Relative Efficacy of Two Regimens of Ante-helminthic Treatment

Study design and population:

The study population will be the children aged 2-5 years old in the study area. All children aged 2-5 years old in one slums of the study area will be listed and will be invited to participate in the study.

Parents will be explained the purpose of the study and will be asked for written consent for participation of their children in the study. If the parents give the consent then a stool pot will be given to them to collect stool samples for microscopic examination for intestinal parasites. The inclusion criteria are; 1) age of the child is 2-5 years old, 2) he/she has not been suffering from serious chronic illness, 3) the child stool test must be positive for STH, 4) he/she had not been taken any antehelminthic drug in the previous six months, 5) parents/guardian are agree for their child participation in the study. The exclusion criteria are; 1) age of the child less than 2 years old and more than 5 years old, 2) his/her stool test negative for any intestinal helminth, 3) he/she has been suffering from serious chronic illness, 4) parents/guardian are not willing to give consent for their child's participation in the study, 5) if he/she receives any antehelminthic drug after survey but before the study interventions. The survey will be done in the first months of the study, and then children will be enrolled according to above mentioned inclusion/exclusion criteria. During screening if any child is found severely malnourished it will be considered as'danger sign' according to WHO and IMCI guideline he/she will be referred to an appropriate facility even if she/he is not enrolled in the study. Simple randomization technique will be applied to divide the children into two groups: A) Conventional treatment group who will receive anti-helminthic treatment 400 mg of Albendazole in a single dose at six month interval and B) Intervention group, who will receive anti-helminthic 400 mg of Albendazole in a single dose treatment at three months interval. Stool samples will be collected from both groups prior to anti-helminthic therapy and will be examined quantitatively. However stool examination will not be carried out for intestinal parasite after giving 400 mg of Albendazole at 12 months.

Sample size calculation:

Sample size has been calculated using different predicted values of different out come variables and is shown in the Table 1. A sample size of 200 children, 100 in each group will be sufficient for the study.

Table 1. Sample size calculation table Indicator Conventional treatment group Intervention treatment group Power of the study 95% CI SD* Number in each group Total number adjusted for 10% drop out Cure rate 40% 65% 90% 95% - 78 170 HAZ < -2 38% 19% 90% 95% - 84 184 Incidence of E. histolytica infection per 100 child-year 20a 15 90% 95% 10 85 188 Average diarrheal episode per child 2a 1 90% 95% 1.5 48 106 Mean haemoglobin mg% 10a 12 90% 95% 4 85 188 Respiratory tract infection episode/child 6a 4 90% 95% 3 48 106 * SD = Within group standard deviation

a= Data from our ongoing cohort study in Mirpur

Methods:

Anthropometric measurement: Field Research Assistant will be trained to take weight and height measurement of the children. Anthropometric measurements will be taken by trained FRA at the time of enrollment and then every 3-months. Each child will be weighed in light clothes with an electronic weighing scale. Inter-observer variation up to 2.5% will be allowed. The standing heights of children will be measured to the nearest 0.1 cm using a locally constructed height stick. Again inter-observer variation up to 2.5% will be allowed. Nutritional status will be assessed by comparing the weight and height of the study children with those of NCHS reference population of the same age and sex with the help of Epi6 computer package program and weight for age "Z" score (WAZ) and height for age "Z" score (HAZ) will be computed (29). Malnourished and stunted will be defined by the WAZ score and HAZ score <-2 respectively.

Other disease morbidity: Each study subject will be visited by a community health worker every week and will collect information by asking parents/guardian according to structured questionnaires about diarrheal disease, fever, cough etc. of the child retrospectively for previous seven days. They will work 6 days weekly and every one of them has to visit about 17 households per day for morbidity data collection. Parents/guardian will be advised to seek health care from study physician in study field office in case of any illness of the study child. The study physician will take history and will carry out physical examination and will give treatment to the sick child. If the child does not respond to the given treatment or if his/her condition deteriorates or if the child is seriously ill initially then he/she will be referred to the appropriate referral facilities for treatment, and treatment cost will not be carried out by the project. Asymptomatic E. histolytica infections will not be treated. But symptomatic E. histolytica infections will be treated according to the ICDDR, B Dhaka Hospital treatment guidelines

Intestinal helminth infections induce Th-2 immune response (27), which might favor others viral, bacterial and protozoan infections. De-worming has been shown to improve antibody response (28). In our ongoing cohort study in Mirpur it has been found that children with heavy Trichuris trichiura (TT) infections suffered significantly more from E. histolytica associated infection (un published data) compare to those children with light infection with TT. Based on these observations it can be hypothesized that a frequent de-worming regimen will be associated with less other disease morbidtity like diarrheal diseases, respiratory infections and intestinal protozoan infections with E. histolytica Clinical definitions Diarrhea was defined as having three or more unformed stools in a 24 hour period. A "diarrheal episode" was defined as being separated from another episode by at least 3 diarrhea-free days.

Respiratory tract infection defined as a 'Perceptions of a child who has a cough, is breathing faster than usual with short, quick breaths or is having difficulty breathing, excluding children that had only a blocked nose. (30). No attempt will be done to identify the etiology of the respiratory infection.

Cure rate of STH infection (CR): Cure rate from STH infection is defined as follows:

• Prevalence before at enrollment - % prevalence at the end of the study CR = --------------------------------------------------------------------------------------------- x 100%
• Prevalence before at enrollment

Laboratory methods:

Blood hemoglobin measurement: Study physician will measure blood hemoglobin of the child at enrollment and at the end of the study period by hemocytometer at field site. (31).

Stool parasite examination: The community health workers will collect stool samples for qualitative and quantitative intestinal parasite measurement at every three months interval. The stool will be examined by conventional microscopy for qualitative measurement and for quantitative measurement of intestinal helminthes by Kato-Katz or Formalin-ether concentration technique will be used. (32).E. histolytica will be detected by stool microscopy and ELISA as described by R Haque el at(33).