diseases (n=15), and digestive neoplasms (n=13). Maternal and neonatal conditions accounted for 8.3% of deaths, primarily pneumonia (n=19) and birth asphyxia (n=16) in newborns. Among the 3.8% of deaths linked to trauma and injury, the main causes were assault (n=6), accidental drowning (n=4), contact with venomous plants/animals (n=4), and traffic-related accidents (n=4). No clear causes were determined in 10.0% of the analyzed deaths. CONCLUSIONS: Communicable diseases remain the predominant cause of death in rural Côte d'Ivoire. Based on these findings, measures are now being implemented in the Taabo HDSS. It will be interesting to monitor patterns of mortality and causes of death in the face of rapid demographic and epidemiological transitions in this part of West Africa.

In Ivorian school-age children, infection with hookworm does not reduce dietary iron absorption or systemic iron utilization, whereas afebrile Plasmodium falciparum infection reduces iron absorption by half.

BACKGROUND: In sub-Saharan Africa, parasitic diseases and low bioavailable iron intake are major causes of anemia. Anemia results from inflammation, preventing iron recycling and decreasing dietary iron absorption. Hookworm, Plasmodium, and Schistosoma infections contribute to anemia, but their influence on dietary iron absorption and recycling is unknown. OBJECTIVE: The objective was to measure inflammation biomarkers, hepcidin, iron absorption, and utilization pre- and posttreatment in children with afebrile malaria, hookworm, and Schistosoma haematobium infection. DESIGN: Ivorian children aged 11-17 y with afebrile Plasmodium falciparum (n = 17), hookworm (n = 16), or S. haematobium infection (n = 8) consumed a syrup containing 3 mg 57Fe as ferrous sulfate and received an intravenous infusion of 50 µg 58Fe as ferrous citrate. Children were treated for their respective infection, and the iron studies were repeated 4 wk later. Iron and inflammation biomarkers and hepcidin were measured. RESULTS: Geometric mean iron absorptions in the afebrile malaria and hookworm groups were 12.9% and 32.2% (P < 0.001) before treatment and 23.6% and 30.0% (P = 0.113) after treatment, respectively. Treatment of afebrile malaria reduced inflammation (P < 0.001) and serum hepcidin (P = 0.004) and improved iron absorption (P = 0.003). Treatment of hookworm infection neither affected inflammation biomarkers nor altered iron absorption. Similarly, there was a lack of treatment effects in the S. haematobium-infected group; however, the small sample size limits conclusions. Geometric mean iron utilization ranged between 79.1% and 88.0% in the afebrile malaria and hookworm groups with no significant differences pre- and posttreatment. CONCLUSIONS: In school-age children, hookworm infection does not produce inflammation or increase serum hepcidin, and it does not influence iron absorption or utilization. In contrast, afebrile malaria causes inflammation, increases hepcidin, and reduces iron absorption but not utilization. These findings provide insights into the iron metabolism and the etiology of anemia in parasitic infections.

Health & Demographic Surveillance System Profile: The Taabo Health and Demographic Surveillance System, Côte d'Ivoire.

The Taabo Health and Demographic Surveillance System (HDSS) is located in south-central Côte d'Ivoire, approximately 150 km north-west of Abidjan. The Taabo HDSS started surveillance activities in early 2009 and the man-made Lake Taabo is a key eco-epidemiological feature. Since inception, there has been a strong interest in research and integrated control of water-associated diseases such as schistosomiasis and malaria. The Taabo HDSS has generated setting-specific evidence on the impact of targeted interventions against malaria, schistosomiasis and other neglected tropical diseases. The Taabo HDSS consists of a small town, 13 villages and over 100 hamlets. At the end of 2013, a total population of 42 480 inhabitants drawn from 6707 households was under surveillance. Verbal autopsies have been conducted to determine causes of death. Repeated cross-sectional epidemiological surveys on approximately 5-7% of the population and specific, layered-on haematological, parasitological and questionnaire surveys have been conducted. The Taabo HDSS provides a database for surveys, facilitates interdisciplinary research, as well as surveillance, and provides a platform for the evaluation of health interventions. Requests to collaborate and to access data are welcome and should be addressed to the secretariat of the Centre Suisse de Recherches Scientifiques en Côte d'Ivoire: [secretariat@csrs.ci].

Scope and Limits of an anamnestic questionnaire in a control-induced low-endemicity helminthiasis setting in south-central Côte d'Ivoire.

