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It is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis.1 Most of those infected remain in a state of latent tuberculosis infection (LTBI) with the potential to convert to active disease at a later time. The lifetime risk for otherwise healthy children ≤15 years of age with LTBI is 5–15%.2 Because most cases of active disease in adults represent reactivation of LTBI, one of the main strategies for eliminating TB in the United States is to identify and treat patients with LTBI, particularly children.3 The most recent published guidelines for treatment of LTBI in children and adolescents pointed out that completion rates for treatment of LTBI are suboptimal and suggested that “strategies to monitor and improve adherence to treatment are needed.”4
PATIENTS AND METHODS
This was a retrospective analysis of prospectively collected data for patients ≤15 years of age with LTBI (tuberculin skin test [TST] of ≥10 mm of induration and a negative chest radiograph) referred to Nationwide Children's Hospital Tuberculosis Clinic (TBC) between August 1, 2005 and July 31, 2006. Patients were evaluated by a physician or nurse practitioner and started on a 9-month regimen of daily isoniazid (INH). These children were mostly foreign born with 54 different birth countries represented.
Whenever parents or legal guardians were unable to speak fluent English, a trained interpreter was present during the first and all subsequent clinic visits. Handout instruction sheets explaining LTBI, the need for medication, and possible medication side effects were available in Somali and Spanish. Patients were followed monthly by a nurse practitioner who examined the children, questioned for adverse drug reactions, obtained a pill count of unused medications and prescribed a new 1 month supply of medication. When patients did not return for the scheduled monthly visit, families were attempted to be contacted by phone or mail for 3 subsequent months. Patients who failed to return to clinic for 3 consecutive months were deemed treatment failures. This review of medical records was approved by the Nationwide Children's Hospital Institutional Review Board.
Completion of therapy was defined as 270 doses of INH within a 12-month period of time. Patients who missed ≥3 consecutive months of therapy but eventually returned to the clinic were restarted on the full course of therapy; no credit was given for previous doses taken. Children who were restarted on therapy after August 1, 2006 and were still being followed in the TBC on therapy by July 31, 2007 were excluded from analysis. The countries of birth were grouped into 6 major geographic regions: Sub-Saharan Africa, Central and South America, Asia, United States, North Africa and Middle East, and Eastern Europe.
Outcome measurements included completion of therapy, reasons for noncompletion of therapy, and duration of attendance in the clinic before discontinuation of medication. Data were stored in an Access database. Statistical comparison of regions was done by χ2 analysis using SPSS software, version 14.
The overall completion rate of the 545 patients evaluated was 54.4%. By χ2 analysis there was no correlation between rates of completion and age, duration in the United States, or exposure to active TB. However, there were significant regional differences. Completion rates by region were as follows: Central and South America (N = 159) 67.9%, Sub-Saharan Africa (N = 284) 56.3%, Asia (N = 37) 48.6%, United States (N = 32) 43.8%, Northern Africa and Middle East (N = 18) 38.9%, and Eastern Europe (N = 15) 0%. The fact that none of the children from Eastern European countries completed the full course of therapy was significantly different than all other groups (χ2 = 33.349, P = 0.001). The high rate of completion in children from Central and South America (67.9%) was just below significance compared with the rest of the group.
Analysis of the reasons that children failed to complete therapy is shown in the table by region (table available online only). There were significant differences among the regions with regard to parental refusal to start medication which was noted in 54% of Eastern European children and 80% of Asian children who failed to complete therapy. This is in sharp contrast to children from Central and South America, Sub-Saharan Africa, and the United States where <10% of parents refused to allow treatment (χ2 = 102.67, P = 0.001). Children in those 3 groups who did not complete therapy and were not referred to other health care providers, had a “no-show” rate of >75%.
