Treatment of asymptomatic (latent) tuberculosis infection in children - AAP News
Editor’s note:This is the second of two articles on latent tuberculosis infection in children. The first article is available at http://bit.ly/2PZtTDu.
Tuberculosis is a rapidly growing global health problem. One-quarter of the world’s population is estimated to have latent (asymptomatic) tuberculosis defined as infection by Mycobacterium tuberculosis in a person who has a positive tuberculin skin test (TST) or positive interferon gamma release assay (IGRA) result, no physical evidence of disease and a chest radiograph that is normal or reveals evidence of a healed infection. Latent tuberculosis infection can only be diagnosed by a positive TST or a positive IGRA result.
More than 10 million new cases of tuberculosis occurred worldwide in 2015. Up to 10% of asymptomatically infected people will develop active tuberculosis, emphasizing the importance of identifying and treating the enormous reservoir of asymptomatically infected people.
Which of the following statements are true?
a) Almost 80% of childhood tuberculosis disease is associated with some form of foreign contact by the child, parent or household member.
b) Children younger than 10 years of age with only hilar adenopathy and only a nonproductive cough rarely are contagious.
c) Interpretation of a TST after 48 to 72 hours can be performed by a family member.
d) Secondhand smoke exposure increases the risk of tuberculosis disease in a child with a latent infection.
e) The risk of developing tuberculosis disease is highest during the six months after infection, but many years can elapse between the initial infection and subsequent disease.
f) When applying a TST, creation of a palpable wheal 6 to 10 millimeters (mm) in diameter should be formed.
Answer: a, b, d, e and f are true
For children 2 years and older, either a TST or IGRA may be used to address the possibility of tuberculosis. For children younger than 24 months of age, a TST (Mantoux test) is the preferred method for detection.
Evidence that increases the probability that a positive TST or IGRA result is due to a latent tuberculosis infection and is unlikely to be a false-positive result includes contact with a person with contagious tuberculosis, a family history of tuberculosis disease, more than five years since bacille Calmette-Guérin (BCG) immunization and a TST reaction 15 mm or greater.
Routine use of either TST or IGRA testing of children in populations at low risk is discouraged because testing results in a low yield of positive results and a large number of false-positive results, contributing to inefficient use of health care resources.
Several schedules are available for management of infants, children and adolescents with latent infection caused by drug-susceptible M. tuberculosis. Traditionally, nine months of isoniazid administered once a day has been recommended. Efficacy approaches 100% if compliance is high. However, studies suggest adherence rates over nine months may be as low as 50%. Few data are available regarding the efficacy of an interrupted course of therapy.
If daily therapy is not anticipated to be reliable or possible, therapy twice a week for nine months can be used, but each dose must be directly observed and a higher dose of isoniazid is used.
Routine determination of serum transaminase concentrations before or during therapy with isoniazid is not recommended. Monthly observation for signs of clinical hepatitis are recommended (without routine transaminase measurements) during a course of therapy.
Four months of monotherapy with rifampin administered once a day is an acceptable regimen for treatment of latent, asymptomatic infection. This regimen requires continuous daily therapy; alternate daily therapy is not recommended.
A recently published randomized study evaluated the safety, side effect profile and adherence to four months of rifampin monotherapy compared to nine months of isoniazid monotherapy in children with latent tuberculosis (Diallo T, et al. N Engl J Med. 2018;379:454-463). The study evaluated 829 children from 0 through 17 months of age in Australia, Benin, Brazil, Canada, Ghana, Guinea and Indonesia. Seventy-nine of the children were under 2 years, the age group with the highest risk of life-threatening tuberculosis disease.
There were no significant differences between the groups in rates of adverse events related to trial drug. Active tuberculosis, including one case with resistance to isoniazid, was diagnosed in two children in the isoniazid group as compared with no cases in the rifampin group.
Depending on circumstances, another option for treatment of isoniazid-susceptible latent tuberculosis is 12 weeks of isoniazid plus rifapentine administered once a week as directly observed therapy. Some experts consider isoniazid-rifapentine to be the preferred regimen for treatment of latent tuberculosis in children as young as 2 years. Dosing for this option is discussed in the 2018 Red Book (page 843).
Jeffrey R. Starke, M.D., FAAP, American Thoracic Society liaison to the AAP Committee on Infectious Diseases, offered the following comment:
“The recommendations by the AAP and the CDC for the diagnosis and management of tuberculosis infection (also known as latent tuberculosis infection [LTBI]) in children have undergone substantial changes in the past year. It is known that the IGRAs are more specific than the TST. They contain only two or three antigens compared with the hundreds of antigens in tuberculin used in the TST, and they do not become positive because of previous BCG vaccination or infection with most nontuberculous mycobacteria as does the TST. Therefore, the IGRAs are especially advantageous for children who have or may have received a BCG vaccine.
“The concern always has been with the sensitivity of the IGRAs, especially for children less than 2 years of age who have a much higher risk of rapidly progressing to severe TB disease soon after infection. IGRAs do lack sensitivity for children with advanced tuberculosis disease, but so does the TST because TB disease suppresses the immune system even in the absence of an underlying cause such as HIV infection. This lack of sensitivity is much less likely to apply to otherwise healthy children with TB infection.
“Additional data have shown that the IGRAs perform well in younger children, which is why the 2018 Red Book has extended the routine use of the IGRAs down to children ages 2 years and above. Some experts and health departments are using IGRAs in children of all ages with no apparent increased incidence in TB disease owing to false-negative IGRA results.”
The other major area of change in the 2018 Red Book is in the treatment of TB infection, Dr. Starke noted.
“While nine months (270 doses) of isoniazid is effective if adherence is high and treatment is completed, many studies have demonstrated completion rates of only 50% to 70%,” he said. “There are now sufficient data on safety, tolerability and efficacy to recommend four months of daily rifampin (120 doses) for children of all ages and 12 doses of once weekly isoniazid plus rifapentine (a long-acting “cousin” of rifampin) for children ages 2 years and above. Several studies have demonstrated that these two regimens are at least as efficacious as nine months of isoniazid with lower rates of adverse reactions and higher completion rates.
“The major limiting factors for the isoniazid-rifapentine regimen are the relatively high cost of the rifapentine, the ability to obtain rifapentine outside of a health department, and that there currently is no pediatric dosing form for rifapentine, although the capsule can be opened up. Many experts and health department now consider the isoniazid-rifapentine regimen to be the preferred one for individuals who can obtain and take it.”
Dr. Meissner is professor of pediatrics at Floating Hospital for Children, Tufts Medical Center. He also is an ex officio member of the AAP Committee on Infectious Diseases and associate editor of the AAP Visual Red Book.
Copyright © 2018 American Academy of Pediatrics
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