It is estimated that 2 million children (younger than 15 years of age) are infected with multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (TB), known as MDR-TB infection.1 Data on the natural history of TB infection—which are often extrapolated to MDR-TB infection—show that young children (younger than 5 years of age) with TB infection are at high risk (up to 25%) of progressing to TB disease within 2–3 years of exposure, with infants’ risk of progression approaching 50%.2 It is noteworthy that older children and adolescents (10–20 years of age) also have an increased risk of developing TB disease after infection. Most children who develop MDR-TB disease are not diagnosed and started on appropriate therapy; mortality is high. However, even if diagnosed and treated, individuals must tolerate long (up to 18–24 months) courses of therapy with multiple (4–6) second-line drugs associated with far more adverse effects (AEs) than the 6–9 months of treatment with first-line drugs for drug-susceptible (DS)-TB disease. Thus, treatment of MDR-TB infection (often referred to as “preventive therapy”) to prevent progression to disease is critical.
KNOWLEDGE GAPS FOR IMPLEMENTATION
Treatment of TB infection with isoniazid, a low-cost medication for which there are extensive safety and efficacy data, has received little traction in many high-burden countries.3 The situation for MDR-TB infection is more complex, as there are unresolved questions surrounding whether to give any drug treatment, the number of drugs that should be used, which drugs may be most effective, the duration of therapy and the optimal dose of medications for children of different ages.4 Some of these issues will be addressed in ongoing clinical trials. The higher cost of many of these medications, the lack of child-friendly formulations and difficulties in identifying which children would benefit most from treatment are additional challenges. Not surprisingly, treatment of MDR-TB infection in children has been operationalized in few high-burden countries. Given the large potential benefit in high-risk young child contacts, however, MDR-TB infection therapy has been widely implemented in low-burden, high-resource settings.
SCREENING FOR INFECTION AND DISEASE
The most important aspects of caring for children with MDR-TB infection are to screen comprehensively for TB disease at baseline and to follow children closely. These activities are recommended by all guidelines, despite the highly variable guidance about whether to treat MDR-TB infection, and should be implemented in all settings regardless of the use of MDR-TB infection treatment.
The critical first step when evaluating a child after exposure to MDR-TB is to ensure that the child does not have TB disease at baseline. A thorough symptom screen and physical examination are needed, with the latter focusing on evaluation of anthropometry (eg, evaluating for weight stasis or decline across growth curves), lung findings, mental status, meningeal signs, peripheral lymphadenitis, organomegaly, spinal deformities and abdominal masses.
In most high-resource settings, a chest radiograph (CXR) is undertaken to rule out TB disease after exposure to both DS- and MDR-TB, before provision of TB infection. A CXR is a low-risk evaluation that may provide valuable information to guide clinical decision making, particularly in children with subclinical TB. If possible, a CXR (frontal and lateral) should be obtained to evaluate for intrathoracic TB before initiation of therapy. Lateral films are advised for evaluation of intrathoracic lymphadenopathy, particularly in children in the first 2 years, where the thymic silhouette can make discernment of adenopathy difficult on the frontal CXR. Respiratory samples (via gastric aspiration or sputum induction with several samples collected over consecutive days) should be considered only if a child has symptoms or an abnormal CXR and should not otherwise be routinely obtained. For children exposed to MDR-TB, the risk of inadequately treating TB disease is possibly more serious than for DS-TB, and so the benefit of performing a CXR to rule out TB disease before starting TB infection treatment is likely greater. However, in circumstances where it is not possible to undertake CXR, a thorough symptom screen will detect the vast majority of children with TB disease, and the lack of a CXR should not stop the evaluation of children exposed to MDR-TB and the provision of MDR-TB infection treatment.
As for CXR, in high-resource settings, tests of infection (tuberculin skin tests) or interferon gamma release assays) are routinely performed to decide who to treat for TB infection. With certain caveats, this is likely the optimal strategy as it targets the intervention at those most likely to benefit and avoids toxicity/unnecessary pill burden in the others. Children of all ages with positive test results are then offered TB infection treatment. Tests of infection may not be reliable in some high-risk children (eg, HIV-infected, malnourished), and they may not be available in many high-burden settings. A validated exposure screening scale5 could be used in lieu of tests of infection, keeping in mind that using this score to make decisions whether to treat TB infection or not has not been studied. A strategy of providing TB infection treatment for drug-susceptible TB, based on household exposure, without tests of infection is cost-effective in high-burden settings.6
Whether or not therapy for MDR-TB infection is initiated, children should be followed regularly, ideally for up to 2 years, as it is during this period that most children will progress to disease. They should be evaluated regularly for symptom screening and physical examinations. Anthropometrics (eg, height, weight) should be measured to evaluate for failure to thrive or weight stasis. CXRs may be considered at baseline and if the child were to develop symptoms. After this period, families should be instructed on symptoms that should prompt immediately seeking medical attention. Of note, there are no uniformly accepted guidelines on the frequency or extent of evaluation in follow-up. Studies in Europe have found wide variation in the duration and evaluation that child contacts of MDR-TB cases receive.7 Children receiving MDR-TB infection therapy should be seen every few months to assess adherence and to evaluate for AEs and the development of symptoms of TB disease. Caregivers should be instructed on what symptoms should prompt communication with the clinic for a more urgent visit to assess for AEs.