There have been numerous studies that have addressed the completion rates of therapy for LTBI showing completion rates from 20% to 60%.5 However, the criteria for completion varied greatly among studies, and the majority of studies were performed on adults and adolescents where the recommendations for completion of INH therapy were 6 months rather than 9 months. Data on successful completion of therapy in children are limited.6–8 Two of these studies6,7 with completion rates of 28% and 74% were based on a 6-month course of INH. The only other study in children where 9 months of INH was prescribed demonstrated a completion rate of 58%, a number very similar to the finding in our study. The only predictor of completion of therapy in that study was having ≥2 family members brought in for TB screening. Our data did not address that factor but observed that age, duration in the United States, and exposure to active TB had no impact on whether children completed therapy. In contrast, region of birth and parental refusal to begin their child on INH therapy were significant variables.
A recent study in Minneapolis, a city like Columbus with a large number of Somali and sub-Saharan African immigrants documented only 49% of adult or pediatric refugees with a positive TST had completed treatment for LTBI.9 Aside from age >35 years, the 3 most common identified reasons for failure to complete treatment were “declined therapy, provider decision, and lost to follow-up.” In our study, lost to follow-up was the major factor for children from all countries except those from Asian and Eastern European countries where parental refusal to begin therapy was the major factor. We found parents from those regions to be adamant that the reason for their child's positive TST was receipt of Calmette-Guérin bacillus (BCG) vaccine, and that the BCG vaccine would protect their children from a risk of developing active TB. That sentiment is in line with a survey of 217 adults (90% foreign born) with a 28.5% completion rate of LTBI therapy where the highest predictor of noncompletion was a low risk perception of progressing to active TB without LTBI treatment.5
The highest rate of completion of therapy in our study was in the Spanish speaking population with a 67.9% completion rate. Because we did have children from 54 different countries represented in our study population, this finding might suggest that the availability of trained Hispanic interpreters and fact sheets about LTBI and INH therapy translated into Spanish in simplistic terms were the factors that dictated such positive results. However, we also had trained interpreters who spoke Somali (most of the patients from Sub-Saharan Africa), and the exact same literature was interpreted into the Somali language. However, the treatment completion rate in our Somali patients was only 53%. Parents of these patients as well as parents from the remainder of Sub-Saharan African countries, Central and South America countries, and the United States almost never objected to begin therapy or raised concern that the positive TST was the result of BCG. They usually started their children on INH and returned to the clinic for several months but then simply stopped coming. We had no child who was taken off of medication for definite adverse reactions. We suspect that many of these families moved (phones disconnected and letters returned) or that transportation to come to the TBC became a stumbling block.
Because 90% of children who failed to complete a full course of therapy for LTBI remained in our TBC for ≤5 months, one approach to enhancing compliance could also be to provide a shorter course of therapy. Data from a recent 11-year randomized trial in Greece support similar outcomes with INH and rifampin for 3–4 months compared with a 9-month course of INH monotherapy.10
In the 2004 publication authored by the Pediatric Tuberculosis Collaborative Group, several interventions were suggested to promote adherence to LTBI treatment.4 Among those were school clinics, language and culture-specific educational material at an appropriate cognitive level, minimal waiting time in clinics, dedicated staff, medication on site, appointment reminders, reinforcement at each visit, and incentives (monetary, entertainment coupons, refreshments). We addressed many of these as we began the NCH latent TB clinic. Patients receive their chest radiograph and begin therapy typically within a 2-hour period of time. We now have 2 dedicated nurse practitioners who care for these patients and offer inducements such as coupons and movie tickets. We have interpreters present at all of the clinic visits, and we have educational material available in the 2 most common languages of children attending the clinic. Despite this there is an obvious need to continue to explore means to improve the compliance with LTBI treatment.
1. Bjune G, Cotton M, El Sony A, et al. Guidance for national tuberculosis programmes on the management of tuberculosis in children. World Health Organization Publication WHO/HTTM/TB/2006.371; 2006. Available at: http://www.who.int/child-adolescent-health/New_Publications/CHILD_HEALTH/WHO_FCH_CAH_2006.7.pdf
. Accessed October 10, 2007.
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