Effect of TB Therapy on the Health and Nutritional Status of Infants Aged 6 Months to 5 Years Diagnosed with Latent TB

Background: Infants with latent tuberculosis are often subject to high morbidity, nutritional deficiency and mortality. Early treatment can prevent the onset of TB by reducing morbidity and improving nutritional status. This paper assessed whether preventive chemotherapy for TB can improve health and nutritional status of infants diagnosed with latent TB in Kisangani City. Method: Children diagnosed TB+ by tuberculin skin test and other clinical examinations were treated with Rifampicin, Isoniazid, Pyrazinamide and Ethambutol. Clinical symptoms and nutritional status were determined before to start treatment and at the 5th month of treatment. Results: Out of 161 infants treated, 73 (45.3%) were 37d the difference was statistically significant (p < 0.001). Similarly, the proportion of children with weights below the ideal weight adjusted for each age decreased from 21.7% before treatment to 8.1% after treatment. Infants younger than one year were more likely to have fever than older children, while girls were more likely to be malnourished than boys (p < 0.05) before treatment, but the recovery rates were not different. Conclusion: Treatment of infants diagnosed of latent TB prevents TB disease and improves nutritional status, but not in all cases. Control of fever and weight gain can be an indicator of good outcome in poor health care settings.


Introduction
Childhood tuberculosis (CTB) is a very preoccupant public health problem all over the world, and more particularly in developing countries [1]. CTB accounts for about 15% to 40% of all tuberculosis (TB) cases. It is an important sentinel event suggesting a recent infection of infants through a contact with infectious adults in a community [1] [2] [3] [4] [5]. Early detection of CTB in children at high enough risk is useful for initiating preventive chemotherapy to avoid the active TB phase [6]. When screening is done, treatment is recommended for all children and adolescents diagnosed TB positive [7] [8] [9] [10]. This treatment requires strong adherence to prevent drug resistance and ensure good therapeutic results [11], but other factors such as age, gender, nutrition, and drug-related problems are susceptible to influence the treatment outcome [11] [12] [13]. For nutrition, there is evidence suggesting that malnutrition affects gene expression and immune function and predisposes children to progression of TB; this results in active TB phase and inflammatory response that further worsen nutritional status [12] [13] [14] [15].
Thus, treatment of latent tuberculosis infection (LTBI) is the most effective strategy to prevent future cases of disease. Most cases of CTB in low-prevalence countries are preventable by screening for risk factors, testing for LTBI, and offering therapy [7] [8] [9] [10]. However, although LTBI therapy has been available and emphasized in rich nations, its use is limited in most resource-limited countries [16]. Various regimens have been used for a decade, but concerns about low completion rates, costs, and increasing rates of drug resistance have prompted research on shorter-course LTBI regimens and the use of combination regimens [17] [18]. The International Union against Tuberculosis and Lung Disease [17] completed a direct comparison of 3-, 6-, and 12-month regimens of INH in 27730 adults with tuberculin skin test (TST) induration > 6 mm and fibrotic pulmonary lesions seen on chest radiograph. During 5 years of follow-up, 1.4% of participants in the placebo group developed TB disease compared with 1.1%, 0.5%, and 0.4% in the 3-, 6-, and 12-month regimen groups, respectively.
Among persons taking ≥ 80% of their INH doses, efficacy for the 12-month regimen was higher (0.1% disease progression). Participants receiving the 6-month regimen had a 4-fold higher risk of TB disease than those receiving the 12-month regimen. Similar studies are rare in children. However, Hsu's observational studies [18] of 2494 children who were treated with INH daily for 1 year and followed on average for 6 years, showed greater than 99% protective efficacy

Ethical Issue
The study was conducted according to the guidelines laid down in the Declara-

Study Design
The complete protocol has been published elsewhere [19]. In summary ( Figure   1), a cross-sectional study was conducted in 2013 to assess the prevalence of TB in children and adolescents 6 months to 17 years of age suspected of being infected with TB, using TST, chest X-ray, and clinical investigation.   3 : first 2 months (intensive phase) and last 7 months (maintenance phase). To prevent polyneuritis as a treatment-related side effect, vitamin B6 therapy has been consistently associated with anti-TB drugs throughout the course of treatment. For this analysis, the 239 files of children treated for TB were retrieved and only 161 records of children less than 5 years of age, deemed appropriate to provide information on the clinical and nutritional response to treatment, were selected.

Diagnostic Criteria
Every child or adolescent aged 6 months to 17 years suspected of TB at the health center was eligible. TST was negative when the induration diameter (and not of the erythema) developed at the site of injection was <5 mm. In our case, given that Kisangani is a highly endemic area, there is a high probability of detecting both clinical silent and clinical active infection. A diameter ≥ 10 was considered as active TB while between 5 and 10 was taken roughly as latent form.

