Baseline Predictors of Treatment Outcomes in Children With Multidrug-Resistant Tuberculosis: A Retrospective Cohort Study.

BACKGROUND: Globally, >30 000 children fall sick with multidrug-resistant (MDR) tuberculosis every year. Without robust pediatric data, clinical management follows international guidelines that are based on studies in adults and expert opinion. We aimed to identify baseline predictors of death, treatment failure, and loss to follow-up among children with MDR tuberculosis disease treated with regimens tailored to their drug susceptibility test (DST) result or to the DST result of a source case. METHODS: This retrospective cohort study included all children ≤15 years old with confirmed and probable MDR tuberculosis disease who began tailored regimens in Lima, Peru, between 2005 and 2009. Using logistic regression, we examined associations between baseline patient and treatment characteristics and (1) death or treatment failure and (2) loss to follow-up. RESULTS: Two hundred eleven of 232 (90.9%) children had known treatment outcomes, of whom 163 (77.2%) achieved cure or probable cure, 29 (13.7%) were lost to follow-up, 10 (4.7%) experienced treatment failure, and 9 (4.3%) died. Independent baseline predictors of death or treatment failure were the presence of severe disease (adjusted odds ratio [aOR], 4.96; 95% confidence interval [CI], 1.61-15.26) and z score ≤-1 (aOR, 3.39; 95% CI, 1.20-9.54). We did not identify any independent predictors of loss to follow-up. CONCLUSIONS: High cure rates can be achieved in children with MDR tuberculosis using tailored regimens containing second-line drugs. However, children faced significantly higher risk of death or treatment failure if they had severe disease or were underweight. These findings highlight the need for early interventions that can improve treatment outcomes for children with MDR tuberculosis.

Using Changes in Weight-for-Age z Score to Predict Effectiveness of Childhood Tuberculosis Therapy.

BACKGROUND: International guidelines recommend monitoring weight as an indicator of therapeutic response in childhood tuberculosis (TB) disease. This recommendation is based on observations in adults. In the current study, we evaluated the association between weight change and treatment outcome, the accuracy of using weight change to predict regimen efficacy, and whether successfully treated children achieve catch-up weight gain. METHODS: We enrolled children treated for drug-susceptible TB disease (group 1) and multidrug-resistant TB disease (group 2) in Peru. We calculated the change in weight-for-age z score (ΔWAZ) between baseline and the end of treatment months 2-5 for group 1, and between baseline and months 2-8 for group 2. We used logistic regression and generalized estimating equation models to evaluate the relationship between ΔWAZ and outcome. We plotted receiver operating characteristic curves to determine the accuracy of ΔWAZ for predicting treatment failure or death. RESULTS: Groups 1 and 2 included 100 and 94 children, respectively. In logistic regression, lower ΔWAZ in months 3-5 and month 7 was associated with treatment failure or death in groups 1 and 2, respectively. In generalized estimating equation models, children in both groups who experienced treatment failure or death had lower ΔWAZ than successfully treated children. The ΔWAZ predicted treatment failure or death with 60%-90% sensitivity and 60%-86% specificity in months 2-5 for group 1 and months 7-8 for group 2. All successfully treated children-except group 2 participants with unknown microbiologic confirmation status-achieved catch-up weight gain. CONCLUSIONS: Weight change early in therapy can predict the outcome of childhood TB treatment.

Treatment of multidrug-resistant tuberculosis during pregnancy: long-term follow-up of 6 children with intrauterine exposure to second-line agents.

Treatment of gestational multidrug-resistant tuberculosis (MDR-TB) is controversial. We describe follow-up of 6 children exposed to second-line antituberculous agents in utero. Each child (average age, 3.7 years) underwent comprehensive clinical evaluation. One child had MDR-TB diagnosed. There was no evidence of significant late-presentation toxicity among the children. The results suggest that aggressive management of gestational MDR-TB may benefit both mother and child.

Evaluation of health-care providers' knowledge of childhood tuberculosis in Lima, Peru.

BACKGROUND: As most national tuberculosis programmes (NTPs) focus on adult tuberculosis (TB), NTP providers may not appreciate differences in the pathophysiology and presentation of childhood TB. OBJECTIVES: This study aimed to identify strengths and weaknesses in knowledge of childhood TB among the 326 NTP providers in Lima Ciudad and Lima Este--two of the Peruvian capital's four health districts. METHODS: 310 providers--103 physicians, 106 nurses, 101 nursing technicians--accepted personal invitations to complete self-administered surveys, which included 14 childhood TB questions grouped into five sections: transmission, symptoms, diagnosis, prevention and treatment. Physicians were asked ten additional questions targeting their NTP diagnostic and management responsibilities. RESULTS: All three groups scored 97-99% on the transmission section and 83-85% on the treatment section; however, no group scored above 66% on any other section. Fewer than 50% of nurses and technicians recognised young children's high risk of extrapulmonary TB, extrapulmonary TB symptoms or the causes of false negative tuberculin skin tests. Twenty-three per cent of physicians correctly identified gastric aspirate culture sensitivity, and 42% the radiographical findings of pulmonary TB. Less than two-thirds of providers recognised the definition of latent TB infection (LTBI), young children's high risk of progression from LTBI to disease or indications for isoniazid preventive therapy. CONCLUSIONS: Providers at the frontline of Peru's TB control efforts demonstrated weaknesses in the areas of extrapulmonary disease, diagnosis and prevention. These knowledge gaps are likely to have resulted in delayed or missed diagnoses and lost opportunities for prevention. Educational interventions targeting NTP personnel may improve childhood TB care and outcomes.

