An increasing number of children in southern Africa are contracting drug-resistant TB. Simon Schaaf, Department of Paediatrics and Child Health, University of Stellenbosch, reviewed special issues in the diagnosis and management of pediatric MDR TB, illustrated by the family case study in Box 7-1.
EPIDEMIOLOGY OF PEDIATRIC DRUG-RESISTANT TB1
Drug susceptibility testing and DNA fingerprinting have demonstrated that MDR TB in children results mainly from transmitted drug resistance.
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The Emerging Threat of Drug-Resistant Tuberculosis in Southern Africa: Global and Local Challenges and Solutions - Summary of a Joint Workshop by the Institute of Medicine and the Academy of Science of South Africa 7 Drug-Resistant TB in Children Key Messages An increasing number of children in southern Africa are contracting drug-resistant TB, mainly through transmission. Diagnosis of drug-resistant TB and assessment of side effects are often more difficult in children than in adults. The optimal duration of treatment in children is unknown but is likely shorter than in adults. Better data on mortality and causes of death would clarify the extent of the epidemic among children. An increasing number of children in southern Africa are contracting drug-resistant TB. Simon Schaaf, Department of Paediatrics and Child Health, University of Stellenbosch, reviewed special issues in the diagnosis and management of pediatric MDR TB, illustrated by the family case study in Box 7-1. EPIDEMIOLOGY OF PEDIATRIC DRUG-RESISTANT TB1 Drug susceptibility testing and DNA fingerprinting have demonstrated that MDR TB in children results mainly from transmitted drug resistance. 1 The remainder of this chapter is based on the presentation of Schaaf.
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The Emerging Threat of Drug-Resistant Tuberculosis in Southern Africa: Global and Local Challenges and Solutions - Summary of a Joint Workshop by the Institute of Medicine and the Academy of Science of South Africa BOX 7-1a A Family Case Study Illustrating Issues in Pediatric MDR TB MDR TB and drug-susceptible TB cases commonly live in the same household in South Africa. In one family, the maternal grandmother had her fourth episode of TB in 2007 and had previously been identified as an MDR TB case. The grandfather died of MDR TB before 2004. An uncle had drug-susceptible TB during that same period and has since been treated and cured. When the uncle left the household, the mother and a child aged 10 months remained. At the time, the child was asymptomatic and had a negative Tine tuberculin skin test;b it was unknown whether a chest xray had been taken. He was started on a regimen of isoniazid prophylaxis. The child presented 4 months later when the grandmother was again admitted for confirmed MDR TB. The child had had a cough for a week; his weight was in the 75th percentile; he was clinically well, but his Mantoux testc converted to positive at 30 mm and was ulcerating; his chest x-ray showed some nodes and opacification; and he was HIV-negative. The child was started on a treatment regimen of isoniazid, pyrazinamide, ethambutol, ethionamide, ofloxacin, and amikacin. Gastric aspirates were taken, two of which were culture positive, resistant to isoniazid and rifampicin, and susceptible to ethambutol. The grandmother’s second-line drug resistance returned a few months later—this time not only to isoniazid and rifampicin but also to amikacin. The child’s treatment was changed from amikacin to capreomycin, and terizidone was added. During the child’s follow-up, hearing tests could not be administered because the child was too young, but renal function was normal. Each of the six monthly follow-up cultures was negative. The child was treated for 18 months after the first negative culture. The capreomycin was stopped after 4 months, for a total of 6 months of injectable drug treatment. The child was discharged in April 2008. The grandmother was diagnosed with pre-XDR TBd and died in March 2008. The mother was pregnant and moved to live with the paternal grandmother in a nearby town. She was diagnosed with TB in August 2008, 4 months after the child was discharged, and did not disclose that the paternal grandmother had MDR TB. The child was still on MDR TB treatment. The mother started treatment but defaulted and, not surprisingly, did not respond to the treatment. She was smear positive at 2 months, when her baby was born, and MDR TB was confirmed in December 2008. She died of MDR TB 3 months later. It was confirmed 3 months after her death that her TB had been susceptible to second-line drugs.