BACKGROUND: Schistosomiasis and soil-transmitted helminthiasis are two high-burden neglected tropical diseases. In highly endemic areas, control efforts emphasize preventive chemotherapy. However, as morbidity, infection, and transmission begin to decrease, more targeted treatment is likely to become more cost-effective, provided that comparatively cheap diagnostic methods with reasonable accuracy are available. METHODOLOGY: Adults were administered an anamnestic questionnaire in mid-2010 during a cross-sectional epidemiological survey in the Taabo health demographic surveillance system in south-central Côte d'Ivoire. Questions pertaining to risk factors and signs and symptoms for schistosomiasis and soil-transmitted helminthiasis were included. The individuals' helminth infection status and their belonging to three different anthelmintic treatment groups were compared with the questionnaire results (i) to inform the local health authorities about the epidemiological and clinical footprint of locally prevailing helminthiases, and (ii) to explore the scope and limits of an anamnestic questionnaire as monitoring tool, which eventually could help guiding the control of neglected tropical diseases in control-induced low-endemicity settings. PRINCIPAL FINDINGS: Our study sample consisted of 195 adults (101 males, 94 females). We found prevalences of hookworm, Trichuris trichiura, Schistosoma haematobium, and Schistosoma mansoni of 39.0%, 2.7%, 2.1%, and 2.1%, respectively. No Ascaris lumbricoides infection was found. Helminth infection intensities were generally very low. Seven, 74 and 79 participants belonged to three different treatment groups. Multivariable logistic regression models revealed statistically significant (p<0.05) associations between some risk factors, signs, and symptoms, and the different helminth infections and treatment groups. However, the risk factors, signs, and symptoms showed weak diagnostic properties. CONCLUSIONS/SIGNIFICANCE: The generally low prevalence and intensity of helminth infection in this part of south-central Côte d'Ivoire indicates that recent control efforts have turned our study area into a low endemicity setting. Our anamnestic questionnaire had low sensitivity and specificity to identify infected individuals or treatment groups.

Patients routinely report more symptoms to experienced field enumerators than physicians in rural Cote d'Ivoire.

Medical history-taking is among the most powerful diagnostic tools for healthcare professionals. However, its accuracy and reliability are underexplored areas. The present post-hoc study compares medical histories from 463 people in a rural part of Côte d'Ivoire. The medical histories of the same individuals were taken by physicians and experienced field enumerators who were blinded to the results of the others. Kappa (κ) statistics for 14 symptoms revealed only poor-to-moderate agreement between physicians and field enumerators (κ = 0.01-0.54). Participants reported consistently more symptoms to field enumerators than physicians. Only 33 (7.1%) participants gave no discordant statement at all. The average number of discordant statements per participant was 3.7. Poisson regression revealed no significant association between the number of discordant statements and participants' age, sex, educational attainment, occupation, or socioeconomic status. Operational research should further explore best practices to obtain reliable medical histories in resource-constrained settings.

Effects of inflammation and Plasmodium falciparum infection on soluble transferrin receptor and plasma ferritin concentration in different age groups: a prospective longitudinal study in Côte d'Ivoire.

BACKGROUND: Iron deficiency (ID) is a major cause of anemia, along with other nutritional, parasitic, and genetic factors. Accurate biomarkers are needed to estimate the relative contribution of ID to anemia. Soluble transferrin receptor (sTfR) is thought to be unaffected by inflammation. OBJECTIVES: The objectives were to determine the difference in sTfR and plasma ferritin (PF) concentrations among infants (6-23 mo of age), school-age children (6-8 y of age), and women (15-25 y of age) with and without inflammation and with and without Plasmodium falciparum infection and to assess the effect of adjusting sTfR and PF for inflammation or for P. falciparum infection on the estimated prevalence of ID. DESIGN: The data were derived from a 14-mo prospective longitudinal survey on anemia, which was conducted in the Taabo area, south-central Côte d'Ivoire. RESULTS: At baseline, sTfR concentration was significantly higher in infants and school-age children with either inflammation or P. falciparum infection than in control individuals without inflammation or without P. falciparum infection. Individuals with inflammation had significantly higher PF concentrations than did subjects without inflammation. Adjustments in sTfR concentrations for inflammation or P. falciparum infection in infants and school-age children resulted in significantly lower ID prevalence. Adjustment of PF for inflammation and Plasmodium infection resulted in a higher ID prevalence in infants and women. CONCLUSIONS: In Ivorian infants and school-age children, ID prevalence was considerably lower after adjustment of sTfR for inflammation. However, as the prevalence estimates for ID differed widely if based on sTfR or PF, caution is still needed when estimating ID prevalence in areas with a high prevalence of inflammation or malaria. This trial was registered at controlled-trials.com as ISRCTN02181959.

Dynamics of anemia in relation to parasitic infections, micronutrient status, and increasing age in South-Central Côte d'Ivoire.

BACKGROUND: Parasitic diseases (eg, malaria and helminthiases) exert enormous burdens on public health and social well-being. Moreover, parasitic infections are important causes of anemia in tropical Africa, exacerbated by lack of a diversified diet and inflammatory and genetic diseases. There is a paucity of longitudinal studies monitoring the dynamics of anemia in relation to the aforementioned parameters. METHODS: We designed a 14-month prospective longitudinal study in 3 cohorts (ie, infants aged 6-23 months, children aged 6-8 years, and women aged 15-25 years) in the Taabo health demographic surveillance system located in south-central Côte d'Ivoire. Parasitological, hematological, and micronutrient data were obtained from repeated cross-sectional surveys, utilizing standardized, quality-controlled methods. RESULTS: We found that young age, Plasmodium and Schistosoma infections, cellular iron deficiency, and stunting were significantly negatively associated with hemoglobin concentration. Moreover, iron status biomarkers (ie, ferritin and soluble transferrin receptor) were significantly associated with inflammatory parameters. CONCLUSIONS: Based on our results, effective prevention and control measures that target parasitic diseases and iron deficiency are needed. These measures might include the distribution of long-lasting insecticidal nets, intermittent preventive treatment for malaria, regular anthelmintic drug administration, and improved intake of bioavailable iron, coupled with health and nutritional education and improved hygiene, water, and sanitation.