In hyperendemic settings, children may have multiple exposures to adults with different drug susceptibility patterns, leading to the practice in some settings of treating child contacts of MDR-TB patients with isoniazid alone, in the event that the child was infected with a susceptible Mycobacterium tuberculosis isolate. This strategy is likely to be inadequate if the child is infected with an MDR organism.8
There are several regimens that could be considered for the MDR-TB infection treatment (Table).4,9,10 Medication(s) should have the following characteristics: (1) good antimycobacterial effects; (2) resistance should be unlikely based on known susceptibilities for the isolate in the child’s identified source case; (3) well tolerated; (4) safe; and (5) adequate data on drug dosing in children. Ideally, a child-friendly formulation should exist. This constellation of characteristics effectively rules out several categories of medications, including injectable agents, cycloserine, clofazimine, linezolid and para-amino salicylic acid because of AEs. Two newer drugs, delamanid and bedaquiline, are better tolerated than other second-line drugs and may be integrated into MDR-TB infection regimens in the future once optimal dosing and safety is determined in the youngest children. While there are few data on the development of secondary drug resistance during treatment for MDR-TB infection, data from isoniazid use in the treatment of DS-TB infection indicate that acquisition of isoniazid resistance while on therapy is exceedingly low, and there is no reason to suspect that this will be different for MDR-TB infection.11
As such, the focus for MDR-TB infection therapy has been on higher-generation fluoroquinolones, alone or with a second medication. While adults and children receiving fluoroquinolone-containing regimens noted AEs in up to one third of cases, these AEs usually were not of sufficient severity to warrant treatment discontinuation.12 In contrast, several studies have found that patients receiving pyrazinamide-containing regimens reported AEs in up to two thirds of cases, with over one-half resulting in treatment discontinuation.12 Pediatricians should be cognizant that children generally tolerate TB medications better than adults. In one study in Micronesia, 95% of children with MDR-TB infection completed therapy with a fluoroquinolone with either ethambutol or ethionamide.9 Eighty percent of South African MDR-TB child contacts completed treatment in an observational study of a fluoroquinolone, ethambutol and isoniazid; no child suffered an AE requiring treatment discontinuation.10 A recent systematic review and meta-analysis estimated TB incidence risk reduction with therapy for MDR-TB infection is up to 90%12 and found that all treatment regimens were cost-effective compared with no treatment. It also found that for children, fluoroquinolone monotherapy was the most cost-effective.12 There are no data on the optimal duration of therapy for MDR-TB infection. Courses of 6–12 months have been used most often.
There will be times when no obvious therapeutic regimen can be crafted, and expert opinion should be sought on optimal management in these scenarios. These situations may include (1) the source case isolate is resistant to the fluoroquinolones; (2) the isolate is only susceptible to agents to which the child has had hypersensitivity reactions; or (3) susceptible agents have unacceptable drug interactions with a child’s existing medications. If not treated, these children should be carefully followed for the development of symptoms.
CONSIDERATIONS FOR THE HIV-INFECTED CHILD
The approach to the HIV-infected child should generally follow that for HIV-uninfected children, with a few additional considerations. HIV infection is a risk factor for progression from infection to disease. Although effective antiretroviral therapy with immune reconstitution substantially reduces that risk, there may remain a slightly higher risk than uninfected children even when the CD4 count is normal. HIV-infected children may have a higher risk of false-negative tests of infection, particularly if they have low CD4+ cell counts. HIV-infected children with MDR-TB infection are high priority group for provision of treatment. Potential drug–drug interactions and additive or overlapping toxicities between HIV-infected children’s antiretroviral therapy regimen and medications used for MDR-TB infection should be carefully considered. Most of the second-line antituberculosis drugs, including the fluoroquinolones, do not have clinically significant drug–drug interactions with most antiretroviral therapy, and there is no evidence to date that HIV-infected children have a higher risk of AEs from MDR-TB infection treatment.10
Three clinical trials are underway or planned to evaluate MDR-TB infection treatment. Tuberculosis Child and Adolescent Multidrug-Resistant Preventive Therapy (TB-CHAMP) compares levofloxacin to placebo in children younger than 5 years of age, in South Africa, exposed in their home to MDR-TB. V-QUIN also compares levofloxacin to placebo, but in all household contacts, in Vietnam. Protecting Households on Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis patients (PHOENIx) is a multisite trial that will compare delamanid with isoniazid in household MDR-TB contacts, providing treatment to children younger than 5 years of age and to those with HIV and a positive test of infection. The results of these trials will not be available for a number of years.
After the exclusion of TB disease by symptom screening and, whenever possible, by CXR, some children exposed to an MDR-TB source case may be candidates for treatment. Fluoroquinolone-based regimens have been found to be safe and effective in multiple observational cohorts. While optimal treatment is being investigated, results will not be available for a number of years. The data published to date show that children tolerate MDR-TB infection treatment with fewer AEs than adults and that failure to treat will result in potentially preventable cases of disease. Dissemination of studies on programmatic implementation, including observational evidence from low- and high-burden settings, can facilitate larger-scale roll-out of MDR-TB infection treatment.
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