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The Emerging Threat of Drug-Resistant Tuberculosis in Southern Africa: Global and Local Challenges and Solutions - Summary of a Joint Workshop by the Institute of Medicine and the Academy of Science of South Africa The baby was not given a BCG vaccine at birth and was started on a low dose of isoniazid treatment a few weeks after birth (as prophylaxis because the mother had TB). The local doctor interpreted a chest x-ray as normal. The baby’s treatment was changed to isoniazid (high dose), ethambutol, and ofloxacin, with questionable compliance, as prophylaxis against MDR TB (when the mother was confirmed to have MDR TB). The baby’s first visit to the local clinic was in March 2009. He was a healthy-looking baby who had good weight gain, a 1-week fever, and no other symptoms. The prophylactic treatment was defaulted for only 2 weeks during the mother’s funeral. The baby was HIV-negative, and his Mantoux test was 10 mm. A chest x-ray showed progression of the disease despite the prophylaxis, and the regimen was changed to isoniazid, pyrazinamide, ethambutol, ethionamide, ofloxacin, terizidone, para-aminosalycilic acid, and capreomycin. Baseline renal function and liver function tests were normal, and the baby was progressing well on the treatment. However, the culture results and drug susceptibility tests showed that his TB was resistant to isoniazid, rifampicin, and ofloxacin. The paternal grandmother took over the care of both children once the injectable drug regimen had been completed, and both are doing well. According to Schaaf, lessons learned from this case study include the following: It is critical to take a full history of all adult TB cases, and it is important to know when to screen for MDR TB. Screening for TB is important in child contacts. If there is no disease, children need the appropriate prophylaxis, and they must be put on the correct regimen at the right time. Follow-up must be done to ensure that they are well. Screening with chest x-rays is necessary for children, but the x-rays must be interpreted correctly. TB in children should be treated according to the drug susceptibility tests of the adult source case until the results of the child’s own culture and drug susceptibility tests are available. Good weight gain is not always a sign of a good clinical response. Management of MDR TB in pregnancy needs to be studied and discussed further. MDR TB and pre-XDR TB are curable diseases. aThis box is based on the presentation of Simon Schaaf, University of Stellenbosch. bThe Tine test is a multiple-puncture tuberculin skin test used to aid in the medical diagnosis of TB. It uses a small “button” that has four short needles coated with TB antigens (tuber-
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The Emerging Threat of Drug-Resistant Tuberculosis in Southern Africa: Global and Local Challenges and Solutions - Summary of a Joint Workshop by the Institute of Medicine and the Academy of Science of South Africa culin). The needles are pressed into the skin (usually on the inner side of the forearm), forcing the antigens into the skin. The test is read by measuring the size of the largest papule that emerges. A negative result is the presence of no papules. cThe Mantoux test (also known as the Mantoux screening test, Tuberculin Sensitivity Test, Pirquet test, or PPD test [for purified protein derivative]) uses a glycerol extract of the tubercle bacillus. PPD tuberculin is a precipitate of non-species-specific molecules obtained from filtrates of sterilized, concentrated cultures. A standard dose of 5 tuberculin units (0.1 mL) is injected intradermally and read 48 to 72 hours later. A person who has been exposed to the bacteria is expected to mount an immune response in the skin containing the bacterial proteins. dPre-XDR TB refers to MDR TB plus one-half of the resistance equation for XDR TB. As defined in Chapter 1 (Box 1-1), XDR TB is resistant to the same drugs as MDR TB (isoniazid and rifampicin), as well as any fluoroquinolone (levofloxacin, moxifloxacin, or ofloxacin) and at least one second-line injectable drug (kanamycin, amikacin, or capreomycin). Pre-XDR TB is MDR TB that displays resistance to one of the fluoroquinolones or a second-line injectable drug. Acquisition of MDR TB is more difficult because of the paucibacillary nature of the primary disease, but it is possible with cavitary pulmonary disease. Disease in children usually develops within 12 months of infection. Epidemiological surveillance undertaken at the Tygerberg Children’s Hospital in the Western Cape between 1994 and 2009 produced several important findings related to the epidemiology of drug-resistant TB in children: There is a high prevalence of drug-resistant TB in the Western Cape. Despite previous treatment, more than 90 percent of all drug-resistant TB in children was most likely due to transmitted resistance. Hospital-based surveys are potentially biased because sicker children or children with complications usually are referred to a hospital. However, no significant difference was found in drug-resistant TB in children in a community-based versus a hospital-based survey. Drug resistance is not significantly different between HIV-infected and HIV-uninfected cases. A lack of drug susceptibility tests in adult source cases hampers effective management of child TB contacts.