Nutritional Status
Anthropometry-Body weight and length, or height, are important indications of nutritional status of infants and young children. The nutritional status of children was appreciated by the degree of weight-loss and according to UNICEF-WHO classification which devises stunting by height-for-age index. The ideal weight for each age was estimated by the index (HAZ-score) which was calculated with ENA software for SMART 2011. A child below two standard deviations (−2 SD) from the median of the Child Growth Standards in terms of Weight-for-age was considered bad status [20].

Data Analysis
The data collected was analyzed with Excel Windows and SPSS v20 IBM soft- ware. We took underweight as weight 15% below the ideal-weight and fever when body temperature was >37.5˚C. Pearson's chi-square was used to test the significance of differences at p < 0.05.   Table 3 shows the difference in body weight and body temperature before and after treatment. Before treatment, 62.7% had permanent fever (T > 37.5˚C), but after treatment, the score was reduced to 17.4% giving an improvement in 45.3% (p < 0.001). The improvement was not influenced by gender (p = 0.952) or age range (p = 0.121). Similarly, regarding nutritional status, 21.7% were below the ideal weight, and after treatment, the score was reduced to 8.1% giving improvement of 13.6% (p < 0.001). All boys were upper the ideal weight before

Limitation
This study was not a highly randomized trial. Also the sample size is limited.
However, the finding constitutes interesting starting point for an extended study

Discussion
The high prevalence of infants from Makiso health zone is due to the proximity of this zone with the healthcare facility that received children for screening and also because this HZ is the municipality that offers a lot of commercial activities compared to others; this may drain a lot of people including bacilliferous coughers as source of infection for children.
The distribution of the sample by gender and age showed that the risk of developing TB in infants is the same for both boys and girls even though slightly biased to males (OR = 1.01). Generally, infectious diseases rarely affect males and females equally and tuberculosis is no exception [21]. Globally in adult persons, far more men than women are significantly at risk of contracting and dying from TB. According to the WHO report 2013, the degree of male bias varies by geographic location and by year [22]. Considering the overall trends in the 20 high-burden countries for which data are available, the median male-to-female ratio is 1.8:1, with only Afghanistan reporting a ratio of <1:1. The consistent global trend for male bias in tuberculosis has been attributed to environment factors as well as to biological or physiological differences [22] [23] [24]. Smoking, alcohol drinking, travelling and place of work expose men to TB while hormonal system may protect women. In children under-5, those risk factors are less likely to apply.
The incidence of TB in this study decreased inversely with age, 45.3% in children < 1 year of age, 30.4% in 1 -2 years old and 24.2% in 3 -5 years old; this is consistent with the concept of age pyramid. Many studies have found that the lower is the age, the higher is the risk for a child exposed to have a TB infection [1] [3] [19]. The predominance of children under one year of age confirms the vulnerability of this period of childhood development in relation with the immaturity of cellular immunity [25]. It has been reported that among children under 1 year of age, approximately 30% -40% may progress from primary infection to active disease; for children aged between 1 and 5 years old, this risk is approximately 24%; the risk of progression declines slowly beyond 5 years and increases again at around 10 years of age [25] [26] [27]. The risk factors for progression from primary infection to disease include duration and burden of exposure, the virulence of the mycobacterial strain, HIV infection or other clinical conditions that impair the immune system, malnutrition, and exposure to tobacco smoke [28].
The general functional signs found in adults TB patients are fever (38˚C), profuse nocturnal sweating, anorexia, asthenia, chronic cough with sputum, chest pain and/or dyspnea [1] [2]. Among the functional or physical signs found in this study, more than 98% had no asthenia, anorexia, perspiration; only the prevalence of fever, loss of weight and elevation of sedimentation rate were significantly indicative signs of the disease. It is known that the diagnosis of TB in  [39]. To treat TB+ children in this study, the standard treatment regimen (first-line anti-tuberculosis drugs) which included rifampicin, isoniazid, pyrazinamide and ethambutol for the first 2 months and only rifampicin and isoniazid at the continuation phase was applied. This scheme is recommended when resistance to the usual isoniazid is suspected [40]. We have used this scheme as at priory we could not discriminate sensitive and resistant cases.
We also systematically added Vitamin B6 to prevent isoniazid peripheral neuropathy side effect that occurs especially in malnourished children and in slow acetylors [40] [41] [42].
Globally, the clinical treatment outcome was good in more than 90% of cases.
This result demonstrates that the success of chemotherapy for antitubercular prophylaxis is maximal in children [12]. This success is explained by a good adherence to treatment, which is due to the rarity of side effects in children [40].
The intervention reduced the prevalence of fever as well as that of underweight.

Conclusion
There is a significant statistical difference between pre-treatment and posttreatment values. Girls under one year of age are at higher risk of fever and malnutrition during the pre-phase of active tuberculosis. The study highlights that TST remains the most useful tool for quickly diagnosing TB in children.
Children under 5 years of age are most at risk of developing active TB in an endemic environment. The first-line anti-tuberculosis drugs still work for the management of childhood tuberculosis. Since the metabolic rate of isoniazid may be slow leading to peripheral polynevritis, vitamin B6 may be combined to the treatment regimen.

Conflicts of Interest
The authors declare no conflict of interest.