1

MDR-TB in ChildrenSession 8

USAID TB CARE II PROJECT

Risk of TB disease varies by age

• Greatest in infants (< 4 years);

• Declines slowly to nadir at 5-10 years;

• Rapid increase in risk with a second peak between 20-30 years.

Donald PR. Age and the epidemiology and pathogenesis of tuberculosis. Lancet 2010;375:1852-4.

USAID TB CARE II PROJECT

Wallgren A. Primary tuberculous infections in young adult life and in childhood. Am J Dis Child 1941; 61: 577-589

Mortality in relation to age

• Infection in children less than 4 years old progresses rapidly;

• Greater risk of dissemination and extrapulmonary involvement.

Age (years)

Number Mortality

0-1 39 36.9%

1-3 64 15.6%

3-7 225 4.4%

7-16 125 0.8%

USAID TB CARE II PROJECT

High risk of infection

• TST studies in the pre-chemotherapy era (1920-1950)†

– Cohorts included thousands of children and adults.– Follow-up for up to 27 years.

• Infectiousness of the index case:– 60–80% of children became infected when the source case was

smear-positive.– 30–40% of children became infected when the source case was

smear negative.

† Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic TB. Int J Tuberc Lung Dis 2004;8(4):392-402.

USAID TB CARE II PROJECT

MDR-TB in Children

• Difficulty of bacteriological confirmation often leads to late diagnosis of MDR-TB.

• Lack of DST often leads to inadequate treatment regimens and amplification of resistance.

• Contact history is important: almost all resistance in children is primary.

• Empiric MDR-TB treatment should be initiated in children based on the DST of the contact.

USAID TB CARE II PROJECT

Schaaf HS, Gie RP, Kennedy M, et al. Evaluation of young children in contact with adult multidrug-resistant pulmonary tuberculosis: a 30-month follow-up. Pediatrics 2002;109(5):765-71.

High risk of infection in children who are contacts of MDR-TB patients

• In 119 South African children less than 5 years of age who had contact with an adult with MDR-TB in the prior 30 months:– 24% had active TB– 51% had latent infection (TST+)– 37% had no evidence of infection

USAID TB CARE II PROJECT

MDR-TB outcomes in pediatric patients with low HIV prevalence

• 29 children treated for MDR-TB in South Africa 1994-2000:– All clinically and radiologically well at 30 months of follow-up.

• 16 children treated for MDR-TB in Peru 1999-2002:– 3 cured, 1 (6%) failure/death, remaining 12 children have

intermediate outcomes demonstrating favorable response.

Schaaf HS, Gie RP, Kennedy M, et al. Evaluation of young children in contact with adult multidrug-resistant pulmonary tuberculosis: a 30-month follow-up. Pediatrics 2002; 109: 765-771.

Mukherjee JS, Joseph JK, Rich ML, et al. Clinical and programmatic considerations in the treatment of MDR-TB in children: a series of 16 patients from Lima, Peru. Int J Tuberc Lung Dis 2003; 7: 637-644.

USAID TB CARE II PROJECT

MDR-TB outcomes in pediatric patients with low HIV prevalence

• 38 children treated for MDR-TB in Peru 1999-2003 (28 with culture-confirmed disease):– 32 (94%) cured, 1 (3%) failure/death, 1 (3%) LTFU, and 4

probable cures.• 20 children treated for active MDR-TB in NYC 1995-2003 (6 with

culture-confirmed disease):– 16 (80%) successfully completed treatment, 1 (5%) death, 2 left

NYC, 1 had incomplete record.

Drobac PC, Mukherjee JS, Joseph JK, et al. Community-based therapy for children with multidrug-resistant tuberculosis. Pediatrics 2006; 117(6): 2022-9.

Feja K, McNelley E, Tran CS, Burzynski J, Saiman L. Management of pediatric multidrug-resistant tuberculosis and latent tuberculosis infections in New York City from 1995 to 2003. Pediatr Infect Dis J 2008; 27: 907-912.

USAID TB CARE II PROJECT

Household contacts of MDR-TB patients almost always have MDR-TB

• A Peru study looked at 4503 household contacts of 693 MDR-TB and XDR-TB index patients:– 117 (2.6%) had active TB at the time the index patient began

MDR-TB treatment;– 242 contacts developed TB during 4-year follow-up;– Of the 359 cases of active TB, 142 had DST, of whom 129

(91%) had MDR-TB.

Becerra MC, Appleton SC, Franke MF, et al. Tuberculosis burden in households of patients with multidrug-resistant and extensively drug-resistant tuberculosis: a retrospective cohort study. Lancet 2011; 377: 147-52.

USAID TB CARE II PROJECT

MDR-TB outcomes in pediatric patients with high HIV prevalence

• 19 children treated for MDR-TB in Lesotho– 74% HIV co-infected– 84% had cavitary lesions or bilateral disease– 10 (53%) were smear-negative at the time of MDR-TB initiation

• Outcomes for 17 who had finished treatment: – 15 (88%) completed treatment or were cured,– 2 (12%) died late in treatment from unknown causes

Satti H, McLaughlin MM, Omotayo DB et al. Outcomes of comprehensive care for children empirically treated for MDR-TB in a setting of high HIV prevalence. PLoS One 2012; 7/(5): e37114.

USAID TB CARE II PROJECT

Adverse effects in children

Al-Dabbagh M, Lapphra K, McGloin R, et al. Drug-resistant tuberculosis: pediatric guidelines. Pediatr Infect Dis J 2011; 30(6): 501-505.

Adverse effectsIncidence in children (%)

Potential causative agents

Hearing loss 7 – 9 % Km, Amk, Cm

Renal toxicity 3 % Km, Amk, Cm

Gastrointestinal symptoms 12 – 50 % H, Z, Eto, fluoroquinolones, PAS, macrolides, amoxicillin/clavulanate

Hepatotoxicity 9 % Z, H, R, PAS, Eto, FQs, macrolides

Hypothyroidism 6 – 9 % Eto, PAS

Psychiatric effects 6 – 11 % Cs, FQs, thioamides

Skin manifestations 3 – 8 % H, R, fluoroquinolones, Cs, Eto, E, clofazimine, amoxicillin/clavulanate

Arthralgia, arthritis 0.7 – 4.5 % Fluoroquinolones, Z

Blurring of vision 9 % E, linezolid

Electrolyte abnormalities 3 % Km, Amk, Cm

USAID TB CARE II PROJECT

Recommendations

• Diagnosis of MDR-TB is difficult in children:– Children have lower bacillary load; the majority of children do not

have positive smears or cultures.– Uses aggressive methods such as gastric lavage and sputum

induction.– New technologies may prove to have a higher yield.

USAID TB CARE II PROJECT

Recommendations

• Contact history is the most important:– Almost all resistance in children is primary. – Household contacts of MDR-TB patients almost always have

MDR-TB.– Bacteriological confirmation should not be a barrier to initiation of

treatment. – Empiric MDR-TB treatment can be initiated in children based on

the DST of the contact.

USAID TB CARE II PROJECT

Recommendations

• MDR-TB regimens for children follow the same principles as for adults:– 4 or more effective drugs,– 18-24 months of treatment,– Pill splitting is usually necessary since there are few pediatric

formulations, and– Monitor weight frequently since children grow.

• Children tend to tolerate second-line TB drugs better than adults.