Interactions and potential implications of Plasmodium falciparum-hookworm coinfection in different age groups in south-central Côte d'Ivoire.

BACKGROUND: Given the widespread distribution of Plasmodium and helminth infections, and similarities of ecological requirements for disease transmission, coinfection is a common phenomenon in sub-Saharan Africa and elsewhere in the tropics. Interactions of Plasmodium falciparum and soil-transmitted helminths, including immunological responses and clinical outcomes of the host, need further scientific inquiry. Understanding the complex interactions between these parasitic infections is of public health relevance considering that control measures targeting malaria and helminthiases are going to scale. METHODOLOGY: A cross-sectional survey was carried out in April 2010 in infants, young school-aged children, and young non-pregnant women in south-central Côte d'Ivoire. Stool, urine, and blood samples were collected and subjected to standardized, quality-controlled methods. Soil-transmitted helminth infections were identified and quantified in stool. Finger-prick blood samples were used to determine Plasmodium spp. infection, parasitemia, and hemoglobin concentrations. Iron, vitamin A, riboflavin, and inflammation status were measured in venous blood samples. PRINCIPAL FINDINGS: Multivariate regression analysis revealed specific association between infection and demographic, socioeconomic, host inflammatory and nutritional factors. Non-pregnant women infected with P. falciparum had significantly lower odds of hookworm infection, whilst a significant positive association was found between both parasitic infections in 6- to 8-year-old children. Coinfected children had lower odds of anemia and iron deficiency than their counterparts infected with P. falciparum alone. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that interaction between P. falciparum and light-intensity hookworm infections vary with age and, in school-aged children, may benefit the host through preventing iron deficiency anemia. This observation warrants additional investigation to elucidate the mechanisms and consequences of coinfections, as this information could have important implications when implementing integrated control measures against malaria and helminthiases.

Schistosomiasis, soil-transmitted helminthiasis, and sociodemographic factors influence quality of life of adults in Côte d'Ivoire.

BACKGROUND: Burden of disease estimates are widely used for priority setting in public health and disability-adjusted life years are a powerful "currency" nowadays. However, disability weights, which capture the disability incurred by a typical patient of a certain condition, are fundamental to such burden calculation and their determination remains a widely debated issue. METHODOLOGY: A cross-sectional epidemiological survey was conducted in the recently established Taabo health demographic surveillance system (HDSS) in south-central Côte d'Ivoire, to provide new, population-based evidence on the disability caused by schistosomiasis and soil-transmitted helminthiasis. Parasitological results from stool, urine, and blood examinations were juxtaposed to quality of life (QoL) questionnaire results from 187 adults. A multivariable linear regression model with stepwise backward elimination was used to identify significant associations, considering also sociodemographic characteristics obtained from the Taabo HDSS database. PRINCIPAL FINDINGS: Prevalences for hookworm, Plasmodium spp., Trichuris trichiura, Schistosoma haematobium and Schistosoma mansoni were 39.0%, 18.2%, 2.7%, 2.1% and 2.1%, respectively. S. mansoni and T. trichiura infections of any intensity reduced the participants' self-rated QoL by 16 points (95% confidence interval (CI): 4-29 points) and 13 points (95% CI: 1-24 points), respectively, on a scale from 0 (worst QoL) to 100 points (best QoL). The only other statistically significant effect was a 1-point (95% CI: 0.1-2 points) increase on the QoL scale per one unit increase in a calculated wealth index. CONCLUSIONS/SIGNIFICANCE: We found consistent and significant results on the negative effects of schistosomiasis and soil-transmitted helminthiasis on adults' self-rated QoL, also when taking sociodemographic characteristics into account. Our results warrant further investigation on the disability incurred by helmintic infections and the usefulness of generic QoL questionnaires in this endeavor.

Etiology of anemia among infants, school-aged children, and young non-pregnant women in different settings of South-Central Cote d'Ivoire.

Anemia affects one-quarter of the world's population, but its etiology remains poorly understood. We determined the prevalence of anemia and studied underlying risk factors in infants (6-23 months), young school-aged children (6-8 years), and young non-pregnant women (15-25 years) in south-central Côte d'Ivoire. Blood, stool, and urine samples were subjected to standardized, quality-controlled methods. We found high prevalence of anemia, malaria, inflammation, and deficiencies of iron, riboflavin, and vitamin A but low prevalence and intensities of soil-transmitted helminth and schistosome infections. Multivariate regression analysis revealed significant associations between anemia and Plasmodium falciparum for infants, inflammation for school-aged children, and cellular iron deficiency for both school-aged children and non-pregnant women. Women with riboflavin deficiency had significantly lower odds of anemia. Our findings call for interventions to protect infants from malaria, improved intake of dietary iron, better access to health care, and health education.