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The Emerging Threat of Drug-Resistant Tuberculosis in Southern Africa: Global and Local Challenges and Solutions - Summary of a Joint Workshop by the Institute of Medicine and the Academy of Science of South Africa PROPHYLAXIS AND DIAGNOSIS OF PEDIATRIC DRUG-RESISTANT TB Contact tracing and follow-up of children exposed to MDR and XDR TB should receive high priority so prophylactic treatment can be initiated, suggested Schaaf. When adults present with TB, the entire household should be screened. A 2002 study showed that giving a child two drugs to which the adult case is susceptible can prevent MDR TB cases. A combination of high-dose isoniazid plus ethambutol or ethionamide plus ofloxacin for 6 months has been used in the Western Cape, but studies are needed to determine whether a single drug could be used. Failure of isoniazid or isoniazid plus rifampicin to prevent MDR TB has been reported in many cases. The solution to isoniazid monoresistance is to give rifampicin for 4 months. Rifampicin monoresistance is treated with isoniazid for 6 months. Pre-XDR or XDR TB cases can be given only a high dose of isoniazid (15–20 mg/kg). In both MDR and XDR TB cases, regular followup for a minimum of 12 months is essential. In general, the prophylactic treatment of children in South Africa is not optimal, said Schaaf, although there is a policy that children under age 5 and all HIV-infected children should be screened for TB and if there is no disease, should be placed on prophylactics. Schaaf’s policy is to start children with HIV infection, who constitute about 30 percent of his pediatric patients, on antiretrovirals as soon as possible. He has experienced very few problems with antiretrovirals and second-line TB drugs. Diagnosis of MDR and XDR TB in children requires a microbiological diagnosis, which is often difficult because of paucibacillary TB. The use of line probe assays for diagnosis of children may mean that about 10 percent of MDR TB cases are misdiagnosed as rifampicin-monoresistant TB. Drug-resistant TB is probable, however, if a child has had known contact with an adult drug-resistant pulmonary TB case. Drug-resistant TB should further be suspected if a child is adhering to treatment and fails therapy or if an adult source case with an unknown drug susceptibility test result is a treatment failure, is a retreatment case, or has died of TB during adherent treatment. DRUG TREATMENT REGIMENS FOR PEDIATRIC DRUG-RESISTANT TB According to the 2008 updated WHO guidelines on drug-resistant TB, the drugs used to treat MDR TB in children fall into five groups: Group 1—Remaining first-line drugs: a combination of a high dose of isoniazid and ethionamide can create one effective drug.
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The Emerging Threat of Drug-Resistant Tuberculosis in Southern Africa: Global and Local Challenges and Solutions - Summary of a Joint Workshop by the Institute of Medicine and the Academy of Science of South Africa Although ethambutol and pyrazinamide are used, they are not regarded as reliable, and 50 percent of cases of MDR TB in children are resistant to ethambutol.2 Group 2—Second-line injectables: kanamycin, amikacin, and capreomycin. The reason for using amikacin is that it causes fewer side effects in children, and the doses are relatively easy to administer. Group 3—Fluoroquinolones: although said not to be suitable for children, maximum doses are used. These are very important drugs in MDR TB therapy. Group 4—Second-line oral bacteriostatic drugs: split into two doses per day initially to alleviate any adverse effects. Group 5—Drugs that have an unclear role in the treatment of drug-resistant TB. Linezolid and clarithromycin are sometimes used, although they are very expensive and difficult to obtain. Schaaf emphasized the importance of documenting and trying to prevent adverse effects associated with these drugs. About 30 percent of children have experienced hearing loss, and a high percentage have developed hypothyroidism. Other common adverse effects in adults are not common in children. The optimal duration of treatment in children is still unknown. Cavitary or extensive pulmonary TB needs to be treated as for adults. Primary, noncavitary MDR TB is often culture negative, and treatment for 12 to 15 months should suffice. Treatment in the intensive phase includes a second-line injectable drug, which is usually discontinued in the continuation phase. Schaaf said health care providers have become more aware of potential adverse effects of drug treatment in children and need to monitor patients carefully to detect such effects and determine when the drugs must be stopped. The World Health Organization (WHO) calls for the administration of drugs for 2 years, but Schaaf believes children can be treated for shorter times, particularly for early, paucibacillary disease. He has treated many patients for 12 months and has seen no relapses, but the length of treatment for each child needs to be evaluated individually. In addition, new drugs should be tested on children as well as adults, said Schaaf. Not enough is known about the pharmacokinetics and adverse effects of 2 During the discussion period, Schaaf was asked whether he has noticed problems with vision in children caused by ethambutol. He responded that it is difficult to test vision in younger children, and only color charts are used. Studies have shown that as long as the dose of the drug is lower than 25 mg/kg, the chances of developing such problems are small, and none of Schaaf’s patients have had adverse reactions related to vision. Ethambutol is used in drug-resistant as well as drug-susceptible cases since isoniazid resistance is very high in the Western Cape.
