Isoniazid Resistance Is Common in Pediatric Tuberculosis

By Will Boggs MD

NEW YORK (Reuters Health) - Worldwide, about 1 in 8 children with tuberculosis have isoniazid-resistant disease, according to a literature review.

"There is no quick fix here because the childhood TB diagnosis predicament is not just about drug resistance," Dr. Mercedes C. Becerra, from Harvard Medical School, Boston, told Reuters Health by email. "The primary problem is that, even in the best-resourced settings, the tests available to bacteriologically confirm TB disease simply perform very poorly in children."

Undiagnosed isoniazid resistance can lead to the inadvertent use of ineffective treatment regimens, increasing the risk of treatment failure and death, but the number of children with isoniazid-resistant disease and the proportion of children with TB who have resistant disease are unknown.

Dr. Becerra's team used surveillance-based and published estimates of isoniazid resistance among all patients with TB to estimate the proportion and number of child TB cases that are resistant to isoniazid.

Their analysis revealed that 12.1% of all incident TB cases among children worldwide were isoniazid-resistant. This translates into an estimated 120,872 new cases of isoniazid-resistant TB in children in 2010.

Isoniazid resistance rates varied greatly, ranging from 5.7% of cases in the Americas to 26.1% in Europe, although the majority of cases overall occur in the Western Pacific and Southeast Asia regions, according to the June 1 Pediatrics online report.

Because of the shortcomings of diagnosis in children, the researchers wrote, "it is likely that the majority of these 120,000 children receive either no TB treatment or a standardized empirical first-line regimen."

But the problem is even larger when latent infections are included. Global estimates could exceed a million children newly infected with isoniazid-resistant strains each year.

"Testing for drug resistance is a secondary problem, since you cannot test for drug resistance without a bacteriologic sample," Dr. Becerra said. "Therefore, when there is no sample available, of utmost importance is the clinician's assessment of each sick child's risk of drug resistance and, given the natural history of childhood TB, the knowledge that the child was likely infected recently."

"If your patient was identified through contact tracing in a TB patient's home, or if through a careful social history you have discovered a known TB patient in that child's close circle, then the drug-susceptibility profile of that likely source case should guide the decision to treat the child as a case of drug-resistant TB," she said.

"There are two scenarios in which you would use empirical treatment," Dr. Becerra said. "In the first scenario, where you know that there is another TB patient in the child's family or close circle who has drug-resistant disease, you would design an empirical regimen based on the drug-susceptibility profile of that likely source case. In the second scenario, where your patient has no known contacts with drug-resistant TB, then in most places in the world the odds are still that your patient has drug-susceptible disease."

"Thus," the authors advise, "when the risk of isoniazid resistance is unknown and when a bacteriologic sample cannot be obtained, a minimum four-drug regimen should be used for the initiation phase of treatment. Moreover, if isoniazid monoresistance is known or suspected based on the child's exposure to a mono-resistant source case, prudence would call for the child to be given at least three effective drugs (rifampicin, pyrazinamide, and ethambutol) for the full six months of treatment."

"TB is a family disease: the child in front of you is never an isolated case," Dr. Becerra concluded. "This has two critical implications for providers. First it is vital to know about the drug-susceptibility profile of any other TB patients in that child's close circle to guide your management. That is because children are more likely than adults to have been infected recently and to progress rapidly from infection to disease. The second major implication is that finding TB disease in a child should always lead to a contact investigation, in other words, a careful screening of close contacts, both adults and children. This has two objectives: treating others already sick and treating those with infection to prevent disease."

Dr. Ben J. Marais, from the University of Sydney's Centre for Research Excellence in Tuberculosis, New South Wales, Australia, told Reuters Health by email, "Concerns about possible isoniazid (INH) resistance should not delay efforts to roll out INH preventive therapy to vulnerable children following TB exposure, something that is not done in TB-endemic settings. Even with relatively high rates of INH resistance, the majority of children still stand to benefit. Use of INH preventive therapy in young children does not contribute to rising rates of INH resistance."

"We need better monitoring of INH resistance, especially among new adult cases (this equates to the risk experienced by children)," Dr. Marais said. "Optimal treatment and preventive therapy in cases with likely INH mono-resistance requires further evaluation."

Dr. Becerra's comments were jointly prepared with Dr. Courtney M. Yuen, the lead author of the report, from Brigham and Women's Hospital, Boston.

This research was supported by a grant from Janssen to Harvard Medical School and by the National Institutes of Health. Four coauthors reported receiving salary support based on the Janssen grant.

SOURCE: http://bit.ly/1JnR12v

Pediatrics 2015.

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