Parasite infection and tuberculosis disease among children: a case-control study.

We conducted a case-control study to examine associations between parasite infection, including protozoa infection, and tuberculosis (TB) in children in Lima, Peru. We enrolled 189 matched-pairs. In multivariable conditional logistic regression analyses, Blastocystis hominis infection (rate ratio = 0.30, 95% confidence interval = 0.14-0.64, P = 0.002) was strongly associated with a lower risk of TB. We observed a statistically significant inverse linear dose-response relationship between Blastocystis hominis infection and TB. These findings should be confirmed in future prospective studies.

Modifiable factors associated with tuberculosis disease in children: a case-control study.

We conducted a case-control study among children in Lima, Peru to identify factors associated with tuberculosis disease. Known close contact with someone with tuberculosis disease, prior hospitalization, and history of anemia were associated with a higher tuberculosis disease rate. Consumption of fruits/vegetables ≥5 days/week was associated with a lower rate. Isoniazid uptake was low among children with a known contact.

[Association between severe tuberculosis in children and previous BCG immunization in a national referral hospital, Peru 1990-2000]. / Asociación entre tuberculosis infantil grave e inmunización previa con BCG en un hospital de referencia nacional, Perú 1990-2000.

The objective of the study was to determine the association between BCG immunization and severe tuberculosis (TB). We performed a retrospective study, including medical records from patients of the pneumology department at the National Children's Institute in Peru, between the years 1990-2000. A total of 2106 TB cases were reviewed, from them 259 patients were severe (miliary TB or meningoencephalitic TB). From all, 497 cases did not have history of BCG vaccination, 202 had severe TB and 295 non-severe TB (OR = 0.05, 95% CI = 0.03 to 0.07). In conclusion, children diagnosed with TB and who have been immunized with BCG, has 94% lower risk of developing severe TB, compared to children with TB non-immunized with BCG.

Risk factors for in-hospital mortality among children with tuberculosis: the 25-year experience in Peru.

OBJECTIVE: We examined factors associated with in-hospital death among children with tuberculosis (TB). We hypothesized that a negative response to tuberculin skin testing (TST) would predict decreased survival. METHODS: This retrospective cohort comprised 2392 children ages 0 to 14 years hospitalized with TB at a Peruvian referral hospital over the 25-year study period. Detailed chart abstraction captured clinical history including TB contacts, physical examination findings, diagnostic data, treatment regimen, and hospitalization outcome. We used Cox proportional hazards regression analyses to determine risk factors for mortality. RESULTS: Of 2392 children, 2 (0.1%) were known to be HIV-positive, 5 (0.2%) had documented multidrug-resistant TB, and 266 (11%) died. The median time from hospitalization to death was 16 days (interquartile range: 4-44 days). Reaction of <5 mm induration on TST predicted death in a multivariable analysis (hazard ratio [HR]: 3.01; 95% confidence interval [CI]: 2.15-4.21; P < .0001). Younger age, period of admission, alteration of mental status (HR: 3.25; 95% CI: 2.48-4.27; P < .0001), respiratory distress (HR: 1.40; 95% CI: 1.07-1.83; P = .01), peripheral edema (HR: 1.97; 95% CI: 1.42-2.73; P < .0001), and hemoptysis (HR: 0.57; 95% CI: 0.32-1.00; P = .05) were associated with mortality. Treatment regimens that contained rifampicin (HR: 0.47; 95% CI: 0.33-0.68; P < .0001) were associated with improved survival. CONCLUSIONS: Negative reaction to TST is highly predictive of death among children with active TB. In children with clinical and radiographic findings suggestive of TB, a negative TST should not preclude or delay anti-TB therapy.

Community-based therapy for children with multidrug-resistant tuberculosis.

OBJECTIVES: The goals were to describe the management of multidrug-resistant tuberculosis among children, to examine the tolerability of second-line antituberculosis agents among children, and to report the outcomes of children treated for multidrug-resistant tuberculosis in poor urban communities in Lima, Peru, a city with high tuberculosis prevalence. METHODS: A retrospective analysis of data for 38 children <15 years of age with multidrug-resistant tuberculosis, either documented with drug sensitivity testing of the child's tuberculosis isolate or suspected on the basis of the presence of clinical symptoms for a child with a household contact with documented multidrug-resistant tuberculosis, was performed. All 38 children initiated a supervised individualized treatment regimen for multidrug-resistant tuberculosis between July 1999 and July 2003. Each child received 18 to 24 months of therapy with > or =5 first- or second-line drugs to which their Mycobacterium tuberculosis strain was presumed to be sensitive. RESULTS: Forty-five percent of the children had malnutrition or anemia at the time of diagnosis, 29% had severe radiographic findings (defined as bilateral or cavitary disease), and 13% had extrapulmonary disease. Forty-five percent of the children were hospitalized initially because of the severity of illness. Adverse events were observed for 42% of the children, but no events required suspension of therapy for >5 days. Ninety-five percent of the children (36 of 38 children) achieved cures or probable cures, 1 child (2.5%) died, and 1 child (2.5%) defaulted from therapy. CONCLUSIONS: Multidrug-resistant tuberculosis disease among children can be treated successfully in resource-poor settings. Treatment is well tolerated by children, and severe adverse events with second-line agents are rare.