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The Emerging Threat of Drug-Resistant Tuberculosis in Southern Africa: Global and Local Challenges and Solutions - Summary of a Joint Workshop by the Institute of Medicine and the Academy of Science of South Africa drugs in children, including their interactions with antiretrovirals. Finally, management of children and adolescents to ensure compliance with drug regimens is necessary. MANAGEMENT OF PEDIATRIC DRUG-RESISTANT TB The management of MDR TB in children should be carried out as follows, according to Schaaf: Confirm MDR TB if at all possible. If MDR TB is confirmed, also do drug susceptibility testing for second-line drugs. Manage cases at a specialized MDR TB clinic. Use first-line drugs to which the isolate is susceptible plus second-line drugs, taking into account that 50 percent of cases of MDR TB in children are resistant to ethambutol. Be aware of different drug groups and cross-resistance. Recognize that second-line drugs are generally more toxic than first-line drugs. Recognize that adverse events can be more difficult to assess in children than in adults. Be mindful of the difficulty of preserving the correct dosage when breaking tablets up to make them easier for the child to swallow. Isolate children who are infected with TB. In practice, this can be difficult since the adults accompanying children are often infected with MDR or XDR TB but not diagnosed. Schaaf outlined the following principles of childhood MDR TB treatment: Directly observed therapy with daily treatment is essential. Three, four, or more drugs to which the patient’s isolate is susceptible and/or naïve should be administered, depending on the extent of the disease. If a treatment regimen is failing, a single drug should not be added (combination therapy should be used). The drug susceptibility test pattern of the adult index case’s isolate should be used if no isolate from the child is available. Patients, parents, and family members should be counseled at every visit with respect to adverse events and the importance of adherence to treatment, as well as to offer support. It is essential to ensure that follow-up occurs, including clinical and radiological follow-up, as well as cultures.
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The Emerging Threat of Drug-Resistant Tuberculosis in Southern Africa: Global and Local Challenges and Solutions - Summary of a Joint Workshop by the Institute of Medicine and the Academy of Science of South Africa OUTCOMES OF PEDIATRIC DRUG-RESISTANT TB Very few studies have reported on the outcomes of drug-resistant TB in children. One such study is from Peru, where 36 of 38 MDR TB cases were cured (Drobac et al., 2006). Another, conducted in South Africa in 2003, showed that of 39 confirmed MDR TB cases, the majority were clinically cured (Schaaf et al., 2003). More data on morbidity and longterm mortality in children, as well as on HIV-infected and HIV-uninfected children, are needed, said Schaaf. Asked about the mortality figures for children with MDR and XDR TB, Schaaf replied that data since 2003 show 150 culture-confirmed cases of MDR TB, with a mortality rate of about 10 percent. There are currently 6 confirmed XDR TB cases, 3 with culture confirmation and 3 having had contact with adults with XDR TB. Schaaf said he has not had a child die from XDR TB. Schaaf emphasized that if children are treated incorrectly when there is a known adult index case with MDR TB in the household, much lung damage can be done, leading to chronic lung disease. He suggested that mortality and morbidity should both be examined in looking at the outcomes of pediatric patients with MDR TB.